Late-Stage Modification of Medicine: Pd-Catalyzed Direct Synthesis and Biological Evaluation of N-Aryltacrine Derivatives

Lin-Xi Wan; Yong-Qi Zhen; Zhen-Xiang He; Yang Zhang; Lan Zhang; Xiaohuan Li; Feng Gao; Xian-Li Zhou

doi:10.1021/acsomega.1c01404

Late-Stage Modification of Medicine: Pd-Catalyzed Direct Synthesis and Biological Evaluation of N-Aryltacrine Derivatives

ACS Omega. 2021 Apr 2;6(14):9960-9972. doi: 10.1021/acsomega.1c01404. eCollection 2021 Apr 13.

Authors

Lin-Xi Wan¹, Yong-Qi Zhen¹, Zhen-Xiang He¹, Yang Zhang¹, Lan Zhang¹, Xiaohuan Li¹, Feng Gao¹, Xian-Li Zhou¹

Affiliation

¹ School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, People's Republic of China.

Abstract

A new series of N-aryltacrine derivatives were designed and synthesized as cholinesterase inhibitors by the late-stage modification of tacrine, using the palladium-catalyzed Buchwald-Hartwig cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) demonstrated that most of the synthesized compounds had potent AChE inhibitory activity with negative inhibition of BuChE. Among them, N-(4-(trifluoromethyl)phenyl)-tacrine (3g) and N-(4-methoxypyridin-2-yl)-tacrine (3o) showed the most potent activity against AChE (IC₅₀ values of 1.77 and 1.48 μM, respectively). The anti-AChE activity of 3g and 3o was 3.5 times more than that of tacrine (IC₅₀ value of 5.16 μM). Compound 3o also displayed anti-BuChE activity with an IC₅₀ value of 19.00 μM. Cell-based assays against HepG2 and SH-SY5Y cell lines revealed that 3o had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H₂O₂-induced damage in SH-SY5Y cells. The advantages including synthetic accessibility, high potency, low toxicity, and adjunctive neuroprotective activity make compound 3o a new promising multifunctional candidate for the treatment of Alzheimer's disease.