The development of 2-acetylphenol-donepezil hybrids as multifunctional agents for the treatment of Alzheimer’s disease

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Abstract

A series of 2-acetylphenol-donepezil hybrids was designed and synthesized based on multi-target-directed ligands strategy. The biological activities were evaluated by AChE/BChE inhibition and MAO-A/MAO-B inhibition. The results revealed that the tertiary amines and methylene chain length significantly affected the eeAChE inhibitory potency, in particular, compound TM-14 showed the best eeAChE inhibitory activity with IC50 value of 2.9 μM, in addition, both kinetic analysis of AChE inhibition and docking study displayed that TM-14 could simultaneously bind to the catalytic active site and peripheral anionic site of AChE. Moreover, compound TM-14 was a selective metal chelator and could form 1:1 TM-14-Cu2+ complex. The structure-active-relationship also indicated that the O-alkylamine fragment remarkably decreased hMAO-B inhibitory activity, compound TM-2 exhibited potent hMAO-B inhibitory activity (IC50 = 6.8 μM), which was supported by the molecular docking study. More interestingly, compounds TM-14 and TM-2 could cross the blood-brain barrier in vitro. Therefore, the structure-active-relationship of 2-acetylphenol-donepezil hybrids could encourage the development of multifunction agents with selective AChE inhibition or selective MAO-B inhibition for the treatment of Alzheimer’s disease.

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Declaration of Competing Interest

The authors declare no competing financial interest.

Acknowledgments

This work was supported in part by the Foundation and Frontier Projects of Nanyang Science and Technology Bureau (2017JCQY020 and 2017 JCQY021). The Special Project of Nanyang Normal University (SYKF2018081 and 2019QN001). The Key Scientific Research Project of Colleges and Universities in Henan Province (NO.20A350006). International Training of High-level Talents in Henan Province in 2019 (NO.17) (Henan Foreign Experts Bureau). Graduate Innovation Fund Project of Nanyang Normal University

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These authors contributed equally.

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