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

作者：Liu, Hao-Ran^*; Zhou, Chao; Fan, Hao-Qun; Tang, Jing-Jing; Liu, Lin-Bo; Gao, Xiao-Hui; Wang, Qiu-An; Liu, Wu-Kun

来源：Chemical Biology & Drug Design, 2015, 86(4): 517-522.

DOI：10.1111/cbdd.12514

• AChE inhibitors
• chalcone
• fluorine
• molecular modeling
• selectivity

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.

• 出版日期2015-10
• 单位湖南大学; 湖南中医药大学