Synthesis and molecular modeling studies of 1-benzyl-2-indolinones as selective AChE inhibitors

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 [K-i] = 0.22 mu M; selectivity index [SI] = 26.22), 6i (K-i = 0.24 mu M; SI = 25.83), 6k (K-i = 0.22 mu M; SI = 28.31) and 6n (K-i = 0.21 mu M; SI = 27.14) were approximately twofold more effective against and >12-fold more selective for acetylcholinesterase compared with donepezil (K-i = 0.41 mu M; 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.

Automated summary

In this study, a series of 1-benzyl-2-indolinone compounds were designed, synthesized, and evaluated for their inhibitory effects on acetylcholinesterase and butyrylcholinesterase. Several compounds showed superior potency and selectivity against acetylcholinesterase compared with donepezil. Molecular dynamics simulations suggested the preferred binding of these compounds at allosteric binding pocket 4 of the enzyme.