Synthesis and Molecular Modeling Studies of 1-Benzyl-2-Indolinones As Selective AChE Inhibitors

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

Highly efficient, catalyst-free, one-pot sequential four-component synthesis of novel spiroindolinone-pyrazole scaffolds as anti-Alzheimer agents: in silico study and biological screening

“…In vitro evaluations exhibited significant inhibition of derivatives, in which the most potent analog exhibited more than 2-fold potency compared with donepezil. 64 The structure-activity relationship (SAR) also demonstrated that substitution at the different positions of the indolidinone ring significantly affects the potency.…”