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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 (IC 50  = 6.7 nM,  Ki  = 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

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