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.

摘要

在此，合理设计了两个新的N-取代的基于吲哚的系列类似物，通过微波加热技术对其进行了合成，并被评估为值得注意的MAO-B潜在抑制剂。与报道的基于吲唑的命中VI和VII相比，化合物4b和4e的抑制活性超过MAO-B，IC ₅₀值分别为1.65和0.78 µM。与雷沙吉兰的适度选择性指数（II，众所周知的MAO-B抑制剂，SI> 50）相比，其4b和4e还显示出更好的选择性指数（分别为SI> 60和120）。最有效的衍生物（4e）的进一步动力学评估显示了竞争性的抑制模式（抑制常数（K _i）/ MAO-B = 94.52 nM）。通过SAR研究和分子对接模拟，对引起的生物活性进行了合理的解释。因此，4e（N-（1-（3-氟苯甲酰基）-1 H-吲哚-5-基）吡嗪-2-羧酰胺）的显着MAO-B抑制活性具有选择性和竞争性抑制作用，提倡其潜在作用作为值得进一步优化的有前途的潜在客户。