3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles were designed, synthesized, and tested as inhibitors against human monoamine oxidase (MAO) A and B isoforms. Several compounds, obtained as racemates, were identified as selective MAO-B... more
3-Acetyl-2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoles were designed, synthesized, and tested as inhibitors against human monoamine oxidase (MAO) A and B isoforms. Several compounds, obtained as racemates, were identified as selective MAO-B inhibitors. The enantiomers of some derivatives were separated by enantioselective HPLC and tested. The R-enantiomers always showed the highest activity. Docking study and molecular dynamic simulations demonstrated the putative binding mode. We conclude that these 1,3,4-oxadiazoles derivatives are promising reversible and selective MAO-B inhibitors.
Research Interests: Chemistry, Organic Chemistry, Medicinal Chemistry, Molecular Dynamics Simulation, Medicine, and 14 moreCell line, Humans, Animals, Insects, Drug Design, Molecular docking, Isoenzymes, Medicinal, Structure activity Relationship, Recombinant Proteins, Protein Binding, Pharmacology and pharmaceutical sciences, stereoisomerism, and Monoamine oxidase inhibitors
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A series of 4-[(3-cyclohexyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides was synthesised and the activity of the new compounds as inhibitors of hCA I, II, IX, and XII was evaluated. These new derivatives... more
A series of 4-[(3-cyclohexyl-4-aryl-2,3-dihydro-1,3-thiazol-2-ylidene)amino]benzene-1-sulfonamides was synthesised and the activity of the new compounds as inhibitors of hCA I, II, IX, and XII was evaluated. These new derivatives exhibited some peculiarities with respect to previously reported sulfonamide based inhibitors of CA. We observed that the nature of the substituents in the position 3 and 4 of the dihydro-thiazole ring was relevant in determining both activity and selectivity profiles.
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Research Interests: Biochemistry, Organic Chemistry, Medicinal Chemistry, Magnetic Resonance Spectroscopy, Bioinorganic Chemistry, and 14 moreOrganic Synthesis, Cell line, Humans, Candida, Candida albicans, Central Nervous System, Antifungal Activity, Cytotoxic Activity, Functional Group, Antifungal Agents, Microbial Sensitivity Tests, Biological activity, Species Specificity, and Anticancer Drug
Research Interests: Organic Chemistry, Cercopithecus aethiops, In Vitro, Tuberculosis, Models, and 17 moreMycobacterium tuberculosis, TB, Resistance, Animals, Drug Resistance, Bacteria, Quantitative Structure Activity Relationship, SAR, Pi, European, Indexation, Biological activity, XDR, Structure activity Relationship, Chemical Synthesis, Vero cells, and Minimum inhibitory concentration
Monoamine oxidase B (MAO-B) is a promising target for the treatment of neurodegenerative disorders. We report the synthesis and the biological evaluation of halogenated derivatives of 1-aryliden-2-(4-phenylthiazol-2-yl)hydrazines. The... more
Monoamine oxidase B (MAO-B) is a promising target for the treatment of neurodegenerative disorders. We report the synthesis and the biological evaluation of halogenated derivatives of 1-aryliden-2-(4-phenylthiazol-2-yl)hydrazines. The fluorinated series shows interesting activity and great selectivity toward the human recombinant MAO-B isoform expressed in baculovirus infected BTI insect cells. The multiple crystal structures alignment of the enzyme highlighted pronounced induced fit (IF) adaptations with respect to bound ligands. Therefore, IF docking (IFD) experiments and molecular dynamic (MD) simulations were carried out to reveal the putative binding mode and to explain the experimentally observed differences in the activity of 1-(aryliden-2-(4-(4-chlorophenyl)thiazol-2-yl)hydrazines. The importance of water molecules within the binding site was also investigated. These are known to play an important role in the binding site cavity and to mediate protein-ligand interactions. Detailed analyses of the trajectories provide insights on the chemical features required for the activity of this scaffold. In particular it was highlighted the importance of fluorine atom interacting with the water close to the cofactor and the influence of steric bulkiness of substituents in the arylidene moiety. Free energy perturbation (FEP) analysis confirmed experimental data. The information we deduced will help to develop novel high-affinity MAO-B inhibitors.