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 |
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| Authors: | Hao‐Ran Liu Chao Zhou Hao‐Qun Fan Jing‐Jing Tang Lin‐Bo Liu Xiao‐Hui Gao Qiu‐An Wang Wu‐Kun Liu |
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| Affiliation: | 1. College of Chemistry and Chemical Engineering, Hu'nan University, Changsha, China;2. College of Pharmacy, Hu'nan University of Chinese Medicine, Changsha, China |
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| Abstract: | 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 (IC50 = 0.21 ± 0.03 μmol/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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| Keywords: | AChE inhibitors chalcone fluorine molecular modeling selectivity |
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