Journal
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
Volume 35, Issue 1, Pages 1568-1580Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/14756366.2020.1800666
Keywords
Monoamine oxidase B; carboxamide; MAO-B inhibitor; microwave synthesis; molecular modelling
Funding
- KIST Institutional Programs from Korea Institute of Science and Technology [2E30240]
- Creative Fusion Research Program through the Creative Allied Project - National Research Council of Science Technology [CAP-12-1-KIST]
- National Research Foundation of Korea (NRF) - Korea Government (MSIT) [NRF-2018R1A5A2023127, NRF-2018M3A9C8016849]
- Korea Institute of Science and Technology (KIST)
- National Research Foundation of Korea [2018M3A9C8016849] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Herein, two new series ofN-substituted indole-based analogues were rationally designed, synthesizedviamicrowave heating technology, and evaluated as noteworthy MAO-B potential inhibitors. Compared to the reported indazole-based hitsVIandVII, compounds4band4eexhibited higher inhibitory activities over MAO-B with IC(50)values of 1.65 and 0.78 mu M, respectively. When compared to the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), both4band4ealso showed better selectivity indices (SI > 60 and 120, respectively). A further kinetic evaluation of the most potent derivative (4e) displayed a competitive mode of inhibition (inhibition constant (K-i)/MAO-B = 94.52 nM). Reasonable explanations of the elicited biological activities were presentedviaSAR study and molecular docking simulation. Accordingly, the remarkable MAO-B inhibitory activity of4e(N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide), with its selectivity and competitive inhibition, advocates its potential role as a promising lead worthy of further optimization.
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