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Novel Potent and Selective Acetylcholinesterase Inhibitors as Potential Drugs for the Treatment of Alzheimer's Disease: Synthesis, Pharmacological Evaluation, and Molecular Modeling of Amino‐Alkyl‐Substituted Fluoro‐Chalcones Derivatives
Author(s) -
Liu HaoRan,
Zhou Chao,
Fan HaoQun,
Tang JingJing,
Liu LinBo,
Gao XiaoHui,
Wang QiuAn,
Liu WuKun
Publication year - 2015
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12514
Subject(s) - butyrylcholinesterase , acetylcholinesterase , chemistry , chalcone , ic50 , selectivity , stereochemistry , enzyme , biochemistry , aché , in vitro , catalysis
A new series of‐fluoro chalcones‐substituted amino‐alkyl derivatives ( 3a˜3l ) were designed, synthesized, characterized and evaluated for the inhibitory activity against acetylcholinesterase and butyrylcholinesterase. The results showed that the alteration of fluorine atom position and amino‐alkyl groups markedly influenced the activity and the selectivity of chalcone derivates in inhibiting acetylcholinesterase and butyrylcholinesterase. Among them, compound 3l possesses the most potent inhibitory against acetylcholinesterase ( IC 50 = 0.21 ± 0.03 μ mol/L), and the highest selectivity for acetylcholinesterase over butyrylcholinesterase ( IC 50 (BuChE)/ IC 50 ( AC hE) = 65.0). Molecular modeling and enzyme kinetic study on compound 3l supported its dual acetylcholinesterase inhibitory profile, simultaneously binding at the catalytic active and peripheral anionic site of the enzyme.