Background: 2-Indolinone-based hydrazinecarbothioamides carrying a 3-phenylsulfonamide moiety (7–9) were designed by replacement of donepezil's pharmacophore group indanone with a 2-indolinone ring. Method: Compounds 7–9 were synthesized by reaction of N-(3-sulfamoylphenyl)hydrazinecarbothioamide (6) with 1 H-indolin-2,3-diones (1–3). Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory effects of compounds 7–9 were assayed. Molecular modeling studies of 5-chloro-1,7-dimethyl-substituted compound 8e were carried out to determine the possible binding interactions at the active site of AChE. Results: Compound 8e showed the strongest inhibition against AChE ( Ki = 0.52 ± 0.11 μM) as well as the highest selectivity (SI = 37.69). The selectivity for AChE over BuChE of compound 8e was approximately 17-times higher than donepezil and 26-times higher than galantamine. Conclusion: Further development of compounds 7–9 may present new promising agents for Alzheimer's treatment.
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.
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