☆ 4.4 Article

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

CHEMICAL BIOLOGY & DRUG DESIGN (2015)

期刊

CHEMICAL BIOLOGY & DRUG DESIGN

卷 86, 期 4, 页码 517-522

出版社

WILEY-BLACKWELL

DOI: 10.1111/cbdd.12514

关键词

AChE inhibitors; chalcone; fluorine; molecular modeling; selectivity

类别

Biochemistry & Molecular Biology Chemistry, Medicinal

资金

Natural Science Foundation of China [21342015]
project of science and technology of Hu'nan Province [2012SK3183]
Fundamental Research Funds for the Central Universities of Hu'nan University

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Protocol

Reagent

摘要

A new series of-fluoro chalcones-substituted amino-alkyl derivatives (3a3l) 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 (IC50=0.21 +/- 0.03mol/L), and the highest selectivity for acetylcholinesterase over butyrylcholinesterase (IC50 (BuChE)/IC50 (AChE)=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.

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