Pd-Catalyzed Direct Modification of an Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of α-Aryl Donepezil Analogues

Lin-Xi Wan; Shi-Xing Miao; Zhen-Xiang He; Xiaohuan Li; Xian-Li Zhou; Feng Gao

doi:10.1021/acsomega.1c03103

Pd-Catalyzed Direct Modification of an Anti-Alzheimer's Disease Drug: Synthesis and Biological Evaluation of α-Aryl Donepezil Analogues

ACS Omega. 2021 Sep 1;6(36):23347-23354. doi: 10.1021/acsomega.1c03103. eCollection 2021 Sep 14.

Authors

Lin-Xi Wan^{1

2}, Shi-Xing Miao¹, Zhen-Xiang He¹, Xiaohuan Li¹, Xian-Li Zhou¹, Feng Gao¹

Affiliations

¹ School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
² Key Laboratory of Advanced Technology of Materials, Ministry of Education, Southwest Jiaotong University, Chengdu 610031, PR China.

Abstract

Palladium/BuAd₂P efficiently catalyzed the direct α-arylation of ketone in the anti-Alzheimer's disease drug donepezil, leading to 15 aryldonepezil analogues exhibiting high selective inhibition of acetylcholinesterase (AChE). The cell-based assays revealed that the 3-methylpridinyl analogue (12) shows significantly lower toxicity compared to donepezil and remarkable neuroprotective activity against H₂O₂-induced damage in SH-SY5Y cells. Docking results of compound 12 also interpreted the possible mechanism of the selective inhibition between AChE and butyrylcholinesterase (BuChE).