1-1-diphenyl-2-picrylhydrazyl and Alzheimer-Disease

On the basis of our previous work, a novel series of (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives were synthesized and evaluated as multifunctional ligands for the treatment of Alzheimer's disease (AD). Biological evaluations indicated that the derivatives can be used as anti-AD drugs that have multifunctional properties, inhibit the activity of butyrylcholinesterase (BuChE), inhibit neuroinflammation, have neuroprotective properties, and inhibit the self-aggregation of Aβ. Compound f9 showed good potency in BuChE inhibition (IC

Topics: Acetamides; Alzheimer Disease; Amyloid beta-Peptides; Antioxidants; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Humans; Molecular Structure; Neuroprotective Agents; Oxadiazoles; Picrates; Protein Aggregates; Structure-Activity Relationship

Black soybeans contain several bioactive compounds and commonly consumed due to their health-related activities but rarely cultivated as edible sprouts. The present study investigated the changes that occurred during germination in two new genotypes black soybeans. Raw and germinated seeds were tested against in vitro Alzheimer's disease (AD) biomarkers, including oxidative stress, inflammatory factors and cholinesterase enzymes as well as γ-aminobutyric acid (GABA) levels. Sprouts significantly inhibited the cholinesterase enzymes and inflammatory factors (protein denaturation, proteinase and lipoxygenase) than seeds. An increase in phenolic, flavonoid and GABA (10-folds) content and antioxidant capacity (ABTS, DPPH, and FRAP) was observed in germinated seeds. However, anthocyanin content was decreased in sprouts. UHPLC-ESI-QTOF-MS2 metabolites profiling approach identified 22 compounds including amino acids, peptides, fatty acids, and polyphenols. Among identified compounds, daidzein, genistein, gallic acid, spermidine, L-asparagine, and L-lysine exhibited the highest increase after germination. The current study reveals that germination of black soybeans have promising potential to inhibit/prevent AD and can be used to develop functional foods.

Topics: Alzheimer Disease; Anthocyanins; Antioxidants; Benzothiazoles; Biphenyl Compounds; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Flavonoids; Fluorescence Recovery After Photobleaching; gamma-Aminobutyric Acid; Germination; Glycine max; Metabolome; Phenols; Phytochemicals; Picrates; Plant Extracts; Principal Component Analysis; Spectrometry, Mass, Electrospray Ionization; Sulfonic Acids; Tandem Mass Spectrometry

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Biological Products; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Coumaric Acids; Dose-Response Relationship, Drug; Horses; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Picrates; Piperazine; Structure-Activity Relationship

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid; Antioxidants; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Indolizines; Molecular Structure; Picrates; Pyridinium Compounds; Structure-Activity Relationship

The pathogenesis of Alzheimer's disease (AD) is still unclear, and presently there is no cure for the disease that can be used for its treatment or to stop its progression. Here, we investigated the therapeutic potential of ramalin (isolated from the Antarctic lichen,

Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Anti-Inflammatory Agents; Antioxidants; Aspartic Acid Endopeptidases; Biphenyl Compounds; Glutamates; Humans; Molecular Structure; Picrates

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Benzothiazoles; Benzylamines; Biphenyl Compounds; Butyrylcholinesterase; Cell Survival; Cells, Cultured; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Design; Electrophorus; Horses; Male; Mice; Mice, Inbred Strains; Molecular Structure; Neuroprotective Agents; Picrates; Rats; Structure-Activity Relationship; Sulfonic Acids; Xanthones

A series of novel dihydropyranoindole derivatives containing sulphonamide group were designed, synthesized and evaluated for in-vitro anti-cholinesterase activity. The result showed that all the compounds exhibited potent acetylcholinesterase (AChE) activity (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Biphenyl Compounds; Butyrylcholinesterase; Cell Line, Tumor; Cell Survival; Cholinesterase Inhibitors; DNA Damage; Dose-Response Relationship, Drug; Drug Design; Free Radical Scavengers; Humans; Hydrogen Peroxide; Indoles; Molecular Structure; Picrates

A set of novel hydrazone derivatives were synthesized and analyzed for their biological activities. The compounds were tested for their inhibitory effect on the phosphorylating activity of the protein kinase CK2, and their antioxidant activity was also determined in three commonly used assays. The hydrazones were evaluated for their radical scavenging against the DPPH, ABTS and peroxyl radicals. Several compounds have been identified as good antioxidants as well as potent protein kinase CK2 inhibitors. Most hydrazones containing a 4-N(CH

Topics: Alzheimer Disease; Antioxidants; Benzothiazoles; Biphenyl Compounds; Casein Kinase II; Fluorocarbons; Humans; Hydrazones; Picrates; Protein Kinase Inhibitors; Sulfonic Acids

Alzheimer's disease (AD) is multi-factorial disorder characterized by impaired memory and cognition deficit. AD is characterized by impaired cholinergic transmission, extracellular amyloid beta deposits, neurofibrillary tangles and oxidative stress. A multi-target directed ligand (MTDL) approach is required to devise a therapeutic strategy against AD. In the present study, Asparagus racemosus aqueous extract was chosen, as it possess abundant medicinal properties including nootropic effect mentioned in ancient Ayurvedic texts. Moreover, its secondary metabolite sarsasapogenin (SRS) was also selected for this multi-target study for the very first time. The current study demonstrated that sarsasapogenin significantly inhibits key enzymes involved in pathogenesis of AD which are acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), BACE1 and MAO-B in a concentration dependent manner. SRS also exhibited anti-amyloidogenic, anti-oxidant and neuroprotective effects by in vitro studies. The IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Amyloid Precursor Protein Secretases; Animals; Antioxidants; Asparagus Plant; Aspartic Acid Endopeptidases; Biphenyl Compounds; Butyrylcholinesterase; Cell Survival; Electrophorus; Enzyme Inhibitors; Horses; Humans; Ligands; Monoamine Oxidase; Neuroprotective Agents; Oxidative Stress; PC12 Cells; Picrates; Rats; Spirostans

Multi-target drugs can better address the cascade of events involved in oxidative stress and the reduction in cholinergic transmission that occur in Alzheimer's disease than cholinesterase inhibitors alone. We synthesised a series of 3-arylbenzofuranone derivatives and evaluated their antioxidant activity, cholinesterase inhibitory activity, and monoamine oxidase inhibitory activity. 3-Arylbenzofuranone compounds exhibit good antioxidant activity as well as selective acetylcholinesterase inhibitory activity. The IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Anti-Anxiety Agents; Antioxidants; Benzofurans; Biphenyl Compounds; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Picrates; Rats; Rats, Wistar; Structure-Activity Relationship

Acylhydrazones 1a-o, derived from isoniazid, were synthesized and evaluated for Myeloperoxidase (MPO) and Acetylcholinesterase (AChE) inhibition, as well as their antioxidant and metal chelating activities, with the purpose of investigating potential multi-target profiles for the treatment of Alzheimer's disease. Synthesized compounds were tested using the 2,2-diphenyl-2-picrylhydrazyl (DPPH) method and 1i, 1j and 1 m showed radical scavenging ability. Compounds 1b, 1 h, 1i, 1 m and 1o inhibited MPO activity (10 μM) at 96.1 ± 5.5%, 90 ± 2.1%, 100.3 ± 1.7%, 80.1 ± 9.4% and 82.2 ± 10.6%, respectively, and only compound 1 m was able to inhibit 54.2 ± 1.7% of AChE activity (100 μM). Docking studies of the most potent compound 1 m were carried out, and the computational results provided the theoretical basis of enzyme inhibition. Furthermore, compound 1 m was able to form complexes with Fe

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Biphenyl Compounds; Chelating Agents; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Humans; Hydrazones; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; Peroxidase; Picrates; Structure-Activity Relationship

A number of novel naphthalimido and phthalimido vanillin derivatives were synthesised, and evaluated as antioxidants and cholinesterase inhibitors in vitro. Antioxidant activity was assessed using DPPH, FRAP, and ORAC assays. All compounds demonstrated enhanced activity compared to the parent compound, vanillin. They also exhibited BuChE selectivity in Ellman's assay. A lead compound, 2a (2-(3-(bis(4-hydroxy-3-methoxybenzyl)amino)propyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione), was identified and displayed strong antioxidant activity (IC

Topics: Acetylcholinesterase; Alzheimer Disease; Antioxidants; Benzaldehydes; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Humans; Models, Molecular; Molecular Structure; Neuroprotective Agents; Picrates; Structure-Activity Relationship

Facing the complexity of Alzheimer's disease (AD), it is now currently admitted that a therapeutic pleiotropic intervention is needed to alter its progression. Among the major hallmarks of the disease, the amyloid pathology and the oxidative stress are closely related. We propose in this study to develop original Multi-Target Directed Ligands (MTDL) able to impact at the same time Aβ protein accumulation and toxicity of Reactive Oxygen Species (ROS) in neuronal cells. Such MTDL were obtained by linking on a central piperidine two scaffolds of interest: a typical aminochlorobenzophenone present in numerous 5-HT

Topics: Alzheimer Disease; Animals; Antioxidants; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorocebus aethiops; COS Cells; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Ligands; Molecular Structure; Picrates; Reactive Oxygen Species; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship

A group of N-benzylpiperidine-3/4-carbohydrazide-hydrazones were designed, synthesized and evaluated for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) activities, Aβ

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Benzothiazoles; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Horses; Humans; Hydrazones; Models, Molecular; Molecular Structure; Neuroprotective Agents; Picrates; Piperidines; Structure-Activity Relationship; Sulfonic Acids

Alzheimer's disease (AD) is a well-known neurodegenerative disorder affecting millions of old people worldwide and the corresponding epidemiological data emphasize the importance of the disease. As AD is a multifactorial illness, various single target directed drugs that have reached clinical trials have failed. Therefore, various factors associated with outset of AD have been considered in targeted drug discovery. In this work, various benzochromenoquinolinones were synthesized and evaluated for their cholinesterase and BACE1 inhibitory activities as well as neuroprotective and metal-chelating properties. Among the synthesized compounds, 14-amino-13-(3-nitrophenyl)-2,3,4,13-tetrahydro-1H-benzo[6,7]chromeno[2,3-b]quinoline-7,12-dione (6m) depicted the best inhibitory activity toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) with IC

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Electrophorus; Horses; Kinetics; Molecular Docking Simulation; Molecular Structure; Neurons; Neuroprotective Agents; PC12 Cells; Peptide Fragments; Picrates; Quinolones; Rats; Structure-Activity Relationship

Alzheimer disease is a complex neurodegenerative disorder. It is the common form of dementia in elderly people. The etiology of this disease is multifactorial, pathologically it is accompanied with accumulation of amyloid beta and neurofibrillary tangles. Accumulation of amyloid beta and mitochondrial dysfunction leads to oxidative stress. In this study, neuroprotective effect of Artemisiaamygdalina against H

Topics: Alzheimer Disease; Animals; Artemisia; Biphenyl Compounds; Cell Line, Tumor; Cell Nucleus; Cell Shape; Cell Survival; Free Radical Scavengers; Heme Oxygenase-1; Humans; Hydrogen Peroxide; Hydroxyl Radical; Membrane Potential, Mitochondrial; Mice; Neurons; Neuroprotective Agents; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Phenols; Picrates; Plant Extracts; Superoxides; Up-Regulation

A series of compounds following the lead compounds including deferasirox and tacrine were designed, synthesized and evaluated as multifunctional agents against Alzheimer's disease (AD). In vitro studies showed that most synthesized compounds exhibited good multifunctional activities in inhibiting acetylcholinesterase (bAChE), and chelating metal ions. Especially, compound TD

Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Biphenyl Compounds; Cattle; Cell Survival; Chelating Agents; Cholinesterase Inhibitors; Coordination Complexes; Dose-Response Relationship, Drug; Drug Design; Free Radical Scavengers; Hydrogen Peroxide; Models, Molecular; Molecular Structure; Neuroprotective Agents; PC12 Cells; Picrates; Rats; Structure-Activity Relationship

A series of (3-hydroxy-4-pyridinone)-benzofuran hybrids have been developed and studied as potential multitargeting drugs for Alzheimer's disease (AD). Their design envisaged mainly to mimic the donepezil drug, a marketed inhibitor of acetylcholinesterase (AChE), and to endow the conjugate molecules with extra-properties such as metal chelation, radical scavenging and inhibition of amyloid peptide (Aβ) aggregation. Thus, a set of eleven new hybrid compounds was developed and evaluated for chemical and biological properties, in solution and in neuronal cell environment. The results are discussed in terms of the type of substituents on both main moieties and the linker size. The closest similarity with donepezil, in terms of AChE inhibitory activity, was obtained for the O-benzyl-hydroxypyridinone hybrids containing a 2-methylene linker, although still less active than the drug. However, the free-hydroxypyridinone hybrids present higher activity for the Aβ aggregation inhibition, metal chelating capacity and radical scavenging activity. Overall, some compounds demonstrated capacity to exert a multiple action by hitting three- (7d) or four- (8d, 8f) pathophysiological targets of AD. Furthermore, the compounds showed neuroprotective effects in neuronal cells subjected to model stressors of AD, but not significant dependence on the substituent groups. Importantly, the compounds evidenced drug-likeness properties, including good membrane permeability.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Benzofurans; Biphenyl Compounds; Cholinesterase Inhibitors; Copper; Free Radical Scavengers; Iron; Iron Chelating Agents; Molecular Docking Simulation; Neuroprotective Agents; Peptide Fragments; Picrates; Protein Multimerization; Pyridones

Plane tree (Platanus orientalis L.) leaves have been employed for centuries in various countries due to their pharmacological value. Therefore, determination of the biological activity of the leaves is of interest. The aim of the study was to evaluate the inhibitory effects against Alzheimer's disease-related enzymes Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE), diabetes mellitus related enzymes α-glucosidase and α-amylase. The antioxidant, anticancer, and antimicrobial activities of the leaves were also studied. According to the results, both water and methanol extracts of P. orientalis demonstrated more α-glucosidase and α-amylase inhibition activity than the antidiabetic drug-acarbose at the same concentration level. In addition, extracts showed good inhibition activity against AChE and BuChE. Significant results were obtained regarding antioxidant, anticancer, and antimicrobial activities. These results are very promising especially for the improvement of pharmaceutical formulations to treat various diseases such as age-related diseases, cancer, diabetes etc. and it is necessary to conduct further experiments.

Topics: Alzheimer Disease; Anti-Infective Agents; Antioxidants; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Diabetes Mellitus; Fluorescence Recovery After Photobleaching; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Picrates; Plant Extracts; Plant Leaves

Nine new phenylpropanoids, one new coumarin, and 43 known polyphenols were isolated from wolfberry. Their structures were determined by spectroscopic analyses, chemical methods, and comparison of NMR data. Polyphenols, an important type of natural products, are notable constituents in wolfberry. 53 polyphenols, including 28 phenylpropanoids, four coumarins, eight lignans, five flavonoids, three isoflavonoids, two chlorogenic acid derivatives, and three other constituents, were identified from wolfberry. Lignans and isoflavonoids were firstly reported from wolfberry. 22 known polyphenols were the first isolates from the genus Lycium. This research presents a systematic study on wolfberry polyphenols, including their bioactivities. All these compounds exhibited oxygen radical absorbance capacity (ORAC), and some compounds displayed DPPH radical scavenging activity. One compound had acetylcholinesterase inhibitory activity. The discovery of new polyphenols and their bioactivities is beneficial for understanding the scientific basis of the effects of wolfberry.

Topics: Acetylcholinesterase; Alzheimer Disease; Benzothiazoles; Biphenyl Compounds; Chlorogenic Acid; Cholinesterase Inhibitors; Flavonoids; Food Analysis; Free Radical Scavengers; Free Radicals; Lignans; Lycium; Molecular Structure; Oxygen; Picrates; Plant Extracts; Polyphenols; Spectrophotometry, Ultraviolet; Structure-Activity Relationship; Thiazoles

In this study, a series of novel ferulic and caffeic acid dimers was designed and synthesised, and their multifunctional properties against Alzheimer's disease (AD) were evaluated. Results showed that our multifunctional strategy was great supported by enhancing the inhibition of Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Biphenyl Compounds; Caffeic Acids; Cell Death; Cell Line; Coumaric Acids; Free Radical Scavengers; Glutamic Acid; Humans; Mice; Neurons; Peptide Fragments; Picrates

A novel series of tacrine derivatives containing sulfonamide group were synthesized and their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were evaluated. The result showed that all the synthesized tacrine-sulfonamides (VIIIa-o) exhibited inhibitory activity on both cholinesterases. VIIIg showed the highest inhibitory activity on AChE IC

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Benzothiazoles; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Electrophorus; Free Radicals; Horses; Humans; Microwaves; Picrates; Sulfonamides; Sulfonic Acids; Tacrine

Combining tacrine with trolox in a single molecule, novel multifunctional hybrids have been designed and synthesized. All these hybrids showed ChE inhibitory activity in nanomolar range and strong antioxidant activity close to the parent compound trolox. Among them, compound 6d was the most potent inhibitor against AChE (IC50 value of 9.8 nM for eeAChE and 23.5 nM for hAChE), and it was also a strong inhibitor to BuChE (IC50 value of 22.2 nM for eqBuChE and 20.5 nM for hBuChE). Molecular modeling and kinetic studies suggested that 6d was a mixed-type inhibitor, binding simultaneously to CAS and PAS of AChE. In vivo hepatotoxicity assays indicated that 6d was much less toxic than tacrine. In addition, it showed neuroprotective effect and good ability to penetrate the BBB. Overall, all these results highlighted 6d a promising multifunctional agent for AD treatment.

Topics: Alzheimer Disease; Animals; Antioxidants; Biphenyl Compounds; Blood-Brain Barrier; Cell Survival; Chemical and Drug Induced Liver Injury; Cholinesterase Inhibitors; Chromans; Drug Design; In Vitro Techniques; Kinetics; Male; Molecular Docking Simulation; Molecular Structure; Neuroprotective Agents; PC12 Cells; Picrates; Rats; Swine; Tacrine

The aim of this study was to investigate chemical constituents of the leaves of Acanthopanax henryi, and their antioxidant, acetyl cholinesterase inhibitory activities. Caffeoyl quinic acid derivates and flavonoids were obtained from A. henry, through column chromatography technologies, and the content of major constituents was determined by the HPLC-UV method. Anti-oxidant activity of the isolated metabolites was evaluated by free radical scavenging (DPPH, ABTS radicals) and superoxide anion scavenging. The results showed that di-caffeoyl quinic acid derivates had stronger antioxidant activity than positive controls (ascorbic acid, trolox and allopurinol). Acetyl cholinesterase inhibitory activity was estimated on the constituents, among which, quercetin, 4-caffeoyl-quinic acid and 4,5-caffeoyl quinic acid were found to have strong acetyl cholinesterase inhibitory activity with IC50 values ranging from 62.6 to 121.9 μM. The present study showed that some of the tested constituents from the leaves of A. henryi exhibit strong antioxidant and acetyl cholinesterase inhibitory effects. This suggest that the leaves of A. henryi can be used as a new natural complementary source of acetyl cholinesterase inhibitors and anti-oxidant agents, thus being a promising potential complementary source against Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Antioxidants; Benzothiazoles; Biphenyl Compounds; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Eleutherococcus; Humans; Molecular Structure; Phytotherapy; Picrates; Plant Extracts; Plant Leaves; Plants, Medicinal; Quercetin; Quinic Acid; Spectrophotometry, Ultraviolet; Sulfonic Acids

The present study aimed to evaluate acetylcholinesterase (AChE) inhibitory and antioxidant activities of Lamiaceae medicinal plants growing wild in Croatia. Using Ellman's colorimetric assay all tested ethanolic extracts and their hydroxycinnamic acid constituents demonstrated in vitro AChE inhibitory properties in a dose dependent manner. The extracts of Mentha x piperita, M. longifolia, Salvia officinalis, Satureja montana, Teucrium arduini, T. chamaedrys, T. montanum, T. polium and Thymus vulgaris at 1 mg/mL showed strong inhibitory activity against AChE. The antioxidant potential of the investigated Lamiaceae species was assessed by DPPH• scavenging activity and total antioxidant capacity assays, in comparison with hydroxycinnamic acids and trolox. The extracts differed greatly in their total hydroxycinnamic derivatives content, determined spectrophotometrically. Rosmarinic acid was found to be the predominant constituent in most of the investigated medicinal plants (by RP-HPLC) and had a substantial influence on their AChE inhibitory and antioxidant properties, with the exception of Teucrium species. These findings indicate that Lamiaceae species are a rich source of various natural AChE inhibitors and antioxidants that could be useful in the prevention and treatment of Alzheimer's and other related diseases.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Biphenyl Compounds; Cholinesterase Inhibitors; Chromans; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Cinnamates; Coumaric Acids; Depsides; Drug Discovery; Eels; Fish Proteins; Free Radical Scavengers; Free Radicals; Humans; Lamiaceae; Picrates; Plant Extracts; Plants, Medicinal; Rosmarinic Acid

To investigate the effect of C-glycosylation at different positions of luteolin, the structure-activity relationships of luteolin and a pair of isomeric C-glycosylated derivatives orientin and isoorientin, were evaluated. We investigated the effects of C-glycosylation on the antioxidant, anti-Alzheimer's disease (AD), anti-diabetic and anti-inflammatory effects of luteolin and its two C-glycosides via in vitro assays of peroxynitrite (ONOO(-)), total reactive oxygen species (ROS), nitric oxide (NO), 1,1-diphenyl-2-picrylhydraxyl (DPPH), aldose reductase, protein tyrosine phosphatase 1B (PTP1B), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor cleaving enzyme 1 (BACE1), and cellular assays of NO production and inducible nitric oxide synthase (iNOS)/cyclooxygenase-2 expression in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. Of the three compounds, isoorientin showed the highest scavenging activity against DPPH, NO, and ONOO(-), while luteolin was the most potent inhibitor of ROS generation. In addition, luteolin showed the most potent anti-AD activity as determined by its inhibition of AChE, BChE, and BACE1. With respect to anti-diabetic effects, luteolin exerted the strongest inhibitory activity against PTP1B and rat lens aldose reductase. Luteolin also inhibited NO production and iNOS protein expression in LPS-stimulated macrophages, while orientin and isoorientin were inactive at the same concentrations. The effects of C-glycosylation at different positions of luteolin may be closely linked to the intensity and modulation of antioxidant, anti-AD, anti-diabetic, and anti-inflammatory effects of luteolin and its C-glycosylated derivatives.

Topics: Aldehyde Reductase; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Anti-Inflammatory Agents; Antioxidants; Aspartic Acid Endopeptidases; Biphenyl Compounds; Cell Survival; Cells, Cultured; Cholinesterase Inhibitors; Cyclooxygenase 2 Inhibitors; Flavonoids; Glucosides; Glycosylation; Hypoglycemic Agents; In Vitro Techniques; Luteolin; Nitric Oxide; Nitric Oxide Synthase Type II; Peroxynitrous Acid; Picrates; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Rats; Reactive Oxygen Species; Structure-Activity Relationship

Herein, we report the antioxidant properties of some selected substituted 2-indolyl carbohydrazides (JL34, JL40, JL71, JL87, JL317, JL432, JL436), the substituted 3-indolyl carbohydrazide JL344, 3-(3-hydrazinylpropyl)-1H-indole (JL72) and 3-(1H-indol-3-yl)propanehydrazide (JL418), throughout the assessment of their antioxidative potential using different antioxidant assays such as DPPH, lipid peroxidation in the APPH, or the DMSO method. We conclude that these compounds are convenient templates for the design of useful drugs in to treat Alzheimer's disease (AD), a pathology characterized by extensive oxidative stress and inflammation, thus essentially affected by reactive oxygen species (ROS). Most of them are potent hydroxyl radical scavengers and inhibit in vitro lipid peroxidation. Compounds JL40 and JL432 presenting higher lipoxygenase inhibitory activity among the tested derivatives, were found to present a promising anti-inflammatory in vivo result, as well as antioxidant and LOX inhibitory profile. These results in combination to their known AChE/BuChE inhibitory activities led us to propose these indolyl carbohydrazides as new multifunctional compounds against AD.

Topics: Alzheimer Disease; Animals; Antioxidants; Biocatalysis; Biphenyl Compounds; Carrageenan; Edema; Female; Free Radical Scavengers; Humans; Hydrazines; Lipid Peroxidation; Lipoxygenase; Male; Molecular Structure; Oxidation-Reduction; Picrates; Rats; Rats, Inbred F344; Structure-Activity Relationship

Egyptians recognized the healing power of herbs and used them in their medicinal formulations. Nowadays, "Attarin" drug shops and the public use mainly the Unani medicinal system for treatment of their health problems including improvement of memory and old age related diseases. Numerous medicinal plants have been described in old literature of Arabic traditional medicine for treatment of Alzheimer's disease (AD) (or to strengthen memory).. In this study, some of these plants were evaluated against three different preliminary bioassays related to AD to explore the possible way of their bio-interaction. Twenty three selected plants were extracted with methanol and screened in vitro against acetylcholinesterase (AChE) and cycloxygenase-1 (COX-1) enzymes. In addition, anti-oxidant activity using DPPH was determined.. Of the tested plant extracts; Adhatoda vasica and Peganum harmala showed inhibitory effect on AChE at IC50 294 μg/ml and 68 μg/ml respectively. Moreover, A. vasica interacted reversibly with the enzyme while P. harmala showed irreversible inhibition. Ferula assafoetida (IC50 3.2 μg/ml), Syzygium aromaticum (34.9 μg/ml) and Zingiber officinalis (33.6 μg/ml) showed activity against COX-1 enzyme. Potent radical scavenging activity was demonstrated by three plant extracts Terminalia chebula (EC50 2.2 μg/ml), T. arjuna (3.1 μg/ml) and Emblica officinalis (6.3 μg/ml).. Interestingly, differential results have been obtained which indicate the variability of the mode of actions for the selected plants. Additionally, the reversible interaction of A. vasica against AChE and the potent activity of F. assafoetida against COX-1 make them effective, new and promising agents for treatment of AD in the future, either as total extracts or their single bioactive constituents.

Topics: Acetylcholinesterase; Aged; Alzheimer Disease; Antioxidants; Biphenyl Compounds; Cholinesterase Inhibitors; Cyclooxygenase 1; Egypt; Ferula; Herbal Medicine; Humans; Justicia; Magnoliopsida; Medicine, Traditional; Peganum; Phyllanthus emblica; Phytotherapy; Picrates; Plant Extracts; Plants, Medicinal; Terminalia

A new series of tacrine-flavonoid hybrids (13a-u) had been designed, synthesized, and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). In vitro studies showed that most of the molecules exhibited a significant ability to inhibit ChE and self-induced amyloid-β (Aβ₁₋₄₂) aggregation. Kinetic and molecular modeling studies also indicated compounds were mixed-type inhibitors, binding simultaneously to active, peripheral and mid-gorge sites of AChE. Particularly, compound 13k was found to be highly potent and showed a balanced inhibitory profile against ChE and self-induced Aβ₁₋₄₂ aggregation. Moreover, it also showed excellent metal chelating property and low cell toxicity. These results suggested that 13k might be an excellent multifunctional agent for AD treatment.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Biphenyl Compounds; Cell Line, Tumor; Cell Proliferation; Chelating Agents; Cholinesterase Inhibitors; Cholinesterases; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Flavonoids; Free Radical Scavengers; Humans; Mice; Neuroblastoma; Organometallic Compounds; Oxidation-Reduction; Peptide Fragments; Picrates; Structure-Activity Relationship; Tacrine

In this study, the protective effects of Brussels sprouts extract and its major constituents against oxidative stress-induced damages were investigated in rat pheochromocytoma cells and Institute of Cancer Research mice. The major constituents of Brussels sprouts (3,4',5,7-tetrahydroxyflavone (kaempferol), indole-3-carbinol, and phenethyl isothiocyanate) were selectively tested. Of these, the flavonoid compound, kaempferol exhibited the highest potency in radical scavenging activity (1,1-diphenyl-2-picryl hydrazyl assay and oxygen radical absorbance capacity assay) and was most protective against oxidative stress in neuronal cell assays (measurement of intracellular oxidative stress levels and cell viability). In mice, after 4 weeks of kaempferol administration, significant protection against amyloid beta (Aβ) peptide-induced neurotoxicity was also observed, as assessed through the passive avoidance test. Taken together, the results suggest that Brussels sprouts could be protective against Aβ-induced neurotoxicity, possibly due to the antioxidative capacity of its major constituent, kaempferol.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Antioxidants; Biphenyl Compounds; Brain; Brassica; Cell Survival; Indoles; Isothiocyanates; Kaempferols; Mice; Mice, Inbred ICR; Neuroprotective Agents; Neurotoxicity Syndromes; Oxidative Stress; PC12 Cells; Picrates; Plant Extracts; Rats

Our previous research showed that standardized extract from the flowers of the Gossypium herbaceam labeled GHE had been used in clinical trials for its beneficial effects on brain functions, particularly in connection with age-related dementia and Alzheimer's disease (AD). The aim of this work was to determine the components of this herb and the individual constituents of GHE. In order to better understand this herb for AD treatment, we investigated the acetylcholinesterase (AChE) inhibition and antioxidant activity of GHE as well as the protective effects to PC12 cells against cytotoxicity induced by tertiary butyl hydroperoxide (tBHP) using in vitro assays. The antioxidant activities were assessed by measuring their capabilities for scavenging 1,1-diphenyl-2-picylhydrazyl (DPPH) and 2-2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) free radical as well as in inhibiting lipid peroxidation. Our data showed that GHE exhibited certain activities against AChE and also is an efficient free radical scavenger, which may be helpful in preventing or alleviating patients suffering from AD.

Topics: Alkaloids; Alzheimer Disease; Animals; Benzothiazoles; Biphenyl Compounds; Cell Survival; Cholinesterase Inhibitors; Chromatography, High Pressure Liquid; Flavonols; Flowers; Free Radical Scavengers; Free Radicals; Gossypium; Inhibitory Concentration 50; Lipid Peroxidation; Oxidative Stress; PC12 Cells; Picrates; Plant Extracts; Rats; Sesquiterpenes; Sulfonic Acids

Alzheimer's disease (AD) pathogenesis involves an imbalance between free radical formation and destruction. In order to obtain a novel preclinical anti-AD drug candidate, we synthesized a series of novel hydroxyl chalcone analogs which possessed anti-free radical activity, and screened their effects on scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) and OH free radicals in vitro. Compound C7, 4,2'-dihydroxy-3,5-dimethoxychalcone was found to have potent activity in these anti-free radical activity tests. Further research revealed that C7 could elevate glutathione peroxidase (GSH-PX) and super oxide dismutase (SOD) levels and lower malonaldehyde (MDA) level in vivo in the Alzheimer's model. The indication of C7's effect on AD needs further study.

Topics: Alzheimer Disease; Animals; Benzophenones; Biphenyl Compounds; Brain; Chalcone; Disease Models, Animal; Free Radical Scavengers; Free Radicals; Glutathione Peroxidase; Hydroxylation; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Malondialdehyde; Mice; Oxidation-Reduction; Picrates; Scopolamine; Superoxide Dismutase

This study sought to characterize the effects of some citrus fruit juices (shaddock [Citrus maxima], grapefruit [Citrus paradisii], lemon [Citrus limoni], orange [Citrus sinensis], and tangerine [Citrus reticulata]) on acetylcholinesterase activity in vitro. The total phenolic content, radical scavenging abilities, and inhibition of Fe(2+)-induced malondialdehyde (MDA) production in rats brain homogenate in vitro were also assessed. Orange had significantly (P<.05) higher phenolic content than the other juices. The juices scavenged 1,1-diphenyl-2-picrylhydrazyl and hydroxyl radicals in a dose-dependent manner with orange having the highest scavenging ability. Furthermore, the juices inhibited Fe(2+)-induced MDA production in rat brain homogenate in a dose-dependent manner with shaddock having the highest inhibitory ability. Acetylcholinesterase activity was also inhibited in vitro by the juices in a dose-dependent manner. The inhibition of acetylcholinesterase activity and antioxidant properties of the citrus juices could make them a good dietary means for the management of Alzheimer's disease.

Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Antioxidants; Beverages; Biphenyl Compounds; Brain; Cholinesterase Inhibitors; Citrus; Dose-Response Relationship, Drug; Fruit; Iron; Lipid Peroxidation; Malondialdehyde; Oxidative Stress; Phenols; Picrates; Plant Preparations; Rats

In search of multifunctional cholinesterase inhibitors as potential anti-Alzheimer drug candidates, tacrine-ferulic acid-NO donor trihybrids were synthesized and tested for their cholinesterase inhibitory activities, release of nitric oxide, vasodilator properties, cognition improving potency, and hepatotoxicity. All of the novel target compounds show higher in vitro cholinesterase inhibitory activity than tacrine. Three selected compounds (3a, 3f, and 3k) produce moderate vasorelaxation in vitro, which correlates with the release of nitric oxide. Compared to its non-nitrate dihybrid analogue (3u), the trihybrid 3f exhibits better performance in improving the scopolamine-induced cognition impairment (mice) and, furthermore, less hepatotoxicity than tacrine.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Binding Sites; Biphenyl Compounds; Butyrylcholinesterase; Cholinesterase Inhibitors; Coumaric Acids; Humans; Inhibitory Concentration 50; Kinetics; Liver; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred ICR; Models, Molecular; Nitric Oxide; Nitric Oxide Donors; Picrates; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Tacrine; Vasodilation

Several extracts of the leaves and fruits of Juglans regia L. were assessed for their neuroprotective effects through antioxidant and anti-cholinesterase methods. Anticholinesterase activity was determined against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), the enzymes vital for Alzheimer's disease, at 50, 100 and 200 μg ml(-1). Antioxidant activity was tested using radical scavenging activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH), N,N-dimethyl-p-phenylenediamine (DMPD), superoxide (SO), nitric oxide (NO) and hydrogen peroxide (H(2)O(2)) radicals, as well as ferric ion-chelating capacity, ferric- and phosphomolybdenum-reducing antioxidant power at 500, 1000 and 2000 μg ml(-1). Total phenol and flavonoid quantification of the extracts was calculated. The extracts scavenged DPPH radical in varying degrees; however, they did not scavenge DPMD and H(2)O(2). Only the dichloromethane and water extracts were able to quench SO (10.09 ± 1.38%) and NO (24.09 ± 2.19%) radicals, respectively, at low level. The extracts showed either low or no BChE inhibition and no AChE inhibition.

Topics: Alzheimer Disease; Animals; Antioxidants; Biphenyl Compounds; Cholinesterases; Eels; Fruit; Horses; Juglans; Neuroprotective Agents; Nitric Oxide; Phytotherapy; Picrates; Plant Extracts; Plant Leaves; Polyphenols; Superoxides

From the aerial parts of Salsola oppositofolia, S. soda and S. tragus an alkaloid extract was obtained and tested to evaluate antioxidant and anti-cholinesterase activities. The in vitro study of the antioxidant activity by the DPPH method revealed a significant activity of Salsola alkaloid extracts with IC(50) values ranging from 16.30 microg/mL for S. oppositifolia to 26.17 microg/mL for S. tragus. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities were evaluated. S. tragus alkaloid extract exerted the highest inhibitory activity against AChE (IC(50) of 30.2 microg/mL) and BChE (IC(50) of 26.5 microg/mL). Interestingly, S. soda and S. oppositifolia exhibited a selective inhibitory activity against BChE with IC(50) values of 34.3 microg/mL and 32.7 microg/mL, respectively. Tetrahydroisoquinoline alkaloids were identified and quantified by GC/MS analysis.

Topics: Acetylcholinesterase; Alkaloids; Alzheimer Disease; Antioxidants; Biphenyl Compounds; Butyrylcholinesterase; Drugs, Chinese Herbal; Free Radical Scavengers; Inhibitory Concentration 50; Phytotherapy; Picrates; Plant Extracts; Salsola

The mechanism of metal ion-catalyzed oxidative modification of apolipoprotein E (apoE) in human very-low-density lipoprotein (VLDL) and its inhibition by glycosaminoglycan (GAG) was investigated in vitro. The VLDL oxidation catalyzed by Cu2+ led to the lipid peroxidation, the formation of aggregates, and covalent modification of apoE. The modified apoE lost heparin-binding activity. These results suggest that the lipid peroxidation of VLDL and modification of apoE cause impairment of lipid uptake by cells and deposit the oxidized lipids in the tissues. The lipid peroxidation and oxidative modification of apoE in VLDL mediated by Cu2+ and an aqueous radical generator were suppressed by GAG, heparan sulfate, heparin, and chondroitin sulfate A, even though GAGs demonstrated no ability to scavenge alpha,alpha-diphenyl-beta-picrylhydrazyl radical. There were no relationships between inhibitory activity of GAGs in the VLDL oxidation and their number of sulfate groups which possess chelating activity of metal ion. Therefore, it can be considered that the inhibition of VLDL oxidation by GAGs is possibly due to the interaction between GAG and VLDL which bring about the steric hindrance, interference with the reaction between VLDL particle and the reactive oxygen species. These studies suggest that GAGs preserve the biological functions of apoE from oxidative stress.

Topics: Adult; Aldehydes; Alzheimer Disease; Amidines; Apolipoproteins E; Bepridil; Biphenyl Compounds; Chelating Agents; Cholesterol Esters; Chondroitin Sulfates; Copper Sulfate; Dextrans; Free Radical Scavengers; Glutathione; Glycosaminoglycans; Heparin; Hippocampus; Humans; Hydrogen-Ion Concentration; Lipid Peroxidation; Lipoproteins, VLDL; Male; Picrates; Reactive Oxygen Species; Thiobarbituric Acid Reactive Substances