A series of 2-(4-phenylpiperazin-1-yl)pyrimidine-5-carboxamide derivatives as acetylcholinesterase inhibitors (AChEIs) were designed and synthesized for the treatment of Alzheimer’s disease (AD). Their bioactivities were evaluated by the Ellman’s method, and the results showed that most of synthesized compounds displayed moderate acetylcholinesterase inhibitory activities in vitro. Among them, compound 6g exhibited the most potent inhibitory activity against AChE with IC₅₀ of 0.90 μM, and poor inhibitory activity against butyrylcholinesterase (BuChE) with IC₅₀ of 7.53 μM, which indicated that compound 6g was a selective AChE inhibitor, and compound 6g as a selective AChE inhibitor was confirmed by the molecular docking studies of compound 6g with AChE and BuChE. Furthermore, the mechanism of inhibition of compound 6g against AChE was analyzed by the kinetic study, and the result indicated that compound 6g was the mixed-type inhibitor of competitive inhibition and non-competitive inhibition. All the above showed that compound 6g could be considered as a lead compound for the development of AD drugs.

一系列2-(4-苯基哌嗪-1-基)嘧啶-5-甲酰胺衍生物作为乙酰胆碱酯酶抑制剂(AChEIs) 被设计和合成用于治疗阿尔茨海默病(AD)。采用Ellman方法评价它们的生物活性，结果表明大多数合成的化合物在体外显示出中等的乙酰胆碱酯酶抑制活性。其中，化合物6g对AChE的抑制活性最强，IC ₅₀为0.90 μM，对丁酰胆碱酯酶(BuChE)的抑制活性较差，IC ₅₀为7.53 μM，表明化合物6g是选择性AChE抑制剂，化合物6g化合物6g与 AChE 和 BuChE的分子对接研究证实了其作为选择性 AChE 抑制剂。此外，通过动力学研究分析了化合物6g对AChE的抑制作用机制，结果表明化合物6g是竞争性抑制和非竞争性抑制的混合型抑制剂。综上所述，化合物6g可作为开发 AD 药物的先导化合物。