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

• Published in: Future medicinal chemistry Vol. 14; no. 23; pp. 1705 - 1723
• Main Authors: Apaydın, Çağla Begüm, Soylu-Eter, Özge, Eraslan-Elma, Pınar, Özsoy, Nurten, Karalı, Nilgün
• Format: Journal Article
• Language: English
• Published: England Newlands Press Ltd 01.12.2022
• Subjects: 2-indolinones; Acetylcholinesterase - metabolism; acetylcholinesterase inhibitors; Butyrylcholinesterase - metabolism; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Donepezil; molecular docking; Molecular Docking Simulation; molecular dynamics; Oxindoles; Structure-Activity Relationship; sulfonamides; synthesis; synthesis; 2-indolinones; acetylcholinesterase inhibitors; sulfonamides; molecular docking; molecular dynamics
• ISSN: 1756-8919; 1756-8927
• DOI: 10.4155/fmc-2022-0139

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