Discovery of N-(1-(3-fluorobenzoyl)-1H-indol-5-yl)pyrazine-2-carboxamide: a novel, selective, and competitive indole-based lead inhibitor for human monoamine oxidase B. (1st January 2020)

• Record Type: Journal Article
• Authors: Elkamhawy, Ahmed; Paik, Sora; Kim, Hyeon Jeong; Park, Jong-Hyun; Londhe, Ashwini M.; Lee, Kyeong; Pae, Ae Nim; Park, Ki Duk; Roh, Eun Joo
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 35:Number 1(2020)
• Page Start: 1568
• Page End: 1580
• Publication Date: 2020-01-01
• Subjects: Monoamine oxidase B -- carboxamide -- MAO-B inhibitor -- microwave synthesis -- molecular modelling; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2020.1800666
• Languages: English
• ISSNs: 1475-6366

Abstract

Abstract: Herein, two new series of N -substituted indole-based analogues were rationally designed, synthesized via microwave heating technology, and evaluated as noteworthy MAO-B potential inhibitors. Compared to the reported indazole-based hits VI and VII, compounds 4b and 4e exhibited higher inhibitory activities over MAO-B with IC50 values of 1.65 and 0.78 µM, respectively. When compared to the modest selectivity index of rasagiline (II, a well-known MAO-B inhibitor, SI > 50), both 4b and 4e also 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 presented via SAR study and molecular docking simulation. Accordingly, the remarkable MAO-B inhibitory activity of 4e ( N -(1-(3-fluorobenzoyl)-1 H -indol-5-yl)pyrazine-2-carboxamide), with its selectivity and competitive inhibition, advocates its potential role as a promising lead worthy of further optimization.