Synthesis and biological evaluation of novel flavonoid derivatives as dual binding acetylcholinesterase inhibitors

Abstract

A new series of flavonoid derivatives have been designed, synthesised and evaluated as acetylcholinesterase inhibitors that could bind simultaneously to the peripheral and catalytic sites of the enzyme. Among them, fifteen derivatives were found to inhibit the enzyme in the micromolar range and isoflavone derivatives possessed more potent inhibitory activity than other flavonoid derivatives. The best compound 9a had its inhibitory activity (IC₅₀ = 0.093μM) in the same range as the reference compound, donepezil (IC₅₀ = 0.025μM). Preliminary structure-activity relationships and a molecular modeling study for 9a have revealed that the isoflavone moiety plays a key role in the interaction of this series of derivatives with AChE by acting as an anchor in its peripheral anionic site.

Keywords::

• Alzheimer's disease
• acetylcholinesterase
• inhibitors
• flavonoids
• benzylpiperidine

Acknowledgements

This work was supported by the National Natural Science Foundation of China (30572239). We also thank Experimental Center of Pharmaceutial Sciences Zhejiang University.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.