benzofurans and benzofuran

Gram-positive and Gram-negative pathogens are able to evade the host immune system, persist within the human host, and lead to severe disease and even death. At present, bacterial infections are one of the leading causes of morbidity and mortality across the world. The development of novel antibacterial agents still represents a challenging endeavor, which is mainly attributed to the continuous emergence of more virulent and drug-resistant pathogens. Benzofuran constitutes the core of diverse pharmacologically active compounds, and there are a variety of approved benzofuranbased drugs in the market or currently going through different clinical phases or registration statuses. Benzofurans could exert antibacterial activity through various mechanisms and possess pronounced activity; therefore, benzofuran is a useful skeleton for the discovery of novel antibacterial agents. This review focuses on the recent advancement of naturally occurring benzofuran derivatives and hybrids of benzofurans with other pharmacophores as antibacterial agents, covering articles published between January 2015 and July 2021. The chemical structures and structure-activity relationships are also discussed.

Topics: Anti-Bacterial Agents; Benzofurans; Humans; Structure-Activity Relationship

The benzofuran moiety constitutes a main component of enormous biologically active natural and synthetic heterocycles. Such heterocycles have distinctive therapeutic potential and are employed in various clinical drugs. A number of publications have dealt with the synthesis and extraction of benzofuran-based heterocycles to investigate their antimicrobial potential.. This review describes the antimicrobial activity of various natural and synthetic benzofuran scaffolds. The antimicrobial activity of benzofurans is thoroughly investigated against several bacterial (Gram-positive and Gram-negative) and fungal microorganisms compared with several reference antibiotic drugs. The effects of the electronic nature of substituents on the activity of benzofurans through SAR study were reported. This article also highlights the recent natural and synthetic benzofuran-based organic molecules between 2019-2022 that have had success in terms of their antimicrobial activity.. Many of the described benzofurans are promising candidates as antimicrobial agents based on their activity. Most used antibiotics target infections caused by the gram-positive pathogen

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Benzofurans; Drug Design; Humans; Staphylococcus aureus; Structure-Activity Relationship

The alpha (α)-amylase is a calcium metalloenzyme that aids digestion by breaking down polysaccharide molecules into smaller ones such as glucose and maltose. In addition, the enzyme causes postprandial hyperglycaemia and blood glucose levels to rise. α-Amylase is a well-known therapeutic target for the treatment and maintenance of postprandial blood glucose elevations. Various enzymatic inhibitors, such as acarbose, miglitol and voglibose, have been found to be effective in targeting this enzyme, prompting researchers to express an interest in developing potent alpha-amylase inhibitor molecules. The review mainly focused on designing different derivatives of drug molecules such as benzofuran hydrazone, indole hydrazone, spiroindolone, benzotriazoles, 1,3-diaryl-3-(arylamino) propan-1-one, oxadiazole and flavonoids along with their target-receptor interactions, IC

Topics: 1-Deoxynojirimycin; Acarbose; alpha-Amylases; Benzofurans; Blood Glucose; Diabetes Mellitus; Drug Discovery; Flavonoids; Glycoside Hydrolase Inhibitors; Humans; Hydrazones; Hypoglycemic Agents; Indoles; Inositol; Oxadiazoles; Structure-Activity Relationship

The favorability of ring closure reactions as per Baldwin rules has gained immense importance recently. This is evident from the current literature such as research articles, reviews, and books that have been published in this area. This review covers the recent applications of 5-endo-dig cyclization in organic synthesis focusing in the last two decades. A variety of 5-membered heterocycles as well as carbocycles could be synthesized via 5-endo-dig cyclization reactions. The important applications of 5-endo-dig cyclization in organic synthesis covering different aspects have been summarized in this review.

Topics: Benzofurans; Catalysis; Chemistry Techniques, Synthetic; Coumarins; Cyclization; Indoles; Molecular Structure

Grapefruit juice (GFJ) consumption has been shown to increase the bioavailability of certain orally administered drugs. The furanocoumarin derivatives Paradisin A and bergamottin, which are present in GFJ, are potent mechanism-based inhibitors of CYP3A4. The primary aim of this work was to synthesize a series of furanocoumarin derivatives with a view to determining the relationship between the structure of the inhibitors and their inhibitory CYP3A4 activity. Furanocoumarin derivatives that were more stable and accessible than the furanocoumarin derivatives in GFJ were prepared, and their ability to inhibit CYP3A4 was examined. Synthesized furanocoumarin monomers showed strong mechanism-based inhibition of CYP3A4. The furanocoumarin dimers are also mechanism-based inhibitors of CYP3A4. These monomers and dimers are more potent inhibitors of CYP3A4 than bergamottin and Paradisin A, respectively.

Topics: Benzofurans; Citrus paradisi; Coumarins; Cytochrome P-450 CYP3A Inhibitors; Fruit and Vegetable Juices; Furocoumarins; Humans; Structure-Activity Relationship

The majority of heterocycle compounds and typically common heterocycle fragments present in most pharmaceuticals currently marketed, alongside with their intrinsic versatility and unique physicochemical properties, have poised them as true cornerstones of medicinal chemistry. In this context, oxygen heterocycles exhibit diverse biological and pharmacological activities due in part to the similarities with many natural and synthetic molecules with known biological activity. Among oxygen containing heterocycles, benzofuran (synthetic and natural isolated) and its derivatives have attracted medicinal chemists and pharmacologists due to their pronounced biological activities and their potential applications as pharmacological agents such as antioxidant, antitumor, antiplatelet, antimalarial, antiinflammatory, antidepressant and anticonvulsant properties. There are also an amazing number of approved benzofuran-containing drugs in the market as well as compounds currently going through different clinical phases or registration statuses. Due to the wide range of biological activities of benzofurans, their structure activity relationships have generated interest among medicinal chemists, and this has culminated in the discovery of several lead molecules in numerous disease conditions. Recently, this scaffold has emerged as a pharmacophore of choice for designing antioxidant drug development as their derivatives have shown excellent results through different mechanism of action. This review focused on the recent development of benzofuran derivatives as antioxidant agents (including natural products) and their antioxidant activities; summarize the structure property, hoping to inspire new and even more creative approaches. Also, this study systematically provides a comprehensive report on current developments in benzofuran-based compounds as antioxidant agents and is also helpful for the researchers working on a substitution pattern around the nucleus, with an aim to help medicinal chemists to develop structure activity relationships (SAR) on these derivatives as antioxidant drugs.

Topics: Antioxidants; Benzofurans; Drug Design; Drug Discovery; Heterocyclic Compounds; Humans; Structure-Activity Relationship

This review is focused on the analysis of current data on new methods of alkenylation of arenes and heteroarenes with alkynes by transition metal catalyzed reactions, Bronsted/Lewis acid promoted transformations, and others. The synthetic potential, scope, limitations, and mechanistic problems of the alkenylation reactions are discussed. The insertion of an alkenyl group into aromatic and heteroaromatic rings by inter- or intramolecular ways provides a synthetic route to derivatives of styrene, stilbene, chalcone, cinnamic acid, various fused carbo- and heterocycles, etc.

Topics: Alkynes; Benzofurans; Catalysis; Heterocyclic Compounds; Indoles; Metals, Heavy; Quinolines; Transition Elements

Benzofuran heterocycles are fundamental structural units in a variety of biologically active natural products as well as synthetic materials. Over the time, benzofuran derivatives have attracted many researchers due to the broad scope of their biological activity, which include anticancer, antimicrobial, immunomodulatory, antioxidant and anti-inflammatory properties. Egonol, homoegonol and moracin families are biologically active natural products containing benzofuran heterocycle as basic structural units. This paper focuses on the moracin family (moracin A to Z). Morus, a genus of flowering plants in the family Moraceae, comprises 10-16 species of deciduous trees commonly known as mulberries. The root bark, stem bark and leaves of Morus alba, M. lhou, Morus macroura are the main sources for arylbenzofuran derivatives including the moracins. A large volume of research has been carried out on moracins and their derivatives, which has shown the pharmacological importance of this benzofuran heterocyclic nucleus. In this mini-review, we attempt to highlight the importance of moracins, as they have been a major source for drug development. Herein, we also summarize the current state of the art concerning the synthesis and medicinal use of moracins A-Z.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Antioxidants; Benzofurans; Chemistry, Pharmaceutical; Humans; Immunologic Factors

In nature's collection of biologically active heterocycles, benzofuran derivatives constitute a major group. The broad spectrum of pharmacological activity in individual benzofurans indicates that this series of compounds is of an undoubted interest. Benzofuran and its derivatives have attracted medicinal chemists and pharmacologists due to their pronounced biological activities and their potential applications as pharmacological agents. Due to the wide range of biological activities of benzofurans, their structure activity relationships have generated interest among medicinal chemists, and this has culminated in the discovery of several lead molecules in numerous disease conditions. The outstanding development of benzofuran derivatives in diverse diseases in very short span of time proves its magnitude for medicinal chemistry research. The present review is endeavour to highlight the progress in the various pharmacological activities of benzofuran derivatives in the current literature with an update of recent research findings on this nucleus.

Topics: Animals; Benzofurans; Drug Design; Drug Discovery; Humans; Molecular Structure; Structure-Activity Relationship

Benzofuran core is a highly versatile, presents in many important natural products and natural drugs. Many benzofuran containing synthetic drugs and clinical candidates have been derived from natural products. The present review will provide an insight on lead design-developments of the decade, clinical candidates and PET tracer radio-ligands containing benzofuran core along with brief target biology. Brief of the all approved drugs containing benzofuran core also have been enclosed. Main therapeutic areas covered are Cancer, Neurological disorders including anti-psychotic agent and diabetes.

Topics: Animals; Benzofurans; Biological Products; Drug Design; Drug Discovery; Humans; Radiopharmaceuticals

Despite affecting around 8 million people worldwide and representing an economic burden above $7 billion/ year, currently approved medications to treat Chagas disease are still limited to two drugs, nifurtimox and benznidazole, which were developed more than 40 years ago and present important efficacy and safety limitations. Drug repositioning (i.e. finding second or further therapeutic indications for known drugs) has raised considerable interest within the international drug development community. There are many explanations to the current interest on drug repositioning including the possibility to partially circumvent clinical trials and the consequent saving in time and resources. It has been suggested as a particular attractive approach for the development of novel therapeutics for neglected diseases, which are usually driven by public or non-profit organizations. Here we review current computer-guided approaches to drug repositioning and reports on drug repositioning stories oriented to Chagas disease, with a focus on computer-guided drug repositioning campaigns.

Topics: Benzofurans; Chagas Disease; Computational Biology; Drug Repositioning; High-Throughput Screening Assays; Humans; Trypanocidal Agents; Trypanosoma cruzi

This article emphasizes on the importance of benzofuran as a biologically relevant heterocycle. It covers most of the physiologically as well as medicinally important compounds containing benzofuran rings. This article also covers clinically approved drugs containing benzofuran scaffold.

Topics: Animals; Benzofurans; Drug Discovery; Humans

Topics: Benzofurans; Bridged Bicyclo Compounds; Carbon; Cyclobutanes; Cyclohexanes; Cyclopentanes; Cyclopropanes; Nucleosides; Spiro Compounds

Currently, the development of radiotracers for in vivo imaging of beta-amyloid plaques in Alzheimer's disease (AD) brains is an important, active area of molecular imaging. Postmortem brains of AD patients reveal neuropathologic features: the presence of beta-amyloid plaques and neurofibrillary tangles, which contain beta-amyloid peptides and highly phosphorylated tau proteins. Increases in the concentration of beta-amyloid in the course of the disease lead to changes in AD brains. Thus, when used in combination with positron-emission tomography/single-photon emission computed tomography (PET/SPECT), beta-amyloid imaging agents could serve as surrogate markers for the early diagnosis and neuropathogenetic studies of AD. Furthermore, quantitative evaluation of beta-amyloid plaques in the brain could facilitate the evaluation of the efficacy of antiamyloid therapies that are currently being investigated. This paper reviews our research on the development of PET/SPECT imaging agents for in vivo detection of beta-amyloid plaques in Alzheimer's brains.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Brain; Flavonoids; Humans; Positron-Emission Tomography; Radiopharmaceuticals; Stilbenes; Tissue Distribution; Tomography, Emission-Computed, Single-Photon

The H3 receptor is prominently expressed in neuronal tissues, and H3 antagonists have been proposed as drugs with benefits in disorders of cognition, attention, pain, allergic rhinitis, and obesity. The structure-activity relationships (SAR) of various classes of non-imidazole H3 antagonists are reviewed, along with highlights of functional efficacy in tissue-based and animal disease models.

Topics: Animals; Benzofurans; Histamine Antagonists; Humans; Imidazoles; Receptors, Histamine H3; Structure-Activity Relationship

This article describes the exploration of synthetic methodologies on solid phase for combinatorial chemistry. Examples will cover various cyclisation strategies that include; the intramolecular Heck cyclisation leading to the formation of oxindoles, the radical cyclisation mechanism in the synthesis of furans, and a stereoselective cyclisation to form oxopiperazines.

Topics: Benzofurans; Combinatorial Chemistry Techniques; Cyclization; Free Radicals; Furans; Indoles; Molecular Conformation; Piperazines

Topics: Animals; Benzofurans; Carcinogenicity Tests; Carcinogens; Humans

Rayless goldenrod (RG; Isocoma pluriflora) poisons livestock in the southwestern U.S., west Texas, and northern Mexico. The putative toxin(s) have historically been thought to be benzofuran ketones. Goats have been used successfully as a model of RG poisoning. The transmammary transfer of toxicity to offspring from lactating goats has not been studied, thus the objective of this study was to determine if nursing kids would become poisoned via mother's milk when the dams were dosed with RG. Twelve lactating goats (6 controls and 6 treated; all with twin kids) were dosed via oral gavage with alfalfa or rayless goldenrod at 2% of BW per day for 14 days. Two kids showed overt clinical signs near the end of the study; however, no dams showed clinical signs, and none developed exercise intolerance or muscle weakness. After day 11 of treatment, the RG kids showed increased (P < 0.05) serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine kinase (CK) activities until exposure to the plant via mothers' milk ended. Serum CK activity of kids declined rapidly over 7 days after transmammary exposure ended. Histopathology revealed that one kid had extensive myonecrosis that involved both myocardium and skeletal muscles. The other kids from RG-treated does had minimal myocyte degeneration and necrosis characterized by individual myofiber swelling, hypereosinophilia and loss of striation. Benzofuran ketones were not detected in the milk of lactating goats; further, dosing with RG did not alter milk composition. In summary, milk ingestion from does dosed with >300 mg/kg BW of benzofuran ketones from RG over 14 days increased mean CK concentrations in treated kids compared to controls; however kids rapidly recovered when exposure ended. Additional work is needed to better define benzofuran ketone metabolism, toxicity, and animal susceptibility.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Asteraceae; Benzofurans; Creatine Kinase; Female; Goat Diseases; Goats; Ketones; Lactation; Milk; Muscular Diseases; Necrosis; Plant Poisoning; Plants, Toxic

Sortase A (SrtA) is a cysteine transpeptidase of most gram-positive bacteria that is responsible for the anchoring of many surface protein virulence factors to the cell wall. SrtA ablation has demonstrated to alleviate the infection without affecting the viability of bacteria. Herein, a series of benzofuran cyanide derivatives were synthesized and evaluated. Several compounds exhibited excellent inhibitory activity against SrtA with IC

Topics: Aminoacyltransferases; Anti-Bacterial Agents; Bacterial Proteins; Benzofurans; Binding Sites; Biofilms; Cyanides; Cysteine Endopeptidases; Drug Design; Enzyme Inhibitors; HEK293 Cells; Humans; Molecular Docking Simulation; Staphylococcus aureus; Structure-Activity Relationship

The potential of natural and synthetic chalcones as therapeutic leads against different pathological conditions has been investigated for several years, and this class of compounds emerged as a privileged chemotype due to its interesting anti-inflammatory, antimicrobial, antiviral, and anticancer properties. The objective of our study was to contribute to the investigation of this class of natural products as anti-leishmanial agents. We aimed at investigating the structure-activity relationships of the natural chalcone lophirone E, characterized by the presence of benzofuran B-ring, and analogues on anti-leishmania activity. Here we describe an effective synthetic strategy for the preparation of the natural chalcone lophirone E and its application to the synthesis of a small set of chalcones bearing different substitution patterns at both the A and heterocyclic B rings. The resulting compounds were investigated for their activity against

Topics: Antiparasitic Agents; Benzofurans; Biflavonoids; Chalcones; Chemical Phenomena; Chemistry Techniques, Synthetic; Humans; Indoles; Leishmania infantum; Molecular Structure; Structure-Activity Relationship

Benzofuran derivatives are synthetic compounds that are finding an increasing interest in the scientific community not only as building blocks for the realization of new materials, but also as potential drugs thanks to their ability to interact with nucleic acids, interfere with the amyloid peptide aggregation and cancer cell cycle. However, their ability to interact with proteins is a theme still in need of investigation for the therapeutic importance that benzofurans could have in the modulation of protein-driven processes and for the possibility of making use of serum albumins as benzofurans delivery systems. To this scope, we investigated the protein binding ability of two 4-nitrophenyl-functionalized benzofurans previously synthesized in our laboratory and herein indicated as BF1 and BDF1, which differed for the number of furan rings (a single moiety in BF1, two in BDF1), using bovine serum albumin (BSA) as a model protein. By circular dichroism (CD) spectroscopy we demonstrated the ability of the two heteroaromatic compounds to alter the secondary structure of the serum albumin leading to different consequences in terms of BSA thermal stability with respect to the unbound protein (ΔT

Topics: Benzofurans; Binding Sites; Circular Dichroism; Molecular Docking Simulation; Nitrophenols; Protein Binding; Serum Albumin, Bovine; Spectrometry, Fluorescence; Thermodynamics

In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Structure-Activity Relationship

The functional activity and differentiation potential of cells are determined by their interactions with surrounding cells. Approaches that allow unbiased characterization of cell states while at the same time providing spatial information are of major value to assess this environmental influence. However, most current techniques are hampered by a tradeoff between spatial resolution and cell profiling depth. Here, we develop a photocage-based technology that allows isolation and in-depth analysis of live cells from regions of interest in complex ex vivo systems, including primary human tissues. The use of a highly sensitive 4-nitrophenyl(benzofuran) cage coupled to a set of nanobodies allows high-resolution photo-uncaging of different cell types in areas of interest. Single-cell RNA-sequencing of spatially defined CD8

Topics: Benzofurans; CD8-Positive T-Lymphocytes; Humans; Nitrophenols; Single-Cell Analysis

In this study, the following compounds were isolated from the dichloromethane fraction of the stems of Amomum longiligulare and then characterized: a new benzofuran, namely, longifuran A (1); five other phenolic compounds, namely, 4-methoxycinnamic acid (2), 2,5-dimethoxyphenol (3), eudesmic acid (4), 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (5), and 4,4'-dihydroxychalcone (6); and two triterpenoids, namely, 24-methylcycloartan-3β-ol (7) and 24-methylencycloartan-3β-ol (8). They were evaluated in terms of their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophages. Results indicated that 1 and 5 exhibited promising inhibitory activities against NO generation with IC

Topics: Amomum; Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Dose-Response Relationship, Drug; Lipopolysaccharides; Mice; Molecular Structure; Nitric Oxide; Plant Stems; RAW 264.7 Cells

The dual inhibition of adenosine receptors A1 (A

Topics: Adenosine A1 Receptor Antagonists; Adenosine A2 Receptor Antagonists; Antiparkinson Agents; Benzofurans; Catalytic Domain; Computer Simulation; Drug Design; Humans; Ligands; Molecular Conformation; Parkinson Disease; Principal Component Analysis; Protein Binding; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, alpha-2; Receptors, Purinergic P1; Structure-Activity Relationship; Thermodynamics

Topics: Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Benzofurans; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Quorum Sensing; Structure-Activity Relationship; Tumor Cells, Cultured

A new series of 2-phenylbenzofuran derivatives were designed and synthesized to determine relevant structural features for the MAO inhibitory activity and selectivity. Methoxy substituents were introduced in the 2-phenyl ring, whereas the benzofuran moiety was not substituted or substituted at the positions 5 or 7 with a nitro group. Substitution patterns on both the phenyl ring and the benzofuran moiety determine the affinity for MAO-A or MAO-B. The 2-(3-methoxyphenyl)-5-nitrobenzofuran 9 was the most potent MAO-B inhibitor (IC

Topics: Benzofurans; Binding Sites; Blood-Retinal Barrier; Cell Line, Tumor; Cell Survival; Humans; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Protein Structure, Tertiary; Structure-Activity Relationship

A general, sustainable dearomatization reaction for nitrogen-containing heterocycles was developed. Under solvent free conditions and without catalyst, the biorenewable methyl coumalate (MC) reacted as an efficient C

Topics: Anisoles; Benzofurans; Catalysis; Cycloaddition Reaction; Fluorescent Dyes; Heterocyclic Compounds; Hydrocarbons, Aromatic; Immunoglobulin G; Indoles; Molecular Structure; Optical Imaging; Pyrones; Pyrroles; Serum Albumin, Bovine; Solvents

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key factor in several cardiovascular diseases, as it is responsible for the elevation of circulating low-density lipoprotein cholesterol (LDL-C) levels in blood plasma by direct interaction with the LDL receptor. The development of orally available drugs to inhibit this PCSK9-LDLR interaction is a highly desirable objective. Here, we report the synthesis of naturally occurring moracin compounds and their derivatives with a 2-arylbenzofuran motif to inhibit

Topics: Benzofurans; Cell Proliferation; Enzyme Inhibitors; Hep G2 Cells; Humans; PCSK9 Inhibitors; Stilbenes

Plasmodium falciparum glycogen synthase kinase-3 (PfGSK-3) has been identified as a potential target for the development of novel drugs against multi-drug resistant malaria. A series of benzofuran-based compounds was synthesised and evaluated as inhibitors of recombinantly expressed and purified PfGSK-3 and human glycogen synthase kinase-3 beta (HsGSK-3β). Of this series, five compounds (5k, 5m, 5p, 5r, 5s) preferentially inhibited PfGSK-3, with four of these compounds exhibiting IC

Topics: Benzofurans; Dose-Response Relationship, Drug; Glycogen Synthase Kinase 3; Humans; Molecular Structure; Plasmodium falciparum; Protein Kinases; Structure-Activity Relationship

The combination of antiarrhythmic agents, amiodarone or dronedarone, with the anticoagulant rivaroxaban is used clinically in the management of atrial fibrillation for rhythm control and secondary stroke prevention respectively. Renal drug-drug interactions (DDIs) between amiodarone or dronedarone and rivaroxaban were previously ascribed to inhibition of rivaroxaban secretion by P-glycoprotein at the apical membrane of renal proximal tubular epithelial cells. Benzbromarone, a known inhibitor of organic anion transporter 3 (OAT3), shares a benzofuran scaffold with amiodarone and dronedarone. However, inhibitory activity of amiodarone and dronedarone against OAT3 remains arcane. Here, we conducted in vitro transporter inhibition assays in OAT3-transfected HEK293 cells which revealed amiodarone, dronedarone and their respective major pharmacologically-active metabolites N-desethylamiodarone and N-desbutyldronedarone possess inhibitory activity against OAT3, with corrected K

Topics: Amiodarone; Anti-Arrhythmia Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Atrial Fibrillation; Benzofurans; Cell Line; Dronedarone; Drug Interactions; HEK293 Cells; Humans; Organic Anion Transporters, Sodium-Independent; Rivaroxaban

Lysine-specific demethylase 1 (LSD1) is a FAD-dependent enzyme, which has been proposed as a promising target for therapeutic cancer. Herein, a series of benzofuran derivatives were designed, synthesized and biochemical evaluated as novel LSD1 inhibitors based on scaffold hopping and conformational restriction strategy. Most of the compounds potently suppressed the enzymatic activities of LSD1 and potently inhibited tumor cells proliferation. In particular, the representative compound 17i exhibited excellent LSD1 inhibition at the molecular levels with IC

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzofurans; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Histone Demethylases; Humans; Mice; Mice, Nude; Molecular Structure; Neoplasms, Experimental; Structure-Activity Relationship

As one of the most lethal malignancies, lung cancer is considered to account for approximately one-fifth of all malignant tumours-related deaths worldwide. This study reports the synthesis and

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Development; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Molecular Structure; Structure-Activity Relationship

A series of benzofuran piperidine derivatives were designed, synthesized and evaluated as multifunctional Aβ antiaggregant to treat Alzheimer's disease (AD). In vitro results revealed that all of them are very good Aβ antiaggregants and some of the compounds are potent acetylcholinesterase (AChE) inhibitors with moderate antioxidant property. Selected compounds were also tested for neuroprotection activity, LDH release, ATP production and inhibitory activity to prevent Aβ peptides binding to the cell membrane. The different modifications introduced in the structure of our lead compound 3 (hAChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Piperidines; Protein Aggregates; Protein Aggregation, Pathological; Structure-Activity Relationship

In the current work, a new set of carbohydrazide linked benzofuran-isatin conjugates (

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Drug Development; Drug Screening Assays, Antitumor; Humans; Isatin; Molecular Structure; Proto-Oncogene Proteins c-bcl-2

Topics: Anti-Inflammatory Agents; Benzofurans; Benzoic Acid; Biomarkers; Drug Evaluation, Preclinical; Humans; Inflammation; Naphthalenes; Purinergic P2 Receptor Antagonists; Pyrimidines; Receptors, Purinergic P2; Structure-Activity Relationship; Triazoles

Bacterial thiol-disulfide oxidoreductase DsbA is essential for bacterial virulence factor assembly and has been identified as a viable antivirulence target. Herein, we report a structure-based elaboration of a benzofuran hit that bound to the active site groove of Escherichia coli DsbA. Substituted phenyl groups were installed at the 5- and 6-position of the benzofuran using Suzuki-Miyaura coupling. HSQC NMR titration experiments showed dissociation constants of this series in the high µM to low mM range and X-ray crystallography produced three co-structures, showing binding in the hydrophobic groove, comparable with that of the previously reported benzofurans. The 6-(m-methoxy)phenyl analogue (2b), which showed a promising binding pose, was chosen for elaboration from the C-2 position. The 2,6-disubstituted analogues bound to the hydrophobic region of the binding groove and the C-2 groups extended into the more polar, previously un-probed, region of the binding groove. Biochemical analysis of the 2,6-disubsituted analogues showed they inhibited DsbA oxidation activity in vitro. The results indicate the potential to develop the elaborated benzofuran series into a novel class of antivirulence compounds.

Topics: Benzofurans; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors; Escherichia coli Proteins; Models, Molecular; Molecular Structure; Protein Disulfide-Isomerases; Structure-Activity Relationship

Hsp90 (i.e., Heat shock protein 90) is a well-established therapeutic target for several diseases, ranging from misfolding-related disfunctions to cancer. In this framework, we have developed in recent years a family of benzofuran compounds that act as Hsp90 allosteric modulators. Such molecules can interfere with the stability of some relevant Hsp90 client oncoproteins, showing a low μM cytotoxic activity in vitro in cancer cell lines. Here we identify the target profile of these chemical probes by means of chemical proteomics, which established MDH2 (mitochondrial malate dehydrogenase) as an additional relevant cellular target that might help elucidate the molecular mechanism of their citotoxicity. Western blotting, DARTS (i.e., Drug Affinity Responsive Target Stability) and enzymatic assays data confirmed a dose-dependent interaction of MDH2 with several members of the benzofuran Hsp90 modulators family and a computational model allowed to interpret the observed interactions.

Topics: Allosteric Regulation; Antineoplastic Agents; Benzofurans; Dose-Response Relationship, Drug; HSP90 Heat-Shock Proteins; Humans; Malate Dehydrogenase; Models, Molecular; Molecular Structure; Structure-Activity Relationship

Pursuing the widespread interest on multi-target drugs to combat Alzheimer´s disease (AD), a new series of hybrids was designed and developed based on the repositioning of the well-known acetylcholinesterase (AChE) inhibitor, tacrine (TAC), by its coupling to benzofuran (BF) derivatives. The BF framework aims to endow the conjugate molecules with ability for inhibition of AChE (bimodal way) and of amyloid-beta peptide aggregation, besides providing metal (Fe, Cu) chelating ability and concomitant extra anti-oxidant activity, for the hybrids with hydroxyl substitution. The new TAC-BF conjugates showed very good activity for AChE inhibition (sub-micromolar range) and good capacity for the inhibition of self- and Cu-mediated Aβ aggregation, with dependence on the linker size and substituent groups of each main moiety. Neuroprotective effects were also found for the compounds through viability assays of neuroblastoma cells, after Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Benzofurans; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Structure-Activity Relationship; Tacrine

Oxidation and enzymatic browning of food can affect nutritional quality, physical and chemical properties, and food safety, emphasizing the utmost importance of discovering new natural antioxidants and anti-browning agents. The present study aimed to characterize the antioxidant and anti-browning potential of 2-arylbenzofuran derivatives from the root bark of Morus alba Linn. All test compounds showed good antioxidant effects on non-enzymatic antioxidant assays. Only mulberrofuran H demonstrated potent inhibition against substrates l-tyrosine (IC

Topics: Antioxidants; Benzofurans; Color; Molecular Docking Simulation; Morus; Oxidation-Reduction; Plant Bark; Plant Extracts; Plant Roots

Pursuing on our efforts toward searching for efficient hCA IX and hCA XII inhibitors, herein we report the design and synthesis of new sets of benzofuran-based sulphonamides (

Topics: Antigens, Neoplasm; Antineoplastic Agents; Benzofurans; Carbonic Anhydrase Inhibitors; Carbonic Anhydrase IX; Carbonic Anhydrases; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; Sulfonamides

Herein, we present a short and highly modular synthetic route that involves 8-aminoquinoline directed C-H arylation and transamidation chemistry, and which enables access to a wide range of elaborate benzofuran-2-carboxamides. For the directed C-H arylation reactions, Pd catalysis was used to install a wide range of aryl and heteroaryl substituents at the C3 position of the benzofuran scaffold in high efficiency. Directing group cleavage and further diversification of the C3-arylated benzofuran products were then achieved in a single synthetic operation through the utilization of a one-pot, two-step transamidation procedure, which proceeded via the intermediate

Topics: Amides; Aminoquinolines; Benzene Derivatives; Benzofurans; Catalysis; Molecular Structure

A series of 4H-chromen-4-one derivatives obtained by scaffold morphing of the benzofuran compound, TAM16, were tested for antitubercular activity. Compound 8d was active against drug-sensitive and multidrug-resistant tuberculosis. A preliminary druggability evaluation showed that compound 8d displayed favorable mouse and human microsomal stability, low cytotoxicity, and acceptable oral bioavailability. An in vivo study indicated that compound 8d exhibited modest efficacy in an acute mouse model of TB after 3 weeks of treatment. Thus, 8d is a promising antituberculosis lead compound.

Topics: Animals; Antitubercular Agents; Benzofurans; Benzopyrans; Drug Design; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Microsomes, Liver; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship; Tuberculosis, Multidrug-Resistant

Bacterial infections continue to threaten humankind and the rapid spread of antibiotic resistant bacteria is alarming. Current antibiotics target essential bacterial processes and thereby apply a strong selective pressure on pathogenic and non-pathogenic bacteria alike. One alternative strategy is to block bacterial virulence systems that are essential for the ability to cause disease but not for general bacterial viability. We have previously show that the plant natural product (-)-hopeaphenol blocks the type III secretion system (T3SS) in the Gram-negative pathogens Yersinia pseudotuberculosis and Pseudomonas aeruginosa. (-)-Hopeaphenol is a resveratrol tetramer and in the present study we explore various resveratrol dimers, including partial structures of (-)-hopeaphenol, as T3SS inhibitors. To allow rapid and efficient assessment of T3SS inhibition in P. aeruginosa, we developed a new screening method by using a green fluorescent protein reporter under the control of the ExoS promoter. Using a panel of assays we showed that compounds with a benzofuran core structure i.e. viniferifuran, dehydroampelopsin B, anigopreissin A, dehydro-δ-viniferin and resveratrol-piceatannol hybrid displayed significant to moderate activities towards the T3SS in Y. pseudotuberculosis and P. aeruginosa.

Topics: Anti-Bacterial Agents; Benzofurans; Drug Discovery; Flavonoids; Genes, Reporter; Green Fluorescent Proteins; Phenols; Pseudomonas aeruginosa; Resveratrol; Stilbenes; Type III Secretion Systems; Virulence; Yersinia pseudotuberculosis

In this work ZnO-nanorod (ZnO-NR) as reusable catalyst promoted Strecker-type reaction of 2,4-dihydroxyacetophenone, isopropenylacetylene, trimethylsilyl cyanide (TMSCN), primary amines and isocyanides at ambient temperature under solvent-free conditions and produced α-amino nitriles benzofuran derivatives in high yields. These synthesized compounds may have antioxidant ability.. ZnO-NRs in these reactions were prepared according to reported article. 2,4-dihydroxyacetophenone 1 (2 mmol) and isopropenylacetylene 2 (2 mmol) were mixed and stirred for 30 min in the presence of ZnO-NR (10 mol%) under solvent-free conditions at room temperature. After 30 min, primary amine 3 (2 mmol) was added to the mixture gently and the mixture was stirred for 15 min. After this time TMSCN 4 (2 mmol) was added to the mixture and stirred for 15 min. After completion of the reaction, as indicated by TLC, isocyanides 5 was added to mixture in the presence of catalyst.. In the first step of this research, the reaction of 2,4-dihydroxyacetophenone 1, isopropenylacetylene 2, methyl amine 3a, trimethylsilyle cyanide 4 and tert-butyl isocyanides 5a was used as a sample reaction to attain the best reaction conditions. The results showed this reaction performed with catalyst and did not have any product without catalyst after 12 h.. In conclusion, we investigate multicomponent reaction of 2,4-dihydroxyacetophenone 1, isopropenylacetylene 2, primary amines 3, trimethylsilyl cyanide 4 and isocyanides along with ZnO-NRs as reusable catalyst at room temperature under solvent-free conditions which generates α-amino nitrile benzofuran derivatives in high yields. The advantages of our method are high atom economy, green reaction conditions, higher yield, shorter reaction times, and easy work-up, which are in good agreement with some principles of green chemistry. The compounds 8c exhibit excellent DPPH radical scavenging activity and FRAP compared to synthetic antioxidants BHT and TBHQ.

Topics: Benzofurans; Catalysis; Cyanides; Molecular Structure; Nanotubes; Nitriles; Zinc Oxide

Histone lysine specific demethylase 1 (LSD1 or KDM1A) is a potential therapeutic target in oncology due to its overexpression in various human tumors. We report herein a new class of benzofuran acylhydrazones as potent LSD1 inhibitors. Among the 31 compounds prepared, 14 compounds exhibited excellent LSD1 inhibitory activity with IC

Topics: Benzofurans; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Histone Demethylases; Humans; Hydrazones; Inhibitory Concentration 50; Molecular Docking Simulation; Structure-Activity Relationship

A new isobenzoisofuran(1) has been isolated from the whole plant of Cassia pumila using various chromatographic techniques, including silica gel, Sephadex, MCI-gel resin, and RP-HPLC, and its structure was determined as 9-(2-hydroxyethyl)-2,2-dimethyl-2H-furo[3,4-g]chromen-6(8H)-one. This compound was also evaluated for its antibacterial activity. The results showed that it had prominent antibacterial activity with MIC_(90) value of(45.2±4.2) μg·mL~(-1) for methicillin resistant Staphylococcus aureus(MRSA) strain. This value was closed to that of levofloxacin [with MIC_(90) value(48.5±4.3) μg·mL~(-1)].

Topics: Anti-Bacterial Agents; Benzofurans; Cassia; Levofloxacin; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Phytochemicals; Plants, Medicinal

A series of new benzofuran/oxadiazole hybrids (8a-n) was synthesized from 2H-chromene-3-carbonitriles (3a-c) through the multistep synthetic methodology, and these hybrids are known to exhibit anticancer activities. All the compounds were evaluated for their in vitro cytotoxicity against the HCT116 and MIA PaCa2 cell lines. Compounds 6a (IC

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Molecular Docking Simulation; Molecular Structure; Oxadiazoles; Structure-Activity Relationship

As a part of our drug discovery program for anti-tubercular agents, a total of seventeen 2, 3-diaryl benzofuran hybrids were designed, synthesized and screened for their anti-tubercular potential against Mycobacterium tuberculosis H37Ra avirulent strain. Out of seventeen, four derivatives showed significant activity against M. tuberculosis H37Ra avirulent strain (ATCC 25177) with MIC value ranging from 12.5 to 50 µg/mL but out of four, one derivative (9E) was significantly active (MIC 12.5 μg/mL), which was further supported by the molecular docking energy (-8.4 kcal/mol) with respect to the first line anti-tubercular drug, isoniazid (-6.2 kcal/mol) on the target Polyketide Synthase-13. All the derivatives were also evaluated for their cytotoxicity against the normal lung cell line L-132 by the MTT assay and no toxicity was observed up to 27.4 µg/mL concentration. This report on the antitubercular potential of benzofuran derivatives may be of great help in anti-tubercular drug development.

Topics: Antitubercular Agents; Benzofurans; Cell Line; Dose-Response Relationship, Drug; Drug Design; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Structure-Activity Relationship

A novel "non-aromatic pool" synthetic strategy for the synthesis of benzofuran-based natural products via oxidative haloaromatization of enones is reported. This approach is successfully applied in the first total synthesis of the natural product aspergillusene B. In comparison with a separately executed "aromatic pool" synthesis, the "non-aromatic pool" protocol demonstrates equivalent efficiency but offers a much higher degree of modularity.

Topics: Benzofurans; Biological Products; Halogenation; Ketones; Molecular Structure; Stereoisomerism

Series of 2-arylbenzofuran-1,2,3-selenodiazole hybrids were prepared via multiple reactions and then evaluated in vitro through enzymatic assay for inhibitory effect against α-glucosidase and cyclooxygenase-2 (COX-2) activities including antioxidant activity. The presence of 1,2,3-selenodiazole moiety resulted in increased inhibitory effect for compounds 4a-f against α-glucosidase and COX-2 activities, and increased free radical scavenging activity. 6-Acetoxy-2-phenyl-5-(1,2,3-selenadiazol-4-yl)benzofuran (4a) and its 2-(4-methoxyphenyl) substituted derivative (4f) were, in turn, screened for antiproliferation against the breast MCF-7 cancer cell line and for cytotoxicity on the human embryonic kidney derived Hek293-T cells. A cell-based antioxidant activity assay involving lipopolysaccharide induced reactive oxygen species production in these cells was performed. Molecular docking has also been performed on these two compounds to predict protein-ligand interactions against α-glucosidase and COX-2.

Topics: alpha-Glucosidases; Antioxidants; Azoles; Benzofurans; Binding Sites; Catalytic Domain; Cell Line; Cell Survival; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Kinetics; Lipopolysaccharides; MCF-7 Cells; Molecular Conformation; Molecular Docking Simulation; Reactive Oxygen Species; Structure-Activity Relationship

The bone morphogenetic protein (BMP) pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. This study optimized the structure of the anti-osteoporosis compound 38 by balancing its lipophilicity and improving its stability. Twenty derivatives which were not reported in the literature were designed and synthesized. The ovariectomized rat model of osteoporosis was selected to evaluate the therapeutic effects. Compound 125 showed better therapeutic efficacy than that of 38. We verified the anti-osteoporosis activity and BMP-2 protein upregulation after treatment with 125 in a zebrafish osteoporosis model. We found that 125 improved the ADME properties, therapeutic efficacy, and pharmacokinetics of the drug. Overall, we evaluated the anti-osteoporosis effects of the compounds of this type, preliminarily determined the target patient population, verified the mechanism of action, clarified the level of toxicity, and provided preliminary ADME data. We believe that these compounds can both correct bone loss that is already occurring in patients and have broad clinical applicability.

Topics: Animals; Benzofurans; Bone Morphogenetic Protein 2; Caco-2 Cells; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Mice; Mice, Inbred BALB C; Molecular Structure; Osteoporosis; Ovariectomy; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Thiophenes; Zebrafish

Three new sesquiterpenoids (1-3) and four new benzofuran dimers (+)-4 and (-)-4, (+)-5 and (-)-5, and four known benzofuran dimers (+)-6 and (-)-6, (+)-7 and (-)-7 were isolated from the underground parts of Eupatorium chinense. The enantiomers of racemates (±)-4 ~ (±)-7 were separated by chiral HPLC columns, and their absolute configurations were determined by circular dichroism experiments. The structures of all new compounds were elucidated on the basis of their NMR, and MS data as well as by comparison with literature values. The all of the isolated compounds were tested in vitro for their cytotoxic activities against the Caski, MDA-MB-231 and HepG2 cancer cell lines.

Topics: Antineoplastic Agents, Phytogenic; Benzofurans; China; Eupatorium; Hep G2 Cells; Humans; Molecular Structure; Phytochemicals; Plant Roots; Sesquiterpenes

In continuation of our work on enzyme inhibition, the benzofuran-based-thiazoldinone analogues (1-14) were synthesized, characterized by HREI-MS,

Topics: Benzofurans; Dose-Response Relationship, Drug; Enzyme Inhibitors; Molecular Docking Simulation; Structure-Activity Relationship; Urease

Novel 1,4-bis[(2-(3-(dimethylamino)-1-oxoprop-2-en-1-yl)benzofuran-5-yl)methyl]piperazine was prepared and used as a key synthon for the this study. Therefore, 1,3-dipolar cycloaddition of this synthon with the appropriate hydrazonyl chlorides afforded a new series of bis(1,3,4-trisubstituted pyrazoles), linked via piperazine moiety. Furthermore, it reacted with hydrazine hydrate and phenyl hydrazine individually to afford the corresponding 1,4-bis[(2-(1H-pyrazolyl)benzofuran-5-yl)methyl]piperazines. Different bacterial strains and cell lines were selected to study the in-vitro antibacterial and cytotoxic activities for the new derivatives. 1,4-Bis[((2-(3-acetyl-1-(4-nitrophenyl)-1H-pyrazole-4-yl)carbonyl)benzofuran-5-yl)methyl]piperazine 5e showed the best antibacterial efficacies with MIC/MBC values of 1.2/1.2, 1.2/2.4 and 1.2/2.4 μM against each of E. coli, S. aureus and S. mutans strains, respectively. In addition, the inhibitory activity of some new bis(pyrazoles) as MRSA and VRE inhibitors were studied. Compound 5e gave the best inhibitory activity with MIC/MBC values of 18.1/36.2, 9.0/18.1 and 18.1/18.1 µM, respectively, against MRSA (ATCC:33591 and ATCC:43300) and VRE (ATCC:51575) bacterial strains, respectively. Compound 5e showed more effective biofilm inhibition activities than the reference Ciprofloxacin. It showed IC

Topics: Anti-Bacterial Agents; Antineoplastic Agents; Benzofurans; Biofilms; Carbohydrate Dehydrogenases; Cell Line; Cell Proliferation; Dose-Response Relationship, Drug; Drug Resistance, Bacterial; Drug Screening Assays, Antitumor; Enterococcus faecalis; Escherichia coli; Humans; Microbial Sensitivity Tests; Molecular Structure; Piperazine; Pyrazoles; Staphylococcus aureus; Structure-Activity Relationship

The study presents the influence of structure modulation by introducing selected donor and acceptor substituents on optical properties of benzofuran used in biological imaging. As the starting form, 2-(5-formylbenzofuran-2-yl)acetamide described experimentally was used. This molecule contains an aldehyde group as reactive site, through which conjugation with protein occurs. Structure modulation was carried out by attaching additional electron-donating and electron-withdrawing substituents to the amino group, namely -NH

Topics: Algorithms; Benzofurans; Chemical Phenomena; Fluorescent Dyes; Models, Molecular; Molecular Conformation; Molecular Structure; Spectrum Analysis; Structure-Activity Relationship

Ectonucleotidases are a broad family of ectoenzymes that play a crucial role in purinergic cell signaling. Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) belong to this group and are important drug targets. In particular, NPP1 and NPP3 are known to be druggable targets for treatment of impaired calcification disorders (including pathological aortic calcification) and cancer, respectively. In this study, we investigated a series of sulfonate and sulfamate derivatives of benzofuran and benzothiophene as potent and selective inhibitors of NPP1 and NPP3. Compounds 1c, 1g, 1n, and 1s are the most active NPP1 inhibitors (IC

Topics: Antineoplastic Agents; Benzofurans; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Molecular Docking Simulation; Molecular Structure; Phosphoric Diester Hydrolases; Pyrophosphatases; Structure-Activity Relationship; Sulfonic Acids; Thiophenes; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Binding Sites; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Drug Design; G2 Phase Cell Cycle Checkpoints; Humans; Molecular Docking Simulation; Phosphorylation; src Homology Domains; STAT3 Transcription Factor; Structure-Activity Relationship

A new neoflavonoid, named

Topics: Anti-Infective Agents; Benzofurans; Candida albicans; Dalbergia; Escherichia coli; Flavonoids; Microbial Sensitivity Tests; Molecular Structure; Salmonella enterica; Spectrum Analysis; Staphylococcus aureus

Biotests like the fish embryo toxicity test have become increasingly popular in risk assessment and evaluation of chemicals found in the environment. The large range of possible endpoints is a big advantage when researching on the mode of action of a certain substance. Here, we utilized the frequently used model organism zebrafish (Danio rerio) to examine regulative mechanisms in the pathway of the aryl-hydrocarbon receptor (AHR) in early development. We exposed embryos to representatives of two chemical classes known to elicit dioxin-like activity: benzo[a]pyrene for polycyclic aromatic hydrocarbons (PAHs) and 2,3-benzofuran for polar O-substituted heterocycles as a member of heterocyclic compounds in general (N-, S-, O-heterocycles; NSO-hets). We measured gene transcription of the induced P450 cytochromes (cyp1), their formation of protein and biotransformation activity throughout the whole embryonic development until 5 days after fertilization. The results show a very specific time course of transcription depending on the chemical properties (e.g. halogenation, planarity, K

Topics: Animals; Benzo(a)pyrene; Benzofurans; Cytochrome P-450 CYP1A1; Embryo, Nonmammalian; Receptors, Aryl Hydrocarbon; Toxicity Tests; Transcription, Genetic; Water Pollutants, Chemical; Zebrafish; Zebrafish Proteins

Cyclic AMP promotes EPAC1 and EPAC2 activation through direct binding to a specific cyclic nucleotide-binding domain (CNBD) within each protein, leading to activation of Rap GTPases, which control multiple cell responses, including cell proliferation, adhesion, morphology, exocytosis, and gene expression. As a result, it has become apparent that directed activation of EPAC1 and EPAC2 with synthetic agonists may also be useful for the future treatment of diabetes and cardiovascular diseases. To identify new EPAC agonists we have developed a fluorescent-based, ultra-high-throughput screening (uHTS) assay that measures the displacement of binding of the fluorescent cAMP analogue, 8-NBD-cAMP to the EPAC1 CNBD. Triage of the output of an approximately 350,000 compound screens using this assay identified a benzofuran oxaloacetic acid EPAC1 binder (SY000) that displayed moderate potency using orthogonal assays (competition binding and microscale thermophoresis). We next generated a limited library of 91 analogues of SY000 and identified SY009, with modifications to the benzofuran ring associated with a 10-fold increase in potency towards EPAC1 over SY000 in binding assays.

Topics: Acetates; Benzofurans; Binding Sites; Cell Line; Cyclic AMP; Guanine Nucleotide Exchange Factors; High-Throughput Screening Assays; Humans; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Structure

A new benzofuran, methyl (2S,2″S,3'E)-[2-(1″-acetoxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl]acrylate (1), and 13 known compounds (2-14) were isolated from an ethanol extract of Artemisia halodendron Turcz. ex Bess. The chemical structures of these compounds were determined by 1D and 2D NMR (

Topics: Artemisia; Benzofurans; Ethanol; HeLa Cells; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; NF-kappa B; Plant Extracts

Myeloid cell leukemia 1 (Mcl1), is an antiapoptotic member of the Bcl-2 family proteins, has gained considerable importance due to its overexpression activity prevents the oncogenic cells to undergo apoptosis. This overexpression activity of Mcl1 eventually develops strong resistance to a wide variety of anticancer agents. Therefore, designing novel inhibitors with potentials to elicit higher binding affinity and specificity to inhibit Mcl1 activity is of greater importance. Thus, Mcl1 acts as an attractive cancer target. Despite recent experimental advancement in the identification and characterization of benzothiophene and benzofuran scaffold-merged compounds, the molecular mechanisms of their binding to Mcl1 are yet to be explored. The current study demonstrates an integrated approach - pharmacophore-based 3D-QSAR, docking, molecular dynamics (MD) simulation and free-energy estimation - to access the precise and comprehensive effects of current inhibitors targeting Mcl1 together with its known activity values. The pharmacophore - ANRRR.240 - based 3D-QSAR model from the current study provided high confidence (R

Topics: Apoptosis; Benzofurans; Least-Squares Analysis; Molecular Docking Simulation; Molecular Dynamics Simulation; Myeloid Cell Leukemia Sequence 1 Protein; Quantitative Structure-Activity Relationship; Reproducibility of Results; Thiophenes

Four 4-nitrophenyl-functionalized benzofuran (BF1, BF2) and benzodifuran (BDF1, BDF2) compounds were synthesized by a convenient route based on the Craven reaction. All the compounds underwent a detailed chemical-physical characterization to evaluate their structural, thermal and optical properties. An investigation on the therapeutic potential of the reported compounds was performed by analyzing their antiproliferative activity on prostatic tumour cells (PC-3). In both classes of compounds, anticancer potential is in direct correlation with the lipophilicity. From our study it emerged that antiproliferative activity was higher for benzofuran derivatives as compared to benzodifuran systems. Moreover, we report a mechanistic study relative to the most promising molecule, i.e. the apolar benzofuran BF1, that relates the antiproliferative properties found in our investigation to its ability to bind telomeric DNA (proven by CD and fluorescence techniques on tel

Topics: Antineoplastic Agents; Benzofurans; Cell Proliferation; Cell Survival; DNA; Drug Screening Assays, Antitumor; Humans; Nitrophenols; PC-3 Cells; S Phase Cell Cycle Checkpoints; Structure-Activity Relationship; Telomere

A series of novel Benzofuran-tetrazole derivatives were successfully synthesised by integrating multicomponent Ugi-azide reaction with the molecular hybridization approach. Interestingly, a number of synthesized derivatives (5c, 5d, 5i, 5l, 5q and 5s) exhibited significant reduction of aggregation of "human" amyloid beta peptide, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. Further, in silico docking results have evidenced the exquisite interaction of active compounds with the help of TcAChE-E2020 complex. These findings underscore the potential of these hybrids as lead molecules against Alzheimers's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzofurans; Caenorhabditis elegans; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Molecular Dynamics Simulation; Molecular Structure; Protein Aggregates; Structure-Activity Relationship; Tetrazoles

Novel derivatives of benzo[b]furan were found to be highly toxic towards human chronic myelogenous (K562), acute myelogenous (HL-60) and acute lymphoblastic (MOLT-4) leukemia cells.. The objective was the characterization of the biological activity of novel benzofurans (influence on apoptosis, mitogen-activated protein kinases and on the cell cycle). Cellular protein(s) targeted by test benzofurans and mechanism of action were identified.. The methods utilized in the study were chemical synthesis, fluorescence assays, flow cytometry, gene expression by DNA microarray and real-time RT-PCR, western blotting, cytotoxicity assays, pull-down assay, mass spectroscopy, in vitro polymerization of tubulin, molecular docking.. 1,1'-[3-(bromomethyl)-5,6- dimethoxy-1-benzofuran-2,7-diyldiethanone (1) and methyl 4-bromo-6- (dibromoacetyl)-5-hydroxy-2-methyl-1-benzofuran-3-carboxylate (2) induced apoptosis in K562 and MOLT-4 cells. The profiling of gene expression revealed that 1 and 2 increased the expression of proapoptotic genes involved in both receptor (TNFRSF 10A, TNFRSF 10B, CASP8) and mitochondrial (BAX, BID, NOXA, APAF1) pathways of apoptosis. Test benzo[b]furans activated c-Jun N-terminal kinase (JNK) and p38 kinase in K562 cells. Tubulin was identified as a protein target for benzo[b]furans in pull-down experiments with biotinylated 2. Test benzo[b]furans inhibited polymerization of tubulin monomers in vitro, decreased the level of cellular microtubules and arrested cells in a G2/M phase. Molecular docking suggests that benzo[b]furans 1 and 2 bind to tubulin via colchicine binding pocket and the complex is stabilized mainly by hydrophobic interactions.. Novel benzo[b]furans with anti-microtubule activity were identified. They induce apoptosis in cancer cells and cause G2/M cell cycle arrest. Biological activity of 1 and 2 makes them potential lead compounds for development as anticancer drugs.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Cell Cycle Checkpoints; Cell Division; Cell Proliferation; Cells, Cultured; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; G2 Phase; Humans; Molecular Structure; Structure-Activity Relationship; Tubulin; Tubulin Modulators; Up-Regulation

We have designed, synthesized and evaluated a series of hydroxylated 2-phenylbenzofuran derivatives as potential cholinesterase inhibitors. Starting from a series of 2-phenylbenzofurans previously published, in this paper we present a complete synthesis and the influence on the activity of one or two hydroxyl groups located in meta or in meta and para positions respectively of the 2-phenyl ring and highlight the importance of position of hydroxyl groups. Moreover, simultaneous introduction of halogen at position 7 of the benzofuran scaffold resulted in an improved inhibitory activity against the enzyme. To further provide molecular insight and to identify the most probable ligand-binding site of the protein, docking studies were performed for the top-ranked compounds. Docking results revealed conserved ligand-binding residues and supported the role of catalytic site residues in enzyme inhibition.

Topics: Acetylcholinesterase; Benzofurans; Binding Sites; Butyrylcholinesterase; Catalytic Domain; Cholinesterase Inhibitors; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Structure-Activity Relationship

Benzofuran derivatives have wide range of biological activities as anti-oxidant, anti-inflammatory and anticonvulsant agent. In this study, we investigated whether the novel benzofuran derivative, DK-1014 has the anti-inflammatory effects on macrophage and lung epithelial cells and anti-asthmatic effects on ovalbumin-treated mice. A series of 2-arylbenzofuran analogues were synthesized and evaluated for NO and interleukin-6 (IL-6) inhibition in LPS-stimulated Raw264.7 cells. Of these analogues, compounds 8, 22a, 22d, and 22 f (DK-1014) exhibited notable inhibitory activity with respect to IL-6 and NO production. In particular, compound DK-1014 strongly reduced IL-6, IL-8, and MMP-9 mRNA expression and IL-6, IL-8, and MCP-1 production in phorbol myristate acetate stimulated A549 cells, reduced MAPKs phosphorylation and c-fos translocation, and attenuated AKT, p70S6K and GSK phosphorylation. In vivo experiments were also performed on ovalbumin-sensitized and challenged BALB/c mice. DK-1014 reduced the airway hyperresponsiveness, inflammatory cell counts and cytokine levels (IL-4, 5, 13) in bronchial alveolar lavage fluid (BALF) and immunoglobulin E in serum, and attenuated inflammatory cell infiltration and mucus hypersecretion in lung tissue. These findings indicate that DK-1014 can protect against allergic airway inflammation through the AP-1 and AKT/mTOR pathways and could be useful source for the development of a therapeutic agent for asthma.

Topics: Animals; Anti-Inflammatory Agents; Asthma; Benzofurans; Cells, Cultured; Cytokines; Disease Models, Animal; Humans; Macrophages; Mice; Mice, Inbred BALB C; Nitric Oxide; Pneumonia; Proto-Oncogene Proteins c-akt; Respiratory Mucosa; Signal Transduction; TOR Serine-Threonine Kinases; Transcription Factor AP-1

Leishmaniasis is a parasitic disease representing an important problem of public health. Visceral leishmaniasis, resulting from infection with Leishmania donovani, causes considerable mortality and morbidity in the poorest region of the word. At present there is no current effective treatment, since the approved, drugs are expensive and are not free of undesirable side effects. Therefore, there is a need for the identification of new drugs. In this context, the parasite Ca

Topics: Amiodarone; Animals; Benzofurans; Calcium; Cell Line; Cell Survival; Cytoplasm; Drug Discovery; Homeostasis; Inhibitory Concentration 50; Leishmania donovani; Leishmaniasis, Visceral; Macrophages; Metabolic Networks and Pathways; Mice; Mitochondria; Trypanocidal Agents

A pair of enantiomeric triketone-phloroglucinol hybrids, (+)- and (-)-myrtuspirone A (1), featuring an unprecedented 3-isopropyl-3 H-spiro[benzofuran-2,1'-cyclohexane] backbone, were isolated from the leaves of Myrtus communis. The absolute configuration of each enantiomer of 1 was determined by X-ray diffraction and chemical calculations. Furthermore, the gram-scale total syntheses of (±)-1 and (-)-1 were conducted in four steps using a Michael- N-iodosuccinimide (NIS)-mediated (3 + 2)-annulation reaction. Both (+)- and (-)-1 exhibited antibacterial activities against Gram-positive bacteria including multidrug-resistant strains.

Topics: Anti-Bacterial Agents; Benzofurans; Cyclohexanes; Gram-Positive Bacteria; Molecular Structure; Myrtus; Phloroglucinol; Plant Leaves; Stereoisomerism

Lithocarols A-F (1-6) possessing novel highly-oxygenated isobenzofuran core, together with a related known compound isoprenylisobenzofuran A (7) were isolated from the marine-derived fungus Phomopsis lithocarpus FS508. Among them, lithocarols A-E (1-5) represent the first examples of poly-ketal derivatives in tenellone family. The structures for all these compounds were fully elucidated by spectroscopic analysis, X-ray diffraction, and electronic circular dichroism calculations. Their cytotoxic assay disclosed that compounds 1-4 displayed moderate growth inhibitory effect against four human tumor cell lines with the IC

Topics: Antineoplastic Agents; Ascomycota; Benzofurans; Cell Line, Tumor; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Models, Molecular; Molecular Structure; Structure-Activity Relationship

The results of our previous research indicated that some derivatives of benzofurans, particularly halogeno-derivatives, are selectively toxic towards human leukemia cells. Continuing our work with this group of compounds we here report new data on the synthesis as well as regarding the physico-chemical and biological characterization of fourteen new derivatives of benzofurans, including six brominated compounds. The structures of all new compounds were established by spectroscopic methods (

Topics: Antineoplastic Agents; Benzofurans; Caspase 3; Caspase 7; Cell Death; Cell Line, Tumor; DNA; Human Umbilical Vein Endothelial Cells; Humans; Inhibitory Concentration 50

Four disesquiterpenoid-geranylbenzofuranone conjugates, linderalides A-D (1-4), were isolated from Lindera aggregata. Compounds 1-3 represent the first examples of disesquiterpenoid-geranylbenzofuranone hybrids directly linked by two C-C bonds. Linderalide D (4) bears an unprecedented carbon skeleton featuring an unusual linearly 6/6/5/6/6 pentacyclic ring system fused by a sesquiterpenoid unit and a geranylbenzofuranone moiety. Their structures and absolute configurations were elucidated by extensive spectroscopic data and electronic circular dichroism analysis. Their biosynthetic pathways were also proposed.

Topics: Benzofurans; Lindera; Plant Roots; Sesquiterpenes; Stereoisomerism

This study represents the synthetic approaches of a new set of 2-(((3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazono)-5-(aryl)thiazolidin-4-one derivatives 4-22 aiming to obtain new antiproliferative candidates against human cervix carcinoma cells (Hela) of EGFR PK inhibiting potency. The cancer cells represented promising sensitivity towards the compounds 6, 7, 11, 13, 14, 16, 17 more than or equal to that against the reference drug doxorubicin. In addition, the latter compounds were tested as EGFR protein kinase inhibitors. The results revealed that compound 14 showed more significant EGFR PK inhibitory activity than the reference drug erlotinib (IC50; 0.07, 0.08 µM, respectively). Moreover, cell cycle analysis and apoptosis assay were performed for compound 14 proving its ability to cause G1/S phase arrest and apoptosis in Hela cancer cells, in addition to its activation of the caspases-7 and -3. In addition, derivative 14 increased the expression level of p53 and the ratio of Bax/Bcl-2 which confirmed its mode of action. Molecular docking study of 14 was performed to investigate its binding mode of interaction with EGFR PK in the active site with the aim of rationalizing its promising inhibitory activity. Accordingly, compound 14 might be considered as a promising scaffold anticervical cancer chemotherapeutic and deserves further optimization and in-depth biological studies.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors; Female; HeLa Cells; Humans; Hydrazones; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Pyrazoles; Structure-Activity Relationship; Thiazolidinediones; Uterine Cervical Neoplasms

Previously unreported meroterpene, acremine S (

Topics: Acremonium; Animals; Benzofurans; Cholinesterase Inhibitors; Circular Dichroism; Ergosterol; Flavins; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Porifera; Terpenes

In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a-t, having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH

Topics: Benzofurans; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Isoenzymes; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; Sulfonic Acids; Thiophenes

A new series of 3-benzoylamino-5-(1H-imidazol-4-yl)methylaminobenzo[b]furans were synthesized and screened as antitumor agents. As a general trend, tested compounds showed concentration-dependent antiproliferative activity against HeLa and MCF-7 cancer cell lines, exhibiting GI

Topics: Antineoplastic Agents; Benzofurans; Binding Sites; Cell Cycle Checkpoints; Cell Proliferation; Colchicine; Drug Design; HeLa Cells; Humans; MCF-7 Cells; Molecular Docking Simulation; Protein Structure, Tertiary; Tubulin; Tubulin Modulators

A series of 5-substitutedbenzylideneamino-2-butylbenzofuran-3-yl-4-methoxyphenyl methanones is synthesized and evaluated for antileishmanial and antioxidant activities. Compounds 4f (IC

Topics: Antioxidants; Antiprotozoal Agents; Benzofurans; Benzylidene Compounds; Biological Availability; Cell Proliferation; Dose-Response Relationship, Drug; Leishmania donovani; Microbial Sensitivity Tests; Microwaves; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship

A novel series of benzodihydrofuran derivatives was developed as potent MEK inhibitors through scaffold hopping based on known clinical compounds. Further SAR exploration and optimization led to another benzofuran series with good oral bioavailability in rats. One of the compounds EBI-1051 (28d) demonstrated excellent in vivo efficacy in colo-205 tumor xenograft models in mouse and is suitable for pre-clinical development studies for the treatment of melanoma and MEK associated cancers. Compared to AZD6244, EBI-1051 showed superior potency in some cancer cell lines such as colon-205, A549 and MDA-MB-231.

Topics: Administration, Oral; Animals; Benzofurans; Cell Line, Tumor; Cell Survival; Drug Evaluation, Preclinical; Enzyme Activation; Humans; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Protein Kinase Inhibitors; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Transplantation, Heterologous

The first total synthesis of the antiviral flavonoid houttuynoid A (1) has been achieved from aryl ketone 6 and benzofuran aldehyde 5 in nine linear steps. The C

Topics: Aldehydes; Antiviral Agents; Benzofurans; Biological Products; Catalysis; Chalcone; Flavonoids; Ketones

This letter describes the discovery of a fused benzofuran scaffold viable for preparing a series of novel potent HCV NS5B polymerase non-nucleoside inhibitors. Designed on the basis of the functionalized benzofuran derivative nesbuvir (HCV-796), these compounds presumably bind similarly to the allosteric binding site in the "palm" domain of HCV NS5B protein. SAR of each potential hydrogen-bonding interaction site of this novel scaffold is discussed along with some preliminary genotypic profile and PK data of several advanced compounds.

Topics: Animals; Antiviral Agents; Benzofurans; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; HIV; Humans; Microbial Sensitivity Tests; Molecular Structure; Rats; Structure-Activity Relationship; Viral Nonstructural Proteins

The present work aimed to synthesise promising antioxidant compounds as a valuable alternative to the currently expensive and easily degradable molecules that are employed as stabilizers in industrial preparation. Taking into account our experience concerning domino Friedel-Crafts/lactonization reactions, we successfully improved and extended the previously reported methodology toward the synthesis of 3,3-disubstituted-3

Topics: Acetonitriles; Alkylation; Antioxidants; Benzofurans; Biphenyl Compounds; Electrochemistry; Kinetics; Methanol; Oxidation-Reduction; Phenols; Picrates; Regression Analysis; Solvents

Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disorder characterized by progressive deterioration of memory and cognition. The evidenced multifactorial nature of AD has been considered the main reason for the absence of cure so far. Therefore, the development of novel hybrids to treat the disease is very much essential. Focusing on this, a novel series of coumarin-benzofuran hybrids have been designed and screened as anti-Alzheimer's disease agents. The strategy is to obtain an effective mimetic of donepezil, which is acetylcholinesterase inhibitor. Herein, the two main scaffolds namely coumarin and benzofuran are known pharmacophore moieties and we have performed their molecular design, pharmacokinetic descriptor studies for drug-likeliness. Further, in vitro studies such as antioxidant capacity, acetylcholinesterase (AChE) inhibition and amyloid-β (Aβ) self-aggregation inhibition have also been performed. Most importantly, these studies revealed that the newly synthesized hybrids can be versatile and promising drug-like moieties as efficient anti-AD agents.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Binding Sites; Cholinesterase Inhibitors; Coumarins; Donepezil; Drug Design; Humans; Molecular Docking Simulation; Peptide Fragments; Structure-Activity Relationship

Benzofuran moiety is an important pharmacophore showing positive effects on bone health. In the present study, sixteen benzofuran-pyran hybrids were synthesized and were evaluated for their osteogenic effects on primary osteoblast cells isolated from calvaria. Compounds 22 and 24 were found potent in stimulating osteoblast differentiation as assessed by the alkaline phosphatase activity. These compounds were also found to be nontoxic to osteoblast cells as compared to the control cells in MTT assay. Further, Alizarin Red-S staining for visualization of calcium nodules demonstrated compounds 22 and 34 as active in enhancing mineralization in osteoblast cells. Additionally, transcriptional analysis of these compounds on osteoblast cells revealed that compound 22 up-regulated the expression of osteogenic genes RUNX2, BMP-2, COL-1, thus substantiating that compound 22 having two geminal methyl groups in its R

Topics: Anabolic Agents; Benzofurans; Bone and Bones; Bone Density; Cell Differentiation; Cell Survival; Dose-Response Relationship, Drug; Humans; Mesenchymal Stem Cells; Molecular Structure; Osteoblasts; Osteogenesis; Pyrans; RNA, Messenger; Structure-Activity Relationship

A modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine 20 and 1,3-diketone 14 (R = CH

Topics: Benzofurans; Dronedarone; Ketones; Molecular Structure; Quinones

Herein we propose a facile, versatile and selective chemo-enzymatic synthesis of substituted (E)-2,3-diaryl-5-styryl-trans-2,3-dihydrobenzofurans based on the exploitation of the laccase-mediated oxidative (homo)coupling of (E)-4-styrylphenols. Thanks to this novel synthetic strategy, a library of benzofuran-based potential allosteric activators of the Heat shock protein 90 (Hsp90) was easily prepared. Moreover, considering their structural analogies to previously reported allosteric modulators, the sixteen new compounds synthesized in this work were tested in vitro for their potential stimulatory action on the ATPase activity of the molecular chaperone Hsp90. Combining experimental and computational results, we propose a mechanism of action for these compounds, and expand the structure-activity relationship (SAR) information available for benzofuran-based Hsp90 activators.

Topics: Allosteric Regulation; Benzofurans; Chemistry Techniques, Synthetic; Computer Simulation; Enzymes; HSP90 Heat-Shock Proteins; Molecular Docking Simulation; Protein Conformation; Structure-Activity Relationship

A series of bezofuran appended 1,5-benzothiazepine compounds 7a-v was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. All analogs exhibited varied BChE inhibitory activity with IC

Topics: Acetylcholinesterase; Anti-Infective Agents; Benzofurans; Binding Sites; Butyrylcholinesterase; Catalytic Domain; Cholinesterase Inhibitors; Drug Design; Fungi; Gram-Negative Bacteria; Gram-Positive Bacteria; Inhibitory Concentration 50; Kinetics; Molecular Docking Simulation; Structure-Activity Relationship; Thiazepines

Four new dihydrobenzofuran neolignans 1a/1b and 2a/2b were isolated from the fruit of Rubus ideaus. 1a/1b and 2a/2b as two pairs of enantiomers were separated on a chiral chromatographic column. Their structures were determined using a suite of techniques including 1D and 2D NMR, HRESIMS, together with theoretical electronic circular dichroism (ECD) calculation. All compounds were evaluated for their inhibition of self-induced Aβ

Topics: Amyloid beta-Peptides; Benzofurans; Binding Sites; Circular Dichroism; Fruit; Lignans; Magnetic Resonance Spectroscopy; Molecular Conformation; Molecular Docking Simulation; Peptide Fragments; Plant Extracts; Protein Structure, Tertiary; Rubus; Stereoisomerism

In this study an efficient and straightforward method for obtaining a new class of blue fluorescent bezofuran derivatives, under microwave irradiation, as well as under conventional thermal heating, is presented. Under conventional TH the reactions occur selectively, and a single type of benzofuran ester derivative was obtained. The synthesis under MW irradiation also led to benzofuran derivatives, but in a time-dependent manner. Irradiation for a short period of time led to a mixture of two types of benzofuran derivatives (

Topics: Acetophenones; Benzofurans; Microwaves; Molecular Structure

A novel series of 6-hydroxy-4-methoxy-3-methylbenzofuran-7-carboxamide derivatives featured with various C-2 substituents were designed and synthesized as Mnks inhibitors through fragment-based drug design. Among them, 5b, 5i, 5o and 8k showed the best Mnk2 inhibitory activity with IC

Topics: Amides; Antineoplastic Agents; Benzofurans; Binding Sites; Catalytic Domain; Cell Line, Tumor; Cell Proliferation; Drug Design; Humans; Intracellular Signaling Peptides and Proteins; Molecular Dynamics Simulation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Structure-Activity Relationship

A handy and effective method was established to obtain the cis-2,3-dihydrobenzofuranols having three stereocenters, involving asymmetric transfer hydrogenation of benzofuranones via dynamic kinetic resolution. The general applicability of this method was examined with different benzofuran-3-(2 H)-ones, and stereoselectivities of 85-99% ee and up to 98/2 dr were obtained.

Topics: Benzofurans; Catalysis; Hydrogenation; Kinetics; Models, Molecular; Molecular Conformation; Stereoisomerism

We report the development of a concise method of synthesizing possible cyclooxygenase (COX) inhibitor BRL-37959, which is believed to be a potent nonsteroidal anti-inflammatory drug (NSAID). The four-step synthesis greatly increased the efficiency of compound production from commercially available salicylaldehydes. The synthesis involved an optimized, bismuth(III) trifluoromethanesulfonate catalyzed benzoylation of a benzofuran ring.

Topics: Acylation; Aldehydes; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Bismuth; Catalysis; Cyclooxygenase Inhibitors; Microwaves; Temperature

A series of novel benzofuran derivatives containing biaryl moiety were designed and synthesized by the Suzuki cross-coupling reactions. The reactions, performed in the presence of K₂CO₃, EtOH/H₂O and Pd(II) complex as catalyst, gave the corresponding products in good to excellent yields. The methodology allows the facile production of heterobiaryl compounds, a unique architectural motif that is ubiquitous in medicinal chemistry.

Topics: Benzofurans; Carbonates; Catalysis; Ethanol; Molecular Structure; Palladium; Potassium; Water

A series of 2-arylbenzo[b]furan-appended 4-aminoquinazoline hybrids were prepared and evaluated for cytotoxicity in vitro against the human lung cancer (A549), colorectal adenocarcinoma (Caco-2), hepatocellular carcinoma (C3A) and cervical cancer (HeLa) cell lines. Compounds 10d and 10j exhibited significant cytotoxicity against the C3A and Caco-2 cell lines and induced apoptosis in these cell lines. Likewise, compounds 10d and 10e exhibited significant inhibitory activity towards epidermal growth factor receptor-tyrosine kinase phosphorylation (IC

Topics: Adenosine Triphosphate; Apoptosis; Benzofurans; Binding Sites; Cell Line, Tumor; Enzyme Inhibitors; ErbB Receptors; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Phosphorylation; Proton Magnetic Resonance Spectroscopy; Quinazolines; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship

The current study was aimed to investigate the effect of benzofuran on asthma neonatal rat model. Twenty-five neonatal rats were assigned into five groups; Normal control, untreated, 1 mg/kg, 8 mg/kg and 10 mg/kg treatment groups. Methacholine was administered orally to the rats of untreated and treatment groups. Animals in the normal control group were given PBS as a vehicle. FlexiVent system employing a computer-controlled mouse ventilator along with respiratory mechanics was used for the analysis of airway resistance in the rats. Cytokine level and IFN-γ in the rat serum samples was performed by ELISA in accordance with the instructions of manufacturer. Methacholine administration into the rats caused a marked increase in lung airway resistance. However, treatment with 8 and 10 mg/kg doses of benzofuran led to marked decrease in the airway resistance. Benzofuran treatment prevented accumulation of macrophages and inflammatory cells in the lung airways. Inhibition of inflammation in methacholine administered rats by benzofuran was also confirmed by hematoxylin & eosin-staining. Examination of the rat serum showed significantly higher level of Th2 cytokines (IL-4, -5 and -13) in the untreated rats. However, treatment of methacholine administered rats with benzofuran significantly inhibited Th2 cytokine expression. The level of IFN-γ was increased by benzofuran treatment in methacholine administered rats. In methacholine administered rats the level of IgE was markedly higher however treatment of asthma rats with benzofuran inhibited up-regulation of IgE significantly. The expression of T-bet is decreased and that of GATA-3 is increased by methacholine administration in the rat lungs. Benzofuran treatment of methacholine administered rats prevented reduction in T-bet and up-regulation of GATA-3 expression in the rat lungs. The effect of benzofuran was significant at the doses of 8 and 10 mg/kg and non-significant at 1 mg/kg. These finding suggest that benzofuran inhibits expression of dominant T-helper 2 cytokines through targeting GATA-binding protein 3 transcription factor. Thus benzofuran can be of therapeutic importance for the treatment of asthma.

Topics: Animals; Anti-Asthmatic Agents; Asthma; Benzofurans; Bronchoconstrictor Agents; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; GATA3 Transcription Factor; Histocytochemistry; Inflammation; Lung; Methacholine Chloride; Rats; Serum; Treatment Outcome

Four benzofuran-conjugated iridium(III) or rhodium (III)-based metal complexes are synthesized to screen as an inhibitor of STAT3 activity in prostate cancer cells. All complexes show the high stability and solubility in the biological system. In this study, an iridium(III) complex engages STAT3 and NF-κB to inhibit their translocation and transcriptional activities. Moreover, complex 1 shows more potential antiproliferative activity against DU145 cells and suppresses tumor growth in a prostate cancer xenograft mouse without observable adverse effects. Complex 1 may provide the basis for developing new therapeutic strategy in vivo and in vitro for the treatment of advanced prostate cancer.

Topics: Animals; Benzofurans; Cell Line, Tumor; HEK293 Cells; Humans; Iridium; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Prostatic Neoplasms; Random Allocation; STAT3 Transcription Factor; Xenograft Model Antitumor Assays

Dental caries is one of the most common chronic diseases and is caused by acid fermentation of bacteria adhered to the teeth. Streptococcus mutans (S. mutans) utilizes sortase A (SrtA) to anchor surface proteins to the cell wall and forms a biofilm to facilitate its adhesion to the tooth surface. Some plant natural products, especially several flavonoids, are effective inhibitors of SrtA. However, given the limited number of inhibitors and the development of drug resistance, the discovery of new inhibitors is urgent. Here, the high-throughput virtual screening approach was performed to identify new potential inhibitors of S. mutans SrtA. Two libraries were used for screening, and nine compounds that had the lowest scores were chosen for further molecular dynamics simulation, binding free energy analysis and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties analysis. The results revealed that several similar compounds composed of benzofuran, thiadiazole and pyrrole, which exhibited good affinities and appropriate pharmacokinetic parameters, were potential inhibitors to impede the catalysis of SrtA. In addition, the carbonyl of these compounds can have a key role in the inhibition mechanism. These findings can provide a new strategy for microbial infection disease therapy.

Topics: Aminoacyltransferases; Bacterial Adhesion; Bacterial Proteins; Benzofurans; Biofilms; Computer Simulation; Cysteine Endopeptidases; Dental Caries; Pyrroles; Streptococcus mutans; Thiadiazoles

New molecular hybrids combining benzothiophene or its bioisostere benzofuran with rhodanine were synthesized as potential dual COX-2/5-LOX inhibitors. The benzothiophene or benzofuran scaffold was linked at position -2 with rhodanine which was further linked to various anti-inflammatory pharmacophores so as to investigate the effect of such molecular variation on the anti-inflammatory activity. The target compounds were evaluated for their in vitro COX/LOX inhibitory activity. The results revealed that, compound 5h exhibited significant COX-2 inhibition higher than celecoxib. Furthermore, compounds 5a, 5f and 5i showed COX-2 inhibitory activity comparable to celecoxib. Compound 5h showed selectivity index SI=5.1 which was near to that of celecoxib (SI=6.7). Compound 5h displayed LOX inhibitory activity twice than that of meclofenamate sodium. Moreover, compounds 5a, 5e and 5f showed significant LOX inhibitory activity higher than that of meclofenamate sodium. Compound 5h was screened for its in vivo anti-inflammatory activity using formalin-induced paw edema and gastric ulcerogenic activity tests. The results revealed that, it showed in vivo decrease in formalin-induced paw edema volume higher than celecoxib. It also displayed gastrointestinal safety profile as celecoxib. The biological results were also consistent with the docking studies at the active sites of the target enzymes COX-2 and 5-LOX. Also, compound 5h showed physicochemical, ADMET, and drug-like properties within those considered adequate for a drug candidate.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonate 5-Lipoxygenase; Benzofurans; Catalytic Domain; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Edema; Formaldehyde; Lipoxygenase Inhibitors; Male; Molecular Docking Simulation; Molecular Structure; Rats; Rats, Wistar; Rhodanine; Structure-Activity Relationship; Thiophenes

Pancreatic ductal adenocarcinoma (PDAC) is one of the most common type of pancreatic cancer, and has still been the medicinal mystery. New drugs and treatment strategies are urgently needed. In this study, 32 benzofuran derivatives are designed, synthesized and evaluated as potential agents against the pancreatic cancer. Among them, compound 9o with the best physicochemical and pharmacokinetic properties exhibited excellent cytotoxicity against many tumor cell lines. In vivo study showed that compound 9o dramatically suppressed the tumor growth of nude mice. Furthermore, compound 9o could affect the hypoxia environment through Hif-1α/VEGF pathway, resulting in the anti-angiogenic activity. These studies indicated that compound 9o was a promising candidate for the treatment of PDAC, deserving further studies.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Mice; Molecular Structure; Neoplasms, Experimental; Pancreatic Neoplasms; Structure-Activity Relationship; Tumor Cells, Cultured

The acute and chronic toxicity of several new psychoactive substances (NPS) is unknown, and only little information is available on the pharmacology and toxicology, toxicokinetics, and detectability in body samples of such new compounds. We here propose analytical methods to disclose acute and chronic use of two types of new psychostimulants: benzofurans and ethylphenidate and we applied them to a real case of a subject attending Emergency Department with signs of acute intoxication due to psychotropic drug(s). After a urinary immunoassay screening which gave a positivity to amphetamines, general unknown gas chromatography-mass spectrometry (GC-MS) urine analysis identified 5-(2-methylaminopropyl)benzofuran (5-MAPB), 5-(2-aminopropyl)benzofuran (5-APB), 5-(2-ethylaminopropyl)benzofuran (5-EAPB), ethylphenidate, and ritalinic acid. All these substances were confirmed and quantified not only in urine but also in serum samples at different times after hospitalization by GC-MS and ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Two subsequent 2-cm hair segments were also analyzed and tested positive for the above reported substances, evidencing repeated use. The matching quantitative results in all the analyzed biological matrices demonstrated that both analytical methodologies were suitable to correctly quantify NPS involved in the current intoxication. The objective assessment of acute and chronic intoxication by the above reported compounds demonstrate that the development of analytical methods aiming at the detection of a broad spectrum of compounds in conventional and non-conventional biological matrices is helpful when facing the new challenging threat of intoxications caused by NPS.

Topics: Benzofurans; Chromatography, High Pressure Liquid; Gas Chromatography-Mass Spectrometry; Hair; Humans; Immunoassay; Male; Methylphenidate; Psychotropic Drugs; Substance Abuse Detection; Substance-Related Disorders; Tandem Mass Spectrometry; Young Adult

The α-amylase acts as attractive target to treat type-2 diabetes mellitus. Therefore in discovering a small molecule as α-amylase inhibitor, we have synthesized benzofuran carbohydrazide analogs (1-25), characterized through different spectroscopic techniques such as

Topics: alpha-Amylases; Benzofurans; Binding Sites; Catalytic Domain; Enzyme Inhibitors; Hydrazones; Hydrogen Bonding; Inhibitory Concentration 50; Molecular Docking Simulation; Structure-Activity Relationship

Three new dihydrobenzofuran neolignans, mappiodoinins A-C (1-3), together with nine known analogues (4 -12) were isolated from the stems and leaves of Mappianthus iodoies. Their structures with the absolute configurations were elucidated by extensive spectroscopic methods. This is the first time to find dihydrobenzofuran neolignans from the genus Mappianthus. All isolated compounds were evaluated for their cytotoxicities against five human cancer cell lines: HL-60, SMMC-7721, A-549, MCF-7 and SW-480 in vitro. Neolignans 1-12 showed significant cytotoxic effects against various human cancer cell lines with IC

Topics: Benzofurans; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Humans; Lignans; Magnetic Resonance Spectroscopy; Magnoliopsida; Molecular Conformation; Plant Leaves; Plant Stems

A new series of 2-alkyloxy-pyridine-3-carbonitrile-benzofuran hybrids (

Topics: Animals; Aorta; Benzofurans; Chemistry Techniques, Synthetic; Inhibitory Concentration 50; Mice; Molecular Structure; Quantitative Structure-Activity Relationship; Rats; Vasodilator Agents

Topics: Administration, Oral; Anabolic Agents; Animals; Benzofurans; Bone Morphogenetic Protein 2; Bone Regeneration; Dihydropyridines; Dose-Response Relationship, Drug; Female; Models, Molecular; Molecular Structure; Osteoblasts; Osteogenesis; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship

Topics: Benzofurans; Biodegradation, Environmental; Chryseobacterium; Environmental Pollutants; Escherichia coli; Hydrocarbons, Aromatic; Naphthalenes; Oxidoreductases; Pseudomonas fluorescens; Quinolones; Thiophenes

A new tetrasubstituted pyran-2-one and a new dihydrobenzofuran, named colletochlorins E and F (1 and 2, respectively), were isolated from the culture filtrates of the fungus Colletotrichum higginsianum together with the already known colletochlorin A, 4-chloroorcinol, and colletopyrone. Colletochlorin E, the main metabolite, and colletochlorin F were characterized by spectroscopic (NMR, HRESIMS) and chemical methods as 3-[7-chloro-4-hydroxy-2-(1-hydroxy-1-methylethyl)-6-methyl-2,3-dihydrobenzofuran-5-ylmethyl]-4-hydroxy-5,6-dimethylpyran-2-one and 7-chloro-2-(1-hydroxy-1-methylethyl)-6-methyl-2,3-dihydrobenzofuran-4-ol, respectively. The absolute configuration 2'S of 1 was deduced by X-ray diffractometric analysis, whereas 2S of 2 was deduced by comparison of its NMR and CD data with those of 1. When assayed by leaf puncture on Sonchus arvensis and tomato leaves, 2 caused quite large necrosis (>1 cm), whereas 4-chloroorcinol proved to be the most active compound. These results were confirmed by those obtained in assays on Lemna minor and Phelipanche ramosa seed germination. Furthermore 1, colletochlorin A and colletopyrone were less or modestly active in the latter assay, respectively. Interestingly, the phytotoxicity was not associated with an antibiotic activity, whereas only 4-chloroorcinol and colletochlorin F exhibited zootoxic activity.

Topics: Animals; Artemia; Benzofurans; Colletotrichum; Herbicides; Heterocyclic Compounds, 4 or More Rings; Molecular Structure; Pyrones; Secondary Metabolism; Solanum lycopersicum; Sonchus

Novel series of conformationally constrained 2,4-chloro- and hydroxy-substituted diphenyl benzofuro[3,2-b]pyridines were rationally designed and synthesized. Their biological activities were evaluated for topoisomerase I and II inhibitory activity, and antiproliferative activity against several human cancer cell lines for the development of novel anticancer agents. Most of the compounds with phenol moiety at 4-position of central pyridine exhibited significant dual topoisomerase I and II inhibitory activities, and strong antiproliferative activity in low micromolar range. Structure activity relationship study suggested that phenol moiety at 4-position of the central pyridine regardless of chlorophenyl moiety at 2-position of the central pyridine has an important role in dual topoisomerase inhibitory activity as well as antiproliferative activity. For investigation of mode of action for compound 14 which displayed the most strong dual topoisomerase I and II inhibitory activity and antiproliferative activity against HCT15 cell, we performed cleavable complex assay, band depletion assay, comet assay, and competitive EtBr displacement assay. Compound 14 functioned as non-intercalative catalytic topo I and II dual inhibitor. In addition, compound 14 induced apoptosis in HCT15 cells through increase of Bax, decrease of Bcl-2 and increase of PARP cleavage.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Biocatalysis; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; DNA; DNA Topoisomerases, Type I; DNA Topoisomerases, Type II; Drug Design; Humans; Pyridines; Structure-Activity Relationship; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors

Reported concentrations of dioxin-like compounds accumulated in the European eel (Anguilla anguilla) were used to perform a risk assessment for eel larval survival, taking into account a modeled amplification of tissue concentrations with a factor of 1.33 during spawning migration. The calculated concentrations of dioxin-like compounds finally deposited in the eggs were compared with the internal effect concentrations for survival of early life stages of the European eel; these concentrations, by lack of experimental data, were estimated from a sensitivity distribution based on literature data by assuming that eel larvae are among the 10% most sensitive teleost fish species. Given concentrations of dioxin-like contaminants and assuming a relatively high sensitivity, it can be expected that larvae from eggs produced by eel from highly contaminated locations in Europe will experience increased mortality as a result of maternally transferred dioxin-like contaminants. As historical persistent organic pollutant concentrations in eel tissue were higher, this impact must have been stronger in the past. Potential effects of other compounds or effects on the migration, condition, and fertility of the parental animals were not taken into account. It is important to further study the overall impact of contaminants on the reproductive success of the European eel as this may have been underestimated until now.

Topics: Anguilla; Animal Migration; Animals; Benzofurans; Dioxins; Europe; Female; Fresh Water; Larva; Polychlorinated Dibenzodioxins; Reproduction; Risk Assessment; Water Pollutants, Chemical; Zygote

We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Benzofurans; Cell Line, Tumor; Cell Membrane Permeability; Dermatitis, Atopic; Half-Life; Humans; Mice; Microsomes; Pruritus; Rats; Uracil

The intramolecular cycloaddition of o-quinone methides (o-QMs) with a carbonyl group has been envisaged and executed successfully in the context of constructing the complex and rare [6,6,6,6]-tetracyclic core found in the integrastatins, epicoccolide A, and epicocconigrone A. These transient o-QMs were generated easily from the oxidative dearomatization of the corresponding C2-(aryl)benzofuran by employing Oxone in acetone-water at rt. The subsequent cycloaddition with the carbonyl (or conjugated olefin) present on the C2-aryl group was spontaneous.

Topics: Benzofurans; Cycloaddition Reaction; Heterocyclic Compounds, Bridged-Ring; Indolequinones; Molecular Structure; Oxidation-Reduction; Stereoisomerism; Sulfuric Acids

The molecular mechanism by which Profilin acts as a tumor suppressor is still unclear. Several chemotherapeutic agents, used till date either have unfavorable side effects or acquired resistance in tumor cells. Our findings show that Profilin enhances cell death mediated by several chemotherapeutic-agents. The activation of NF-κB and its dependent genes, mediated by paclitaxel and vinblastine, was completely inhibited in Profilin overexpressing cells. This inhibition was due to the Profilin mediated attenuation of IκBα degradation, thereby preventing p65 nuclear translocation and low NF-κB DNA binding activity.Moreover, Profilin increases level of p53 in the presence of known inducers, such as doxorubicin, vinblastine, and benzofuran. This increased p53 level leads to enhanced cell death as indicated by activation of caspases 3, 8, 9, which results in cleavage of PARP.Furthermore, knocking down of p53 in Profilin overexpressing cells leads to decreased cell death. Ectopic expression of Profilin in HCT116 p53 knock out cells showed lesser cell death as compared to the HCT116 p53 wild type cells. For the first time, we provide evidences, which suggest that Profilin synergizes with chemotherapeutic drugs to induce tumor cell death by regulating NF-κB and p53. Thus, modulation of Profilin may be a useful strategy for effective combination therapy.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Caspase 3; Caspase 8; Caspase 9; Cell Line, Tumor; Doxorubicin; Enzyme Activation; HCT116 Cells; Humans; Neoplasms; NF-KappaB Inhibitor alpha; Paclitaxel; Poly(ADP-ribose) Polymerases; Profilins; Proto-Oncogene Proteins c-mdm2; RNA Interference; RNA, Small Interfering; Transcription Factor RelA; Transcriptional Activation; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation; Vinblastine

We report on two highly brominated polyphenyl ether flame retardants, tetradecabromo-1,4- diphenoxybenzene (TeDB-DiPhOBz) and 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209), that formed photolytic degradation products in tetrahydrofuran (THF)/hexane solvent after 21 days of natural sunlight irradiation (SI). These degradation products of SI-TeDB-DiPhOBz and SI-BDE-209 included the numerous polybrominated homologue groups of polybenzofurans and dibenzofurans, respectively. Formation of similar polybenzofuran and dibenzofuran products was also observed following a 3 month exposure of the solid powder forms of TeDB-DiPhOBz and BDE-209 to natural SI. These resulting degradation product mixtures were administered to chicken embryonic hepatocytes (CEH) to determine effects on mRNA expression levels of 27 dioxin-responsive genes. For the solvent-based SI study, equivalent concentrations of 1 or 25 μM of SI-TeDB-DiPhOBz or 1 or 10 μM of SI-BDE-209 resulted in gene expression profiles that were similar to those of the most potent dioxin-like compound, 2,3,7,8-tetrachlorodibenzo-p-dioxin. In addition, a concentration-dependent induction of CYP1A4 and CYP1A5 mRNA was observed following exposure to SI-TeDB-DiPhOBz and SI-BDE-209. Based on ECthreshold values for CYP1A4/5 mRNA expression, relative potency (ReP) values were 1 × 10(-6) and 1 × 10(-5) for SI-TeDB-DiPhOBz and SI-BDE-209, respectively. The SI TeDB-DiPhOBz and BDE-209 powder degradation product mixture also significantly induced CYP1A4 mRNA levels in CEH. Our findings clearly show that the environmental stability of TeDB-DiPhOBz and BDE-209, and possibly other highly brominated polyphenyl ethers, is of great concern from a dioxin-like degradation products and toxicity perspective.

Topics: Animals; Aryl Hydrocarbon Hydroxylases; Avian Proteins; Benzofurans; Chick Embryo; Chickens; Chromatography, Liquid; Female; Gene Expression Regulation; Halogenated Diphenyl Ethers; Hepatocytes; Ions; Mass Spectrometry; Photolysis; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; RNA, Messenger; Sunlight; Transcription, Genetic

Tissue-nonspecific alkaline phosphatase (TNAP) by hydrolyzing pyrophosphate, an inhibitor of apatite formation, promotes extracellular matrix calcification during bone formation and growth, as well as during ectopic calcification under pathological conditions. TNAP is a target for the treatment of soft tissue pathological ossification. We synthesized a series of benzofuran derivatives. Among these, SMA14, displayed TNAP activity better than levamisole. SMA14 was found to be not toxic at doses of up to 40μM in osteoblast-like Saos-2 cells and primary osteoblasts. As probed by Alizarin Red staining, this compound inhibited mineral formation in murine primary osteoblast and in osteoblast-like Saos-2 cells.

Topics: Alkaline Phosphatase; Animals; Benzofurans; Calcification, Physiologic; Cell Line; Cell Survival; Dose-Response Relationship, Drug; Humans; Mice; Molecular Structure; Osteoclasts; Structure-Activity Relationship; Substrate Specificity

During the process of treating and recycling Municipal Solid Waste Incinerators (MSWIs) fly ash, polychlorinated dibenzo-p-dioxins (PCDD/Fs) and polychlorinated dibenzofurans (dl-PCBs) in fly ash may potentially mobilize in the atmosphere and be widely distributed in the environment because of the inevitable re-suspension. Thus, this work presents the distributions of PCDD/Fs and dl-PCBs in inhalable coarse particles (Dp10-2.5 (particle diameter in μm)), fine particles (Dp<2.5) of fly ash and original fly ash from four MSWI plants in China. The results show that PCDD/Fs and dl-PCBs preferentially concentrated in Dp10-2.5 and Dp<2.5. Their mass concentrations and TEQ were significantly higher than those in the original fly ash, but the distribution of PCDD/Fs congeners in Dp10-2.5 and Dp<2.5 was close to that in the original fly ash. The main TEQ contribution included 1,2,3,7,8-PeCDD, 2,3,7,8-TeCDD in PCDDs and 2,3,4,7,8-PeCDF in PCDFs for Dp10-2.5, Dp<2.5 fractions and the original fly ash. Furthermore, the mass and TEQ contribution of dl-PCBs was relatively low. In addition, compared with the fluidized bed, the samples from the grate-type furnaces had significantly lower dioxin concentrations. In terms of potential health risk, the non-carcinogenic risk of PCDD/Fs in Dp10-2.5 and Dp<2.5 were estimated at 9.87 × 10(-1) to 4.81 and 1.19-7.95. For the carcinogenic risk of PCDD/Fs, both accumulation of Hazard Quotients (HQ) in Dp10-2.5 and Dp<2.5 exceeded the threshold limit and should be considered as unacceptable risk for onsite workers. The above findings could provide data to support the risk management of MSWI fly ash during the process of recycle and disposal.

Topics: Benzofurans; China; Coal Ash; Health Status Indicators; Humans; Particle Size; Polychlorinated Dibenzodioxins; Risk Assessment; Solid Waste

Well-defined palladium N-heterocyclic carbene (NHC) complexes were employed in the one-pot tandem Heck alkynylation/cyclization sequence for preparing biologically relevant benzofuran compounds under copper-free conditions in a time-efficient step-reduced fashion. In particular, a series of binuclear palladium complexes, 1b-1e and 2b-2e, of the alkyl-bridged NHC ligands, namely, {1,1'-di-R1-4,4'-R2-di-1,2,4-triazoline-5,5'-diylid-2-ene] (R1 = i-Pr; R2 = -(CH2)2-, -(CH2)3-), and their mononuclear analogues, trans-(NHC)PdBr2(pyridine) (3b) and cis-(NHC)PdBr2(PPh3) (3c), successfully catalyzed the one-pot tandem Heck alkynylation/cyclization reaction of 2-iodophenol with a variety of terminal alkyne substrates, yielding 2-substituted benzofuran derivatives. The mononuclear complexes 3b and 3c were nearly half as active as the representative dinuclear analogue 1c under analogous reaction conditions, thereby implying that, at the same mole percent of the palladium loading, the monometallic 3b and 3c and the bimetallic 1c complexes were equally effective as catalysts. The two sites of the bimetallic complex 1c performed as two separate independent catalytic sites, displaying no cooperativity effect in the catalysis. Finally, the practical utility of the aforementioned catalysts was demonstrated for a representative catalyst 1c through the convenient synthesis of a key intermediate, 3-[2-(benzo[d][1,3]dioxol-5-yl)-7-methoxybenzofuran-5-yl]propan-1-ol, in a total-synthesis protocol of the natural product Egonol.

Topics: Alkynes; Benzofurans; Cyclization; Heterocyclic Compounds; Magnetic Resonance Spectroscopy; Methane; Models, Molecular; Palladium; Spectrometry, Mass, Electrospray Ionization

Labeling and imaging mitochondria have attracted considerable interest because of its involvement in early stage apoptosis and necrotic cell death. Various highly specific and photostable fluorescent probes for mitochondria are in demand. In the present study, two novel Ru(II) polypyridine complexes Ru1 and Ru2 were developed to act as mitochondrial fluorescence probes. In comparison with the commercially available mitochondrial trackers, Ru1 possesses high mitochondria-specificity, superior photostability, high resistance to the loss of mitochondrial membrane potential and appreciable tolerance to environmental change, allowing imaging of the mitochondrial morphological changes over long periods of time. Combined results indicate that Ru1 may contribute to the future development of staining agents for organelle-selective imaging in living cells.

Topics: Benzofurans; Fluorescent Dyes; HEK293 Cells; HeLa Cells; Humans; Microscopy, Fluorescence; Mitochondria; Ruthenium

A series of 2-phenylbenzofurans compounds was designed, synthesized and evaluated as cholinesterase inhibitors. The biological assay experiments showed that most of the compounds displayed a clearly selective inhibition for butyrylcholinesterase (BChE), while a weak or no effect towards acetylcholinesterase (AChE) was detected. Among these benzofuran derivatives, compound 16 exhibited the highest BChE inhibition with an IC50 value of 30.3 μM. This compound was found to be a mixed-type inhibitor as determined by kinetic analysis. Moreover, molecular dynamics simulations revealed that compound 16 binds to both the catalytic anionic site (CAS) and peripheral anionic site (PAS) of BChE and it displayed the best interaction energy value, in agreement with our experimental data.

Topics: Benzofurans; Butyrylcholinesterase; Cholinesterase Inhibitors; Models, Molecular

Blocking the staphyloxanthin biosynthesis process has emerged as a new promising antivirulence strategy. Previously, we first revealed that CrtN is a druggable target against infections caused by pigmented Staphylococcus aureus (S. aureus) and that naftifine was an effective CrtN inhibitor. Here, we identify a new type of benzofuran-derived CrtN inhibitor with submicromolar IC50 values that is based on the naftifine scaffold. The most potent analog, 5m, inhibits the pigment production of S. aureus Newman and three MRSA strains, with IC50 values of 0.38-5.45 nM, without any impact on the survival of four strains (up to 200 μM). Notably, compound 5m (1 μM) could significantly sensitize four strains to immune clearance and could effectively attenuate the virulence of three strains in vivo. Moreover, 5m was determined to be a weak antifungal reagent (MIC > 16 μg/mL). Combined with good oral bioavailability (F = 42.2%) and excellent safety profiles, these data demonstrate that 5m may be a good candidate for the treatment of MRSA infections.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Bacterial Proteins; Benzofurans; Biological Availability; Drug Discovery; Enzyme Inhibitors; Female; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Oxidoreductases; Rats; Rats, Sprague-Dawley; Staphylococcal Infections; Tissue Distribution

p53-independent malignant cancer is still severe health problem of human beings. HIF-1 pathway is believed to play an important role in the survival and developing progress of such cancers. In the present study, with the aim to inhibit the proliferation of p53-independent malignant cells, we disclose the optimization of 6a, the starting compound which is discovered in the screening of in-house compound collection. The structure-activity relationship (SAR) is summarized. The most potent derivative 8d, inhibits the proliferation of both p53-null and p53-mutated cells through inhibition of HIF-1 pathway. Our findings here provide a new chemotype in designing potent anticancer agent especially against those p53-independent malignant tumors.

Topics: Antineoplastic Agents; Benzofurans; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Hypoxia-Inducible Factor 1; MCF-7 Cells; Molecular Structure; Neoplasms; Structure-Activity Relationship; Tumor Suppressor Protein p53

The PI3K/Akt/mTOR signaling pathway plays a key regulatory function in cell survival, proliferation, migration, metabolism and apoptosis. Aberrant activation of the PI3K/Akt/mTOR pathway is found in many types of cancer and thus plays a major role in breast cancer cell proliferation. In our previous studies, benzo[b]furan derivatives were evaluated for their anticancer activity and the lead compounds identified were 26 and 36. These observations prompted us to investigate the molecular mechanism and apoptotic pathway of these lead molecules against breast cancer cells. Benzo[b]furan derivatives (26 and 36) were evaluated for their antiproliferative activity against human breast cancer cell lines MCF-7 and MDA MB-231. These compounds (26 and 36) have shown potent efficiency against breast cancer cells (MCF-7) with IC50 values 0.057 and 0.051μM respectively. Cell cycle analysis revealed that these compounds induced cell cycle arrest at G2/M phase in MCF-7 cells. Western blot analysis revealed that these compounds inhibit the PI3K/Akt/mTOR signaling pathway and induced mitochondrial mediated apoptosis in human breast cancer cells (MCF-7).

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Breast Neoplasms; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Humans; MCF-7 Cells; Molecular Structure; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; Structure-Activity Relationship; TOR Serine-Threonine Kinases

The identification and quantification of functional cytochromes P450 (CYPs) in biological samples is proving important for robust analyses of drug efficacy and metabolic disposition. In this study, a novel CYP activity-based probe was rationally designed and synthesised, demonstrating selective binding of CYP isoforms. The dependence of probe binding upon the presence of NADPH permits the selective detection of functionally active CYP. This allows the detection and analysis of these enzymes using biochemical and proteomic methodologies and approaches.

Topics: Benzofurans; Cytochrome P-450 Enzyme System; Humans; Immunoblotting; Kinetics; Liver; Mass Spectrometry; Molecular Probes; NADP; Protein Binding; Protein Isoforms; Proteomics

A series of benzofuran derivatives with neuroprotective activity in collaboration with IGF-1 was discovered using a newly developed cell-based assay involving primary neural cells prepared from rat hippocampal and cerebral cortical tissues. A structure-activity relationship study identified compound 8 as exhibiting potent activity and brain penetrability. An in vitro pharmacological study demonstrated that although IGF-1 and 8 individually exhibited the neuroprotective effect, the latter acted in collaboration with IGF-1 to enhance neuroprotective activity.

Topics: Animals; Benzofurans; Cells, Cultured; Dose-Response Relationship, Drug; Drug Discovery; Insulin-Like Growth Factor I; Molecular Structure; Neurons; Neuroprotection; Neuroprotective Agents; Rats; Structure-Activity Relationship

While islet amyloid deposition comprising amylin is one of pathological hallmarks of type 2 diabetes mellitus (T2DM), no useful amylin-imaging probe has been reported. In this study, we evaluated two (99m)Tc-labeled pyridyl benzofuran derivatives as novel amylin-imaging probes using the newly established islet amyloid model mouse. Binding experiments in vitro demonstrated that [(99m)Tc]1 displayed a higher affinity for amylin aggregates than [(99m)Tc]2. Autoradiographic studies using human pancreas sections with T2DM revealed that [(99m)Tc]1 clearly labeled islet amyloid in T2DM pancreatic sections, while [(99m)Tc]2 did not. Although the initial uptake of [(99m)Tc]1 by the normal mouse pancreas was low (0.74%ID/g at 2 min post-injection), [(99m)Tc]1 showed higher retention in the model mouse pancreas than that of the normal mouse, and exhibited strong binding to amylin aggregates in the living pancreas of the model mice. These results suggest that [(99m)Tc]1 is a potential imaging probe targeting islet amyloids in the T2DM pancreas.

Topics: Animals; Benzofurans; Drug Stability; Humans; Islet Amyloid Polypeptide; Isotope Labeling; Male; Mice; Pancreas; Protein Aggregates; Pyridines; Technetium; Tissue Distribution

Tremetone and possibly other benzofuran ketones are believed to be the toxic compounds in white snakeroot. However, disease has not been reproduced with purified toxins and the concentrations of the benzofuran ketones in white snakeroot populations that cause toxicosis have not been documented. The objectives of this study were to compare the toxicity of seven plant populations, better characterize the clinical and pathologic changes of poisoning, and correlate intoxication with benzofuran ketone content. Four of the seven white snakeroot collections were toxic at the dose and duration used in the study. Affected goats became exercise intolerant, had significant serum enzyme changes and histological lesions in the large appendicular muscles. The incidence and severity of poisoning was not correlated with total doses of tremetone or total benzofuran ketone concentrations suggesting they may not be closely involved in producing toxicity and the possible involvement of an unidentified toxin. The results also demonstrate that white snakeroot populations vary chemically and toxicologically.

Topics: Ageratina; Animals; Benzofurans; Dose-Response Relationship, Drug; Female; Goat Diseases; Goats; Plant Extracts; Plant Poisoning; Random Allocation

7-hydroxy-5,4'-dimethoxy-2-arylbenzofuran (Ary) is purified from Livistona. It has been demonstrated to have anticancer activity to various tumors in including cervical cancer, but its mechanism is still unclear. In the present, we show that Ary induces cervical cancer cells apoptosis through mitochondria degradation and mediates cervical cancer cell arrest. Further, Ary-inducing cell cycle G1/S-phase arrest is associated with increased cyclin A2 and cyclin dependent kinase 2 (Cdk2) proteins. Knockdown of cyclin A2 using small interfering RNA (siRNA), and inhibiting Cdk2 activity with flavopiridol, strikingly reduced G1/S-phase arrest. Moreover, Ary sustainedly induced phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). And ERK1/2 phosphorylation inhibition using specific inhibitor U0126 effectively suppressed cyclin A2 expression, and reduced G1/S-phase arrest induced by Ary. All the experiments in vitro and in vivo verified that Ary has an anticancer effect on cervical cancer. These data provide novel evidences that Ary induces cervical cancer cells apoptosis through mitochondria degradation and cell G1/S-phase arrest. These findings also suggest that ERK-mediated Cdk2/cyclin A signaling pathway is involved in Ary-induced G1/S-phase arrest.

Topics: Animals; Apoptosis; Benzofurans; Cell Line, Tumor; Cyclin A2; Cyclin-Dependent Kinase 2; Female; G1 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Molecular Structure; Phytotherapy; Plant Extracts; Protein Kinases; Signal Transduction; Tumor Burden; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

A series of novel benzofuran-triazole hybrids was designed and synthesized by click chemistry, and their structures were characterized by HRMS, FTIR and NMR. The in vitro antifungal activity of target compounds was evaluated using the microdilution broth method against five strains of pathogenic fungi. The result indicated that the target compounds exhibited moderate to satisfactory activity. Furthermore, molecular docking was performed to investigate the binding affinities and interaction modes between the target compound and N-myristoyltransferase. Based on the results, preliminary structure activity relationships (SARs) were summarized to serve as a foundation for further investigation.

Topics: Benzofurans; Click Chemistry; Drug Design; Fungi; Molecular Docking Simulation; Molecular Structure; Structure-Activity Relationship; Triazoles

A series of novel hybrid compounds between benzofuran and N-aryl piperazine have been designed and prepared. These derivatives were evaluated for their in vitro anti-tumor activity against a panel of human tumor cell lines by MTT assay. The results demonstrated that amide derivatives were more bioactive than sulfonamide compounds in general, and that chloro or trifluoromethyl substituent was vital for modulating cytotoxic activity. In particular, compound 13 was found to be the most potent compound against 4 strains human tumor cell lines, and exhibited cytotoxic activity selectively against Hela (0.03μM).

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Piperazine; Piperazines; Structure-Activity Relationship

To evaluate the stability of salvianolic acid B (Sal B) under ultrasound-assisted extraction in the pharmaceutical industry, degradation of Sal B under ultrasonic irradiation was investigated as the function of buffer concentration, pH, and temperature. With regard to Sal-B concentration, a first-order degradation process was determined, with 10% change in assay from its initial concentration as t90=4.81h, under maximum stability acidic conditions (pH 2.0) and at 25°C. The logkpH-pH profile described by specific acid-base catalysis and water molecules supported the experimental results. Liquid chromatography-mass spectrometry (LC-MS) analyses revealed 7 major degradation products whose structures were characterized by electrospray ionization/mass spectrometry. A primary degradation pathway involved cleavage of the ester bond and ring-opening of benzofuran in Sal B was proposed. The complete degradation pathway of Sal B was also proposed. Results showed that ultrasonic irradiation leads to degradation of Sal B in aqueous solution.

Topics: Benzofurans; Chromatography, Liquid; Drug Stability; Hydrogen-Ion Concentration; Solutions; Spectrometry, Mass, Electrospray Ionization; Temperature; Ultrasonics; Water

A palladium catalyzed intermolecular annulation of cinnamic acids and phenols has been achieved for the selective synthesis of 3-substituted benzofurans. Isotope labeling, competition experiments, kinetic studies, and intermediate trapping have supported a sequence of C-C bond formation and decarboxylation followed by the C-O cyclization pathway.

Topics: Alkenes; Benzofurans; Catalysis; Cinnamates; Kinetics; Molecular Structure; Organometallic Compounds; Palladium; Phenols

A new chiral benzofuran receptor has been synthesized and its properties in the association of amino acid derivatives have been studied. X-ray structures were obtained and these corroborate the presence of an oxyanion-hole motif in these structures.

Topics: Anions; Benzofurans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Stereoisomerism

We developed fluorescent turn-on probes containing a fluorescent nucleoside, 5-(benzofuran-2-yl)deoxyuridine (dU(BF)) or 5-(3-methylbenzofuran-2-yl)deoxyuridine (dU(MBF)), for the detection of single-stranded DNA or RNA by utilizing DNA triplex formation. Fluorescence measurements revealed that the probe containing dU(MBF) achieved superior fluorescence enhancement than that containing dU(BF). NMR and fluorescence analyses indicated that the fluorescence intensity increased upon triplex formation partly as a consequence of a conformational change at the bond between the 3-methylbenzofuran and uracil rings. In addition, it is suggested that the microenvironment around the 3-methylbenzofuran ring contributed to the fluorescence enhancement. Further, we developed a method for detecting RNA by rolling circular amplification in combination with triplex-induced fluorescence enhancement of the oligonucleotide probe containing dU(MBF).

Topics: Base Sequence; Benzofurans; Deoxyuridine; DNA; DNA, Single-Stranded; Fluorescent Dyes; Models, Molecular; Molecular Sequence Data; Nucleic Acid Conformation; Oligonucleotides; RNA; Spectrometry, Fluorescence; Uracil

5-APB (5-(2-aminopropyl)benzofuran) and its N-methyl derivative 5-MAPB (N-methyl-5-(2-aminopropyl)benzofuran) are analogues of amphetamine and methamphetamine, respectively, and belong to the so-called novel psychoactive substances (NPS). They were consumed as stimulants or entactogens with euphoric and empathogenic effects. Being controlled in some countries, both compounds should be covered by drug testing in clinical and forensic toxicology. Therefore, metabolism studies have been performed by working up rat urine samples after a high single dose of the corresponding NPS with solid-phase extraction without and after enzymatic conjugates cleavage. The phase I metabolites were separated and identified after acetylation by GC-MS and/or LC-HR-MS(n) and the phase II metabolites by LC-HR-MS(n). The main metabolite of 5-APB was 3-carboxymethyl-4-hydroxy amphetamine and the main metabolites of 5-MAPB were 5-APB (N-demethyl metabolite) and 3-carboxymethyl-4-hydroxy methamphetamine. The cytochrome P450 (CYP) isoenzymes involved in the 5-MAPB N-demethylation were CYP1A2, CYP2B6, CYP2C19, and CYP2D6, and according to the kinetic parameters, CYP2B6 was responsible for the main part of the total CYP-dependent clearance. An intake of a common users' dose of 5-APB or 5-MAPB could be confirmed in rat urine using the authors' GC-MS and the LC-MS(n) standard urine screening approaches with the corresponding parent drugs as major target. In authentic human urine samples after ingestion of unknown doses of 5-MAPB, both metabolites could also be detected besides the parent drug. The plasma concentrations determined in six clinical cases ranged from 5 to 124 μg/L for 5-MAPB and from 1 to 38 μg/L for its N-demethyl metabolite 5-APB.

Topics: Amphetamine; Animals; Benzofurans; Chromatography, Liquid; Cytochrome P-450 Enzyme System; Gas Chromatography-Mass Spectrometry; Humans; Male; Mass Spectrometry; Methamphetamine; Rats; Rats, Wistar

A series of seven derivatives of 1,1'-(5,6-dimethoxy-3-methyl-1-benzofuran-2,7-diyl)diethanone was synthesized and characterized by (1)HNMR and ESI MS spectra and elemental analyses. The obtained new compounds and three halogen derivatives of benzofuran, reported in our earlier work, were tested for their cytotoxic properties in human chronic (K562) and acute (HL60) leukemia cells, human cervical cancer (HeLa), and normal endothelial cells (HUVEC). Four compounds (2, 3, 4, 5), which contain halogens in their structure showed significant anticancer activity. The most promising was 1,1'-[3- (bromomethyl)-5,6-dimethoxy-1-benzofuran-2,7-diyl]diethanone (2), which was highly and selectively toxic for K562 cells (IC50 of 5µM) and HL60 cells (IC50 of 0.1µM), which showed no cytotoxicity toward HeLa and HUVEC cells. Moreover, the observed remarkable cytotoxicity of this compound toward K562 cells resulted from cells apoptosis.

Topics: Apoptosis; Benzofurans; Cell Line; Cell Line, Tumor; Halogens; HeLa Cells; HL-60 Cells; Human Umbilical Vein Endothelial Cells; Humans; K562 Cells; Structure-Activity Relationship

In order to clarify the suitability of zebrafish (Danio rerio) embryos for the detection of neurotoxic compounds, the acetylcholinesterase assay was adapted and validated with a series of priority pollutants listed as relevant for the European water policy (Aroclor 1254, 2,3-benzofuran, bisphenol A, chlorpyrifos, paraoxon-methyl, quinoline, and methyl mercury chloride) as well as acetonic extracts from three sediments of known contamination. The acute toxicities of the model substances and the sediment extracts were determined by means of the fish embryo test as specified in OECD TG 236, and concentrations as low as the effective concentration at 10% inhibition (EC10) were used as the highest test concentration in the acetylcholinesterase test in order to avoid nonspecific systemic effects mimicking neurotoxicity. Among the model compounds, only the known acetylcholinesterase inhibitors paraoxon-methyl and chlorpyrifos produced a strong inhibition to about 20 and 33%, respectively, of the negative controls. For the sediment extracts, a reduction of acetylcholinesterase activity to about 60% could only be shown for the Vering Canal sediment extracts; this could be correlated to high contents of acetylcholinesterase-inhibiting polycyclic aromatic hydrocarbons (PAHs) as identified by chemical analyses. Co-incubation of the Vering Canal sediment extracts with chlorpyrifos at EC10 concentrations each did not significantly increase the inhibitory effect of chlorpyrifos, indicating that the mode of action of acetylcholinesterase inhibition by the sediment-borne PAHs is different to that of the typical acetylcholinesterase blocker chlorpyrifos. Overall, the study documents that zebrafish embryos represent a suitable model not only to reveal acetylcholinesterase inhibition, but also to investigate various modes of neurotoxic action.

Topics: Acetylcholinesterase; Animals; Benzofurans; Chlorpyrifos; Cholinesterase Inhibitors; Embryo, Nonmammalian; Geologic Sediments; Inhibitory Concentration 50; Paraoxon; Polycyclic Aromatic Hydrocarbons; Toxicity Tests, Acute; Water Pollutants, Chemical; Zebrafish; Zebrafish Proteins

An efficient protocol was developed to access 3-fluoro-2-hydroxy-2-substituted benzo[b]furans with Selectfluor™ as the fluorinating reagent in MeCN and water. By utilizing SOCl2/Py as the dehydrating agent, the compounds above were readily converted to 3-fluorinated, 2-substituted benzo[b]furans in high yields.

Topics: Benzofurans; Diazonium Compounds; Hydrocarbons, Fluorinated; Molecular Structure

This study synthesized a series of hydroxyl-functionalized 2-arylbenzo[b]furans based on the structure of tournefolic acid A and evaluated them for antioxidant and α-glucosidase inhibitory activities. Compounds 5a, 5e, and 5n showed remarkable inhibition of α-glucosidase (IC50 values of 1.9-3.0 μM), and they appear to be even more potent than quercetin. A kinetic binding study indicated that compounds 5a and 5n used a mechanism of mixed-competition to inhibit α-glucosidase. This study also revealed that compounds 5a and 5n bind to either the α-glucosidase or α-glucosidase-4-NPGP complex. Using the crystal structure of the Saccharomyces cerevisiae α-glucosidase, the molecular docking study has predicted the binding of compounds 5a and 5n to the active site of α-glucosidase through both hydrophobic and hydrogen interactions. A DPPH radical scavenging assay further showed that most hydroxyl-functionalized 2-arylbenzo[b]furans possess antioxidant activity. The exception was compound 5p, which has only one hydroxyl group on the 2-phenyl ring of 2-arylbenzo[b]furan. Our results indicate that hydroxyl-functionalized 2-arylbenzo[b]furans possess both antidiabetic as well as antioxidant properties.

Topics: alpha-Glucosidases; Antioxidants; Benzofurans; Catalytic Domain; Glycoside Hydrolase Inhibitors; Hydroxides; Molecular Docking Simulation; Saccharomyces cerevisiae; Structure-Activity Relationship

Our ongoing research focused on targeting transcription initiation in bacteria has resulted in synthesis of several classes of mono-indole and mono-benzofuran inhibitors that targeted the essential protein-protein interaction between RNA polymerase core and σ(70)/σ(A) factors in bacteria. In this study, the reaction of indole-2-, indole-3-, indole-7- and benzofuran-2-glyoxyloyl chlorides with amines and hydrazines afforded a variety of glyoxyloylamides and glyoxyloylhydrazides. Similarly, condensation of 2- and 7-trichloroacetylindoles with amines and hydrazines delivered amides and hydrazides. The novel molecules were found to inhibit the RNA polymerase-σ(70)/σ(A) interaction as measured by ELISA, and also inhibited the growth of both Gram-positive and Gram-negative bacteria in culture. Structure-activity relationship (SAR) studies of the mono-indole and mono-benzofuran inhibitors suggested that the hydrophilic-hydrophobic balance is an important determinant of biological activity.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Benzofurans; DNA-Directed RNA Polymerases; Humans; Indoles; Models, Molecular; Structure-Activity Relationship; Transcriptional Activation

Intramolecular sp(3) C-H insertion reaction of α-imino rhodium carbene generated from N-sulfonyl-1,2,3-triazoles has been described. A number of 2,3-dihydrobenzofuran and benzofuran derivatives have been obtained in good to excellent yields.

Topics: Benzofurans; Carbon; Catalysis; Chemistry Techniques, Synthetic; Hydrogen; Rhodium

The vibrational and electronic properties of 2-(bromoacetyl)benzo(b)furan have been studied in the ground state using experimental techniques (FT-IR, FT-Raman and UV) and density functional theory (DFT) employing B3LYP exchange correlation with the 6-31G(d,p) basis set. The theoretically calculated optimized parameters, vibrational frequencies etc., were compared with the experimental values, which yield good agreement between the observed and calculated values. The complete assignments of fundamental modes were performed on the basis of the potential energy distribution (PED). UV-visible spectrum of the compound was recorded in the region 300-600 nm and compared with the theoretical spectrum obtained from SAC-CI calculations. A good agreement is observed between the experimental and theoretical spectra. Fluorescence microscopic imaging studies proved that the compound can be used as one of the potential light sources in the yellow region with suitable excitation. Further, the predicted electronic transitions between the MOs 47→64, 52→62, 56→65, 56→72, 56→77 of the compound show a strong line at 569.8 nm.

Topics: Acetylation; Benzofurans; Halogenation; Models, Molecular; Optical Imaging; Quantum Theory; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis, Raman

The BMP pathway is a promising new target for the design of therapeutic agents for the treatment of low bone mass. To enrich our understanding of SAR and based on our previously concluded structure-effect relationship, 23 derivatives were prepared in this work. The synthesis, up-regulating activities on BMP-2 expression, and bone loss prevention efficacies of these compounds in rats with glucocorticoid-induced osteoporosis are presented. The bone histology of the tested rats assessed through light microscopy showed that compounds 1, 21, 35, and 38 significantly increased the trabecula compared with the model group, and the trabecula of the groups treated with 8a was similar to that obtained with raloxifene and alfacalcidol. The compounds exhibited potential for development as anabolic agents.

Topics: Animals; Benzofurans; Bone Morphogenetic Protein 2; Cell Line; Female; Glucocorticoids; Male; Mice; Mice, Inbred Strains; Osteoporosis; Rats; Rats, Wistar; Thiophenes; Up-Regulation

Herein, we report the Pd-catalyzed regioselective direct arylation of heteroarenes in which benzenesulfonyl chlorides are used as coupling partners through a desulfitative cross-coupling that can be performed in diethyl carbonate (DEC) or cyclopentyl methyl ether (CPME) as green and renewable solvents or even in neat conditions instead of dioxane or dimethylacetamide (DMA). Under these solvent conditions, the reaction proceeds with a wide range of heteroarenes. C2- or C5-arylated products were obtained with furan and pyrrole derivatives. Benzofuran was also arylated regioselectively at the C2-position, whereas the reaction proceeds selectively at the C3- or C4-positions if thiophenes and benzothiophenes are used. Moreover, in some cases, especially with 1-methylindole, solvent-free conditions afforded better regioselectivities and/or yields than the reaction performed in the presence of solvents.

Topics: Benzofurans; Catalysis; Diethyl Pyrocarbonate; Ethers; Indoles; Palladium; Pyrroles; Solvents; Sulfones; Thiophenes

This study was focused on evaluation of the cytotoxicity and apoptotic affects of benzofuran derivative on MCF-7 breast cancer cell line. This effective compound was isolated from the root of Petasites hybridus plant. For experiments, the MCF-7 cells were treated with several concentrations (0-500μM) of 1-(6-hydroxy-2- isopropenyl-1-benzofuran-5-yl)-1-ethanone 1 at different times. In this study, test of neutral red was also employed for cytotoxicity assay and quantity of P53, P21. Bax genes expression was analyzed using Real-Time PCR and ELISA techniques. Results show that compound 1 has cytotoxicity and apoptotic effects on Human breast cancer (Michigan Cancer Foundation-7) MCF-7 cells.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzofurans; Biological Products; Breast Neoplasms; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; MCF-7 Cells; Molecular Structure; Petasites; Plant Roots; Structure-Activity Relationship

With the aim of developing novel scaffolds as anticancer agents and inhibitors of NF-κB activity, 60 novel benzofuran- and 2,3-dihydrobenzofuran-2-carboxylic acid N-(substituted)phenylamide derivatives (1a-s, 2a-k, 3a-s, and 4a-k) were designed and synthesized from the reference lead compound KL-1156, which is an inhibitor of NF-κB translocation to the nucleus in LPS-stimulated RAW 264.7 macrophage cells. The novel benzofuran- and 2,3-dihydrobenzofuran-2-carboxamide derivatives exhibited potent cytotoxic activities (measured by the sulforhodamine B assay) at low micromolar concentrations against six human cancer cell lines: ACHN (renal), HCT15 (colon), MM231 (breast), NUGC-3 (gastric), NCI-H23 (lung), and PC-3 (prostate). In addition, these compounds also inhibited LPS-induced NF-κB transcriptional activity. The +M effect and hydrophobic groups on the N-phenyl ring potentiated the anticancer activity and NF-κB inhibitory activity, respectively. However, according to the results of structure-activity relationship studies, only benzofuran-2-carboxylic acid N-(4'-hydroxy)phenylamide (3m) was the lead scaffold with both an outstanding anticancer activity and NF-κB inhibitory activity. This novel lead scaffold may be helpful for investigation of new anticancer agents that act through inactivation of NF-κB.

Topics: Amides; Animals; Antineoplastic Agents; Benzofurans; Carboxylic Acids; Cell Line; Cell Survival; Drug Design; Drug Screening Assays, Antitumor; Humans; Lipopolysaccharides; Mice; NF-kappa B; Protein Binding; Signal Transduction; Structure-Activity Relationship

Heteroaromatic analogs of DMU-212 (8-15) have been synthesized and evaluated for their anti-cancer activity against a panel of 60 human cancer cell lines. These novel analogs contain a trans-3,4,5-trimethoxystyryl moiety attached to the C2 position of indole, benzofuran, benzothiazole or benzothiophene ring (8, 11, 13 and 14, respectively) and showed potent growth inhibition in 85% of the cancer cell lines examined, with GI50 values <1 μM. Interestingly, trans-3,4- and trans-3,5-dimethoxystyryl DMU-212 analogs 9, 10, 12 and 15 exhibited significantly less growth inhibition than their 3,4,5-trimethoxystyryl counterparts, suggesting that the trans-3,4,5-trimethoxystyryl moiety is an essential structural element for the potent anti-cancer activity of these heterocyclic DMU-212 analogs. Molecular modeling studies showed that the four most active compounds (8, 11, 13 and 14) all bind to the colchicine binding site on tubulin, and that their binding modes are similar to that of DMU-212.

Topics: Antineoplastic Agents; Benzofurans; Benzothiazoles; Binding Sites; Cell Line, Tumor; Cell Survival; Colchicine; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Protein Structure, Tertiary; Resveratrol; Stilbenes; Thiophenes; Tubulin

Phenethylamine-based designer drugs are prevalent within the new psychoactive substance market. Characterisation of their metabolites is important in order to identify suitable biomarkers which can be used for better monitoring their consumption. Careful design of in vitro metabolism experiments using subcellular liver fractions will assist in obtaining reliable outcomes for such purposes. The objective of this study was to stepwise investigate the in vitro human metabolism of seven phenethylamine-based designer drugs using individual families of enzymes. This included para-methoxyamphetamine, para-methoxymethamphetamine, 4-methylthioamphetamine, N-methyl-benzodioxolylbutanamine, benzodioxolylbutanamine, 5-(2-aminopropyl) benzofuran and 6-(2-aminopropyl) benzofuran. Identification and structural elucidation of the metabolites was performed using liquid chromatography-quadrupole-time-of-flight mass spectrometry. The targeted drugs were mainly metabolised by cytochrome P450 enzymes via O-dealkylation as the major pathway, followed by N-dealkylation, oxidation of unsubstituted C atoms and deamination (to a small extent). These drugs were largely free from Phase II metabolism. Only a limited number of metabolites were found which was consistent with the existing literature for other phenethylamine-based drugs. Also, the metabolism of most of the targeted drugs progressed at slow rate. The reproducibility of the identified metabolites was assessed through examining formation patterns using different incubation times, substrate and enzyme concentrations. Completion of the work has led to a set of metabolites which are representative for specific detection of these drugs in intoxicated individuals and also for meaningful evaluation of their use in communities by wastewater-based drug epidemiology.

Topics: 3,4-Methylenedioxyamphetamine; Amines; Amphetamines; Benzodioxoles; Benzofurans; Butylamines; Catalysis; Chromatography, Liquid; Cytochrome P-450 Enzyme System; Cytosol; Designer Drugs; Dose-Response Relationship, Drug; Female; Humans; Likelihood Functions; Liver; Male; Mass Spectrometry; Methamphetamine; Microsomes, Liver; Models, Chemical; Phenethylamines; Propylamines; Reproducibility of Results; Substance Abuse Detection; Wastewater; Water Purification

Paeoveitols A-E (1-5), involving three monoterpenes and two benzofuran constituents, were isolated from Paeonia veitchii. Their structures were determined based on extensive spectral analyses (IR, UV, MS, 1D and 2D NMR), and the absolute configuration of compound 1 was confirmed by single-crystal X-ray diffraction. By the agitating human melatonin receptor 1 (MT1) assay on HEK293 cell line in vitro, compound 4 showed weak activity with the agitation rate of 22.52% at the concentration of 1.79 mM.

Topics: Benzofurans; Diterpenes; HEK293 Cells; Humans; Molecular Structure; Monoterpenes; Paeonia; Plant Roots

A series of benzofuran-based chalconoids 6a-v were designed and synthesized as new potential AChE inhibitors. The in vitro assay of synthesized compounds 6a-v showed that most compounds had significant anti-AChE activity at micromolar or sub-micromolar levels. Among the tested compounds, 3-pyridinium derivative 6m bearing N-(2-bromobenzyl) moiety and 7-methoxy substituent on the benzofuran ring exhibited superior activity. This compound with IC₅₀ value of 0.027 μM was as potent as standard drug donepezil.

Topics: Acetylcholinesterase; Animals; Benzofurans; Chalcones; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Molecular Structure; Pyridinium Compounds; Structure-Activity Relationship

A novel naturally occurring compound with a benzofuran skeleton was isolated from a plant, Tephrosia purpurea collected in Bangladesh. The chemical synthesis of this compound confirmed its structure, and preliminary biological results showed its suppressive activity towards histamine H1 gene expression. One isomer and four derivatives were also synthesized, and their suppression activity was investigated. Although only small quantities of this compound can be isolated from its natural source, a 10 g scale synthesis was demonstrated by the newly developed method.

Topics: Anti-Allergic Agents; Benzofurans; Gene Expression Regulation; HeLa Cells; Humans; Isomerism; Plant Components, Aerial; Receptors, Histamine H1; Tephrosia

Successive [2+4] cycloadditions of arynes and isobenzofurans by site-selective halogen-lithium exchange of 1,2-dihaloarenes were developed, allowing the rapid construction of polycyclic compounds which serve as a useful synthetic intermediates for the preparation of various polyacene derivatives.

Topics: Benzofurans; Bromides; Catalysis; Cycloaddition Reaction; Iodides; Lithium; Polycyclic Compounds

The intramolecular Diels-Alder reaction has been used as a powerful method to access the tricyclic core of the eunicellin natural products from a number of 9-membered-ring precursors. The endo/exo selectivity of this reaction can be controlled through a remarkable organocatalytic approach, employing MacMillan's imidazolidinone catalysts, although the mechanistic origin of this selectivity remains unclear. We present a combined experimental and density functional theory investigation, providing insight into the effects of medium-ring constraints on the organocatalyzed intramolecular Diels-Alder reaction to form the isobenzofuran core of the eunicellins.

Topics: Benzofurans; Catalysis; Cycloaddition Reaction; Diterpenes; Molecular Structure; Stereoisomerism

A series of benzo[b]furans was synthesized with modification at the 5-position of the benzene ring by introducing C-linked substituents (aryl, alkenyl, alkynyl, etc.). These compounds were evaluated for their antiproliferative activities, inhibition of tubulin polymerization, and cell-cycle effects. Some compounds in this series displayed excellent activity in the nanomolar range against lung cancer (A549) and renal cell carcinoma (ACHN) cancer cell lines. (6-Methoxy-5-((4-methoxyphenyl)ethynyl)-3-methylbenzofuran-2-yl)(3,4,5-trimethoxyphenyl)methanone (26) and (E)-3-(6-methoxy-3-methyl-2-(1-(3,4,5-trimethoxyphenyl)vinyl)benzofuran-5-yl)prop-2-en-1-ol (36) showed significant activity in the A549 cell line, with IC₅₀ values of 0.08 and 0.06 μM, respectively. G₂/M cell-cycle arrest and subsequent apoptosis was observed in the A549 cell line after treatment with these compounds. The most active compound in this series, 36, also inhibited tubulin polymerization with a value similar to that of combretastatin A-4 (1.95 and 1.86 μM, respectively). Furthermore, detailed biological studies such as Hoechst 33258 staining, DNA fragmentation and caspase-3 assays, and western blot analyses with the pro-apoptotic protein Bax and the anti-apoptotic protein Bcl-2 also suggested that these compounds induce cell death by apoptosis. Molecular docking studies indicated that compound 36 interacts and binds efficiently with the tubulin protein.

Topics: Apoptosis; bcl-2-Associated X Protein; Benzofurans; Binding Sites; Caspase 3; Cell Line, Tumor; DNA Fragmentation; Humans; Molecular Docking Simulation; Polymerization; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2; Structure-Activity Relationship; Tubulin; Tubulin Modulators

A palladium(0)-catalyzed cascade reaction for the efficient synthesis of 2,3-disubstituted benzofuran derivatives 3 containing a 3-trisubstituted alkene functional group in moderate yields from alkynyl-substituted benzynes 1 and aryl halides 2 has been developed. This method provides an efficient and alternative approach to benzofurans which are very useful heterocyclic compounds with biological and pharmacological potentials. A plausible mechanism involving intramolecular ene reaction, intermolecular insertion, and β-H elimination is proposed.

Topics: Alkynes; Benzene Derivatives; Benzofurans; Catalysis; Hydrocarbons, Halogenated; Models, Molecular; Molecular Structure; Organometallic Compounds; Palladium

Total syntheses of the structures, 1, 2, and 4, assigned to the biologically active natural products ribisins A, B, and D, respectively, have been achieved using the microbially derived and enantiomerically pure cis-1,2-dihydrocatechol 5 as starting material. Key steps include Suzuki-Miyaura cross-coupling, intramolecular Mitsunobu, and tandem epoxidation/rearrangement reactions. As a result of these studies, the structures of ribisins A and D have been confirmed while that of congener B was shown to be represented by 31 rather than 2.

Topics: Benzofurans; Biological Products; Catechols; Crystallography, X-Ray; Magnetic Resonance Spectroscopy; Molecular Structure; Nerve Growth Factor; Stereoisomerism

A straightforward synthetic method for the construction of benzofuro[2,3-b]pyrrol-2-ones by a novel domino reaction through a radical addition/[3,3]-sigmatropic rearrangement/cyclization/lactamization cascade has been developed. The domino reaction of O-phenyl-conjugated oxime ether with an alkyl radical allows the construction of two heterocycles with three stereogenic centers as a result of the formation of two C-C bonds, a C-O bond, and a C-N bond in a single operation, leading to pyrrolidine-fused dihydrobenzofurans, which are not easily accessible by existing synthetic methods. Furthermore, asymmetric synthesis of benzofuro[2,3-b]pyrrol-2-one derivatives through a diastereoselective radical addition reaction to a chiral oxime ether was also developed.

Topics: Benzofurans; Cyclization; Free Radicals; Oximes; Pyrroles; Pyrrolidines; Stereoisomerism

An efficient lanthanide(III)-catalyzed diastereo- and enantioselective Michael addition of 3-substituted benzofuran-2(3H)-ones to 4-oxo-enoates was developed. The desired adducts with contiguous quaternary-tertiary stereocenters were obtained in up to 99% yield with up to >95/5 dr and 98% ee.

Topics: Benzofurans; Catalysis; Coordination Complexes; Lanthanum; Stereoisomerism

An unexpected and previously unknown resorcinarene mono-crown with a fused benzofuran moiety in its macrocyclic core was obtained as a byproduct from a bridging reaction of tetramethoxy resorcinarene with tetraethylene glycol ditosylate. The formation of the fused benzofuran moiety in the resorcinarene macrocycle resulted in a unique rigid and puckered boat conformation, as shown by XRD studies in the solid state. Modification of the macrocycle was also observed to affect the photophysical properties in solution by enhancing the fluorescence brightness compared with a conventional resorcinarene macrocycle. The fluorescent properties enabled unique detection of structural features, that is, the rigid boat conformation with the conjugated benzofuran system and the more flexible crown bridge part, in solution.

Topics: Benzofurans; Calixarenes; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Fluorescence; Molecular Conformation; Molecular Structure; Phenylalanine; Spectrometry, Fluorescence; Structure-Activity Relationship

Benzofuro[6,7-d]thiazoles, benzofuro[7,6-d]thiazoles and 6-arylaminobenzo[d]thiazole-4,7-diones were synthesized and tested for in vitro antifungal activity against Candida, Aspergillus species and Cryptococcus neoformans. Among them tested, many of synthesized compounds showed potent antifungal activity. The compounds 4d, 6e and 6h completely inhibited the growth of all Candida and Aspergillus species tested at the MIC level of 6.3 µg/mL. The results suggest that benzofuro[6,7-d]thiazoles and 6-arylaminobenzo[d]thiazole-4,7-diones would be promising antifungal agents.

Topics: Antifungal Agents; Aspergillus; Benzofurans; Candida; Cryptococcus neoformans; Microbial Sensitivity Tests; Thiazoles

As the prototypical member of the PTP family, protein tyrosine phosphatase 1B (PTP1B) is an attractive target for therapeutic interventions in type 2 diabetes. The extremely conserved catalytic site of PTP1B renders the design of selective PTP1B inhibitors intractable. Although discovered allosteric inhibitors containing a benzofuran sulfonamide scaffold offer fascinating opportunities to overcome selectivity issues, the allosteric inhibitory mechanism of PTP1B has remained elusive. Here, molecular dynamics (MD) simulations, coupled with a dynamic weighted community analysis, were performed to unveil the potential allosteric signal propagation pathway from the allosteric site to the catalytic site in PTP1B. This result revealed that the allosteric inhibitor compound-3 induces a conformational rearrangement in helix α7, disrupting the triangular interaction among helix α7, helix α3, and loop11. Helix α7 then produces a force, pulling helix α3 outward, and promotes Ser190 to interact with Tyr176. As a result, the deviation of Tyr176 abrogates the hydrophobic interactions with Trp179 and leads to the downward movement of the WPD loop, which forms an H-bond between Asp181 and Glu115. The formation of this H-bond constrains the WPD loop to its open conformation and thus inactivates PTP1B. The discovery of this allosteric mechanism provides an overall view of the regulation of PTP1B, which is an important insight for the design of potent allosteric PTP1B inhibitors.

Topics: Allosteric Site; Benzofurans; Catalytic Domain; Drug Design; Molecular Dynamics Simulation; Mutation; Principal Component Analysis; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Signal Transduction

A series of 32 derivatives and isosteres of the mTOR inhibitor 2 were synthesized and compared for their cytotoxicity in radioresistant SQ20B cancer cell line. Several of these compounds, in particular 30b, were significantly more cytotoxic than 2. Importantly, 30b was shown to block both mTORC1 and Akt signaling, suggesting insensitivity to the resistance associated to Akt overactivation observed with rapamycin derivatives currently used in clinic.

Topics: Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; HCT116 Cells; HT29 Cells; Humans; Molecular Structure; Signal Transduction; Structure-Activity Relationship; TOR Serine-Threonine Kinases

Sulfhydryl-containing compounds, including thiols and hydrogen sulfide (H2S), play important but differential roles in biological structure and function. One major challenge in separating the biological roles of thiols and H2S is developing tools to effectively separate the reactivity of these sulfhydryl-containing compounds. To address this challenge, we report the differential responses of common electrophilic fluorescent thiol labeling reagents, including nitrobenzofurazan-based scaffolds, maleimides, alkylating agents, and electrophilic aldehydes, toward cysteine and H2S. Although H2S reacted with all of the investigated scaffolds, the photophysical response to each scaffold was significantly different. Maleimide-based, alkylating, and aldehydic thiol labeling reagents provided a diminished fluorescence response when treated with H2S. By contrast, nitrobenzofurazan-based labeling reagents were deactivated by H2S addition. Furthermore, the addition of H2S to thiol-activated nitrobenzofurazan-based reagents reduced the fluorescence signal, thus establishing the incompatibility of nitrobenzofurazan-based thiol labeling reagents in the presence of H2S. Taken together, these studies highlight the differential reactivity of thiols and H2S toward common thiol-labeling reagents and suggest that sufficient care must be taken when labeling or measuring thiols in cellular environments that produce H2S due to the potential for both false-positive and eroded responses.

Topics: Benzofurans; Fluorescent Dyes; Hydrogen Sulfide; Indicators and Reagents; Sulfhydryl Compounds

CLC-K chloride channels play a crucial role in kidney physiology and genetic mutations, affecting their function are responsible for severe renal salt loss in humans. Thus, compounds that selectively bind to CLC-Ka and/or CLC-Kb channels and modulate their activity may have a significant therapeutic potential. Here, we compare the biophysical and pharmacological behaviors of human CLC-K channels expressed either in HEK293 cells or in Xenopus oocytes and we show that CLC-K channel properties are greatly influenced by the biochemical environment surrounding the channels. Indeed, in HEK293 cells the potentiating effect of niflumic acid (NFA) on CLC-Ka/barttin and CLC-Kb/barttin channels seems to be absent while the blocking efficacy of niflumic acid and benzofuran derivatives observed in oocytes is preserved. The NFA block does not seem to involve the accessory subunit barttin on CLC-K1 channels. In addition, the sensitivity of CLC-Ks to external Ca(2+) is reduced in HEK293 cells. Based on our findings, we propose that mammalian cell lines are a suitable expression system for the pharmacological profiling of CLC-Ks.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Chloride Channels; Drug Delivery Systems; HEK293 Cells; Humans; Kidney; Niflumic Acid; Oocytes; Species Specificity; Xenopus laevis

New, small molecule Hedgehog (Hh) pathway inhibitors, such as the furanoditerpenoid taepeenin D, are of high medicinal importance. To establish key structure-activity relationships (SARs) for this lead, a synthetic sequence has been developed for the expedient preparation of several derivatives and their evaluation as Hh inhibitors exploiting its structural similarity to abietic acid. While C(14) substitution is not essential for biological activity, the presence of a hydrogen bond acceptor at C(6) and an intact benzofuran moiety are.

Topics: Acacia; Benzofurans; Hedgehog Proteins; Molecular Structure; Signal Transduction; Structure-Activity Relationship; Terpenes

Coumestan is a natural tetracycle with a C═C bond shared by a coumarin moiety and a benzofuran moiety. In addition to the function of the hydroxyl group on the antioxidant activity of coumestan, it is worth exploring the influence of the oxygen-abundant scaffold on the antioxidant activity as well. In this work, seven coumestans containing electron-withdrawing and electron-donating groups were synthesized to evaluate the abilities to trap 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(•+)), 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH), and galvinoxyl radical, respectively, and to inhibit the oxidations of DNA mediated by (•)OH, Cu(2+)/glutathione (GSH), and 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), respectively. It was found that all of the coumestans used herein can quench the aforementioned radicals and can inhibit (•)OH-, Cu(2+)/GSH-, and AAPH-induced oxidations of DNA. In particular, substituent-free coumestan exhibits higher ability to quench DPPH and to inhibit AAPH-induced oxidation of DNA than Trolox. In addition, nonsubstituted coumestan shows a similar ability to inhibit (•)OH- and Cu(2+)/GSH-induced oxidations of DNA relative to that of Trolox. The antioxidant effectiveness of the coumestan can be attributed to the lactone in the coumarin moiety and, therefore, a hydroxyl group may not be a necessary functional group for coumestan to be an antioxidant.

Topics: Amidines; Antioxidants; Benzofurans; Biphenyl Compounds; Coumarins; DNA; Glutathione; Hydroxyl Radical; Oxidation-Reduction; Picrates

Parkinson disease (PD) is a neurodegenerative disease with multifactorial etiopathogenesis. The discovery of drug candidates that act on new targets of PD is required to address the varied pathological aspects and modify the disease process. In this study, a small compound, 2-(5-methyl-1-benzofuran-3-yl)-N-(5-propylsulfanyl-1,3,4-thiadiazol-2-yl) acetamide (MBPTA) was identified as a novel Rho-associated protein kinase inhibitor with significant protective effects against 1-methyl-4-phenylpyridinium ion (MPP(+))-induced damage in SH-SY5Y neuroblastoma cells. Further investigation showed that pretreatment of SH-SY5Y cells with MBPTA significantly suppressed MPP(+)-induced cell death by restoring abnormal changes in nuclear morphology, mitochondrial membrane potential, and numerous apoptotic regulators. MBPTA was able to inhibit MPP(+)-induced reactive oxygen species (ROS)/NO generation, overexpression of inducible NO synthase, and activation of NF-κB, indicating the critical role of MBPTA in regulating ROS/NO-mediated cell death. Furthermore, MBPTA was shown to activate PI3K/Akt survival signaling, and its cytoprotective effect was abolished by PI3K and Akt inhibitors. The structural comparison of a series of MBPTA analogs revealed that the benzofuran moiety probably plays a crucial role in the anti-oxidative stress action. Taken together, these results suggest that MBPTA protects against MPP(+)-induced apoptosis in a neuronal cell line through inhibition of ROS/NO generation and activation of PI3K/Akt signaling.

Topics: Acetamides; Alkanesulfonic Acids; Antioxidants; Benzofurans; Cell Death; Cell Line, Tumor; Cytoprotection; Drug Discovery; Humans; Membrane Potential, Mitochondrial; Molecular Targeted Therapy; Oncogene Protein v-akt; Oxidants; Oxidative Stress; Parkinson Disease; Phosphatidylinositol 3-Kinases; Pyridinium Compounds; rho-Associated Kinases; Signal Transduction; Thiadiazoles

Given the biological and therapeutic significance of telomeres and other G-quadruplex forming sequences in human genome, it is highly desirable to develop simple methods to study these structures, which can also be implemented in screening formats for the discovery of G-quadruplex binders. The majority of telomere detection methods developed so far are laborious and use elaborate assay and instrumental setups, and hence, are not amenable to discovery platforms. Here, we describe the development of a simple homogeneous fluorescence turn-on method, which uses a unique combination of an environment-sensitive fluorescent nucleobase analogue, the superior base pairing property of PNA, and DNA-binding and fluorescence quenching properties of graphene oxide, to detect human telomeric DNA repeats of varying lengths. Our results demonstrate that this method, which does not involve a rigorous assay setup, would provide new opportunities to study G-quadruplex structures.

Topics: Base Sequence; Benzofurans; Graphite; Humans; Nucleic Acid Hybridization; Oxides; Peptide Nucleic Acids; Spectrometry, Fluorescence; Telomere; Uracil

We report a protocol for oxidative [3+2] cycloadditions of phenols and alkenes applicable to the modular synthesis of a large family of dihydrobenzofuran natural products. Visible-light-activated transition metal photocatalysis enables the use of ammonium persulfate as an easily handled, benign terminal oxidant. The broad range of organic substrates that are readily oxidized by photoredox catalysis suggests that this strategy may be applicable to a variety of useful oxidative transformations.

Topics: Alkenes; Benzofurans; Biological Products; Catalysis; Cycloaddition Reaction; Light; Oxidation-Reduction; Phenols; Ruthenium

Since the imaging of β-amyloid (Aβ) plaques in the brain is believed to be a useful tool for the early diagnosis of Alzheimer's disease (AD), a number of imaging probes to detect Aβ plaques have been developed. Because the radionuclide (68)Ga (t1/2=68 min) for PET imaging could become an attractive alternative to (11)C and (18)F, we designed and synthesized a benzofuran derivative conjugated with a (68)Ga complex ((68)Ga-DOTA-C3-BF) as a novel Aβ imaging probe. In an in vitro binding assay, Ga-DOTA-C3-BF showed high affinity for Aβ(1-42) aggregates (Ki=10.8 nM). The Ga-DOTA-C3-BF clearly stained Aβ plaques in a section of Tg2576 mouse, reflecting the affinity for Aβ(1-42) aggregates in vitro. In a biodistribution study in normal mice, (68)Ga-DOTA-C3-BF displayed low initial uptake (0.45% ID/g) in the brain at 2 min post-injection. While improvement of the brain uptake of (68)Ga complexes appears to be essential, these results suggest that novel PET imaging probes that include (68)Ga as the radionuclide for PET may be feasible.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzofurans; Disease Models, Animal; Gallium Radioisotopes; Mice; Mice, Transgenic; Molecular Imaging; Organometallic Compounds; Peptide Fragments; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals

In the search for effective multifunctional agents for the treatment of Alzheimer's disease (AD), a series of novel hybrids incorporating benzofuran and chalcone fragments were designed and synthesized. These hybrids were screened by using a transgenic Caenorhabditis elegans model that expresses the human β-amyloid (Aβ) peptide. Among the hybrids investigated, (E)-3-(7-methyl-2-(4-methylbenzoyl)benzofuran-5-yl)-1-phenylprop-2-en-1-one (4 f), (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-phenylprop-2-en-1-one (4 i), and (E)-3-(2-benzoyl-7-methylbenzofuran-5-yl)-1-(thiophen-2-yl)prop-2-en-1-one (4 m) significantly decreased Aβ aggregation and increased acetylcholine (ACh) levels along with the overall availability of ACh at the synaptic junction. These compounds were also found to decrease acetylcholinesterase (AChE) levels, reduce oxidative stress in the worms, lower lipid content, and to provide protection against chemically induced cholinergic neurodegeneration. Overall, the multifunctional effects of these hybrids qualify them as potential drug leads for further development in AD therapy.

Topics: Acetylcholine; Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Animals, Genetically Modified; Antioxidants; Benzofurans; Binding Sites; Caenorhabditis elegans; Chalcone; Chalcones; Crystallography, X-Ray; Disease Models, Animal; Humans; Microscopy, Fluorescence; Molecular Conformation; Molecular Docking Simulation; Oxidative Stress; Protein Structure, Tertiary; Structure-Activity Relationship; Thiophenes

The evolution of a program directed at the enantioselective total synthesis of maoecrystal V, a highly modified ent-kauranoid, is described. An early stage chiral auxiliary-directed asymmetric C-H functionalization for the construction of a key benzofuran intermediate enabled the first asymmetric synthesis of the natural enantiomer of maoecrystal V, confirming the assigned stereochemistry. A divergent course of the central intramolecular Diels-Alder reaction, which is dependent on the nature of the dienophile, initially led to the development of an unanticipated and previously unknown isomer of maoecrystal V, which we named maoecrystal ZG. In light of the reported selective and potent cytotoxic activity of maoecrystal V, the cytotoxic properties of maoecrystal ZG were also investigated.

Topics: Antineoplastic Agents; Benzofurans; Carbon; Catalysis; Cell Line, Tumor; Cell Proliferation; Cycloaddition Reaction; Diterpenes; Humans; Hydrogen; Rhodium; Stereoisomerism; Substrate Specificity

A series of twenty eight molecules of ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate and 3-(piperazin-1-yl)benzo[d]isothiazole were designed by molecular hybridization of thiazole aminopiperidine core and carbamide side chain in eight steps and were screened for their in vitro Mycobacterium smegmatis (MS) GyrB ATPase assay, Mycobacterium tuberculosis (MTB) DNA gyrase super coiling assay, antitubercular activity, cytotoxicity and protein-inhibitor interaction assay through differential scanning fluorimetry. Also the orientation and the ligand-protein interactions of the top hit molecules with MS DNA gyrase B subunit active site were investigated applying extra precision mode (XP) of Glide. Among the compounds studied, 4-(benzo[d]isothiazol-3-yl)-N-(4-chlorophenyl)piperazine-1-carboxamide (26) was found to be the most promising inhibitor with an MS GyrB IC50 of 1.77 ± 0.23 μM, 0.42 ± 0.23 against MTB DNA gyrase, MTB MIC of 3.64 μM, and was not cytotoxic in eukaryotic cells at 100 μM. Moreover the interaction of protein-ligand complex was stable and showed a positive shift of 3.5 °C in differential scanning fluorimetric evaluations

Topics: Animals; Antitubercular Agents; Benzofurans; Benzothiazoles; Cell Line; DNA Gyrase; Dose-Response Relationship, Drug; Humans; Macrophages; Mice; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mycobacterium tuberculosis; Piperazines; Structure-Activity Relationship; Topoisomerase II Inhibitors

Three new compounds (1-3) and 20 known compounds were isolated from the rhizomes and roots of Sophora tonkinensis, and all the isolates were tested for their inhibitory activity against IL-6 production in HMC-1 cells stimulated by PMA plus ionophore, A23187. Of the tested compounds, compounds 1, 5, 9, and 21 were found to potently inhibit IL-6 production with IC50 values of 1.62, 0.73, 3.01, and 4.02 μM, respectively.

Topics: Benzofurans; Calcimycin; Cell Line; Flavanones; Flavonoids; Humans; Interleukin-6; Magnetic Resonance Spectroscopy; Mast Cells; Molecular Conformation; Plant Extracts; Plant Roots; Rhizome; Sophora; Terpenes; Tetradecanoylphorbol Acetate

The use of selective inhibitors of monoamine oxidase A (MAO-A) and B (MAO-B) holds a therapeutic relevance in the treatment of depressive disorders and Parkinson's disease (PD), respectively. Here, the discovery of a new class of compounds acting as monoamine oxidase inhibitors (MAO-Is) and bearing a 6'-substituted (E)-2-(benzofuran-3(2H)-ylidene)-N-alkylacetamide skeleton is reported. 6'-Sulfonyloxy derivatives exhibited outstanding affinities to MAO-A (7.0 nM < IC50 < 49 nM, much higher than moclobemide) and a pronounced MAO-A/B selectivity. The corresponding 6'-benzyloxy derivatives showed potent MAO-B inhibition and inverted selectivity profile. The rigid E-geometry of the exocyclic double bond allowed a more efficient binding conformation compared to more flexible and less active 2-(1-benzofuran-3-yl)-N-methylacetamide isomers and 4-N-methylcarboxamidomethylcoumarin analogues. Focused structural modifications and docking simulations enabled the identification of key molecular determinants for high affinity toward both MAO isoforms. These novel MAO-Is may represent promising hits for the development of safer therapeutic agents with a potential against depression, PD, and other age-related neurodegenerative pathologies.

Topics: Benzofurans; Drug Discovery; Humans; Molecular Docking Simulation; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Protein Conformation; Stereoisomerism; Structure-Activity Relationship

Screening of our sample collection led to the identification of a set of benzofurano[3,2-d]pyrimidine-2-one hits acting as nucleotide-competing HIV-1 reverse transcriptase inhibitiors (NcRTI). Significant improvement in antiviral potency was achieved when substituents were introduced at positions N1, C4, C7 and C8 on the benzofuranopyrimidone scaffold. The series was optimized from low micromolar enzymatic activity against HIV-1 RT and no antiviral activity to low nanomolar antiviral potency. Further profiling of inhibitor 30 showed promising overall in vitro properties and also demonstrated that its potency was maintained against viruses resistant to the other major classes of HIV-1 RT inhibitors.

Topics: Animals; Benzofurans; HIV Reverse Transcriptase; HIV-1; Humans; Microsomes, Liver; Nucleotides; Protein Binding; Pyrimidinones; Rats; Reverse Transcriptase Inhibitors; Structure-Activity Relationship

Two different types of hydrogen bond, which are classified into a familiar OH-O and a relatively weak OH-π one, have been compared in the 1:1 hydrogen-bonded 2,3-benzofuran clusters with water and methanol molecules. By applying fluorescence-detected infrared spectroscopy and dispersed fluorescence spectroscopy, two isomers having different types of hydrogen bonds are distinguished. From the calculated stabilization energy as well as the frequency shift of the OH stretching vibration in each cluster, these two isomers are almost equally stable, although that of OH-π type is usually thought to be relatively weak. It is suggested that the origin of the weak OH-O hydrogen bond is derived from the lower availability for a hydrogen bond acceptor on the oxygen atom of a heteroaromatic ring, which is attributed to the larger furan aromaticity.

Topics: Benzofurans; Electrons; Hydrogen Bonding; Methanol; Models, Molecular; Oxygen; Spectrometry, Fluorescence; Spectrophotometry, Infrared; Spectroscopy, Fourier Transform Infrared; Thermodynamics; Water

A HTS screen led to the identification of a benzofurano[3,2-d]pyrimidin-2-one core structure which upon further optimization resulted in 1 as a potent HIV-1 nucleotide competing reverse transcriptase inhibitor (NcRTI). Investigation of the SAR at N-1 allowed significant improvements in potency and when combined with the incorporation of heterocycles at C-8 resulted in potent analogues not requiring a basic amine to achieve antiviral activity. Additional modifications at N-1 resulted in 33 which demonstrated excellent antiviral potency and improved physicochemical properties.

Topics: Benzofurans; Caco-2 Cells; Cell Membrane Permeability; HIV Reverse Transcriptase; HIV-1; Humans; Microsomes, Liver; Nucleotides; Protein Binding; Pyrimidinones; Reverse Transcriptase Inhibitors; Stereoisomerism; Structure-Activity Relationship

A palladium-catalyzed addition of potassium aryltrifluoroborates to aliphatic nitriles has been developed, leading to a wide range of alkyl aryl ketones with moderate to excellent yields. Moreover, several dinitriles (e.g., malononitrile, glutaronitrile, and adiponitrile) were applicable to this process for the construction of 1,3-, 1,5-, or 1,6-dicarbonyl compounds. The scope of the developed approach is successfully explored toward the one-step synthesis of 2-arylbenzo[b]furans via sequential addition and intramolecular annulation reactions. The methodology accepted a wide range of substrates and is applicable to library synthesis.

Topics: Benzofurans; Borates; Catalysis; Ketones; Molecular Structure; Nitriles; Organometallic Compounds; Palladium; Potassium

We recently designed a group of novel exosite-2-directed sulfated, small, allosteric inhibitors of thrombin. To develop more potent inhibitors, monosulfated benzofuran tri- and tetrameric homologues of the parent designed dimers were synthesized in seven to eight steps and found to exhibit a wide range of potencies. Among these, trimer 9a was found to be nearly 10-fold more potent than the first generation molecules. Michaelis-Menten studies indicated an allosteric mechanism of inhibition. Competitive studies using a hirudin peptide (exosite 1 ligand) and unfractionated heparin, heparin octasaccharide, and γ'-fibrinogen peptide (exosite 2 ligands) demonstrated exosite 2 recognition in a manner different from that of the parent dimers. Alanine scanning mutagenesis of 12 Arg/Lys residues of exosite 2 revealed a defect in 9a potency for Arg233Ala thrombin only confirming the major difference in site of recognition between the two structurally related sulfated benzofurans. The results suggest that multiple avenues are available within exosite 2 for inducing thrombin inhibition.

Topics: Allosteric Regulation; Benzofurans; Binding Sites; Blood Coagulation; Dimerization; Drug Design; Humans; Kinetics; Models, Molecular; Protein Conformation; Serine Proteinase Inhibitors; Substrate Specificity; Sulfates; Thrombin

Selective activation of the estrogen receptor β (ERβ) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ERβ and ERα, occasionally causing severe side effects. The selective ERβ agonist AC-131 has shown efficacy in animal models of Parkinson's disease and neuropathic pain. With the use of AC-131 as template, herein we report the discovery, synthesis, and structure-activity relationship (SAR) study of a new class of dihydrobenzofurans as potent and selective ERβ agonists. The SAR was established by enantioselective synthesis, molecular modeling, and whole-cell-based functional assays. The most potent diastereomer, cis-10-SR, was shown to have an EC50 value of <1 nM, potency 100-fold higher than that of AC-131. Even more interestingly, compound trans-10-SS exhibited 1000-fold ERβ/ERα selectivity while still maintaining good potency (∼10 nM). In addition, trans-10-SS showed only partial agonist activity (30-60 % Eff.) toward ERα at 10 μM. This unprecedented selectivity could be rationalized by molecular modeling. Compound trans-10-SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the α- and β-faces of the binding cavities of ERα and ERβ.

Topics: Benzofurans; Crystallography, X-Ray; Cyclohexanes; Drug Design; Estrogen Receptor alpha; Estrogen Receptor beta; Heterocyclic Compounds, 3-Ring; Molecular Conformation; Phenols; Protein Binding; Stereoisomerism; Structure-Activity Relationship

(Z)-2-((1H-Indazol-3-yl)methylene)-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one is a potent and selective proviral integration site in moloney murine leukemia virus kinase 1 (PIM1) inhibitor with an IC₅₀ value of 3 nM. (Z)-2-((1H-Indazol-3-yl)methylene)-6-[(11)C]methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one, a new potential PET probe for imaging of the enzyme PIM1, was first designed and synthesized in 20-30% decay corrected radiochemical yield and 370-740 GBq/μmol specific activity at end of bombardment (EOB). The synthetic strategy was to prepare a carbon-11-labeled Boc-protected intermediate followed by a quick acidic de-protection.

Topics: Animals; Benzofurans; Carbon Isotopes; Fungal Proteins; Humans; Indazoles; Mice; Mitogen-Activated Protein Kinases; Neoplasms; Piperazines; Positron-Emission Tomography; Protein Kinase Inhibitors; Radiopharmaceuticals

A series of novel hybrid compounds of 2-phenyl-3-alkylbenzofuran and imidazole or triazole were prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the 2-ethyl-imidazole ring, and substitution of the imidazolyl-3-position with a 2-bromobenzyl or naphthylacyl group, were vital for modulating inhibitory activity. In particular, hybrid compound 31 was found to be the most potent derivative with IC₅₀ values of 0.08-0.55 μM against five strains human tumor cell lines and was found to be more selective against breast carcinoma (MCF-7) and colon carcinoma (SW480) (IC₅₀ values 40.8-fold and 40.1-fold lower than cisplatin (DDP)).

Topics: Antineoplastic Agents; Benzofurans; Binding Sites; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Imidazoles; MCF-7 Cells; Molecular Docking Simulation; Phosphatidylinositol 3-Kinases; Protein Structure, Tertiary; Structure-Activity Relationship; Triazoles

We first report the application of 3-acyl-5-hydroxybenzofurans as a scaffold to develop potential drugs for breast cancer. Seven novel derivative compounds were synthesized by using a microwave-assisted synthesis method. Those compounds exhibited different antiproliferation against human breast cancer MCF-7 cells, with the best activity of IC50=43.08μM for compound 1. A Quantum Mechanics Polarized Ligand Docking (QPLD) study was carried out to investigate the binding interactions between these compounds and estrogen receptor alpha (ERα). The simulation results showed that the trend of receptor-ligand binding interactions was same as that of their antiproliferative activities. A detailed analysis indicated that compound 1 possesses the highest Van der Waals and hydrogen bond interactions compared to the other six compounds and better inhibitors are achievable by enhancing the hydrogen bond interactions. Based on these results, we addressed that 3-acyl-5-hydroxybenzofuran is an attractive scaffold for designing drugs against breast cancer.

Topics: Antineoplastic Agents, Hormonal; Benzofurans; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Estrogen Receptor alpha; Female; Humans; Hydroxylation; MCF-7 Cells; Molecular Structure; Quantum Theory

Rayless goldenrod (Isocoma pluriflora) sporadically poisons horses and other livestock in the southwestern United States. Similar to livestock poisoning by white snakeroot (Ageratina altissima) in the midwestern United States, previous research suggests that benzofuran ketones (BFK: tremetone, dehydrotremetone, 6-hydroxytremetone, and 3-oxyangeloyl-tremetone) are responsible for the toxicity of rayless goldenrod. However, experimental reproduction of rayless goldenrod-induced disease and detailed descriptions of poisoning in horses with known concentrations of tremetone and other BFK has not been documented. In this study four horses were fed increasing amounts of rayless goldenrod to obtain doses of approximately 0, 10, 30, and 60 mg BFK/kg BW for 14 days. After seven days of dosing the horse dosed with 60 mg BFK/kg BW horse developed depression, reluctance to eat, dehydration, trembling, and muscle fatigue. Biochemical alterations including increases in the serum enzyme activities of CK, AST, ALT, and LDH, and increased cardiac troponin I concentration, were also identified. Physiologically the clinically poisoned horse had decreased endurance seen as reluctance to perform on the treadmill with increased resting heart rate and a prolonged recovery of heart rate following treadmill exercise. The condition of the horse continued to decline and it was euthanized and necropsied on day 10. At necropsy the myocardium was pale and soft and many of the appendicular and large apical muscles were pale and moist. Histologically, the myocardium had extensive myocardial degeneration and necrosis with extensive fibrosis and multifocal mineralization. Several of the large appendicular muscles in this horse also had small foci of skeletal muscle degeneration and necrosis. Less severe myocardial changes were also identified in the horse dosed with 30 mg BFK/kg BW after 14 days of dosing. No clinical, biochemical or histologic changes were identified in the control horse and the horse dosed with 10 mg BFK/kg BW. These results suggest that doses of 60 mg BFK/kg BW for seven days produce extensive myocardial lesions in horses. The horse dosed with 30 mg BFK/kg BW developed less severe, but similar myocardial lesions over a longer duration, this suggests that poisoning may be cumulative and lower doses of longer duration are also toxic. Horses seem to be uniquely sensitive to rayless goldenrod-induced myocardial disease, therefore cardiac troponin I may be a useful marker o

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Asteraceae; Benzofurans; Cardiomyopathies; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Histological Techniques; Horses; Ketones; Plant Poisoning; Southwestern United States; Troponin I

In the course of a search for new classes of hydrogen bonding catalysts, we have examined diarylacetylenediols as potential catalysts for the Diels-Alder reaction. General and efficient methods have been developed for the preparation of these diols. Their structures were systematically modified, and increased activity was observed for those possessing an electron-withdrawing group on the aryl groups. The electron-deficient diarylacetylenediol catalysts, while more active, undergo spontaneous cyclization to the corresponding benzo[b]furans. A mechanism is postulated to explain this facile transformation. Computational studies performed on 2-ethynylphenol help to explain the effect of the alkyne on the conformation and hydrogen bond donating ability of the adjacent OH group. Finally, the crystal structure of one of the diols is reported, and it displays an intricate network of intermolecular hydrogen bonds.

Topics: Acetylene; Benzofurans; Catalysis; Cyclization; Hydrogen Bonding; Molecular Structure; Phenols

A series of polysubstituted benzofuran derivatives was easily and rapidly prepared using a tandem Sonogashira coupling/cyclization reaction. Subsequent acylation afforded a small library of 39 new compounds that were assayed in cellulo on Plasmodium falciparum and Trypanosoma brucei parasites. Some of them exhibited good inhibitory activity on T. brucei proliferation.

Topics: Acylation; Antiprotozoal Agents; Benzofurans; Cyclization; Parasitic Sensitivity Tests; Plasmodium falciparum; Structure-Activity Relationship; Trypanosoma brucei brucei

Human microsomal cytochrome P450 (CYP) 2A6 contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. We prepared a series of benzofuran and coumarin derivatives that have inhibitory effects on the activity of human CYP2A6. The reported compounds methoxalen and menthofuran had potent inhibitory effects on the activity of CYP2A6 with IC50 values of 0.47 µM and 1.27 µM, respectively. Synthetic benzofuran (4-methoxybenzofuran: IC₅₀=2.20 µM) and coumarin (5-methoxycoumarin: IC₅₀=0.13 µM and 6-methoxycoumarin: IC₅₀=0.64 µM) derivatives, which have more selective effects than those of methoxalen and menthofuran, exhibited comparable activities against CYP2A6. These compounds can be used as a lead compounds in the design of CYP2A6 inhibitor drugs to reduce smoking and tobacco-related cancers.

Topics: Aryl Hydrocarbon Hydroxylases; Benzofurans; Coumarins; Cytochrome P-450 CYP2A6; Enzyme Inhibitors; Humans; Models, Chemical; Monoterpenes; Protein Binding

Benzofurazane has been attached to nucleosides and dNTPs, either directly or through an acetylene linker, as a new redox label for electrochemical analysis of nucleotide sequences. Primer extension incorporation of the benzofurazane-modified dNTPs by polymerases has been developed for the construction of labeled oligonucleotide probes. In combination with nitrophenyl and aminophenyl labels, we have successfully developed a three-potential coding of DNA bases and have explored the relevant electrochemical potentials. The combination of benzofurazane and nitrophenyl reducible labels has proved to be excellent for ratiometric analysis of nucleotide sequences and is suitable for bioanalytical applications.

Topics: Benzofurans; DNA; DNA-Directed DNA Polymerase; Electrochemical Techniques; Nucleosides; Oxidation-Reduction

A dihydroxyterphenylphosphine bearing cyclohexyl groups on the phosphorus atom (Cy-DHTP) was found to be a powerful ligand for the palladium-catalyzed one-pot synthesis of substituted benzo[b]furans from 2-chlorophenols and terminal alkynes. This catalyst system was also applicable to the sequential one-pot synthesis of disubstituted benzo[b]furans from dichlorophenols via the Suzuki-Miyaura cross-coupling of chlorobenzo[b]furan with boronic acids. The use of two ligands, Cy-DHTP and XPhos, is the key to promoting the reactions. Mechanistic studies suggest that the Pd-Cy-DHTP catalyst is the active species in the Sonogashira cross-coupling step, while the Pd-XPhos catalyst accelerates the Suzuki-Miyaura cross-coupling step.

Topics: Benzofurans; Catalysis; Chlorophenols; Molecular Structure; Organometallic Compounds; Organophosphorus Compounds; Palladium

A series of novel natural product like 2-substiuted-3H-benzofurobenzofurans designed by molecular hybridization were synthesized in very good yields. The key reactions involved in the synthesis are iodination of 2-dibenzofuranol using iodine monochloride followed by palladium-copper catalyzed Sonagashira-coupling of 1-iododibenzofuran-2-ol with various alkyl and aryl acetylenes. Among the all 10 new compounds screened for in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv, 2-(4-methoxy-2-methyl phenyl)-3H-benzofuro[3,2-e]benzofuran (7c) was found to be most active with MIC 3.12 μg/mL and has shown lower cytotoxicity with good therapeutic index.

Topics: Animals; Antitubercular Agents; Benzofurans; Catalysis; Copper; Drug Design; Heterocyclic Compounds, 4 or More Rings; Humans; Microbial Sensitivity Tests; Molecular Structure; Mycobacterium tuberculosis; Palladium; Structure-Activity Relationship

A series of different benzofuran-bisindole hybrids were synthesized and evaluated in vitro for their antioxidant and in vivo for antidyslipidemic activity in triton WR-1339 induced hyperlipidemic rats. Among the series, compounds 4a, 4c, 4h and 4j showed significant decrease in plasma levels of total cholesterol (TC), phospholipids (PL) and triglycerides (TG) followed by increase in post heparin lipolytic activity (PHLA). In addition, the active hybrids possessed moderate antioxidant properties and increased the plasma lecithin cholesterol acyltransferase (LCAT) activity, which plays a key role in lipoprotein metabolism contributing to an increased level of HDL-C in serum. These results indicate that these hybrids constitute novel prototypes for the management of dyslipidemia.

Topics: Animals; Antioxidants; Benzofurans; Cholesterol; Enzyme Activation; Hypolipidemic Agents; Indoles; Lipolysis; Male; Molecular Structure; Phosphatidylcholine-Sterol O-Acyltransferase; Phospholipids; Rats; Triglycerides

Lymphoid tyrosine phosphatase (LYP), encoded by the PTPN22 gene, has a critical negative regulatory role in T-cell antigen receptor (TCR) and emerged as a promising drug target for human autoimmune diseases. A five-point pharmacophore with two hydrogen bond acceptors, one hydrogen bond donor and two aromatic ring features was generated for a series of benzofuran salicylic acid derivatives as LYP inhibitors in order to elucidate their anti-autoimmune activity. The generated pharmacophore yielded a significant 3D-QSAR model with r(2) of 0.9146 for a training set of 27 compounds. The model also showed excellent predictive power with Q(2) of 0.7068 for a test set of eight compounds. The investigation of the 3D-QSAR model has revealed the structural insights which could lead to more potent analogues. The most active and inactive compounds were further subjected to electronic structure analysis using density functional theory (DFT) at B3LYP/3-21(∗)G level to support the 3D-QSAR predictions. The results obtained from this study are expected to be useful in the proficient design and development of benzofuran salicylic acid derivatives as inhibitors of LYP.

Topics: Benzofurans; Enzyme Inhibitors; Humans; Hydrogen Bonding; Models, Molecular; Protein Tyrosine Phosphatase, Non-Receptor Type 22; Quantitative Structure-Activity Relationship; Reproducibility of Results; Salicylic Acid; Static Electricity

Based on the structure activity relationship of 2-(4-phenoxybenzoyl)-5-hydroxyindole (1), a novel structural class of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) inhibitors were synthesized. We show in this study that the acidic proton at the N(1)-position of the indole moiety is not essential for CaMKII inhibitory activity. Among the synthesized compounds, we found the benzofuran and benzothiazole derivative as promising scaffolds for the developement of potent CaMKII inhibitors. In particular, compounds 8 and 14 inhibited CaMKII with IC₅₀ values of 24 nM and 32 nM, respectively.

Topics: Benzofurans; Benzothiazoles; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Indoles; Protein Binding; Protein Kinase Inhibitors; Structure-Activity Relationship

A novel series of 3-methyl-1-benzofuran derivatives were synthesized and screened in vitro for their antiproliferative activity against two human NSCLC cell lines (NSCLC-N6 mutant p53 and A549 wild type p53). Most promising compounds presented a structural analogy with the west part of cercosporamide, a natural product of biological interest. In particular, compounds 10, 12 and 31 showed cytotoxic activities at micromolar concentrations (IC₅₀ < 9.3 μM) and compounds 13, 18 and 32 displayed moderate IC₅₀ values (25-40 μM).

Topics: Antineoplastic Agents; Benzofurans; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Molecular Structure; Structure-Activity Relationship

Starting from benzofuran-2-methanal, 6-substituted benzothiazole-2-amines and malonic esters, sixteen title compounds were designed and synthesized seeking to introduce anti-TMV activity. The structures of the newly synthesized compounds were confirmed by 1H-NMR, 13C-NMR, IR spectra, and MS (HREI) analysis. The bioassays identified some of these new compounds as having moderate to good anti-TMV activity. The compounds 5i and 5m have good antiviral activity against TMV with a curative rate of 52.23% and 54.41%, respectively, at a concentration of 0.5 mg/mL.

Topics: Antiviral Agents; Benzofurans; Benzothiazoles; Malonates; Microbial Sensitivity Tests; Molecular Structure; Tobacco Mosaic Virus

Six new benzofuran neolignans (1-6) were isolated from the EtOAc-soluble fraction of the aerial part of Aristolochia fordiana, together with twelve known analogues (7-18). The structures of the isolated compounds were elucidated by spectroscopic methods. All isolates were evaluated for their inhibitory effects on nitric oxide production in lipopolysaccaride-activated RAW264.7 macrophages and for their cytotoxic activities on three human cancer cell lines. Compound 2 showed significant nitric oxide production inhibitory activity with an IC50 value of 10.00 µM, while compound 16 exhibited cytotoxic activity with an IC50 value of 11.9 µM against MG-63 and compound 18 of 9.15 µM against HepG2 cell lines, respectively.

Topics: Animals; Aristolochia; Benzofurans; Cell Line; Cell Line, Tumor; Cell Survival; Humans; Inhibitory Concentration 50; Lignans; Lipopolysaccharides; Macrophages; Mice; Molecular Structure; Nitric Oxide; Plant Extracts; Plants, Medicinal

A screening of metals, persistent organic pollutants, pharmaceuticals and personal care products (PPCPs), and other organic contaminants in sludge from seven Swedish sewage treatment plants (STPs) was performed in this study. This extensive screening provides information on mass flows of 282 compounds used in the Swedish society to sewage sludge. It reveals constant relative contaminant concentrations (ng mg kg(-1) d.w.), except for some pesticides and perfluorinated compounds, indicating that these originate from broad usage and diffuse dispersion rather than (industrial) point sources. There was a five order of magnitude difference in the sum concentrations of the most and least abundant species (metals and polychlorinated dibenzo-p-dioxins and -furans, respectively). Lower total concentrations were found in sludge from STPs processing primarily food industry or household sewage. Proportions of the amounts used (in Sweden) found in sludge were lower for compounds that are present in consumer goods or are diffusely dispersed into the environment (0.01-1% recovered in sludge) than for compounds used as detergents or PPCPs (17-63%). In some cases, the recovery seemed to be affected by evaporation (e.g. octamethylcyclotetrasiloxane) or biotransformation (e.g. adipates) losses, while polychlorinated alkanes and brominated diphenyl ethers were recovered to disproportionately high degree (ca. 4%); likely due to incomplete statistics for imported goods.

Topics: Benzofurans; Dioxins; Environmental Monitoring; Halogenated Diphenyl Ethers; Household Products; Metals; Pesticides; Sewage; Sweden; Waste Disposal, Fluid; Water Pollutants, Chemical; Water Pollution, Chemical

A general and practical method to synthesize 2-substituted benzofurans and indoles is described. This method employs easily accessible N-tosylhydrazones and o-hydroxy or o-amino phenylacetylenes as substrates. The reaction proceeds through a CuBr-catalyzed coupling-allenylation-cyclization sequence under ligand-free conditions.

Topics: Acetylene; Benzofurans; Catalysis; Copper; Hydrazones; Indoles; Molecular Structure

Leukotrienes (LT's) are known to play a physiological role in inflammatory immune response. Leukotriene A(4) hydrolase (LTA(4)H) is a cystolic enzyme that stereospecifically catalyzes the transformation of LTA(4) to LTB(4). LTB(4) is a known pro-inflammatory mediator. This paper describes the identification and synthesis of substituted benzofurans as LTH(4)H inhibitors. The benzofuran series demonstrated reduced mouse and human whole blood LTB(4) levels in vitro and led to the identification one analog for advanced profiling. Benzofuran 28 showed dose responsive target engagement and provides a useful tool to explore a LTA(4)H inhibitor for the treatment of inflammatory diseases, such as asthma and inflammatory bowel disease (IBD).

Topics: Animals; Benzofurans; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Inhibitory Concentration 50; Mice; Molecular Structure; Rats; Rats, Sprague-Dawley

Topics: Alcohols; Aldehydes; Benzofurans; Catalysis; Crystallography, X-Ray; Molecular Conformation; Oxygen; Stereoisomerism

The RAS-RAF-MEK-ERK pathway is hyperactivated in 30% of human cancers. BRAF is a serine-threonine kinase, belonging to this pathway that is mutated with high frequency in human melanoma and other cancers thus BRAF is an important therapeutic target in melanoma. We have designed inhibitors of BRAF based on 2,4,5-trisubstituted imidazoles with naphthyl and benzothiophene-4-substituents. Two compounds were discovered to be potent BRAF inhibitors: 1-(6-{2-[4-(2-dimethylamino-ethoxy)phenyl]-5-(pyridin-4-yl)-1H-imidazol-4-yl} benzo[b]thiophen-3-yl)-2,2,2-trifluoroethanol (1i) with BRAF IC(50)=190 nM and with cellular GI(50)=2100 nM, and 6-{2-[4-(2-dimethylamino-ethoxy)-phenyl]-5-pyridin-4-yl-3H-imidazol-4-yl}-naphthalen-1-ol (1q) with IC(50)=9 nM and GI(50)=220 nM.

Topics: Benzofurans; Cell Line, Tumor; Cell Survival; Humans; Imidazoles; Melanoma; Naphthols; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Structure-Activity Relationship; Thiophenes

Selective modulation of the peroxisome proliferator-activated receptor gamma (PPARγ) by direct binding of small molecules demonstrates a promising tool for treatment of insulin resistance and type 2 diabetes mellitus. Besides its blood pressure-lowering properties, the AT1-receptor blocker telmisartan has been shown to be a partial agonist of PPARγ with beneficial metabolic effects in vitro and in mice. In our previous work, comprehensive structure-activity relationship (SAR) studies discussed the different parts of the telmisartan structure and various moieties. Based on these findings, we designed and synthesized new PPARγ ligands with a benzimidazole (agonists 4-5 and 4-6), benzothiophene (agonists 5-5 and 5-6) or benzofuran (agonists 6-5 and 6-6) moiety either at position 5 or 6 of the benzimidazole core structure. Lipophilicity and EC50 values were improved for all new compounds compared with telmisartan. Regarding PPARγ activation, the compounds were characterized by a differentiation assay using 3T3-L1 cells and a luciferase assay with COS-7 cells transiently transfected with pGal4-hPPARgDEF, pGal5-TK-pGL3 and pRL-CMV. A decrease in both potency and efficacy was observed after the shift of either the benzothiophene or the benzofuran moiety from position 6 to position 5. Selective recruitment of the coactivators TRAP220, SRC-1 and PGC-1α, and release of corepressor NCoR1 determined by time-resolved fluorescence resonance energy transfer (TR-FRET) was detected depending on residues in position 5 or 6.

Topics: 3T3-L1 Cells; Animals; Benzimidazoles; Benzoates; Benzofurans; Chlorocebus aethiops; COS Cells; Diabetes Mellitus, Type 2; Humans; Ligands; Mice; PPAR gamma; Structure-Activity Relationship; Telmisartan; Thiophenes

A novel and efficient route for the synthesis of 2-(polyfluoroaryl)benzofurans via a copper(I)-catalyzed tandem reaction of 2-(2,2-dibromovinyl)phenol with polyfluoroarene is reported. The corresponding products are generated in good yields. During the reaction process, a copper-catalyzed intramolecular C-O bond formation and a C-H activation are involved.

Topics: Benzofurans; Bromine; Catalysis; Copper; Fluorine; Molecular Structure; Phenol; Vinyl Compounds

(±)-8-Deisopropyladunctin B, the deisopropyl form of adunctin B, which was isolated from the leaves of Piper aduncum (Piperaceae) collected in Papua New Guinea, was synthesized in 0.77% overall yield in 17 steps from 5,7-dimethoxycoumarin-3-carboxylate. The key step was our original stereoconvergent skeleton transformation from 1,2,2a,8b-tetrahydro-3H-benzo[b]cyclobuta[d]pyran-3-one to 1,2,4a,9b-tetrahydrodibenzofuran-4-ol with dimethylsulfoxonium methylide.

Topics: Benzofurans; Dicarboxylic Acids; Piper; Plant Leaves; Pyrans; Stereoisomerism; Sulfonium Compounds

The synthesis, characterization and photophysical properties of the tetra- {6-(-benzofuran-2-carboxylate)-hexylthio} substituted copper(II), cobalt(II), manganese(III) and zinc (II) phthalocyanines, {M[Pc(β-S(CH(2))(6)OCOBz-Furan)(4)], which were derived from 6-(3,4-dicyanophenylthio)-hexyl-2-benzofuranate (BzF) (1-4) are reported for the first time. The new compounds have been synthesized and fully characterized by elemental analysis, FTIR, UV-vis, (1)H- and (13)C NMR, MS (Maldi-TOF). In this work, we also report the effects of peripherally bound BzF substituent on the photophysical properties of metallo phthalocyanine derivatives. The effects of changing the central metal ions on quantum yield are discussed. It was found that the substitution of BzF groups on the framework of phthalocyanines diminished the fluorescence quantum yield of these complexes depending on paramagnetic behavior of central metal atoms. In addition, central metal atoms like Co and Cu also caused to decrease in quantum yield of phthalocyanine backbone.

Topics: Benzofurans; Cobalt; Copper; Fluorescent Dyes; Indoles; Isoindoles; Manganese; Metals; Spectrometry, Fluorescence; Zinc

Ailanthoidol is a benzofuran-type neolignan containing an alcoholic and a phenolic hydroxyl groups and can be synthesized following the description in a previous report. In this work, its antioxidant effect was estimated in the experimental system of 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH)-induced oxidation of DNA. It was found that ailanthoidol can scavenge 1.5 radicals in protecting DNA against AAPH-induced oxidation. Moreover, a benzyl group was used to etherize the phenolic hydroxyl group of ailanthoidol, resulting in the formation of (E)-2-(4'-benzyloxy-3'-methoxyphenyl)-5-(3″-hydroxypropenyl)-7-methoxybenzofuran (BBF). However, BBF cannot protect DNA against AAPH-induced oxidation. This result demonstrated that the alcoholic hydroxyl group cannot play the antioxidative role in protecting DNA. Furthermore, a ferrocenyl group was used to substitute the alcoholic hydroxyl group, leading to the formation of (E)-1-ferrocenyl-3-(2'-(4″-hydroxy-3″-methoxyphenyl)-7'-methoxybenzofuran-5'-yl)prop-2-en-1-one (FBF). FBF can scavenge 2.0 radicals in protecting DNA against AAPH-induced oxidation. This result indicated that the antioxidant ability of FBF was higher than that of ailanthoidol. Finally, FBF and ailanthoidol were applied to trap 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS(+.)). It was found that FBF can trap 1.92 ABTS(+.), while ailanthoidol can trap 1.58 ABTS(+.). Therefore, the modification of ailanthoidol by ferrocenyl group enhanced radical-scavenging and antioxidative ability of ailanthoidol.

Topics: Amidines; Antioxidants; Benzofurans; DNA; Ferrous Compounds; Free Radical Scavengers; Kinetics; Metallocenes; Oxidation-Reduction

In search for a new antioxidant and antimicrobial agent with improved potency, we synthesized a series of benzofuran based 1,3,5-substituted pyrazole analogues (5a-l) in five step reaction. Initially, o-alkyl derivative of salicyaldehyde readily furnish corresponding 2-acetyl benzofuran 2 in good yield, on treatment with 1,8-diaza bicyclo[5.4.0]undec-7-ene (DBU) in the presence of molecular sieves. Further, aldol condensation with vanillin, Claisen-Schmidt condensation reaction with hydrazine hydrate followed by coupling of substituted anilines afforded target compounds. The structures of newly synthesized compounds were confirmed by IR, (1)H NMR, (13)C NMR, mass, elemental analysis and further screened for their antioxidant and antimicrobial activities. Among the tested compounds 5d and 5f exhibited good antioxidant property with 50% inhibitory concentration higher than that of reference while compounds 5h and 5l exhibited good antimicrobial activity at concentration 1.0 and 0.5 mg/mL compared with standard, streptomycin and fluconazole respectively.

Topics: Anti-Infective Agents; Antioxidants; Benzofurans; Biocompatible Materials; Microbial Viability; Molecular Structure; Pyrazoles; Structure-Activity Relationship

A new prenylated benzofuran derivative, named flemiphilippinone A, was isolated together with ten known flavonoids from the roots of Flemingia philippinensis. Flemiphilippinone A was identified as (2S,3aS)-5-(1-hydroxy-3-(4-methoxyphenyl)-propylidene)-2-(2-hydroxypropan-2-yl)-3a,7-bis(3-methylbut-2-en-1-yl)tetrahydrobenzofuran-4,6(2H,5H)-dione, and its structure was established by a combination of HR EIMS, ¹H-NMR, ¹³C-NMR, HMQC, HMBC and NOESY spectra data.

Topics: Benzofurans; Fabaceae; Magnetic Resonance Spectroscopy

Transmembrane protein 16A (TMEM16A) channels are recently discovered membrane proteins that functions as a calcium activated chloride channel (CaCC). CaCCs are major regulators of various physiological processes, such as sensory transduction, epithelial secretion, smooth muscle contraction and oocyte fertilization. Thirty novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids (B01-B30) were synthesized and evaluated for their TMEM16A inhibitory activity by using short circuit current measurements in Fischer rat thyroid (FRT) cells expressing human TMEM16A. IC(50) values were calculated using YFP fluorescence plate reader assay. Final compounds, having free carboxylic group displayed significant inhibition. Eight of the novel compounds B02, B13, B21, B23, B25, B27, B28, B29 exhibit excellent CaCCs inhibition with IC(50) value <6 μM, with compound B25 exhibiting the lowest IC(50) value of 2.8 ± 1.3 μM. None of the tested ester analogs of final benzofuran derivatives displayed TMEM16A/CaCCs inhibition.

Topics: Animals; Anoctamin-1; Benzofurans; Calcium; Carboxylic Acids; Cell Line; Chloride Channels; Humans; Membrane Potentials; Neoplasm Proteins; Rats; Structure-Activity Relationship

2-Substituted benzo[b]furans were synthesized by a one-step metal-free photochemical reaction between 2-chlorophenol derivatives and terminal alkynes by tandem formation of an aryl-C and a C-O bond via an aryl cation intermediate. The mild conditions and the application to chlorophenols rather of the more expensive bromo or iodo analogues makes this procedure environmentally convenient.

Topics: Benzofurans; Molecular Structure; Photochemical Processes; Quantum Theory

Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.

Topics: Animals; Antiviral Agents; Benzofurans; Enzyme Inhibitors; Furans; Half-Life; Hepacivirus; Liver; Pyrimidine Nucleosides; Pyrimidines; Rats; RNA-Dependent RNA Polymerase; Structure-Activity Relationship; Virus Replication

Enzymatic cis-dihydroxylation of benzo[b]thiophene, benzo[b]furan and several methyl substituted derivatives was found to occur in both the carbocyclic and heterocyclic rings. Relative and absolute configurations and enantiopurities of the resulting dihydrodiols were determined. Hydrogenation of the alkene bond in carbocyclic cis-dihydrodiols and ring-opening epimerization/reduction reactions of heterocyclic cis/trans-dihydrodiols were also studied. The relatively stable heterocyclic dihydrodiols of benzo[b]thiophene and benzo[b]furan showed a strong preference for the trans configuration in aqueous solutions. The 2,3-dihydrodiol metabolite of benzo[b]thiophene was utilized as a precursor in the chemoenzymatic synthesis of the unstable arene oxide, benzo[b]thiophene 2,3-oxide.

Topics: Benzofurans; Biocatalysis; Crystallography, X-Ray; Hydroxylation; Models, Molecular; Molecular Structure; Oxygenases; Stereoisomerism; Thiophenes

A novel series of combretastatin A-4 heterocyclic analogues was prepared by replacement of the B ring with indole, benzofurane or benzothiophene, attached at the C2 position. These compounds were evaluated for their abilities to inhibit tubulin assembly: derivative cis3b, having a benzothiophene, showed an activity similar to those of colchicine or deoxypodophyllotoxine. The antiproliferative and antimitotic properties of cis3b against keratinocyte cancer cell lines were also evaluated and the intracellular organization of microtubules in the cells after treatment with both stereoisomers of 3b was also determined, using confocal microscopy.

Topics: Antimitotic Agents; Benzofurans; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colchicine; Heterocyclic Compounds; Humans; Indoles; Microscopy, Confocal; Microtubules; Stereoisomerism; Stilbenes; Thiophenes

The reaction of copper(I) iodide with 6-n-propylthiouracil (ptu) in the presence or absence of the triphenylphosphine (tpp) or tri(p-tolyl)phosphine (tptp) in a 1:1:2 molar ratio forms the mixed ligand Cu(I) complex with formula [CuI(ptu)2](toluene) (1), [CuI(tpp)2(ptu)] (2), and [CuI(tptp)2(ptu)] (3). The complexes have been characterized by FT-IR, (1)H NMR, UV-vis, spectroscopic techniques, and single crystal X-ray crystallography. Two sulfur atoms from two ptu ligands and one iodide form a trigonal geometry around the metal center in 1. Intramolecular interactions through hydrogen bonds lead to a bend ribbon polymeric supramolecular architecture with zigzag conformation. Two phosphorus atoms from two arylphosphines, one sulfur atom, and one iodide anion form a tetrahedron around the copper ion in case of 2 and 3. Intramolecular hydrogen bonding interactions lead to dimerization. Complexes 1-3 and the already known ones with formulas, [(tpSb)2Cu(μ2-I)2Cu(tpSb)2] (4) (tbSb = triphenylstibine), [(tpp)Cu(μ2-I)2Cu(tpp)2] (5), [(tpp)Cu(μ2-Cl)2Cu(tpp)2] (6), [CuCl(tpp)3·(CH3CN)] (7), and [AuCl(tpp)] (8), were used to study their catalytic activity on the intermolecular cycloaddition of iodonium ylides toward benzo[b]furans formation. The results show that both the metal and the ligand type affect the catalytic affinity of the complexes. The highest yield of benzo[b]furan was derived when complexes 2, 3, and 4 were used as catalysts. The mechanism of the Cu(I)-catalyzed and uncatalyzed intramolecular cycloaddition of iodonium ylide has been also thoroughly explored by means of ab initio electronic structure calculation methods, and the results are compared with the experimental ones.

Topics: Antithyroid Agents; Benzofurans; Catalysis; Copper; Crystallography, X-Ray; Cyclization; Iodides; Iodine; Models, Molecular; Molecular Structure; Organometallic Compounds; Pharmaceutical Preparations; Quantum Theory; Thiourea

An efficient three-step approach was developed to assemble indole- or benzofuran-fused benzocarbazole-1,4-diones in 42-53% overall yield. This approach includes AgOAc-promoted oxidative cyclization of 2,6-di-bromocyclohexene-1,4-dione with indol-3-ylpropanoid acid, condensation of the resulting bromocarbazole intermediates with phenols or anilines, followed by Pd(OAc)-catalyzed cyclization. Such convenient synthetic protocol and the novelty of the corresponding products will largely assist our drug design and development program.

Topics: Benzofurans; Carbazoles; Catalysis; Cyclization; Indoles

This perspective reports on some of the main copper-catalyzed routes to the construction of the pyrrole and furan rings incorporated into the indole and benzo[b]furan systems, respectively. The first part illustrates the synthesis of indoles through cyclizations of 2-alkynylanilid(n)es, preformed or generated in situ, and cyclizations via intramolecular N-arylation, N-vinylation, and C-C bond forming reactions. The second part illustrates the synthesis of benzo[b]furans through cyclizations of preformed 2-alkynylphenols, domino synthesis of 2-alkynylphenols/cyclization processes, and cyclizations via intramolecular O-arylation reactions.

Topics: Benzofurans; Catalysis; Copper; Indoles; Ligands

In contrast to the reaction of benzoquinones with β-enaminoesters providing indoles (Nenitzescu reaction), the tandem one-pot reaction of the Blaise reaction intermediate, zinc bromide complex of β-enaminoesters, with benzoquinone affords 5-hydroxy-α-(aminomethylene)benzofuran-2(3H)-ones in good to excellent yields (tandem Blaise-Nenitzescu reaction).

Topics: Amines; Benzofurans; Hydroxylation; Molecular Structure; Nitriles

Topics: Alkenes; Benzofurans; Catalysis; Cyclization; Furans; Mesylates; Naphthols; Phenol

Laccase-catalyzed oxidation of substituted catechols followed by reaction with 4-hydroxy-pyrone/-benzopyrone afforded substituted benzofuran regioisomers whose structures with only two aromatic protons in total prevent a rapid structural assignment. Based on the evaluation of (1)H-(13)C long-range coupling constants a rule of thumb could be deduced for an easy and unambiguous differentiation between the possible regioisomers formed. DFT frontier orbital calculations of the reactants offer an interesting tool to explain the regioselectivity of the key reaction.

Topics: Benzofurans; Biocatalysis; Fourier Analysis; Laccase; Magnetic Resonance Spectroscopy; Molecular Structure; Oxidation-Reduction; Phenols; Protons; Stereoisomerism; Time Factors; Trametes

Ras proteins are small GTPases (G-proteins) that play a key role in cell growth and cell proliferation in the mitogen-activated protein kinase signal transduction pathway. Farnesylation is a critical step for membrane binding and the biological function of G-proteins. In the present investigation, we have studied the structural features of some molecules that are acting on the farnesyltransferase (FTase) enzyme for the inhibition of the farnesylation step in G-proteins. The benzofuran derivatives have activity against FTase inhibition and antiproliferative activity on QG56 cell lines. The result obtained from the quantitative structure-activity relationship study of these compounds shows that the models have significant predictive power and stability, as shown by statistical parameters such as R(2), Q(2), R(2)(pred), R(2)(m), F-value, Durbin-Watson, variable inflation factor values, Mahalanobis, and Cook's distances. The contribution of each descriptor for the activities (β-coefficients) reveals that the P-VSA descriptors (van der Waals surface area descriptors) such as vsa_pol, vsa_acc and SMR_VSA3 are the major contributors for the activity, along with other descriptors such as the partition coefficient, the partial charge, the atom and bond count and the adjacency, and distance descriptors. Earlier study on the FTase enzyme in our laboratory reveals that the existence of positively-charged groups on the FTase active site is important for drug design. It is also showing that the presence of hydrogen bonding donor and acceptor groups, together with negatively charged substituents is critical for improved activity by this series of molecules. These results offer important clues for the development of novel FTase inhibitors.

Topics: Benzofurans; Enzyme Inhibitors; Farnesyltranstransferase; Models, Molecular; Molecular Structure; Quantitative Structure-Activity Relationship

The performance of recently reported highly cis-diastereoselective Rh(I) cyclopropanation catalysts has been significantly improved by a systematic study of different reaction parameters (catalyst activation, solvent, temperature, stoichiometry). The catalyst efficiency and diastereoselectivity were enhanced by changing the activating agent from AgOTf to NaBArf. With this new system, the Rh(I) catalyst was shown to be a highly efficient and cis-diastereoselective cyclopropanation catalyst in reactions between α-diazoacetates and a range of different alkenes and substituted derivatives. Particularly noteworthy is the remarkable reactivity and cis-diastereoselectivity displayed in the reactions between ethyl diazoacetate and cyclopentene, 2,5-dihydrofuran, and benzofuran, with yields up to 99% and cis-selectivities greater than 99%.

Topics: Alkenes; Anti-Infective Agents; Antineoplastic Agents; Benzofurans; Catalysis; Cyclization; Cyclopentanes; Cyclopropanes; Diazonium Compounds; Models, Molecular; Molecular Structure; Rhodium; Solvents; Stereoisomerism; Temperature

A facile synthesis of 4-indole benzofurans from the one-pot reaction of 4-alkyl-2-ynylphenols and indoles via a hypervalent iodine-induced oxidative dearomatization, a silver-catalyzed cascade Michael addition-annulation, and an aromatization is reported.

Topics: Benzofurans; Catalysis; Oxidation-Reduction; Phenols; Silver

In this paper, a novel and applicable synthesis of benzofurans from commercially available phenols and propiolate through the direct oxidative cyclization has been developed. In the presence of Pd(OAc)(2)/PPh(3) and CF(3)CO(2)Ag, (E)-type 3-phenoxyacrylates underwent reaction smoothly to generate the corresponding benzofurans in good yields in benzene at 110 °C under the air pressure. In addition, this transformation of phenols into benzofurans can also be carried out in one pot. The process was simple and efficient. A tentative mechanism of palladium-catalyzed oxidative cyclization of 3-phenoxyacrylates was proposed.

Topics: Acrylates; Benzofurans; Catalysis; Cyclization; Oxidation-Reduction; Palladium; Phenols

Topics: Alkynes; Benzofurans; Catalysis; Crystallography, X-Ray; Cyclization; Gold; Methane; Molecular Conformation; Silanes

Topics: Amination; Benzofurans; Catalysis; Crystallography, X-Ray; Molecular Conformation; Naphthols; Organophosphorus Compounds; Stereoisomerism

A series of benzofuran-2-yl(phenyl)methanone derivatives were synthesized and evaluated as novel probes for β-amyloid plaques. These derivatives were produced by a Rap-Stoermer condensation reaction. Compounds with a N,N-dimethylamino group displayed high affinity for Aβ(1-42) aggregates with K(i) values in the nanomolar range. Autoradiography with brain sections of AD model mice (APP/PS1) revealed that a radioiodinated probe, [(125)I]10, labeled β-amyloid plaques selectively and displayed good brain uptake (3.53% ID/g) at 2 min. The results suggest that benzofuran-2-yl(phenyl)methanone derivatives should be investigated further as potential probes for detecting β-amyloid plaques in the AD brain.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Autoradiography; Benzofurans; Brain; Iodine Radioisotopes; Ligands; Mice; Peptide Fragments; Plaque, Amyloid; Protein Binding; Radionuclide Imaging; Radiopharmaceuticals; Tissue Distribution

We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Cell Line; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Pain; Rats; Receptors, Prostaglandin E, EP1 Subtype; Structure-Activity Relationship

The central portion of purpuromycin has been assembled via a classical spiroketalization reaction. Key to promoting this reaction mode versus benzofuran formation was the oxidation state of the spiroketal core. With a higher oxidation state, even the electron-deficient isocoumarin found in purpuromycin could be employed directly in the spiroketalization. The two halves of the spiroketalization precursor were joined via a nitrile oxide/styrene 1,3-dipolar cycloaddition. A very mild selenium dioxide oxidation was used to introduce the required oxidation state of the spiroketal core.

Topics: Benzofurans; Cyclization; Furans; Ketones; Molecular Structure; Naphthoquinones; Oxidation-Reduction; Spiro Compounds

Selective inhibitors of human peptide deformylase (HsPDF) are predicted to constitute a new class of antitumor agents. We report the identification of benzofuran-4,5-diones as the first known selective HsPDF inhibitors and we describe their selectivity profile in a panel of metalloproteases. We characterize their structure-activity relationships for antitumor activity in a panel of cancer cell lines, and we assess their in vivo efficacy in a mouse xenograft model. Our results demonstrate that selective HsPDF inhibitors based on the benzofuran-4,5-dione scaffold constitute a novel class of antitumor agents that are potent in vitro and in vivo.

Topics: Amidohydrolases; Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Humans; Hydroxamic Acids; Metalloproteases; Mice; Mice, Nude; Neoplasms; Structure-Activity Relationship; Transplantation, Heterologous

Divergent route: a direct C-C bond-forming approach to the key aryl-substituted all-carbon quaternary stereogenic center present in bioactive hydrodibenzofuran alkaloids has been discovered. This approach involves an unprecedented organocatalytic enantioselective Michael addition of α-cyanoketones with acrylates and was used in a novel and divergent synthetic strategy for the title compounds in asymmetric fashion.

Topics: Alkaloids; Amaryllidaceae Alkaloids; Benzofurans; Brassicaceae; Carbon; Catalysis; Cyclization; Galantamine; Liliaceae; Spermidine; Stereoisomerism

Protein kinase CK2 is emerging as a target in neoplastic diseases. Inhibition of CK2 by small compounds could lead to new therapies by counteracting the elevated CK2 activities found in a variety of tumors. Currently, CK2 inhibitors are primarily evaluated by a radiometric in vitro assay tracing the amount of transferred γ-(32)P from ATP to a substrate peptide. Here, we present two alternative assays abandoning radioisotopes. The first assay is based on Förster resonance energy transfer between the fluorescence donor EDANS and the acceptor molecule DABCYL within the CK2 substrate peptide [DABCYL]-RRRDDDSDDD-[EDANS]. This peptide comprises a cleavage site for pancreatic elastase, which is located next to the phosphate acceptor serine. Only the non-phosphorylated peptide can be cleaved by elastase, disrupting the FRET effect. Thus fluorescence intensity is inversely correlated with CK2 activity. The second non-radiometric assay deploys the changing of charge that occurs within the peptide substrate RRRDDDSDDD upon phosphorylation by CK2. Substrate and product of a CK2 reaction consequently show a difference in electrophoretic mobility and thus can be separated by capillary electrophoresis. Absorption detection enabled quantification of both peptide species and allowed the determination of IC(50) values. This method facilitated the testing of a small compound library by which benzofuran derivatives were identified as potent CK2 inhibitors with IC(50) values in the submicromolar range.

Topics: Amino Acid Sequence; Animals; Benzofurans; Biological Assay; Casein Kinase II; Drug Evaluation, Preclinical; Electrophoresis, Capillary; Fluorescence Resonance Energy Transfer; Holoenzymes; Humans; Molecular Sequence Data; Peptides; Protein Kinase Inhibitors; Radiometry; Recombinant Proteins; Substrate Specificity; Sus scrofa

A new arylbenzofuran, 3',5'-dihydroxy-6-methoxy-7-prenyl-2-arylbenzofuran (1), and 25 known compounds, including moracin R (2), moracin C (3), moracin O (4), moracin P (5), artoindonesianin O (6), moracin D (7), alabafuran A (8), mulberrofuran L (9), mulberrofuran Y (10), kuwanon A (11), kuwanon C (12), kuwanon T (13), morusin (14), kuwanon E (15), sanggenon F (16), betulinic acid (17), uvaol (18), ursolic acid (19), β-sitosterol (20), oxyresveratrol 2-O-β-D-glucopyranoside (21), mulberroside A (22), mulberroside B (23), 5,7-dihydroxycoumarin 7-O-β-D-glucopyranoside (24), 5,7-dihydroxycoumarin 7-O-β-D-apiofuranosyl-(1→6)-O-β-D-glucopyranoside (25) and adenosine (26), were isolated from Morus alba var. multicaulis Perro. (Moraceae). Their structures were determined by spectroscopic methods. The prenyl-flavonoids 11-14, 16, triterpenoids 17,18 and 20 showed significant inhibitory activity towards the differentiation of 3T3-L1 adipocytes. The arylbenzofurans 1-10 and prenyl-flavonoids 11-16 also showed significant nitric oxide (NO) production inhibitory effects in RAW264.7 cells.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Benzofurans; Cell Differentiation; Cell Line; Flavonoids; Macrophages; Magnetic Resonance Spectroscopy; Mice; Molecular Structure; Morus; Nitric Oxide; Plant Extracts

Induction of apoptosis is a promising strategy that could lead to the discovery of new molecules active in cancer chemotherapy. This property is generally observed when cells are treated with agents that target microtubules, dynamic structures that play a crucial role in cell division. Small molecules such as benzo[b]furans are attractive as inhibitors of tubulin polymerization. A new class of inhibitors of tubulin polymerization based on the 2-(3',4',5'-trimethoxybenzoyl)benzo[b]furan molecular skeleton, with the amino group placed at different positions on the benzene ring, were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell-cycle effects. The methoxy substitution pattern on the benzene portion of the benzo[b]furan moiety played an important role in affecting antiproliferative activity. In the series of 5-amino derivatives, the greatest inhibition of cell growth occurred if the methoxy substituent is placed at the C6 position, whereas C7 substitution decreases potency. The most promising compound in this series is 2-(3',4',5'-trimethoxybenzoyl)-3-methyl-5-amino-6-methoxybenzo[b]furan (3 h), which inhibits cancer cell growth at nanomolar concentrations (IC(50) =16-24 nM), and interacts strongly with tubulin by binding to the colchicine site. Sub-G(1) apoptotic cells in cultures of HL-60 and U937 cells were observed by flow cytometric analysis after treatment with 3 h in a concentration-dependent manner. We also show that compound 3 h induces apoptosis by activation of caspase-3, -8, and -9, and this is associated with cytochrome c release from mitochondria. The introduction of an α-bromoacryloyl group increased antiproliferative activity with respect to the parent amino derivatives.

Topics: Animals; Anisoles; Antineoplastic Agents; Apoptosis; Benzofurans; Binding Sites; Caspases; Cell Cycle Checkpoints; Cell Line, Tumor; Colchicine; Humans; Mice; Neoplasms; Tubulin; Tubulin Modulators

From the water-soluble portion of the methanol extract of stems of Ficus tikoua Bur., a new benzofuran glucoside, named 6-carboxyethyl-5-hydroxybenzofuran 5-O-β-d-glucopyranoside (1), together with one known benzofuran glucoside (2) were isolated. Their structures were elucidated by 1D and 2D ((1)H-(1)H COSY, HMQC, and HMBC) NMR spectroscopy and HRMS techniques. The antioxidant activities of the isolated compounds were assayed based on the scavenging activities of DPPH free radical. Compounds 1 and 2 exhibited moderate antioxidant activities, and the IC(50) values were 242.8 μg·mL(-1) and 324.9 μg·mL(-1), respectively.

Topics: Antioxidants; Benzofurans; Ficus; Free Radicals; Glucosides; Nuclear Magnetic Resonance, Biomolecular; Plant Extracts

The concentration quenching threshold of upconversion luminescence was broken through for the first time via a designed strategy: spatial separation of the emitter doping area.

Topics: Benzofurans; Erbium; Fluorescence Resonance Energy Transfer; Fluorides; Nanoparticles; Spectrometry, Fluorescence; Yttrium

Ivermectin is an anthelmintic drug that works by activating glutamate-gated chloride channel receptors (GluClRs) in nematode parasites. GluClRs belong to the Cys-loop receptor family that also includes glycine receptor (GlyR) chloride channels. GluClRs and A288G mutant GlyRs are both activated by low nanomolar ivermectin concentrations. The crystal structure of the Caenorhabditis elegans α GluClR complexed with ivermectin has recently been published. Here, we probed ivermectin sensitivity determinants on the α1 GlyR using site-directed mutagenesis and electrophysiology. Based on a mutagenesis screen of transmembrane residues, we identified Ala288 and Pro230 as crucial sensitivity determinants. A comparison of the actions of selamectin and ivermectin suggested the benzofuran C05-OH was required for high efficacy. When taken together with docking simulations, these results supported a GlyR ivermectin binding orientation similar to that seen in the GluClR crystal structure. However, whereas the crystal structure shows that ivermectin interacts with the α GluClR via H-bonds with Leu218, Ser260, and Thr285 (α GluClR numbering), our data indicate that H-bonds with residues homologous to Ser260 and Thr285 are not important for high ivermectin sensitivity or direct agonist efficacy in A288G α1 GlyRs or three other GluClRs. Our data also suggest that van der Waals interactions between the ivermectin disaccharide and GlyR M2-M3 loop residues are unimportant for high ivermectin sensitivity. Thus, although our results corroborate the ivermectin binding orientation as revealed by the crystal structure, they demonstrate that some of the binding interactions revealed by this structure do not pertain to other highly ivermectin-sensitive Cys-loop receptors.

Topics: Animals; Antiparasitic Agents; Benzofurans; Caenorhabditis elegans; Chloride Channels; Crystallography, X-Ray; Cysteine; Electrophysiology; Glycine; Hydrogen Bonding; Ivermectin; Mutagenesis, Site-Directed; Mutation; Receptors, Glycine

Several benzofuran derivatives linked to a 3-indoletetrahydropyridine through an alkyl chain were prepared and evaluated for serotonin transporter and 5-HT(1A) receptor affinities. Their design, synthesis and structure-activity relationships are described.

Topics: Animals; Benzofurans; CHO Cells; Cricetinae; Cricetulus; Humans; Protein Binding; Receptor, Serotonin, 5-HT1A; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship

A new and efficient route to the recently reported 3-nitro-2-ethyldibenzofuran caging group was developed. Furthermore, its installation on a thymidine phosphoramidite is described. This caging group is efficiently removed through light-irradiation at 365 nm.

Topics: Benzofurans; DNA; Organophosphorus Compounds; Photons; Thymidine Monophosphate

A novel coumarin (1, mucodianin A), three new 2-arylbenzofurans (2-4, mucodianins B-D) along with four known ones were isolated from the vine stems of Mucuna birdwoodiana. Their structures were elucidated on basis of spectral analysis. This is the first report of 7-quinonylcoumarin (1) as stable form in natural products.

Topics: Benzofurans; Coumarins; Molecular Structure; Mucuna; Plant Stems

(5-(1H-benzo[d]imidazol-2-yl)-1H-pyrrol-3-yl)(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)methanone (4) and 3-(6-hydroxy-4,7-dimethoxybenzofuran-5-carbonyl)-6H-pyrimido[1,6-a]pyrimidine-6,8(7H)-dione (5) were synthesized by the reaction of 4,7-dimethoxy-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehyde (1) with (1H-benzo[d]imidazol-2-yl)methanamine dihydrochloride and 4-amino-2,6-dihydroxypyrimidine, respectively, via ROR in the presence of alcoholic KOH. The metal complexes 6-9 of compound 4; H(2)L(1) with (CuCl(2), FeCl(3), ZnCl(2), and LaCl(3)) and the metal complexes 10-13 of compound 5; H(2)L(2) with (CuCl(2), FeCl(3), CoCl(2) and LaCl(3)) were synthesized to form 1:1 or 1:2 (metal: ligand) complexes. The HIV inhibitory activity of all new compounds was tested. The EC(50) values showed that, all of tested compounds were more potent than Atevirdine. Moreover, the benzoimidazolylpyrrole derivative 4 (EC(50)=9x10(-6)muM) had higher therapeutic index than the standard. The HIV-1 RT inhibitory activity showed that all of the tested compounds showed significant potency but none of them showed higher activity than Atevirdine. The HCV NS3-4A protease inhibitor activity of the tested compounds revealed that the complex formation had great positive effect on the bioactivity, where the Fe-complex 7 was the most potent compound with higher therapeutic index than VX-950, the standard. Also, the cytotoxicity of the synthesized compounds on hepatocyte cell line, showed that Cu-complex 10 was the most potent compound with potency nearly to that of the standard.

Topics: Antiviral Agents; Benzofurans; Drug Design; Hep G2 Cells; Hepacivirus; HIV; HIV Reverse Transcriptase; Humans; Hydroxides; Lethal Dose 50; Ligands; Models, Molecular; Nitrogen; Organometallic Compounds; Oxidation-Reduction; Protease Inhibitors; Protein Conformation; Reverse Transcriptase Inhibitors; Spectrum Analysis; Transition Elements

Five new 2-arylbenzofuran derivatives wittifurans A-C, F and G (1-5) have been isolated from the stem bark of Morus wittiorum. Their structures were determined on the basis of spectroscopic analysis. Compounds 1, 3-5 were evaluated for their antioxidant and anti-inflammatory activities respectively.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Benzofurans; Glucuronidase; Leukocytes; Lipid Peroxidation; Microsomes, Liver; Molecular Structure; Morus; Plant Bark; Rats

A series of indole, 7-azaindole, benzofuran, and benzothiophene compounds have been prepared and evaluated for affinity at D2-like dopamine receptors. These compounds share structural elements with the classical D2-like dopamine receptor antagonists haloperidol, N-methylspiperone and benperidol. Two new compounds, 4-(4-iodophenyl)-1-((4-methoxy-1H-indol-3-yl)methyl)piperidin-4-ol (6) and 4-(4-iodophenyl)-1-((5-methoxy-1H-indol-3-yl)methyl)piperidin-4-ol (7), were found to have high affinity to and selectivity for D2 versus D3 receptors. Changing the aromatic ring system from an indole to other heteroaromatic ring systems reduced the D2 binding affinity and the D2 versus D3 selectivity.

Topics: Adenylyl Cyclases; Benzofurans; Cell Line; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Indoles; Protein Binding; Receptors, Dopamine D2; Thiophenes

Benzofuran-substituted urea analogs have been identified as novel P2Y(1) receptor antagonists. Structure-activity relationship studies around the urea and the benzofuran moieties resulted in compounds having improved potency. Several analogs were shown to inhibit ADP-mediated platelet activation.

Topics: Benzofurans; Platelet Activation; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y1; Urea

Twenty-eight newer 3-benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone and 3-benzofuran-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin analogs were synthesized by microwave irradiation method and evaluated for in-vitro and in-vivo antitubercular activity against multidrug-resistant M. tuberculosis stains. Structure-activity relationship study was carried out and found NO(2) (o) substituted 3-benzofuran-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin was most potent antitubercular agent against M. tuberculosis, even better than standard drug isoniazid and comparable with rifampin. Other synthesized compounds 7j, 7f, 7a, 7e and 5d, 5f were found moderate to good activity in in-vitro model at lower IC(50) values 85 microM, 154 microM, 157 microM, 164 microM, 170 microM and 190 microML respectively. In in-vivo animal model compound 7j was drastically reduced the bacterial load in lung and spleen tissues at the dose of 25 mg/kg body weight.

Topics: Animals; Antitubercular Agents; Benzofurans; Chlorocebus aethiops; Drug Design; Drug Resistance, Multiple; Mice; Microbial Sensitivity Tests; Mycobacterium tuberculosis; Structure-Activity Relationship; Vero Cells

A catalyst composed of Pd and hydroxyterphenylphosphine was found to be effective for one-pot benzo[b]furan synthesis from 2-chlorophenols and alkynes.

Topics: Benzofurans; Catalysis; Chlorophenols; Magnetic Resonance Spectroscopy; Palladium

A potential probe for PET targeting β-amyloid plaques in Alzheimer's disease (AD) brain, FPYBF-1 (5-(5-(2-(2-(2-fluoroethoxy)ethoxy)ethoxy)benzofuran-2-yl)-N,N-dimethylpyridin-2-amine), was synthesized and evaluated. In experiments in vitro, FPYBF-1 displayed high affinity for Aβ(1-42) aggregates (K(i)=0.9 nM), and substantial labeling of β-amyloid plaques in sections of postmortem AD brains but not control brains. In experiments in vivo, [(18)F]FPYBF-1 displayed good initial uptake (5.16%ID/g at 2 min postinjection) and rapid washout from the brain (2.44%ID/g at 60 min postinjection) in normal mice, and excellent binding to β-amyloid plaques in a murine model of AD. Furthermore, the specific labeling of plaques labeling was observed in autoradiographs of autopsied AD brain sections. [(18)F]FPYBF-1 may be a useful probe for imaging β-amyloid plaques in living brain tissue.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Autopsy; Autoradiography; Benzofurans; Brain; Fluorine Radioisotopes; Humans; Male; Mice; Mice, Transgenic; Plaque, Amyloid; Positron-Emission Tomography; Radiopharmaceuticals

Several series of benzofurans, benzothiophenes, and benzothiazoles, all featuring the thioamide group, were synthesized and tested as novel K(ATP) channel openers in artificial cell systems: CHO cells transfected with SUR1/Kir6.2, and HEK 293 cells transfected with SUR2B/Kir6.1; these served as model systems for insulin-secreting pancreatic β cells and smooth muscle cells, respectively. All compounds were investigated with respect to their binding affinity for the SUR2B-type K(ATP) channels using [(3)H]P1075 as radioligand. Selected compounds were also tested as agonists in intact cells using DiBAC(4)(3) and DyeB (R7260) as membrane potential dyes. Remarkable affinity for SUR2B/Kir6.1 channels in the single-digit micromolar range was observed. In addition, benzothiazole-derived thioamides with sterically demanding, lipophilic substituents showed >100-fold selectivity in favor of SUR2B/Kir6.1. A one-carbon spacer between the heterocyclic skeleton and the thioamide moiety was observed to be crucial for affinity and selectivity. Two of the most potent and selective compounds were studied by crystal structure analyses.

Topics: Animals; Benzofurans; Benzothiazoles; Binding Sites; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; HEK293 Cells; Humans; KATP Channels; Molecular Conformation; Potassium Channels, Inwardly Rectifying; Structure-Activity Relationship; Thioamides; Thiophenes

The electronic structures of a homologous series of indole and benzofuran derivatives, in which the nitrogen or oxygen atom is replaced by group 15 and group 16 heavier heteroatoms, have been investigated by means of various spectroscopic techniques coupled with density functional calculations. It was found that the excitation energies of the group 16 benzoheteroles systematically shift to the red in the order of benzofuran (6), benzothiophene (7), benzoselenophene (8), and benzotellurophene (9). In contrast, the electronic absorption spectra of the group 15 benzoheteroles, 1-phenyl derivatives of indole (1b), phosphindole (2b), arsindole (3b), stibindole (4b), and bismuindole (5b), did not exhibit this type of spectral shift. X-ray analysis and density functional theory (DFT) studies revealed that 2b-5b adopt a bent conformation both in the crystalline and in the solution phases. In contrast, planar structures were calculated for the group 16 heterocycles. Using the observed spectroscopic properties and time-dependent density functional theory (TDDFT) calculations, the electronic absorption spectra of the present heterocycles were assigned. A molecular orbital analysis was performed to rationalize the effect of replacement of the heteroatom on the electronic structures. The observed magnetic circular dichroism (MCD) sign patterns of these heterocycles are interpreted according to Michl's perimeter model.

Topics: Absorption; Benzofurans; Circular Dichroism; Crystallography, X-Ray; Electrons; Indoles; Magnetics; Quantum Theory; Time Factors

In the present study a family of macrocyclic and acyclic analogues as well as seco-analogues of avermectins were prepared from commercial Ivermectin (IVM) and their antileishmanial activity assayed against axenic promastigote and intracellular amastigote forms of Leishmania amazonensis. Contrarily to the filaricidal activity, the leishmanicidal potentiality of avermectin analogues does not appear to depend on the integrity of the non-conjugated Delta(3,4)-hexahydrobenzofuran moiety. Conjugated Delta(2,3)-IVM or its corresponding conjugated secoester show higher anti-leishmania activity than the parent compound. Surprisingly, the diglycosylated northern sub-unit exhibits the same anti-amastigote potentiality as the southern hexahydrobenzofuran. As expected for compounds derived from the widely used Ivermectin antibiotic, little toxicity has been noticed for most of the novel analogues prepared.

Topics: Animals; Benzofurans; Disaccharides; Ivermectin; Leishmania mexicana; Macrophages; Mice; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanocidal Agents

A cascade rhodium-catalyzed addition/cyclization reaction of bifunctional heteroromatic boronate esters to strained bicyclic alkenes has been developed. This method provides an efficient route to generate a variety of polycyclic heteroaromatic molecules containing benzothiophene, benzofuran, and indole moieties.

Topics: Alkenes; Benzofurans; Boronic Acids; Catalysis; Cyclization; Esters; Heterocyclic Compounds; Indoles; Polycyclic Compounds; Rhodium; Thiophenes

Total synthesis of the anticancer 1,4-dioxane containing natural products silvestrol (1) and episilvestrol (2) is described by an approach based on the proposed biosynthesis of these novel compounds. The key steps included an oxidative rearrangement of the protected d-glucose derivative 11 to afford the 1,4-dioxane 12, which could be elaborated to the coupling partner 5 and a photochemical [3 + 2]-cycloadditon between the 3-hydroxyflavone 27 and methyl cinnamate followed by base-induced alpha-ketol rearrangement and reduction to give the cyclopentabenzofuran core 33. The core (-)-6 and 1,4-dioxane fragment 5 were united by a highly stereoselective Mitsunobu coupling with the modified azodicarboxylate DMEAD to afford the axial coupled product 36. Deprotection then gave episilvestrol (2). Silvestrol (1) was synthesized by a coupling between core (-)-6 and the dioxane 44 followed by deprotection. Compound 1 was also synthesized from episilvestrol (2) by a Mitsunobu inversion. In addition, the analogue 4'-desmethoxyepisilvestrol (46) was synthesized via the same route. It was found that 46 and episilvestrol 2 displayed an unexpected concentration-dependent chemical shift variation for the nonexchangeable dioxane protons. Synthetic compounds 1, 2, 38, 46, and 54 were tested against cancer cells lines, and it was found that the stereochemistry of the core was critical for activity. Synthetic analogue 4'-desmethoxyepisilvestrol (46) was also active against lung and colon cancer cell lines.

Topics: Aglaia; Antineoplastic Agents, Phytogenic; Benzofurans; Cell Line, Tumor; Cell Proliferation; Humans; Magnetic Resonance Spectroscopy; Molecular Structure; Triterpenes

Five prenylated arylbenzofurans, moracins Q-U, were isolated from Morus mesozygia (Moraceae). Their structures were elucidated on the basis of spectroscopic evidence. Along with these compounds, 3beta-acetoxyurs-12-en-11-one, marsformoxide, moracin C, moracin M, moracin K, artocarpesin, cycloartocarpesin, morachalcone A were also isolated. Four of the five compounds, (moracins R-U) displayed potent antioxidant activity.

Topics: Antioxidants; Benzofurans; Free Radicals; Magnetic Resonance Spectroscopy; Molecular Structure; Morus; Neoprene

A series of benzofuran-based farnesyltransferase inhibitors have been designed and synthesized as antitumor agents. Among them, 11f showed the most potent enzyme inhibitory activity (IC(50)=1.1nM) and antitumor activity in human cancer xenografts in mice.

Topics: Animals; Antineoplastic Agents; Benzofurans; Chemistry, Pharmaceutical; Crystallography, X-Ray; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Inhibitory Concentration 50; Mice; Neoplasm Transplantation; Quinolones; Structure-Activity Relationship

The binding affinity of four palm and thumb site representative non-nucleoside inhibitors (NNIs) of HCV polymerase NS5B to wild-type and resistant NS5B polymerase proteins was determined, and the influence of RNA binding on NNI binding affinity was investigated. NNIs with high binding affinity potently inhibited HCV RNA polymerase activity and replicon replication. Among the compounds tested, HCV-796 showed slow binding kinetics to NS5B. The binding affinity of HCV-796 to NS5B increased 27-fold over a 3-h incubation period with an equilibrium Kd of 71 +/- 2 nm. Slow binding kinetics of HCV-796 was driven by slow dissociation from NS5B with a k(off) of 4.9 +/- 0.5 x 10(-4) s(-1). NS5B bound a long, 378-nucleotide HCV RNA oligonucleotide with high affinity (Kd = 6.9 +/- 0.3 nm), whereas the binding affinity was significantly lower for a short, 21-nucleotide RNA (Kd = 155.1 +/- 16.2 nm). The formation of the NS5B-HCV RNA complex did not affect the slow binding kinetics profile and only slightly reduced NS5B binding affinity of HCV-796. The magnitude of reduction of NNI binding affinity for the NS5B proteins with various resistance mutations in the palm and thumb binding sites correlated well with resistance -fold shifts in NS5B polymerase activity and replicon assays. Co-crystal structures of NS5B-Con1 and NS5B-BK with HCV-796 revealed a deep hydrophobic binding pocket at the palm region of NS5B. HCV-796 interaction with the induced binding pocket on NS5B is consistent with slow binding kinetics and loss of binding affinity with mutations at amino acid position 316.

Topics: Antiviral Agents; Base Sequence; Benzimidazoles; Benzofurans; Crystallography, X-Ray; DNA, Viral; Hepacivirus; Kinetics; Models, Molecular; Oligoribonucleotides; Protein Conformation; Recombinant Proteins; RNA, Viral; Viral Nonstructural Proteins

A (super)critical transfer: The consecutive hydrogenolysis and hydrogenation of the lignin model compound dihydrobenzofuran was studied in supercritical methanolic solutions using porous metal oxide catalysts. These catalysts promote H(2) production from methanol followed by hydrogenolysis of the ether linkages and reduction of the aromatic rings, leading principally to a mixture of cyclohexanols.

Topics: Benzofurans; Catalysis; Hydrogen; Lignin; Methanol

The reaction of 3-methylbenzofuran-2-carbohydrazide (1) with l-phenyl-2-bromoethanone (2a) or 2-chloro-1-(4-chlorophenyl)ethanone (2b) afforded (Z)-1,2-di[(3-methylbenzofuran-2-carbohydrazido]-1-arylethenes 5a and 5b, respectively. Single crystal X-ray analyses of compound 5a proved that the reaction proceeds in 2:1 molar ratio and ruled out the other possible structures 1,3,4-oxadiazine derivative 6 or E-isomer 7. Furthermore, both of 3-(3-methylbenzofuran-2-yl)-3-oxopropanenitrile (9) and 3-methyl-2-benzofuranoyl chloride (15) were used as starting materials for the synthesis of several compounds, such as pyrazoles 10 and 14, oxime 11, hydrazones 12a, b and 3,1-bezoxazine 19. The newly synthesized compounds were tested for their antimicrobial activity against five fungal species and four bacterial species also their minimum inhibitory concentration (MIC) against most of test organisms was performed. Some of these compounds exhibited a significant antimicrobial activity.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Bacteria; Benzofurans; Crystallography, X-Ray; Fungi; Microbial Sensitivity Tests; Models, Molecular; Pyrazoles

Topics: Aldehydes; Anti-Bacterial Agents; Benzofurans; Carboxylic Acids; Cyclization; Rifabutin

A collection of arotinoids with a central benzofuran or naphthofuran ring structure was efficiently synthesized by a three-step process that comprises a Sonogashira coupling, an iodine-induced 5-endo-dig cyclization of the o-methoxyphenyl- or naphthyl-ethynyl benzoates, and finally a Suzuki/Sonogashira coupling of the corresponding 3-iodobenzo- or naphthofurans. Most of these 3-substituted naphthofuran arotinoids (but not the 5,7-di-tert-butylbenzofurans with the same substitution pattern at the C2 and C3 positions) are potent agonists of the retinoic acid receptor (RAR) subtypes, with activities in the nanomolar range.

Topics: Benzofurans; Cell Line, Tumor; HeLa Cells; Humans; Protein Isoforms; Receptors, Retinoic Acid; Transcription, Genetic

Designing non-saccharide functional mimics of heparin is a major challenge. In this work, a library of small, aromatic molecules based on the sulfated DHP scaffold was synthesized and screened against thrombin and factor Xa. The results reveal that (i) selected monomeric benzofuran derivatives inhibit the two enzymes, albeit weakly; (ii) the two enzymes recognize different structural features in the benzofurans studied suggesting significant selectivity of recognition; and (iii) the mechanism of inhibition is allosteric. The molecules represent the first allosteric small molecule inhibitors of the two enzymes.

Topics: Allosteric Site; Anticoagulants; Benzofurans; Binding Sites; Chemistry, Pharmaceutical; Drug Design; Factor Xa; Heparin; Humans; Kinetics; Models, Chemical; Polymers; Thrombin

Estrogen receptors (ER) belong to the nuclear receptor superfamily, and two subtypes, ERalpha and ERbeta, have been identified to date. The differentiated functions and receptor expressions of ERalpha and ERbeta made it attracted to discover subtype-specified ligands with high selectivity. However, these two subtypes are highly homologous and only two residues differ in the ligand binding pocket. Therefore, the mechanism of ligand selectivity has become an important issue in searching selective ligands of ER subtypes. In this study, steered molecular dynamics simulations were carried out to investigate the unbinding pathways of two selective ERbeta ligands from the binding pocket of both ERalpha and ERbeta, which demonstrated that the pathway between the H11 helix and the H7 approximately H8 loop was the most probable for ligand escaping. Then potentials of mean force for ligands unbinding along this pathway were calculated in order to gain insights into the molecular basis for energetics of ligand unbinding and find clues of ligand selectivity. The results indicated that His524/475 in ERalpha/ERbeta acted as a "gatekeeper" during the ligand unbinding. Especially, the H7 approximately H8 loop of ERbeta acted as a polar "transmitter" that controlled the ligand unbinding from the binding site and contributed to the ligand selectivity. Finally, the mechanism of ligand selectivity of ER subtypes was discussed from a kinetic perspective and suggestions for improving the ligand selectivity of ERbeta were also presented. These findings could be helpful for rational design of highly selective ERbeta ligands.

Topics: Benzofurans; Computer Simulation; Estrogen Receptor alpha; Estrogen Receptor beta; Genistein; Ligands; Models, Molecular; Molecular Conformation; Protein Binding; Receptors, Estrogen; Substrate Specificity

Two vectors, pT7NScamAB and pRED, have been used for the functional expression of bacterial class I cytochrome P450 (P450) genes in Escherichia coli, which utilize putidaredoxin reductase (CamA) and putidaredoxin (CamB), and the reductase domain of a self-sufficient P450RhF respectively, for electron transfer from NAD(P)H to a P450 protein. We here compared the efficiency of bioconversion with the two vectors towards n-octane, cyclohexane, n-butylbenzene, and 2-n-butylbenzofuran using two well-characterized CYP153A genes, aciA and CYP153A13a (P450balk). As for n-octane bioconversion, aciA and pT7camAB was the best combination for the production of 1-octanol and 1,8-octanediol. As for the bioconversion of cyclohexane, n-butylbenzene and 2-n-butylbenzofuran, CYP153A13a with pRED achieved the most efficient bioconversion, as compared by conversion ratio per active CYP153A protein content. It was also found that 2-n-butylbenzofuran is biotransformed into 4-benzofuran-2-yl-butyric acid via 4-benzofuran-2-yl-butan-1-ol with E. coli cells expressing CYP153A.

Topics: Amino Acid Sequence; Benzofurans; Cell Survival; Cyclohexanes; Cytochrome P-450 Enzyme System; Escherichia coli; Gene Expression; Genes, Bacterial; Genetic Vectors; Molecular Sequence Data; Octanes

A series of trans-3-oxospiro[(aza)isobenzofuran-1(3H),1'-cyclohexane]-4'-carboxamide derivatives were synthesized to identify potent NPY Y5 receptor antagonists. Of the compounds, 21j showed high Y5 binding affinity, metabolic stability and brain and cerebrospinal fluid (CSF) penetration, and low susceptibility to P-glycoprotein transporters. Oral administration of 21j significantly inhibited the Y5 agonist-induced food intake in rats with a minimum effective dose of 1mg/kg. This compound was selected for proof-of-concept studies in human clinical trials.

Topics: Administration, Oral; Amides; Animals; ATP-Binding Cassette Transporters; Benzofurans; Brain; Cerebrospinal Fluid; Drug Stability; Eating; Rats; Receptors, Neuropeptide Y; Spiro Compounds

Forty-eight cationically substituted pentamidine congeners possessing benzofuran rings were synthesized by a copper mediated heteroannulation of substituted o-iodophenols with phenyl acetylenes. Activities of compounds 1-48 against Trypanosoma brucei rhodesiense, Plasmodium falciparum, and Leishmania donovani and cytotoxicities for mammalian cells were influenced by the nature of cationic substituents, placement of the benzofuran fragment, and the length of the carbon linker between aromatic moieties. Several dications exhibited superior antiplasmodial and antileishmanial potencies compared to pentamidine.

Topics: Animals; Antiprotozoal Agents; Benzofurans; Cell Line; Leishmania donovani; Pentamidine; Plasmodium falciparum; Rats; Structure-Activity Relationship; Trypanosoma brucei rhodesiense

We present a new facet of isobenzofuran chemistry which allows for its efficient manipulation to generate biologically relevant entities. This methodology has been successfully applied toward the synthesis of ajudazol A.

Topics: Ascomycota; Benzofurans; Biological Products; Coumarins; Crystallography, X-Ray; Models, Molecular; Molecular Structure; Oxidation-Reduction

To study the chemical constituents in the nutmeg (seed of Myristica fragrans).. The chemical constituents were isolated by various column chromatographic methods and structurally elucidated by IR, NMR and MS evidences.. Fifteen compounds were obtained and identified as myristicin (1), methyleugenol (2), safrole (3), 2, 3-dihydro-7-methoxy-2(3, 4-methylenedioxyphenyl)-3-methyl-5-(E) -propenyl-benzofuran (4), dehydrodiisoeugenol (5), 2, 3-dihydro-7-methoxy-2-(3-methoxy-4, 5-methylenedioxyphenyl) -3-methyl-5-(E)-propenyl-benzofuran (6), erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3, 4-dimetho- xyphenyl) propane (7), erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3, 4, 5-trimethoxyphenyl) propane (8), erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3, 4-dimethoxyphenyl) propan-1-ol acetate (9), erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3, 4-dimethoxyphenyl) propan-1-ol (10), erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3, 4, 5-trimethoxyphenyl) propan-1-ol (11), 5-methoxy-dehydrodiisoeugenol (12), erythro-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(4-hydroxy-3-methoxyphenyl)-propan-1-ol (13), guaiacin (14) and threo-2-(4-allyl-2, 6-dimethoxyphenoxy)-1-(3-methoxy-5-hydroxy-phenyl) propan-1-ol (15).. Compound 15 is a new compound and named myrisisolignan. Compound 7 is isolated from the genus Myristica for the first time.

Topics: Allylbenzene Derivatives; Benzofurans; Benzyl Compounds; Dioxolanes; Eugenol; Lignans; Magnetic Resonance Spectroscopy; Molecular Structure; Myristica; Pyrogallol; Safrole; Seeds

HCV-796 selectively inhibits hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase. In hepatoma cells containing a genotype 1b HCV replicon, HCV-796 reduced HCV RNA levels by 3 to 4 log(10) HCV copies/mug total RNA (the concentration of the compound that inhibited 50% of the HCV RNA level was 9 nM). Cells bearing replicon variants with reduced susceptibility to HCV-796 were generated in the presence of HCV-796, followed by G418 selection. Sequence analysis of the NS5B gene derived from the replicon variants revealed several amino acid changes within 5 A of the drug-binding pocket. Specifically, mutations were observed at Leu314, Cys316, Ile363, Ser365, and Met414 of NS5B, which directly interact with HCV-796. The impacts of the amino acid substitutions on viral fitness and drug susceptibility were examined in recombinant replicons and NS5B enzymes with the single-amino-acid mutations. The replicon variants were 10- to 1,000-fold less efficient in forming colonies in cells than the wild-type replicon; the S365L variant failed to establish a stable cell line. Other variants (L314F, I363V, and M414V) had four- to ninefold-lower steady-state HCV RNA levels. Reduced binding affinity with HCV-796 was demonstrated in an enzyme harboring the C316Y mutation. The effects of these resistance mutations were structurally rationalized using X-ray crystallography data. While different levels of resistance to HCV-796 were observed in the replicon and enzyme variants, these variants retained their susceptibilities to pegylated interferon, ribavirin, and other HCV-specific inhibitors. The combined virological, biochemical, biophysical, and structural approaches revealed the mechanism of resistance in the variants selected by the potent polymerase inhibitor HCV-796.

Topics: Antiviral Agents; Benzofurans; Cell Line, Tumor; Cloning, Molecular; Drug Resistance, Viral; Enzyme Inhibitors; Genetic Variation; Genotype; Hepacivirus; Humans; Models, Molecular; Mutation; Replicon; RNA-Dependent RNA Polymerase; Viral Nonstructural Proteins

A series of 3-pyrrol-3-yl-3H-isobenzofuran-1-ones was synthesized and assessed for the ability to inhibit cytosolic phospholipase A(2)alpha (cPLA(2)alpha). Several of these compounds were found to be active in both a cell based assay and an isolated enzyme assay. The most potent inhibitor was the thiazolidine-2,4-dione substituted derivative 35. With IC(50)-values of 0.7 muM and 7.3 muM in the cellular and isolated enzyme assay, respectively, it possesses similar inhibitory potency as the known cPLA(2)alpha inhibitor arachidonyltrifluoromethyl ketone (AACOCF(3)). Structure-activity relationship studies revealed that the evaluated isobenzofuran-1-ones seem to exert their cellular activities not only by a direct interaction with the enzyme but also by other as yet unknown mechanisms.

Topics: Benzofurans; Blood Platelets; Drug Design; Enzyme Inhibitors; Group IV Phospholipases A2; Humans; Molecular Structure; Pyrroles; Structure-Activity Relationship

A pair of epimers of benzofuranols and a benzofuran glucoside were isolated from a traditional Chinese medicine Eupatorium fortunei. Their structures and the relative stereochemistry were elucidated on the basis of the spectral analysis and chemical transformation as 3beta, 6-dimethyl-2, 3-dihydrobenzofuran-2alpha-ol; 3beta, 6-dimethyl-2, 3-dihydrobenzofuran-2beta-ol and 3beta, 6-dimethyl-2, 3-dihydrobenzofuran 2beta-O-beta-D-glucopyranoside.

Topics: Benzofurans; Eupatorium; Glucosides; Magnetic Resonance Spectroscopy; Medicine, Chinese Traditional; Molecular Structure; Plants, Medicinal

The synthesis of both the AEFG macrolactam and the CDEFG bis-indole/tyrosine units found in the marine natural product diazonamide A is presented. Key to the success of the synthesis is the highly stereoselective direct C-arylation of an oxindole by an aryllead(IV) reagent derived from tyrosine.

Topics: Benzofurans; Heterocyclic Compounds, 4 or More Rings; Indoles; Oxazoles; Oxindoles; Stereoisomerism; Substrate Specificity; Tyrosine

A one-pot synthesis of benzofurans which utilizes a palladium-catalyzed enolate arylation is described. The process demonstrates broad substrate scope and provides differentially substituted benzofurans in moderate to excellent yields. The utility of the method is further demonstrated by the synthesis of the natural product eupomatenoid 6 in three steps.

Topics: Benzofurans; Catalysis; Ketones; Palladium; Phenols

The intramolecular Diels-Alder reaction of several amidofurans tethered onto a benzofuran ring was examined as a strategy for the synthesis of morphine. Bromo substitution on the furan ring did not provide sufficient activation to allow the cycloaddition to take place across the aromatic benzofuran. However, the presence of a large o-methylbenzyl group on the amido nitrogen atom causes the reactive s-trans conformation of the amidofuran to be highly populated, thereby facilitating its Diels-Alder cycloaddition across a tethered benzofuran.

Topics: Benzofurans; Morphine

The synthesis of a novel series of aminostyrylbenzofuran derivatives 1a-w and their inhibitory activities for Abeta fibril formation were described. All the synthesized compounds were evaluated by thioflavin T (ThT) assay and displayed potent inhibitory activities for Abeta fibril formation. Among them, compounds 1i and 1q exhibited excellent inhibitory activities (IC(50)=0.07 and 0.08 microM, respectively) than those of Curcumin (IC(50)=0.80 microM) and IMSB (IC(50)=8.00 microM) as reference compounds. Both compounds were selected as promising candidates for further biological evaluation.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Benzothiazoles; Benzoxazoles; Chemistry, Pharmaceutical; Curcumin; Drug Design; Electrons; Humans; Inhibitory Concentration 50; Models, Chemical; Peptide Fragments; Structure-Activity Relationship; Styrenes; Thiazoles

A re-examination of cuticular components of Heliotropium filifolium allowed the isolation of four new compounds: 3'-hydroxy-2',2',6'-trimethyl-3H-spiro[1-benzo-furan-2,1'-cyclohexane]-5-carboxylic acid(2), methyl 3'-acetyloxy-2',2',6'-trimethyl-3H-spiro[1-benzofuran-2,1'-cyclohexane]-5-carboxylate (3), methyl 3'-isopentanoyloxy-2',2',6'-trimethyl-3H-spiro[1-benzofuran-2,1'-cyclohexane]-5-carboxylate (4) and methyl 3'-benzoyloxy-2',2',6'-trimethyl-3H-spiro[1-benzofuran-2,1'-cyclohexane]-5-carboxylate (5).Compounds 2-5 were identified by their spectroscopic analogies with filifolinol (1), and their structures confirmed by chemical correlation with 1. The antimicrobial properties of the compounds were tested against Gram positive and Gram negative bacteria. Some of them proved to be active against Gram positive, but inactive against Gram negative bacteria. In searching for structure-activity relationships from the obtained MIC values, lipophilicity was shown to be an important variable.

Topics: Anti-Infective Agents; Benzofurans; Cyclohexanes; Gram-Negative Bacteria; Gram-Positive Bacteria; Heliotropium; Hydrophobic and Hydrophilic Interactions; Microbial Sensitivity Tests; Molecular Structure; Plant Extracts; Spiro Compounds; Structure-Activity Relationship

A series of 6-substituted and 5,6-disubstituted 2-(6-methyl-benzofuran-3-ylmethyl)-imidazo[2,1-b][1,3,4]thiadiazoles have been synthesized. The new compounds have been tested for their in vivo analgesic, anti-inflammatory activities. Qualitative SAR studies indicate that the chloro substitution in the imidazole ring and introduction of formyl group at C-5 position of the imidazole ring increased the anti-inflammatory and analgesic activity. All the newly synthesized compounds have been characterized by spectral data and ORTEP diagram of one of the intermediates 6-(4-chlorophenyl)-2-(6-methyl-benzofuran-3-ylmethyl)-5-morpholin-4-ylmethyl imidazo[2,1-b][1,3,4]thiadiazole is reported herein.

Topics: Analgesics; Animals; Anti-Inflammatory Agents; Benzofurans; Cross-Linking Reagents; Female; Imidazoles; Male; Methylation; Mice; Models, Molecular; Molecular Structure; Rats; Structure-Activity Relationship; Thiadiazoles

ClC-Ka and ClC-Kb Cl(-) channels are pivotal for renal salt reabsorption and water balance. There is growing interest in identifying ligands that allow pharmacological interventions aimed to modulate their activity. Starting from available ligands, we followed a rational chemical strategy, accompanied by computational modeling and electrophysiological techniques, to identify the molecular requisites for binding to a blocking or to an activating binding site on ClC-Ka. The major molecular determinant that distinguishes activators from blockers is the level of planarity of the aromatic portions of the molecules: only molecules with perfectly coplanar aromatic groups display potentiating activity. Combining several molecular features of various CLC-K ligands, we discovered that phenyl-benzofuran carboxylic acid derivatives yield the most potent ClC-Ka inhibitors so far described (affinity <10 microM). The increase in affinity compared with 3-phenyl-2-p-chlorophenoxy-propionic acid (3-phenyl-CPP) stems primarily from the conformational constraint provided by the phenyl-benzofuran ring. Several other key structural elements for high blocking potency were identified through a detailed structure-activity relationship study. Surprisingly, some benzofuran-based drugs inhibit ClC-Kb with a similar affinity of <10 microM, thus representing the first inhibitors for this CLC-K isoform identified so far. Based on our data, we established a pharmacophore model that will be useful for the development of drugs targeting CLC-K channels.

Topics: Animals; Benzofurans; Binding, Competitive; Chloride Channels; CLC-2 Chloride Channels; Humans; Ligands; Niflumic Acid; Patch-Clamp Techniques; Protein Isoforms; Rats; Xenopus laevis

Potent and selective inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with several new heterocyclic P1' groups in conjunction with cyclic beta-amino hydroxamic acid scaffolds. Among them, the pyrazolopyridine provided the best overall profile when combined with tetrahydropyran beta-amino hydroxamic acid scaffold. Specifically, inhibitor 49 showed IC(50) value of 1 nM against porcine TACE and 170 nM in the suppression of LPS-induced TNF-alpha of human whole blood. Compound 49 also displayed excellent selectivity over a wide panel of MMPs as well as excellent oral bioavailability (F%>90%) in rat n-in-1 PK studies.

Topics: ADAM Proteins; ADAM17 Protein; Administration, Oral; Animals; Benzofurans; Biological Availability; Humans; Hydroxamic Acids; Imidazoles; Indoles; Lipopolysaccharides; Matrix Metalloproteinase Inhibitors; Molecular Structure; Protease Inhibitors; Pyrazoles; Pyridines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tumor Necrosis Factor-alpha

We report here a practical, enantioselective synthesis of benzofuran-derived, cyclic trans-beta-amino acid scaffold. In two cases, tricyclic derivatives having six- and eight-membered unsaturated lactams were obtained from this versatile scaffold. To explore the biological applications, these compounds were subjected to cell-based assays, using NIH3T3 mouse cells to examine their potency as cell motility inhibitors and identified 18 as a potent cell motility inhibitor (IC50 approximately 40 microM in chamber cell migration assay).

Topics: Amino Acids, Cyclic; Animals; Benzofurans; Cell Movement; Flavonoids; Mice; Molecular Probes; NIH 3T3 Cells

Topics: Animals; Behavior, Animal; Benzofurans; Cyclobutanes; Histamine H3 Antagonists; Humans; Male; Molecular Structure; Naphthalenes; Radioligand Assay; Rats; Receptors, Histamine H3; Trans-Activators; Transcriptional Regulator ERG

Phenylalkylamines that possess conformationally rigidified furanyl moieties in place of alkoxy arene ring substituents have been shown previously to possess the highest affinities and agonist functional potencies at the serotonin 5-HT(2A) receptor among this chemical class. Further, affinity declines when both furanyl rings are expanded to the larger dipyranyl ring system. The present paper reports the synthesis and pharmacological evaluation of a series of 'hybrid' benzofuranyl-benzopyranyl phenylalkylamines to probe further the sizes of the binding pockets within the serotonin 5-HT(2A) agonist binding site. Thus, 4(a-b), 5(a-b), and 6 were prepared as homologs of the parent compound, 8-bromo-1-(2,3,6,7-tetrahydrobenzo[1,2-b:4,5-b']difuran-4-yl)-2-aminopropane 2, and their affinity, functional potency, and intrinsic activity were assessed using cells stably expressing the rat 5-HT(2A) receptor. The behavioral pharmacology of these new analogs was also evaluated in the two-lever drug discrimination paradigm. Although all of the hybrid isomers had similar, nanomolar range receptor affinities, those with the smaller furanyl ring at the arene 2-position (4a-b) displayed a 4- to 15-fold greater functional potency than those with the larger pyranyl ring at that position (5a-b). When the furan ring of the more potent agonist 4b was aromatized to give 6, a receptor affinity similar to the parent difuranyl compound 2 was attained, along with a functional potency equivalent to 2, 4a, and 4b. In drug discrimination experiments using rats trained to discriminate LSD from saline, 4b was more than two times more potent than 5b, with the latter having a potency similar to the classic hallucinogenic amphetamine 1 (DOB).

Topics: Animals; Benzofurans; Benzopyrans; DOM 2,5-Dimethoxy-4-Methylamphetamine; Hallucinogens; Ligands; Male; Phenethylamines; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A; Stereoisomerism

In this study, four types of compounds including coumarins, chromones, furoylmethyl amino acid derivative and benzofuran glycoside were isolated from the roots of Saposhnikovia divaricata. The electrospray ionization (ESI) mass spectral fragmentation pathways of these compounds were proposed. In particular, the ESI-MS(n) fragmentation behavior of linear dihydrofurocoumarins, dihydrofuro- and dihydropyranochromones were deduced in detail. For the linear dihydrofurocoumarins, the fragmentation was triggered by the initial loss of the C-4' substituting group. Then, the characteristic ions were observed followed by the losses of 15, 18, 28 and 46 Da. It is noteworthy that the elimination of H(2)O (18 Da) from the cleavage of the dihydrofuran ring is reported for the first time. For the linear dihydrofurochromones, characteristic eliminations of 18, 48 and 72 Da were observed. The loss of 18 Da could arise from two different fragmentation pathways, and the observed ion was composed of a mixture of two different structural ions. For the linear dihydropyranochromones, it was found that the dihydropyran ring was converted into the pyran ring by the elimination of the C-3' substituting group. This fragmentation was followed by the diagnostic losses of 18, 28, 42 and 54 Da in tandem mass spectrometry. The above fragmentation rules were successfully applied for the analysis of the chemical constituents of the roots of Saposhnikovia divaricata. A total of 32 compounds were identified or tentatively characterized by HPLC/DAD/ESI-MS(n). Among them, eight compounds were new and seven compounds were reported from that genus for the first time.

Topics: Amino Acid Sequence; Amino Acids; Apiaceae; Benzofurans; Chromatography, High Pressure Liquid; Chromones; Coumarins; Glycosides; Molecular Structure; Plant Roots; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Time Factors

Drug-induced thyrotoxicosis is not uncommon. It may worsen life-threatening arrhythmias and may be refractory to medical treatment. Near-total thyroidectomy presents a valid alternative to medical therapy and should be considered early in the management of the disease.. To assess whether near-total thyroidectomy was a viable approach for our patients.. Twelve patients--7 men and 5 women, aged 63 to 82 years--presented with drug-induced fulminant thyrotoxicosis following 1 to 12 months of amiodarone treatment (11 patients, mean 7 months) and after a 6 months course of interferon-alpha treatment (one patient). Medical therapy included propylthiouracil in doses up to 1200 mg/day in all patients and a beta-receptor antagonist in seven. Five patients had to stop amiodarone treatment and start high doses of steroids. A thyroid scan was performed in all patients using 5 mCi of Tc-99m pertechnetate. The thyroid scan showed absent uptake of the tracer in the thyroid bed in all patients, precluding the use of radioablation.. Four patients (three with AIT and one with interferon therapy) who did not respond to 3 months of medical therapy required surgical thyroidectomy due to severe unremitting thyrotoxicosis. A near-total thyroidectomy resulted in rapid correction of thyrotoxicosis, enabling continuation of the anti-arrhythmic drug. There were no intraoperative or postoperative arrhythmias. Subsequently, all patients recovered rapidly and remained well and euthyroid on thyroxine replacement therapy.. Since surgery results in rapid control of thyrotoxicosis and permits continued therapy with amiodarone, we suggest that near-total thyroidectomy warrants consideration as a definitive treatment for resistant amiodarone or interferon-induced thyrotoxicosis.

Topics: Aged; Aged, 80 and over; Amiodarone; Angiogenesis Inhibitors; Anti-Arrhythmia Agents; Benzofurans; Female; Humans; Interferon-alpha; Male; Middle Aged; Risk Factors; Thyroidectomy; Thyrotoxicosis

Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.

Topics: Animals; Behavior, Animal; Benzofurans; Dogs; Haplorhini; Histamine Antagonists; Humans; Rats; Receptors, Histamine H3

The first enantioselective synthesis of the 2-isopropenyl-2,3-dihydrobenzofuran skeleton of tremetone and hydroxytremetone from (E)-4-(2-hydroxyphenyl)-2-methyl-2-butenyl methyl carbonate and (E)-4-(2,6-dihydroxyphenyl)-2-methyl-2-butenyl methyl carbonate, respectively, is described. The key step is a catalytic palladium-mediated reaction in the presence of the chiral Trost ligand.

Topics: Benzofurans; Molecular Structure; Plant Extracts; Rotenone; Stereoisomerism; Triamterene

Electrochemical oxidation of hydroquinone, catechol, and some of their monosubstituted derivatives has been studied in the presence of 3-hydroxy-1H-phenalen-1-one (2) as a nucleophile in water/acetonitrile (80/20) solutions using cyclic voltammetry and controlled-potential coulometry methods. The results revealed that quinones derived from oxidation of hydroquinones and catechols participate in Michael addition reactions with 2. The formed adducts convert to the corresponding benzofuran derivatives via different mechanisms. In this work, we derived a variety of products with good yields using controlled potential electrochemical oxidation at a graphite electrode in an undivided cell.

Topics: Benzofurans; Cyclization; Electrochemistry; Molecular Structure; Oxidation-Reduction; Stereoisomerism

Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.

Topics: Animals; Benzofurans; Chemistry, Pharmaceutical; Drug Design; Drug Evaluation, Preclinical; Humans; Indoles; Inhibitory Concentration 50; Ligands; Models, Chemical; PPAR delta; Structure-Activity Relationship; Thiazoles; Thiophenes

We describe a new approach applicable to the determination of organic acids that serve as diagnostic markers for several inherited metabolic disorders. We utilized liquid chromatography/tandem mass spectrometry for analysis of organic acid derivatives of a recently described benzofurazan reagent. The derivatization step was necessary to obtain organic acid derivatives suitable for analysis by reversed-phase liquid chromatography with high ionization efficiency for mass spectrometry in the positive-ion mode. In this work, a group of related dicarboxylic acid markers containing five or six carbon atoms were analyzed and validation was performed for glutaric and 3-hydroxyglutaric acids, the specific markers for glutaric acidemia type 1. Derivatization was achieved by reacting untreated urine with the derivatization reagent under mild conditions. The reaction mixture was analyzed on a C18 ultra-performance liquid chromatography (UPLC) column (50x2.1 mm, 1.7 microm) and detected in the multiple reaction monitoring mode in 5 min. Calibration curves were linear up to at least 1000 microM with detection limits for glutaric and 3-hydroxyglutaric acids of 0.025 and 0.02 microM, respectively (signal-to-noise ratio of 3). Intra-day (n=11) and inter-day (n=6) coefficients of variation were better than 11.2%. The assay was successfully applied to control (n=134) and glutaric acidemia type 1 (n=55) urine samples.

Topics: Acids; Benzofurans; Biomarkers; Case-Control Studies; Chromatography, Liquid; Humans; Metabolism, Inborn Errors; Organic Chemicals; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry; Temperature; Time Factors

Samples of air (gas and particulate phases), bulk deposition, aquatic settling material and sediments were collected in Lake Maggiore (LM) in order to determine their content of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). Air (gas and particulate phases) concentrations were 0.5 pg m(-3), 80 pg m(-3), 13 pg m(-3) and 106 pg m(-3) for SigmaPCDD/Fs, SigmaPCBs, Sigma dioxin-like PCBs (DL-PCBs) and SigmaPBDEs, respectively. Deposition fluxes ranged from 0.7 ng m(-2) d(-1) for SigmaPCDD/Fs to 32 ng m(-2) d(-1) for SigmaPCBs. Aquatic settling material presented concentrations of 0.4 ng g(-1) dry weight (dw) for SigmaPCDD/Fs, 13 ng g(-1) dw for SigmaPCB, 3.4 ng g(-1) dw for SigmaDL-PCBs and 5.7 ng g(-1) dw for SigmaPBDEs. Mean sediment concentrations were 0.4 ng g(-1) dw for SigmaPCDD/Fs, 11 ng g(-1) dw for SigmaPCB, 3 ng g(-1) dw for SigmaDL-PCBs and 5.1 ng g(-1) dw for SigmaPBDEs. Similar PCDD/F and DL-PCB congener patterns in all the environmental compartments of LM point to an important, if not dominant, contribution of atmospheric deposition as source of these pollutants into LM. In contrast, PBDE congener distribution was not similar in the different environmental compartments. BDE 47 dominated air and settling material, while BDE 209 was the predominant congener in the bulk atmospheric deposition. Moreover, sediments showed two distinct PBDE congener profiles. Lower PBDE concentrated sediments were dominated by congeners 47 and 99, while BDE 209 dominated in higher PBDE concentrated samples. This suggests the influence of local sources as well as atmospheric input of PBDEs into LM.

Topics: Benzofurans; Dioxins; Ecosystem; Environmental Monitoring; Fresh Water; Geologic Sediments; Italy; Polybrominated Biphenyls; Polychlorinated Biphenyls; Switzerland; Water; Water Pollutants, Chemical; Water Pollution, Chemical

A novel synthetic route to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of serotonin, has been developed. The new synthesis proceeds via the [3+2] cycloaddition of p-benzoquinone and 2,3-dihydrofuran, followed by a Lewis acid-catalyzed isomerization. This molecule proves to be a competent agonist (equipotent to serotonin) of the 5-HT3 receptor, demonstrating that the indolic proton of serotonin is not essential to its activation of the receptor.

Topics: Benzofurans; Humans; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists

A new 2-arylbenzofuran, sanggenofuran B (3',5'-dihydroxy-6-methoxy-4'-prenyl-2-arylbenzofuran), from the root bark of Chinese Morus cathayana is reported.

Topics: Benzofurans; Humans; Medicine, Chinese Traditional; Morus; Phytotherapy; Plant Bark; Plant Roots

High potency pyrazole-based noncovalent inhibitors of human cathepsin S (CatS) were developed by modification of the benzo-fused 5-membered ring heterocycles found in earlier series of CatS inhibitors. Although substitutions on this heterocyclic framework had a moderate impact on enzymatic potency, dramatic effects on cellular activity were observed. Optimization afforded indole- and benzothiophene-derived analogues that were high affinity CatS inhibitors (IC(50)=20-40 nM) with good cellular potency (IC(50)=30-340 nM).

Topics: Animals; Aza Compounds; Benzofurans; Carboxylic Acids; Cathepsins; Humans; Indoles; Molecular Structure; Protease Inhibitors; Pyrazoles; Structure-Activity Relationship; Thiophenes

Topics: Benzofurans; Macrocyclic Compounds; Models, Chemical; Molecular Structure; Triterpenes

It is now recognized that aldosterone is potentially cardiotoxic, although its local effects in the heart are not well understood. We examined the effects of aldosterone on cultured neonatal rat cardiomyocytes in the presence of normal and elevated extracellular Na+ ([Na+]o). We evaluated the intracellular volume of cardiomyocytes in the presence of normal (141 mEq/liter) and elevated (146 mEq/liter) [Na+]o by measuring cell size. Intracellular Na+ was measured using sodium-binding-benzofuran-isophthalate as a fluorescent sodium indicator, and cardiac hypertrophy was assessed using B-type natriuretic peptide transcription and (3)H-leucine incorporation. Cardiomyocytes shrank in the presence of 146 mEq/liter Na+ due to the increased extracellular osmolarity at early phase. Aldosterone (10(-7) mol/liter) mitigated the shrinkage by stimulating Na+ uptake by the cells. This effect of aldosterone was blocked by SM 20220, a Na+/H+ exchanger 1 (NHE1) inhibitor, but not by eplerenone, a mineralocorticoid receptor blocker. Seventy-two hours of exposure to aldosterone in the presence of 146 mEq/liter Na+ led to increases in cardiomyocyte size, 3H-leucine incorporation, and B-type natriuretic peptide and NHE1 transcription that were significantly greater than were seen in the presence of 141 mEq/liter Na+. All but the last were blocked by either eplerenone or SM 20220; the increase in NHE1 transcription was blocked only by eplerenone. Aldosterone exerts a beneficial effect via NHE1 to block cardiomyocyte shrinkage in the presence of elevated [Na+]o at early phase, but long-time exposure to aldosterone in the presence of elevated [Na+]o leads to cardiomyocyte hypertrophy via genomic effects mediated by the mineralocorticoid receptor.

Topics: Aldosterone; Amides; Animals; Benzofurans; Cells, Cultured; Eplerenone; Hemodynamics; Hypertrophy; Indoles; Leucine; Mineralocorticoid Receptor Antagonists; Myocytes, Cardiac; Phthalic Acids; Rats; Rats, Wistar; Reverse Transcriptase Polymerase Chain Reaction; Sodium; Sodium-Hydrogen Exchangers; Spironolactone; Time Factors

PTPases are considered to be involved in the etiology of diabetes mellitus and neural diseases, such as Alzheimer's disease and Parkinson's disease. Therefore, PTPase inhibitors should be useful tools to study the role of PTPases in these diseases and other biological phenomena, and which can be developed into chemotherapeutic agents. In the present study, we have synthesized novel benzofuran isoxazolines 13-21 via 1,3-dipolar cycloaddition reaction using karanjin (1) and kanjone (2), isolated from Pongamia pinnata fruits. All the synthesized compounds were evaluated against PTPase enzyme. Compounds 19 and 20 displayed significant inhibitory activity with IC50 values 76 and 81 microM, respectively.

Topics: Benzofurans; Benzopyrans; Drug Design; Enzyme Inhibitors; Hypoglycemic Agents; Isoxazoles; Millettia; Models, Chemical; Oxazolone; Protein Binding; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases

Treatment of 2-bromoacetylbenzofuran with 1H-benzotriazole afforded 1-(benzofuran-2-yl)-2-(benzotriazol-1-yl)ethanone which reacted with phenylisothiocyanate to give the corresponding thioacetanilide derivatives. Treatment of the latter ethanone and thioacetanilide derivatives with hydrazonoyl chlorides afforded the corresponding pyrazole and 1,3,4-thiadiazole derivatives. The thioacetanilide derivative reacted with alpha-haloketones and alpha-halodiketones to afford thiophene and thiazole derivatives, respectively. The newly synthesized compounds were found to possess anticonvulsant and anti-inflammatory activities with the same mechanism of action of selective COX-2 inhibitors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticonvulsants; Benzofurans; Cyclooxygenase 2 Inhibitors; Drug Evaluation, Preclinical; Heterocyclic Compounds; Mice; Molecular Structure; Stereoisomerism; Structure-Activity Relationship; Triazoles

The reaction of 5-bromosalicylaldehyde with 1-mesityl-1-methyl-3-(2-chloro-1-oxoethyl)cyclobutane (1) and potassium carbonate was used to prepare (5-bromobenzofuran-2-yl)(3-methyl-3-mesitylcyclobutyl)methanone (2) for the starting reagent purposes. (5-Bromobenzofuran-2-yl)(3-methyl-3-mesitylcyclobutyl)ketonethiosemicarbazone (3) was synthesized from the reaction of the compound (2) with thiosemicarbazide. In the present study, it was aimed to examine the influence of synthetic (5-bromobenzofuran-2-yl)(3-methyl-3-mesityl cyclobutyl)ketonethiosemicarbazone on levels of vitamins (A, E, C), selenium and malondialdehyde in rats. A total of 42 rats were used and the animals were divided into two groups in the study. Only a subcutaneous injection of 250 microl of 75% ethanol was given to the control group every other day. A subcutaneous injection of this compound (25 mg kg-1, dissolved in 250 microl of 75% ethanol) was administered to the other group of rats. After the application of (5-bromobenzofuran-2-yl)(3-methyl-3-mesitylcyclobutyl)ketonethiosemicarbazone for 20 days, the serum vitamins (A, E, C) and malondialdehyde levels were determined with high performance liquid chromatography, the serum selenium level was determined by using fluorescence spectrophotometer. The serum vitamin A, E, C and selenium levels were significantly decreased compared to control group (P<0.005), whereas serum malondialdehyde levels were higher than control group levels (P<0.005). As a result, it could be suggested that this compound induced a severe stress, and also increased the amount of free radicals depending on the stress.

Topics: Animals; Antioxidants; Benzofurans; Male; Molecular Structure; Oxidants; Rats; Rats, Wistar; Thiosemicarbazones

In this study, some aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketones, aryl (3-methyl-benzofuran-2-yl) ketoximes and aryl [3-(imidazol-1-yl/triazol-1-ylmethyl)benzofuran-2-yl] ketoximes were synthesised starting from 2-aryloyl-3-methyl-benzofuranes. The structure elucidation of the compounds was performed by IR, 1H-NMR, MASS spectroscopy and elemental analyses. Antifungal activities of the compounds were examined and moderate activity was obtained.

Topics: Antifungal Agents; Azoles; Benzofurans; Candida; Imidazoles; Methylation; Molecular Structure; Oximes; Structure-Activity Relationship

A novel series of benzofuran derivatives as potential positron emission tomography (PET) tracers targeting amyloid plaques in Alzheimer's disease (AD) were synthesized and evaluated. The syntheses of benzofurans were successfully achieved by an intramolecular Wittig reaction between triphenylphosphonium salt and 4-nitrobenzoyl chloride. When in vitro binding studies using AD brain gray matter homogenates were carried out with a series of benzofuran derivatives, all the derivatives examined displayed high binding affinities with K(i) values in the subnanomolar range. Among these benzofuran derivatives, compound 8, 5-hydroxy-2-(4-methyaminophenyl)benzofuran, showed the lowest K(i) value (0.7 nM). In vitro fluorescent labeling of AD sections with compound 8 intensely stained not only amyloid plaques, but also neurofibrillary tangles. The (11)C labeled compound 8, [(11)C]8, was prepared by reacting the normethyl precursor, 5-hydroxy-2-(4-aminophenyl)benzofuran, with [(11)C]methyl triflate. The [(11)C]8 displayed moderate lipophilicity (log P = 2.36), very good brain penetration (4.8%ID/g at 2 min after iv injection in mice), and rapid washout from normal brains (0.4 and 0.2%ID/g at 30 and 60 min, respectively). In addition, this PET tracer showed in vivo amyloid plaque labeling in APP transgenic mice. Taken together, the data suggest that a relatively simple benzofuran derivative, [(11)C]8, may be a useful candidate PET tracer for detecting amyloid plaques in the brains of patients with Alzheimer's disease.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Benzofurans; Mice; Mice, Transgenic; Molecular Structure; Positron-Emission Tomography

Protein tyrosine phosphatases have a central role in the maintenance of normal cellular functionality. For example, PTP1B has been implicated in insulin-resistance, obesity, and neoplasia. Mitogen-activated protein kinase phosphatase-1 (MKP-1 or DUSP1) dephosphorylates and inactivates mitogen-activated protein kinase (MAPK) substrates, such as p38, JNK, and Erk, and has been implicated in neoplasia. The lack of readily available selective small molecule inhibitors of MKP family members has severely limited interrogation of their biological role. Inspired by a previously identified inhibitor (NSC 357756) of MKP-3, we synthesized seven NSC 357756 congeners, which were evaluated for in vitro inhibition against several protein phosphatases. Remarkably, none displayed potent inhibition against MKP-3, including the desamino NSC 357756 analog NU-154. Interestingly, NU-154 inhibited human PTP1B in vitro with an IC(50) value of 24 +/- 1 microM and showed little inhibition against Cdc25B, MKP-1, and VHR phosphatases. NU-126 [2-((E)-2-(5-cyanobenzofuran-2-yl)vinyl)-1H-indole-6-carbonitrile] inhibited MKP-1 and VHR in vitro but was less active against human MKP-3, Cdc25B, and PTP1B. The inhibition of MKP-1 by NU-126 was independent of redox processes. The benzofuran substructure represents a new potential scaffold for further analog development and provides encouragement that more selective and potent inhibitors of MKP family members may be achievable.

Topics: Benzofurans; cdc25 Phosphatases; Cell Cycle Proteins; Dual Specificity Phosphatase 3; Dual Specificity Phosphatase 6; Enzyme Activation; Enzyme Inhibitors; Humans; Imidazoles; Inhibitory Concentration 50; Kinetics; Mitogen-Activated Protein Kinase 1; Phosphorylation; Protein Phosphatase 1; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Substrate Specificity

Topics: Benzofurans; Fluorescence; Histamine Antagonists; Ligands; Receptors, Histamine H3

The reaction of o-alkynylbenzaldehydes 1 with different alcohols, silylated nucleophiles 5, electron-rich arenes 10, and heteroarenes 12 in the presence of the reagent IPy(2)BF(4), at room temperature, gave functionalized 4-iodo-1H-isochromenes 2, 6, 11, and 13 in a regioselective manner. When alkynes 16 and alkenes 19 and 20 were used as nucleophiles, a regioselective benzannulation reaction took place to form 1-iodonaphthalenes 17 and 1-naphthyl ketones 18, respectively. Moreover, the latter process has been adapted to accomplish the synthesis of indole, benzofuran, and benzothiophene derivatives (23, 27, and 28, respectively). The three patterns of reactivity observed for the o-alkynylbenzaldehyde derivatives with IPy(2)BF(4) stem from a common iodinated isobenzopyrylium ion intermediate, A, that evolves in a different way depending on the nucleophile present in the reaction medium. A mechanism is proposed and the different reaction pathways observed as a function of the type of nucleophile are discussed. Furthermore, the reaction of the o-hexynylbenzaldehyde 1 b with styrene was monitored by NMR spectroscopy. Compound III, a resting state for the common intermediate in the absence of acid, has been isolated. Its evolution in acid media has been also tested, thereby providing support to the proposed mechanism.

Topics: Aldehydes; Alkynes; Benzofurans; Benzopyrans; Heterocyclic Compounds; Indoles; Ions; Naphthalenes; Onium Compounds; Pyridines; Thiophenes

The exploration of the chemical diversity space depends on the discovery of novel bioisosteric elements. As a continuation of our project on bilayered arene surrogates, we herein report on [2.2]paracyclophane-derived dopamine D3 receptor antagonists of type 4 and 6. For the most promising test compound 6a, bearing a 2-methoxyphenyl substituent, a stereocontrolled preparation was performed when the planar chirality of enantiomers (R)-6a (FAUC 418) and (S)-6a caused a considerable differentiation of D3 binding, which is indicated by K(i) values of 0.19 and 3.0 nM, respectively. Functional experiments showed D3 antagonist properties for the paracyclophane derivatives of type 6. To elucidate putative bioactive low-energy conformations, DFT-based studies including the calculation of diagnostic magnetic shielding properties were performed. An 89% increase in volume for the [2.2]paracyclophane moiety compared to that of the monolayered benzofurane of lead compound 3b indicates higher plasticity of GPCR binding regions than usually expected.

Topics: Amides; Animals; Benzene Derivatives; Benzofurans; Binding Sites; Bridged-Ring Compounds; Central Nervous System Agents; CHO Cells; Corpus Striatum; Cricetinae; Cricetulus; Humans; In Vitro Techniques; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Mutation; Radioligand Assay; Receptors, Dopamine D3; Stereoisomerism; Structure-Activity Relationship; Swine; Thymidine

The use of a benzofuran to mask phenol and arylacetaldehyde moieties simultaneously in the synthesis of analogues of mycophenolic acid (MPA) was explored. Benzofuran 4 provided a stable and easily handled intermediate for the preparation of unnatural derivatives at the C-6 position of MPA. Preparation of the highly potent 6-ethyl MPA analogue 2 was accomplished via aldehyde 2c through this facile route with high-yielding steps and crystalline intermediates.

Topics: Aldehydes; Benzofurans; Molecular Structure; Mycophenolic Acid; Phenols; Stereoisomerism

[Structure: see text] A mild and efficient [3+2] nitrile oxide/olefin cycloaddition allows coupling of the highly functionalized naphthalene and isocoumarin hemispheres of purpuromycin. A rationale of the inability of advanced keto alcohols to spirocyclize is presented based upon a systematic examination of the electronic factors present in these systems and suggests that the biosynthesis of purpuromycin does not proceed through open-chain intermediates.

Topics: Benzofurans; Molecular Structure; Naphthoquinones; Spiro Compounds

A series of synthetic dihydrobenzofuran lignans and related benzofurans were evaluated for their cytotoxicity in a screening panel consisting of various human tumour cell lines, and for their antiprotozoal activity against L. donovani (axenic amastigotes), chloroquine resistant Plasmodium falciparum (strain K1), Trypanosoma brucei rhodesiense and T. cruzi, and for cytotoxicity on L6 cells. No promising cytotoxicities against human tumour cell lines were observed for newly synthesised compounds, but the dimerisation product of some lipophylic esters of caffeic acid, such as compound 2g, showed a high activity against chloroquine-resistant P. falciparum (strain K1) (IC50 0.43 microg/mL) and L. donovani (axenic amastigotes) (IC50 0.12 microg/mL), which was confirmed in an infected macrophage assay (IC50 0.19 microg/mL). QSAR models for the cytotoxic and antileishmanial activity were generated using Quasar receptor surface modelling.

Topics: Animals; Antiprotozoal Agents; Benzofurans; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Leishmania; Lignans; Quantitative Structure-Activity Relationship

An SAR study of histamine H3 receptor antagonists based on substituted (R)-2-methyl-1-[2-(5-phenyl-benzofuran-2-yl)-ethyl]-pyrrolidines is presented.

Topics: Benzofurans; Histamine H1 Antagonists; Pyrrolidines; Receptors, Histamine H3; Structure-Activity Relationship

Topics: Animals; Behavior, Animal; Benzofurans; Cyclization; Histamine Antagonists; Humans; Molecular Structure; Rats; Receptors, Histamine H3

A benzoisofuranone derivative, 3xi-(1xi-hydroxyethyl)-7-hydroxy-1-isobenzofuranone, and a dimeric carbazole alkaloid, 3,3'-[oxybis(methylene)]bis(9-methoxy-9H-carbazole), along with six known carbazole alkaloids and three known steroids were isolated from the stem bark of Murraya koenigii. The structures of these compounds were established unambiguously by UV, IR, MS and a series of 1D and 2D NMR analyses. The minimum inhibitory concentrations (MIC) of these compounds were found to be in the range 3.13-100 microg/ml.

Topics: Alkaloids; Anti-Infective Agents; Benzofurans; Carbazoles; Magnetic Resonance Spectroscopy; Microbial Sensitivity Tests; Molecular Structure; Murraya; Plant Stems

In a three-step sequence, an array of angularly fused polycyclic heterocycles with coumarin, benzofuran and pyridine rings were synthesized from 4-bromomethylcoumarins and salicylonitrile. All the final compounds were fully characterized and screened for anti-microbial, anti-inflammatory and analgesic activities. Several compounds exhibited promising inflammation inhibiting and anti-microbial properties.

Topics: Analgesics; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Benzofurans; Colony Count, Microbial; Coumarins; Heterocyclic Compounds, 4 or More Rings; Pain Measurement; Pyridines; Structure-Activity Relationship

A series of benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives were prepared using an efficient 1-step procedure in good yields. In addition furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were also prepared to determine the effect of the benzene ring in benzofuran with respect to inhibitory activity. The pyridylmethanol derivatives were all evaluated in vitro for inhibitory activity against aromatase (P450(AROM), CYP19), using human placental microsomes. The benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives showed good to moderate activity (IC50 = 1.3-25.1 microM), which was either better than or comparable with aminoglutethimide (IC50 = 18.5 microM) but lower than arimidex (IC50 = 0.6 microM), with the 4-methoxyphenyl substituted derivative displaying optimum activity. Molecular modelling of the benzofuran-2-yl-(4-fluorophenyl)-3-pyridylmethanol derivative suggested activity to reside with the (S)-enantiomer. The furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were devoid of activity indicating the essential role of the benzene ring of the benzofuran component for enzyme binding.

Topics: Aromatase; Aromatase Inhibitors; Benzofurans; Enzyme Inhibitors; Furans; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Methanol; Microsomes; Models, Chemical; Models, Molecular; Placenta; Protein Binding; Protons; Software; Temperature

A potent, selective series of MMP-13 inhibitors has been derived from a weak (3.2 microM) inhibitor that did not bear a zinc chelator. Structure-based drug design strategies were employed to append a Zn-chelating group to one end of the molecule and functionality to enhance selectivity to the other. A compound from this series demonstrated rat oral bioavailability and efficacy in a bovine articular cartilage explant model.

Topics: Administration, Oral; Amino Acids; Animals; Benzofurans; Cartilage; Cattle; Chelating Agents; Collagenases; Crystallography, X-Ray; Drug Design; In Vitro Techniques; Inhibitory Concentration 50; Matrix Metalloproteinase 13; Matrix Metalloproteinase Inhibitors; Models, Molecular; Protease Inhibitors; Protein Structure, Tertiary; Rats; Sensitivity and Specificity; Structure-Activity Relationship; Substrate Specificity; Zinc

The preparation of estrone derived benzothieno- and benzofurano fused steroids is described. Keystep is an intramolecular thienyl(/furyl)-ene-yne cyclization of 16-ethynyl-17-heterarylestra-1,3,5(10),16-tetraenes. The cyclization was carried out under Pt as well as under Ru catalysis.

Topics: Azo Compounds; Benzofurans; Catalysis; Cyclization; Estranes; Molecular Structure

5-Hydroxy-3-methyl-3H-benzofuran-2-one, 5, easily obtained from pyruvic acid and 1,4-cyclohexanedione, was used as a starting material to prepare (+/-)-5-hydroxy-3a-methyl-2,3,3a,8a-tetrahydro-furo[2,3-b]benzofuran, 10, and (+/-)-7-hydroxy-5-methyl-4,5-dihydro-2,5-methano-1,3-benzodioxepine, 14. Reduced reactivity relative to 5-hydroxy-3-methoxycarbonylmethylene-3-methyl-3H-benzofuran-2-one, 6, was preliminarily studied. Meanwhile, a plausible mechanism with regard to the formation of 10 and 14, which included cyclization, rearrangement, and ring expansion of hemiacetal, 15, is proposed. Specific carbamates of phenols, 10 and 14, have shown impressive inhibitory activities against human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) ex vivo.

Topics: Benzofurans; Cholinesterase Inhibitors; Cholinesterases; Hot Temperature; Magnetic Resonance Spectroscopy; Molecular Structure; Oxepins

Based on the structure of 4-hydroxy-3-methyl-6-phenylbenzofuran-2-carboxylic acid ethyl ester (1), which exhibits selective cytotoxicity against a tumorigenic cell line, (2,4-dimethoxyphenyl)-(4-hydroxy-3-methyl-6-phenylbenzofuran-2-yl)-methanone (18m) was designed and synthesized as a biologically stable derivative containing no ester group. Although the potency of 18m was almost the same as our initial hit compound 1, 18m is expected to last longer in the human body as an anticancer agent.

Topics: Antineoplastic Agents; Benzofurans; Carboxylic Acids; Cell Line, Tumor; Esters; Humans

The MeOH extract of aerial parts of Flourensia riparia Grisebach (Asteraceae) afforded a sesquiterpene lactone, 4beta-hydroxy-4,10alpha-dimethyl-7alphaH,8alphaH-eudesman-11-ene-8,12-olide, together with septuplinolide, its isomer at positions C-5 and C-10. In addition, known flavonoids, p-hydroxyacetophenone derivatives, carabrone and isoalantolactone were identified. Three known flavonoids and a benzofuran were isolated from Flourensia campestris Wedd.

Topics: Asteraceae; Benzofurans; Flavonoids; Magnetic Resonance Spectroscopy; Molecular Conformation; Molecular Structure; Plant Components, Aerial; Plant Extracts

Eight 2-arylbenzofurans and an isoflavone isolated from medicinal plants were tested for their antimicrobial activities against vancomycin-resistant enterococci (VRE) and methicillin-resistant Staphylococcus aureus (MRSA). Among these compounds, six hydrophobic 2-arylbenzofurans (log P = 4.4-8.7) exhibited considerable antibacterial activity against five VRE strains(VanA-, VanB-, and VanC-phenotypes) (MICs = 3.13-6.25 microg/mL). Five compounds also showed antibacterial activity against ten MRSA strains (MIC80 = 3.13 microg/mL).

Topics: Anti-Infective Agents; Benzofurans; Enterococcus; Glycyrrhiza uralensis; Humans; Isoflavones; Methicillin Resistance; Microbial Sensitivity Tests; Phytotherapy; Plant Extracts; Staphylococcus aureus; Vancomycin Resistance

Six chemicals, known to induce kidney tumors in rats, were examined for their ability to induce DNA fragmentation and formation of micronuclei in primary cultures of rat and human kidney cells, and in the kidney of intact rats. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the Comet assay, and in micronuclei frequency, were obtained in primary kidney cells from both male rats and humans of both genders with the following subtoxic concentrations of five of the six test compounds: bromodichlorometane (BDCM) from 0.5 to 4 mM, captafol (CF) from 0.5 to 2 microM, nitrobenzene (NB) from 0.062 to 0.5 mM, ochratoxin A (OTA) from 0.015 to 1.215 microM, and trichloroethylene (TCE) from 1 to 4 mM. Benzofuran (BF), consistent with its carcinogenic activity for the kidney of female, but not of male rats, at concentrations from 0.125 to 0.5 mM gave positive responses in cells from females but did not induce DNA damage and increased the frequency of micronuclei in cells from males to a lower extent; in contrast, it was active in cells from humans of both genders. DNA-damaging and micronuclei-inducing potencies were similar in the two species. In agreement with these findings, statistically significant increases in the average frequency of both DNA breaks and micronucleated cells were obtained in the kidney of rats, given p.o. a single dose (1/2 LD50) of the six compounds, BF in this assay being more genotoxic in female than in male rats. Taken as a whole, these findings give further evidence that kidney carcinogens may be identified by short-term genotoxicity assays, using as target kidney cells, and show that the six chemicals tested produce, in primary cultures of kidney cells from human donors, effects similar to those observed in rats.

Topics: Animals; Benzofurans; Captan; Carcinogenicity Tests; Carcinogens; Cells, Cultured; Cyclohexenes; DNA Damage; Dose-Response Relationship, Drug; Female; Humans; Kidney; Male; Micronuclei, Chromosome-Defective; Nitrobenzenes; Ochratoxins; Rats; Rats, Sprague-Dawley; Species Specificity; Trichloroethylene; Trihalomethanes

A new benzofuran derivative, named gymnastone [5-hydroxy-6-acetyl-2-(2-propane-1,2,3-triol)-benzofuran (1)], was isolated from the aerial part of Gymnaster koraiensis, together with viscidone (2) by repeated column chromatography. The structures of both compounds were identified by physico-chemical and spectral analysis including COSY, HMQC, and HMBC experiments.

Topics: Acetylene; Asteraceae; Benzofurans; Chromatography; Glycosides; Plant Extracts; Plant Stems

The level of secondary compounds formed by sterile root cultures of Anigozanthos preissii depends on the differentiation state. Cultures showing shoot formation and accelerated growth are depleted in stilbenes, stilbene glucosides, and phenylphenalenones. Three glucosides of anigopreissin A, a benzofuran-type resveratrol dimer, were isolated from slow-growing cultures and their structures elucidated by spectrometric methods.

Topics: Benzofurans; Dimerization; Magnetic Resonance Spectroscopy; Magnoliopsida; Nuclear Magnetic Resonance, Biomolecular; Plant Roots; Resveratrol; Stilbenes

Novel 3-acetoacetylaminobenzo[b]furan derivatives with a modified triene system at the 3-position were prepared through acylation of the 3-aminobenzo[b]furans with 5-methylisoxazole-4-carboxylic acid chloride followed by basic cleavage of the isoxazole ring and several of these compounds showed moderate cysteinyl leukotriene receptor 2 antagonistic activity.

Topics: Asthma; Benzofurans; Chemistry, Organic; Crystallography, X-Ray; Humans; Leukotriene Antagonists; Membrane Proteins; Models, Chemical; Models, Molecular; Receptors, Leukotriene

[reaction: see text] The synthesis of isoquinolines through coupling of 2-alkynylbenzaldehyde derivatives with beta-cyanocarbene complexes has been examined. The reaction involves formation of an isobenzofuran followed by intramolecular Diels-Alder reaction with the nitrile, a process with limited precedent. The unique success of this process in this system has been attributed to deoxygenation of the initial adduct to form the isoquinoline ring system.

Topics: Benzofurans; Isoquinolines; Nitriles

An efficient synthesis of 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl)benzofuran (8), a potent beta-amyloid aggregation inhibitor, is described. 5-Chloro-2-(4-methoxyphenyl)benzofuran (3) was obtained by the one-pot synthesis of 4-chlorophenol with omega-(methylsulfinyl)-p-methoxyacetophenone (1) under Pummerer reaction conditions, and it was followed by the desulfurization of the resultant 5-chloro-3-methylthio-2-(4-methoxyphenyl)benzofuran (2e). Acylation of benzofuran 3 with 4-(3-bromopropoxy)benzoyl chloride (6) gave the ketone 7, which was converted into compound 8 by the treatment of diethylamine.

Topics: Amyloid beta-Peptides; Benzofurans; Structure-Activity Relationship

[reaction: see text] A palladium(II)-mediated cascade carbonylative annulation of o-alkynylphenols was achieved successfully on silyl linker-based macrobeads, which led to an efficient combinatorial synthesis of a 2,3-disubstituted benzo[b]furan library.

Topics: Alkynes; Benzofurans; Biological Factors; Carbon Monoxide; Catalysis; Combinatorial Chemistry Techniques; Palladium; Phenols; Resins, Synthetic

The urinary excretion of metabolites of 2,3-benzofuran was studied in Sprague-Dawley rats (n = 5) given a single dose of 150 mg/kg i.p. Urine samples were collected at defined intervals up to 7 days postdose and analyzed using (1). H NMR and directly coupled high performance liquid chromatography (HPLC)-NMR, HPLC-(mass spectrometry) MS and HPLC-MS-NMR methods. The principal metabolites were determined to be 2-hydroxyphenylacetic acid and 2-(2-hydroxyethyl)phenyl hydrogen sulfate, representing 24.3 +/- 6.0% and 19.6 +/- 6.4% of the dose, respectively. This indicates that metabolism of benzofuran to the polar species excreted in urine involves cleavage of the furan ring.

Topics: Animals; Benzofurans; Chromatography, High Pressure Liquid; Male; Mass Spectrometry; Nuclear Magnetic Resonance, Biomolecular; Rats; Rats, Sprague-Dawley

A facile anionic cyclization approach toward stereocontrolled synthesis of the hexahydrobenzofuran subunit 3 of avermectin is described. As a model study, treatment of iodo compound 7 with n-BuLi at -100 degrees C effected metal-halogen exchange and subsequent anionic cyclization to afford perhydrobenzofuranone 8. For the total synthesis of subunit 3, compound 9 was dihydroxylated to give diol 10. Protection of the hydroxyl groups of diol 10 gave compound 11. Ketone 11 was then converted into the required enone 12 using Saegusa's protocol. On iodination followed by Luche reduction, enone 12 yielded alpha-iodo allylic alcohol 14, which on alkylation afforded ether 15. Conversion of the ester unit of 15 into a Weinreb amide group followed by anionic cyclization gave enone 17. 1,4-Addition of (MeOCH(2))(2)CuCNLi(2) to enone 17 followed by cleavage of the acetal unit afforded ketone 19. Preferential acetylation of the secondary alcoholic function of 19 afforded compound 20. The stereochemistry of 20 is confirmed by single-crystal X-ray analysis. Elimination of HOAc from 20 gave the crucial olefin 21. Hydrolysis of the acetate unit of 21 followed by protection of the resulting alcoholic function yielded tert-butyldimethylsilyl ether 23. Introduction of a hydroxyl group at the ring junction of 23, using Davis's procedure, finally afforded the hexahydrobenzofuran subunit 3.

Topics: Anions; Anthelmintics; Benzofurans; Ivermectin; Molecular Structure; Spectrum Analysis

Angiotensin II (AngII) helps to regulate overall renal tubular reabsorption of salt and water, yet its effects in the distal nephron have not been well studied. The purpose of these studies was to determine whether AngII stimulates luminal Na(+) transport in the cortical collecting duct (CCD). Intracellular Na(+) concentration ([Na(+)](i)), as a reflection of Na(+) transport across the apical membrane, was measured with fluorescence microscopy using sodium-binding benzofuran isophthalate (SBFI) in isolated, perfused CCD segments dissected from rabbit kidneys. Control [Na(+)](i), during perfusion with 25 mM NaCl and a Na(+)-free solution in the bath containing the Na(+)-ionophore monensin (10 microM, to eliminate basolateral membrane Na(+) transport) averaged 19.3 +/- 5.2 mM (n = 16). Increasing luminal [NaCl] to 150 mM elevated [Na(+)](i) by 9.87 +/- 1.5 mM (n = 7; P < 0.05). AngII (10(-9) M) added to the lumen significantly elevated baseline [Na(+)](i) by 6.3 +/- 1.0 mM and increased the magnitude (Delta = 25.2 +/- 3.7 mM) and initial rate ( approximately 5 fold) of change in [Na(+)](i) to increased luminal [NaCl]. AngII when added to the bath had similar stimulatory effects; however, AngII was much more effective from the lumen. Thus, AngII significantly increased the apical entry of Na(+) in the CCD. To determine if this apical entry step occurred via the epithelial Na(+) channel (ENaC), studies were performed using the specific ENaC blocker, benzamil hydrochloride (10(-6) M). When added to the perfusate, benzamil almost completely inhibited the elevations in [Na(+)](i) to increased luminal [NaCl] in both the presence and absence of AngII. These results suggest that AngII directly stimulates Na(+) channel activity in the CCD. AT(1) receptor blockade with candesartan or losartan (10(-6) M) prevented the stimulatory effects of AngII. Regulation of ENaC activity by AngII may play an important role in distal Na(+) reabsorption in health and disease.

Topics: Amiloride; Analysis of Variance; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Benzofurans; Biphenyl Compounds; Hydrogen-Ion Concentration; Intracellular Membranes; Ionophores; Kidney Tubules, Collecting; Losartan; Mice; Microscopy, Fluorescence; Monensin; Rabbits; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Signal Transduction; Sodium Chloride; Tetrazoles

Meso substitution opposite to the spacer provides a convenient approach for tuning the pocket sizes of pillared cofacial bisporphyrins. The synthesis and coordination chemistry of xanthene and dibenzofuran anchored platforms structurally modified with 2,6-dimethoxyaryl groups are described. Comparative structural analysis of xanthene derivatives confirms the ability of the trans-aryl groups to adjust the vertical dimension of the cofacial cleft: 7 (C(97)H(106)Cl(4)N(8)O(5)), monoclinic, space group P2(1)/c, a = 28.8353(12) A, b = 17.1139(7) A, c = 17.5978(7) A, beta = 98.826(1) degrees, Z = 4; 8 (C(101)H(123)Cl(2)N(8)O(11.5)Zn(2)), monoclinic, space group P2(1)/n, a = 14.5517(6) A, b = 22.9226(10) A, c = 28.5155(13) A, beta = 90.312(14) degrees, Z = 4; 12 (C(99)H(102)Cl(14)N(8)O(5)Mn(2)), monoclinic, space group P2/c, a = 19.5891(3) A, b = 15.0741(2) A, c = 33.2019(6) A, beta = 91.947(10) degrees, Z = 4. The convenience and versatility of this synthetic method offers intriguing opportunities to specifically tailor the binding pockets of cofacial bisporphyrins for the study of small-molecule activation within a proton-coupled electron transfer framework.

Topics: Benzofurans; Catalysis; Crystallography, X-Ray; Cyclization; Iron; Magnetic Resonance Spectroscopy; Manganese; Metalloporphyrins; Methane; Molecular Conformation; Molecular Structure; Stereoisomerism; Xanthenes; Zinc

Enantioselective synthesis and absolute configuration of (-)-1-(benzofuran-2-yl)-2-propylaminopentane ((-)-BPAP), which is a highly potent and selective catecholaminergic activity enhancer (CAE) substance, are described. The synthetic approach consists of the coupling reaction of benzofuran with (R)-N-tosyl-2-propylazirizine or (R)-N-methoxy-N-methylnorvaliamide, followed by appropriate modifications of the resulting coupling products. As the results, (-)-BPAP turned out to have the R configuration, which was finally confirmed by X-ray crystallographic analysis.

Topics: Azirines; Benzofurans; Catecholamines; Crystallography, X-Ray; Molecular Conformation; Molecular Structure; Stereoisomerism

The chemical reactions between (-)-BPAP and .OH were studied using molecular orbital theory, with several simplified models. (-)-BPAP was proved to be a good radical scavenger. It was found that every atom of the benzofuran ring, except carbon 3, was capable of easily trapping the radical, where the most active site was carbon 1 on the furan part. The activation energies for the trappings were ca. 10kcal/mol by the calculations at UHF/6-31G(d)//UHF/3-21G level. Since the single radical trapping products were still radicals, these could trap further radicals by way of cascade without any activation energy. Thus, the double radical trapping products were very stable, of which the lowest energy level was about 80kcal/mol lower than the starting reactants.

Topics: Benzofurans; Carbon; Computational Biology; Energy Metabolism; Free Radical Scavengers; Hydroxyl Radical; Models, Molecular; Molecular Conformation; Spin Labels

Two concise syntheses of (+/-)-frondosin B (1), an interleukin-8 receptor antagonist, have been achieved from commercially available 5-methoxysalicylaldehyde. The seven-membered ring in ketone 33, the common intermediate for both syntheses, was built by a classical Friedel-Crafts reaction. The key step of the first route was facile cationic cyclization of the vinylogous benzofuran to the trisubstituted olefin (30 --> 16 + 38) to construct a six-membered carbocycle. Although this route demonstrated the efficacy of the stepwise approach to the frondosin ring-system, it also resulted in olefinic isomers that were easily isomerized in acidic conditions. In the second route, we utilized a Diels-Alder reaction between sterically demanding diene 42 and nitroethylene to fix the double bond in its required position in the resultant dimethylcyclohexane ring. A third total synthesis was devised for the purpose of determining the absolute configuration of frondosin B. It reached diene 42, this time in the enantiomerically defined form. From this point, naturally configured frondosin B was obtained in the enantiomerically enriched form. These studies establish the absolute configuration of the secondary methyl center in frondosin B to be R.

Topics: Aldehydes; Benzofurans; Heterocyclic Compounds, 4 or More Rings; Molecular Conformation; Receptors, Interleukin-8A; Stereoisomerism

As a continuing effort to establish the structure and activity relationship in a benzofuran type of angiotensin II antagonist, we synthesized various regioisomers and performed a series of QSAR analyses. The conformational analyses of target isomers were carried out using molecular mechanics and fine-tuned using the information from the NMR NOE experiment. The conformations of compounds with a good binding activity are quite similar to that of DuP753, a prototype of AII antagonist, suggesting that these compounds also bind to the same site of AII receptor. We then studied the compounds with a varied length of the hydroxyl group bearing side chain to find out the optimum distance between the hydroxyl group and the imidazole ring. The CoMFA with these compounds gave acceptable statistical measures (cross-validated r2 and conventional r2 to be 0.881 and 0.974, respectively) and the map was well consistent with the previously proposed pharmacophore.

Topics: Algorithms; Angiotensin Receptor Antagonists; Benzofurans; Binding, Competitive; Drug Design; Humans; Imidazoles; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Protein Binding; Quantitative Structure-Activity Relationship; Tetrazoles

Replacement of the 3,4-dialkoxyphenyl substructure common to a number of PDE4 inhibitors with a 2-alkyl-7-methoxybenzofuran unit is described. This substitution can result in either enhancement or substantial reductions in PDE4 inhibitory activity depending on the system to which it is applied. An in vitro SAR study of a potent series of 4-(2-heteroaryl-ethyl)-benzoiurans 26 is also presented.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Benzofurans; Cyclic Nucleotide Phosphodiesterases, Type 4; Endotoxemia; Enzyme Inhibitors; Male; Mice; Mice, Inbred BALB C; Structure-Activity Relationship

A cinnamoyl esterase, ferulic acid esterase A, from Aspergillus niger releases ferulic acid and 5-5- and 8-O-4-dehydrodiferulic acids from plant cell walls. The breakage of one or both ester bonds from dehydrodimer cross-links between plant cell wall polymers is essential for optimal action of carbohydrases on these substrates, but it is not known if cinnamoyl esterases can break these cross-links by cleaving one of the ester linkages which would not release the free dimer. It is difficult to determine the mechanism of the reaction on complex substrates, and so we have examined the catalytic properties of ferulic acid esterase A from Aspergillus niger using a range of synthetic ethyl esterified dehydrodimers (5-5-, 8-5-benzofuran and 8-O-4-) and two 5-5-diferulate oligosaccharides. Our results show that the esterase is able to cleave the three major dehydrodiferulate cross-links present in plant cell walls. The enzyme is highly specific at hydrolysing the 5-5- and the 8-5-benzofuran diferulates but the 8-O-4-is a poorer substrate. The hydrolysis of dehydrodiferulates to free acids occurs in two discrete steps, one involving dissociation of a monoesterified intermediate which is negatively charged at the pH of the reaction. Although ferulic acid esterase A was able to release monoesters as products of reactions with all three forms of diesters, only the 5-5- and the 8-O-4-monoesters were substrates for the enzyme, forming the corresponding free diferulic acids. The esterase cannot hydrolyse the second ester bond from the 8-5-benzofuran monoester and therefore, ferulic acid esterase A does not form 8-5-benzofuran diferulic acid. Therefore, ferulic acid esterase A from Aspergillus niger contributes to total plant cell wall degradation by cleaving at least one ester bond from the diferulate cross-links that exist between wall polymers but does not always release the free acid product.

Topics: Absorption; Aspergillus niger; Benzofurans; Carboxylic Ester Hydrolases; Catalysis; Cell Wall; Chromatography, High Pressure Liquid; Cinnamates; Cross-Linking Reagents; Dimerization; Esterases; Hydrogen-Ion Concentration; Hydrolysis; Ions; Kinetics; Magnetic Resonance Spectroscopy; Models, Chemical; Oligosaccharides; Plants; Substrate Specificity; Time Factors; Zea mays

1. The brain constituents beta-phenylethylamine (PEA) and tryptamine enhance the impulse propagation mediated transmitter release (exocytosis) from the catecholaminergic and serotoninergic neurons in the brain ('catecholaminergic/serotoninergic activity enhancer, CAE/SAE, effect'). (-)Deprenyl (Selegiline) and (-)1-phenyl-2-propylaminopentane [(-)PPAP] are amphetamine derived CAE substances devoid of the catecholamine releasing property. 2. By changing the aromatic ring in PPAP we developed highly potent and selective CAE/SAE substances, structurally unrelated to the amphetamines. Out of 65 newly synthetized compounds, a tryptamine derived structure, (-)1-(benzofuran-2-yl)-2-propylaminopentane [(-)BPAP] was selected as a potential follower of (-)deprenyl in the clinic and as a reference compound for further analysis of the CAE/SAE mechanism in the mammalian brain. 3. (-)BPAP significantly enhanced in 0.18 micromol 1(-1) concentration the impulse propagation mediated release of [(3)H]-noradrenaline and [(3)H]-dopamine and in 36 nmol 1(-1) concentration the release of [(3)H]-serotonin from the isolated brain stem of rats. The amount of catecholamines and serotonin released from isolated discrete rat brain regions (dopamine from the striatum, substantia nigra and tuberculum olfactorium, noradrenaline from the locus coeruleus and serotonin from the raphe) enhanced significantly in the presence of 10(-12) - 10(-14) M (-)BPAP. BPAP protected cultured hippocampal neurons from the neurotoxic effect of beta-amyloid in 10(-14) M concentration. In rats (-)BPAP significantly enhanced the activity of the catecholaminergic and serotoninergic neurons in the brain 30 min after acute injection of 0.1 microg kg(-1) s.c. In the shuttle box, (-)BPAP in rats was about 130 times more potent than (-)deprenyl in antagonizing tetrabenazine induced inhibition of performance.

Topics: Animals; Benzofurans; Brain; Cells, Cultured; Dopamine; Electric Stimulation; Mice; Norepinephrine; Phenethylamines; Psychotropic Drugs; Rabbits; Rats; Receptors, Catecholamine; Receptors, Serotonin; Serotonin; Tryptamines

Topics: Angiotensin Receptor Antagonists; Benzofurans; Magnetic Resonance Spectroscopy; Molecular Structure

Topics: Amiloride; Animals; Anti-Arrhythmia Agents; Benzamides; Benzofurans; Cell Hypoxia; Cells, Cultured; Enzyme Inhibitors; Heart; Lidocaine; Morpholines; Myocardium; Ouabain; Rats; Sodium; Sodium-Hydrogen Exchangers; Sodium-Potassium-Exchanging ATPase; Spectrometry, Fluorescence

Topics: Benzofurans; Capillary Permeability; Capillary Resistance; Dogs; Furans; Injections; Injections, Intraperitoneal; Pharmacology; Rabbits; Rats; Research; Toxicology

Topics: Benzofurans; Chemistry, Pharmaceutical; Dioxins; Furans; Pharmacy; Piperoxan

Topics: Antihypertensive Agents; Benzofurans; Chemistry, Pharmaceutical; Coumarins; Furans; Mice; Pharmacology; Research

Topics: Benzofurans; Biochemical Phenomena; Biochemistry; Diiodotyrosine; Enzymes; Furans; Muscle Relaxants, Central; Muscles; Research; Thyroxine; Vasodilator Agents

Topics: Benzofurans; Blood Proteins; Furans; Iodine; Iodine Isotopes; Pharmacology; Thyroid Function Tests; Thyroid Gland; Vasodilator Agents

Topics: Benzofurans; Blood Circulation; Brain; Cats; Heart; Liver Circulation; Muscles; Pharmacology; Research; Vasodilator Agents

Topics: Benzofurans; Capillary Fragility; Capillary Permeability; Capillary Resistance; Furans; Permeability; Pharmacology; Rats; Research

Topics: Benzofurans; Coronary Artery Disease; Coronary Disease; Furans; Humans; Vasodilator Agents

Topics: Benzofurans; Furans; Oxotremorine; Pyrans

Topics: Benzofurans; Blood Circulation; Coronary Vessels; Furans; Heart; Muscle, Smooth; Muscles

Topics: Analgesics; Analgesics, Non-Narcotic; Antipyretics; Benzofurans; Furans

Topics: Alkylation; Benzofurans; Coronary Vessels; Furans; Heart; Humans; Vasodilator Agents

Topics: Benzofurans; Furans; Iodides; Iodine; Research; Thyroid Gland

Topics: Animals; Benzofurans; Biological Transport; Coumarins; Humans; Male

Topics: Benzofurans; Furans; Ketones; Muscle Relaxants, Central; Parasympatholytics

Topics: Benzofurans; Coronary Artery Disease; Coumarins; Heart Failure; Humans

Topics: Benzofurans; Coumarins; Vasodilator Agents

Topics: Antifungal Agents; Benzofurans; Furans

Topics: Benzofurans