Synthesis and molecular modeling studies of 1-benzyl-2-indolinones as selective AChEinhibitors.

Abstract

Background: Possible bioisosteres can be developed by replacing the 1-indanone ring (one of three pharmacophore groups) of donepezil with an indoline ring. As H2S donors, thioamide, thiocarbamate and thiourea groups are also critically important. Materials & methods: The 1-benzyl-2-indolinones 6a-n were designed using molecular modeling and synthesized, and their acetylcholinesterase and butyrylcholinesterase inhibitory effects were then investigated. Results: The compounds 6h (inhibition constant [Ki] =0.22μM; selectivity index [SI] =26.22), 6i (Ki=0.24μM; SI=25.83), 6k (Ki=0.22μM; SI=28.31) and 6n (Ki=0.21μM; SI=27.14) were approximately twofold more effective against and >12-fold more selective for acetylcholinesterasecompared with donepezil (Ki=0.41μM; SI=2.12). Analysis of molecular dynamics simulations with compounds 6k and 6n indicated that the preferred binding might be at allosteric binding pocket 4 of the enzyme. Conclusion: Benzyl substitution at the 1-position of the indole ring significantly increased potency and selectivity.