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

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ID: 125663
2019
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Ranked #145 of 246 articles by views in Bioorganic & medicinal chemistry letters

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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 IC 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-Cu 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 (IC = 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.
Reference Key
zhu2019thebioorganic Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Zhu, Gaofeng;Wang, Keren;Shi, Jian;Zhang, Pengfei;Yang, Dan;Fan, Xiaotian;Zhang, Ziyi;Liu, Wenmin;Sang, Zhipei;
Journal Bioorganic & medicinal chemistry letters
Year 2019
DOI
S0960-894X(19)30567-0
URL
Keywords
alzheimer’s disease 2-acetylphenol-donepezil hybrids structure-active-relationship eeache inhibition hmao-b inhibition

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