Lead optimization study on indoline-2,3-dione derivatives as potential fatty acid amide hydrolase inhibitors

Abstract

Based on the known isatin-based fatty acid amide hydrolase (FAAH) inhibitor BSS-7, we designed and synthesized two small sets (6–13 and 17–20) of N-1 and C-3 substituted isatin derivatives and evaluated them for their in vitro FAAH inhibition properties. The lead simplification by modification of bulky aryl moiety at N-1 with a flexible allyl group produced a nanomolar (IC50 = 6.7 nM, K i = 5 nM) inhibitor 11 (Z)-3-((1H-benzo[d]imidazol-2-yl)imino)-1-allylindolin-2-one which exhibited a reversible and competitive FAAH inhibition with 1500 times more potency to BSS-7 (1.49 ± 0.03 µM). The lead compound 11 also showed a high blood–brain permeability and a significant antioxidant profile with no neurotoxicity. Docking results suggested that the inhibitor molecules occupied the active site of FAAH and offered optimal binding interactions. A molecular dynamics simulation study ascertained the stability of the lead inhibitor 11-FAAH complex. In silico ADMET profiling studies unveiled that compound 11 possesses good drug-like properties and merits further evaluation. Communicated by Ramaswamy H. Sarma. © 2022 Informa UK Limited, trading as Taylor & Francis Group.