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

J Enzyme Inhib Med Chem. 2020 Dec;35(1):1568-1580. doi: 10.1080/14756366.2020.1800666.

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)-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.

Keywords: MAO-B inhibitor; Monoamine oxidase B; carboxamide; microwave synthesis; molecular modelling.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Kinetics
  • Models, Molecular
  • Molecular Structure
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / chemical synthesis
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Indoles
  • Monoamine Oxidase Inhibitors
  • Monoamine Oxidase

Grants and funding

This study was supported by the KIST Institutional Programs (Grant No. 2E30240) from Korea Institute of Science and Technology, the Creative Fusion Research Program through the Creative Allied Project funded by the National Research Council of Science & Technology (CAP-12-1-KIST). This work was also supported by the National Research Foundation of Korea (NRF) Grant funded by the Korea Government (MSIT) (No. NRF-2018R1A5A2023127 and NRF-2018M3A9C8016849). A.E. also extends his appreciation to the Korea Institute of Science and Technology (KIST) for funding this work through the Grant name “2020 KIST School Partnership Project”.