benzofurans and benzothiophene

Diabetes mellitus is a systemic disease responsible for morbidity in the western world and is gradually becoming prevalent in developing countries too. The prevalence of diabetes is rapidly increasing in industrialized countries and type 2 diabetes accounts for 90% of the disease. Insulin resistance is a major pathophysiological factor in the development of type 2 diabetes, occurring mainly in muscle, adipose tissues, and liver leading to reduced glucose uptake and utilization and increased glucose production. The prevalence and rising incidence of diabetes emphasized the need to explore new molecular targets and strategies to develop novel antihyperglycemic agents. Protein Tyrosine Phosphatase 1B (PTP 1B) has recently emerged as a promising molecular level legitimate therapeutic target in the effective management of type 2 diabetes. PTP 1B, a cytosolic nonreceptor PTPase, has been implicated as a negative regulator of insulin signal transduction. Therefore, PTP 1B inhibitors would increase insulin sensitivity by blocking the PTP 1B-mediated negative insulin signaling pathway and might be an attractive target for type 2 diabetes mellitus and obesity. With X-ray crystallography and NMR-based fragment screening, the binding interactions of several classes of inhibitors have been elucidated, which could help the design of future PTP 1B inhibitors. The drug discovery research in PTP 1B is a challenging area to work with and many pharmaceutical organizations and academic research laboratories are focusing their research toward the development of potential PTP 1B inhibitors which would prove to be a milestone for the management of diabetes.

Topics: Acetophenones; Amino Acid Sequence; Animals; Benzoates; Benzofurans; Biphenyl Compounds; Blood Glucose; Catalytic Domain; Catechols; Chromones; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Fluorides; Humans; Insulin; Insulin Resistance; Insulin Secretion; Janus Kinase 2; Models, Molecular; Naphthoquinones; Peptidomimetics; Phosphates; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Pyridazines; Receptor, Insulin; Signal Transduction; STAT3 Transcription Factor; Thiazoles; Thiazolidinediones; Thiophenes; Vanadium Compounds

To determine the anti-amoebic activity of benzofuran/benzothiophene-possessing compounds against Acanthamoeba castellanii of the T4 genotype.. A series of benzofuran/benzothiophene-possessing compounds were tested for their anti-amoebic activities, in particular, to block encystation and excystation processes in amoebae. Cytotoxicity of the compounds were evaluated using lactate dehydrogenase (LDH) assays. The amoebicidal assay results revealed significant anti-amoebic effects against A. castellanii. Compounds 1p and 1e showed the highest amoebicidal activity, eliminating 68% and 64% of the amoebae, respectively. These compounds remarkably repressed both the encystation and excystation processes in A. castellanii. Furthermore, the selected compounds presented minimal cytotoxic properties against human cells, as well as considerably abridged amoeba-mediated cytopathogenicity when compared to the amoebae alone.. Our findings show that benzofuran/benzothiophene derivatives depict potent anti-amoebic activities; thus these compounds should be used as promising and novel agents in the rationale development of therapeutic strategies against Acanthamoeba infections.

Topics: Acanthamoeba castellanii; Amebicides; Amoeba; Benzofurans; Genotype; Humans

DNA polymerases can process a wide variety of structurally diverse nucleotide substrates, but the molecular basis by which the analogs are processed is not completely understood. Here, we demonstrate the utility of environment-sensitive heterocycle-modified fluorescent nucleotide substrates in probing the incorporation mechanism of DNA polymerases in real time and at the atomic level. The nucleotide analogs containing a selenophene, benzofuran, or benzothiophene moiety at the C5 position of 2'-deoxyuridine are incorporated into oligonucleotides (ONs) with varying efficiency, which depends on the size of the heterocycle modification and the DNA polymerase sequence family used. KlenTaq (A family DNA polymerase) is sensitive to the size of the modification as it incorporates only one heterobicycle-modified nucleotide into the growing polymer, whereas it efficiently incorporates the selenophene-modified nucleotide analog at multiple positions. Notably, in the single nucleotide incorporation assay, irrespective of the heterocycle size, it exclusively adds a single nucleotide at the 3'-end of a primer, which enabled devising a simple two-step site-specific ON labeling technique. KOD and Vent(exo-) DNA polymerases, belonging to the B family, tolerate all the three modified nucleotides and produce ONs with multiple labels. Importantly, the benzofuran-modified nucleotide (BFdUTP) serves as an excellent reporter by providing real-time fluorescence readouts to monitor enzyme activity and estimate the binding events in the catalytic cycle. Further, a direct comparison of the incorporation profiles, fluorescence data, and crystal structure of a ternary complex of KlenTaq DNA polymerase with BFdUTP poised for catalysis provides a detailed understanding of the mechanism of incorporation of heterocycle-modified nucleotides.

Topics: Benzofurans; Deoxyuridine; DNA; DNA-Directed DNA Polymerase; Nucleotides; Oligonucleotides; Thiophenes

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

A series of 2-arylbenzofurans and 2-arylbenzothiophenes was synthesized carrying three different side chains in position five. The synthesized compounds were tested for NF-κB inhibition to establish a structure activity relationship. It was found that both, the side chain in position five and the substitution pattern of the aryl moiety in position two have a significant influence on the inhibitory activity.

Topics: Anti-Inflammatory Agents; Benzofurans; HEK293 Cells; Humans; Lignans; NF-kappa B; Structure-Activity Relationship; Thiophenes

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: Benzofurans; Carbazoles; Cyclopentanes; Free Radicals; Gases; Indoles; Kinetics; Models, Chemical; Models, Molecular; Molecular Structure; Polycyclic Aromatic Hydrocarbons; Thiophenes

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

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

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

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

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

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

A facile and general route to 3-((trifluoromethyl)thio)benzofurans and 3-((trifluoromethyl)thio)benzothiophenes is reported. The reactions of trifluoromethanesulfanylamide with 1-methoxy-2-alkynylbenzenes or methyl(2-alkynylphenyl)sulfanes promoted by BiCl3 proceed smoothly with broad functional group tolerance.

Topics: Benzofurans; Chemistry Techniques, Synthetic; Thiophenes

An asymmetric dearomatic Diels-Alder protocol for various heteroarenes, such as benzofuran, benzothiophene, or even furan, has been developed via π-system activation. This method involves in situ generation of formal trienamine species embedding a heteroaromatic moiety, and an array of chiral fused frameworks with high molecular complexity and skeletal diversity were efficiently constructed in good to excellent stereoselectivity by the catalysis of a cinchona-based primary amine.

Topics: Amines; Benzofurans; Catalysis; Cycloaddition Reaction; Furans; Heterocyclic Compounds, 4 or More Rings; Molecular Structure; Stereoisomerism; Thiophenes

In this study, the cometabolic degradation of carbazole (CA), dibenzofuran (DBF), and dibenzothiophene (DBT) by immobilized Arthrobacter sp. W1 cells pregrown with naphthalene was investigated. Four kinds of polymers were evaluated as immobilization supports for strain W1. After comparison with agar, alginate, and κ-carrageenan, gellan gum was selected as the optimal immobilization support. Furthermore, magnetic Fe₃O₄ nanoparticle was selected as most suitable nanoparticle for immobilization and the optimal concentration was 80 mg/L. The relationship between specific degradation rate and the initial concentration of CA, DBF and DBT was described well by Michaelis-Menten kinetics. The recycling experiments demonstrated that the magnetically immobilized cells coupling with activation zeolite showed highly bioremediation activity on the coking wastewater containing high concentration of phenol, naphthalene, CA, DBF and DBT during seven recycles. Toxicity assessment indicated the treatment of the coking wastewater by magnetically immobilized cells with activation zeolite led to less toxicity than untreated wastewater.

Topics: Arthrobacter; Benzofurans; Biodegradation, Environmental; Carbazoles; Cells, Immobilized; Coke; Kinetics; Nanoparticles; Polysaccharides, Bacterial; Thiophenes; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical

C-fused pyranoheterocycles can be readily assembled using an intramolecular oxa-Pictet-Spengler type reaction of vinylogous carbonates in a highly stereoselective manner. Required indole and benzofuran rings tethered to vinylogous carbonates are prepared by a tandem Sonogashira coupling-nucleopalladation reaction. The entire process can also be carried out in a 'one-pot' manner starting from homopropargyl alcohol. The C-fused pyranoindoles could be converted to spirooxindoles as well as to ring expanded products under oxidative conditions.

Topics: Benzofurans; Indoles; Molecular Structure; Pyrans; Stereoisomerism; Thiophenes

An iridium-catalyzed hydrogen transfer has been developed in the presence of p-benzoquinone, allowing the synthesis of a diversity of substituted benzofurans, benzothiophenes, and indoles from substituted benzylic alcohols.

Topics: Benzofurans; Benzyl Alcohols; Catalysis; Indoles; Iridium; Molecular Structure; Stereoisomerism; Thiophenes

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 general preparation of new types of benzofurans, benzothiophenes and indoles is realized via chemoselective intramolecular Wittig reactions with the corresponding ester, thioester and amide functionalities using in situ formed phosphorus ylides as key intermediates. The reaction conditions are very mild, and numerous Michael acceptors and commercially available acid chlorides can be applied very efficiently in a one-step procedure.

Topics: Amides; Benzofurans; Chlorides; Esters; Indoles; Organophosphorus Compounds; Thiophenes

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

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

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

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

Highly useful halogenated benzofurans and benzothiophenes are prepared from readily available gem-dibromoolefins using a mild, ligand-free copper catalyzed cross-coupling procedure.

Topics: Alkenes; Benzofurans; Catalysis; Copper; Halogenation; Thiophenes

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 design, synthesis and biological evaluation of lexitropsins bearing mixed heterocyclic and benzoheterocyclic moieties and tethered to an alpha-bromo acrylic moiety acting as alkylating moiety are reported, and structure-activity relationships determined. With respect to antiproliferative activity against L1210 and K562 cells, compounds 7 and 10 showed the greatest potency, while compounds 4 and 5 exhibit the lowest activity. Among the synthesized compounds 4-12, the derivative 10 was found to be the most potent member of this class and it is 70-fold more active than the bis-pyrrole counterpart 3 against L1210 cell line. In addition, the cytotoxicity of derivatives 5-12 against KB cells and the influence of different glutathione (GSH) concentrations on the cytotoxic effects was also investigated.

Topics: Animals; Antineoplastic Agents, Alkylating; Benzofurans; Drug Screening Assays, Antitumor; Heterocyclic Compounds; Humans; Imidazoles; Mice; Molecular Structure; Netropsin; Pyrazoles; Pyrroles; Structure-Activity Relationship; Thiophenes; Tumor Cells, Cultured

The stability and replication of DNA containing self-pairs formed between unnatural nucleotides bearing benzofuran, benzothiophene, indole, and benzotriazole nucleobases are reported. These nucleobase analogues are based on a similar scaffold but have different hydrogen-bond donor/acceptor groups that are expected to be oriented in the duplex minor groove. The unnatural base pairs do not appear to induce major structural distortions and are accommodated within the constraints of a B-form duplex. The differences between these unnatural base pairs are manifest only in the polymerase-mediated extension step, not in base-pair stability or synthesis. The benzotriazole self-pair is extended with an efficiency that is only 200-fold less than a correct natural base pair. The data are discussed in terms of available polymerase crystal structures and imply that further modifications may result in unnatural base pairs that can be both efficiently synthesized and extended, resulting in an expanded genetic alphabet.

Topics: Base Pairing; Benzofurans; Circular Dichroism; DNA; Hydrogen Bonding; Indoles; Kinetics; Nucleotides; Thiophenes; Triazoles

Bacterial samples were collected from three marine beaches in coastal Newfoundland, Canada, and enriched by growth on 1-methylnaphthalene. The most prominent bacterial cell type for each consortium was isolated in a serial dilutions test, and a substrate utilization profile was obtained for each using the Biolog MicroStation System. Each bacterial community was tested for its ability to co-metabolize sulfur heterocycles (benzothiophene: BT, 3-methylbenzothiophene: 3-MBT, and dibenzothiphene: DBT), a nitrogen heterocycle (carbazole: CARB), and an oxygen heterocycle (dibenzofuran: DBF). Co-metabolism of the starting material was determined using gas chromatography-mass spectroscopy (GC-MS), and formation of products was investigated by GC-MS and Fourier transform infrared (FTIR) spectroscopy. Bacterial growth was monitored turbidimetrically to determine the dry weight (microgram) of cells/ml. The 2-ringed heterocycles were co-metabolized faster and to a greater extent than the 3-ringed compounds. Co-metabolism of BT was not statistically different from that for 3-MBT and, likewise, a comparison of the 3-ringed heterocycles showed no significant differences in degradation rates. Statistical examination showed that no one culture demonstrated a significantly greater ability to co-metabolize the heterocycles studied. This study represents the first comprehensive investigation of the ability of local bacteria to co-metabolize a range of aromatic compounds and provides a preliminary understanding of their fate in sediments should contamination by these compounds occur.

Topics: Aerobiosis; Benzofurans; Biodegradation, Environmental; Carbazoles; Ecosystem; Gas Chromatography-Mass Spectrometry; Gram-Negative Bacteria; Heterocyclic Compounds; Newfoundland and Labrador; Nitrogen; Oxygen; Seawater; Spectroscopy, Fourier Transform Infrared; Sulfur; Thiophenes

Normal human melanocytes were amplified and cultured in a new defined culture medium without phorbol esters or cholera toxin. The medium decreased considerably the doubling time and increased the possible passage number. Melanocytes were co-seeded with normal human keratinocytes into 24 well culture dishes to screen potentially active modulators of melanogenesis. For the assay, the co-cultures were exposed to the compounds under investigation in the presence of 14C-thiouracil and 3H-leucine. Control cultures contain L-tyrosine or kojic acid, modulators which served as internal calibration standards. Changes in the rate of melanin synthesis were measured on the basis of 14C-thiouracil incorporation into newly synthesized melanin. A reduction or increase in 3H-leucine incorporation was taken as an indication of cytotoxicity or induction of proliferation, respectively. The NHK-NHM co-culture screening assay provides a useful tool to compare the activity of known modulators of melanogenesis and to perform structure-activity studies with newly identified modulators to improve their activity. The efficacy of particularly interesting new compounds was further evaluated on reconstructed pigmented epidermis after repeated topical application. The same model was used to assess the anti-pigmenting effect of sunscreens on UV-induced pigmentation. Integration of melanocytes from different ethnic origin resulted in pigmented epidermis reflecting different skin phenotypes, Caucasian, Asian and African.

Topics: 1-Methyl-3-isobutylxanthine; 3T3 Cells; Animals; Arbutin; Asian People; Benzofurans; Black People; Cells, Cultured; Coculture Techniques; Culture Media; Epidermal Cells; Ethnicity; Humans; Hydroquinones; Hydroxybenzoates; Indoles; Keratinocytes; Melanins; Melanocytes; Mice; Phenotype; Pyrones; Skin Pigmentation; Skin, Artificial; Theophylline; Thiophenes; Ultraviolet Rays; White People