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Design, synthesis and biological evaluation of oxygenated chalcones as potent and selective MAO-B inhibitors.

Publication Type : Journal Article

Publisher : Bioorg Chem

Source : Bioorg Chem, Volume 93, p.103335 (2019)

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Keywords : Animals, Chalcones, drug design, kinetics, Molecular Docking Simulation, Monoamine oxidase, Monoamine Oxidase Inhibitors, Oxygen, Rats, spleen, Structure-Activity Relationship

Campus : Kochi

School : School of Pharmacy

Department : Pharmaceutical Chemistry & Analysis

Year : 2019

Abstract : The present study documents the synthesis of oxygenated chalcone (O1-O26) derivatives and their abilities to inhibit monoamine oxidases. All 26 derivatives examined showed potent inhibitory activity against MAO-B. Compound O23 showed the greatest inhibitory activity against MAO-B with an IC value of 0.0021 µM, followed by compounds O10 and O17 (IC = 0.0030 and 0.0034 µM, respectively). In addition, most of the derivatives potently inhibited MAO-A and O6 was the most potent inhibitor with an IC value of 0.029 µM, followed by O3, O4, O9, and O2 (IC = 0.035, 0.053, 0.072, and 0.082 µM, respectively). O23 had a high selectivity index (SI) value for MAO-B of 138.1, and O20 (IC value for MAO-B = 0.010 µM) had an extremely high SI of >4000. In dialysis experiments, inhibitions of MAO-A and MAO-B by O6 and O23, respectively, were recovered to their respective reversible reference levels, demonstrating both are reversible inhibitors. Kinetic studies revealed that O6 and O23 competitively inhibited MAO-A and MAO-B, respectively, with respective K values of 0.016 ± 0.0007 and 0.00050 ± 0.00003 µM. Lead compound are also non-toxic at 200 µg/mL in normal rat spleen cells. Molecular docking simulations and subsequent Molecular Mechanics/Generalized Born Surface Area calculations provided a rationale that explained experimental data.

Cite this Research Publication : D. Grace Thom Parambi, Oh, J. Min, Baek, S. Cheol, Lee, J. Pil, Tondo, A. Rita, Nicolotti, O., Kim, H., and Bijo Mathew, “Design, synthesis and biological evaluation of oxygenated chalcones as potent and selective MAO-B inhibitors.”, Bioorg Chem, vol. 93, p. 103335, 2019.

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