邻苯二甲酰亚胺−多奈哌齐杂合物的合成及活性评价  

Synthesis and biological activity evaluation of phthalimide-donepezil hybrids

作　　者：王军杰 穆叶舒[2,3] 洪琛 罗稳 WANG Jun-jie;MU Ye-shu;HONG Chen;LUO Wen(Huaihe Hospital,Henan University,Kaifeng 475004,China;Key Laboratory of Natural Medicine and ImmunoEngineering,Henan University,Kaifeng 475004,China;School of Pharmacy,Henan University,Kaifeng 475004,China)

机构地区：[1]河南大学淮河医院,河南开封475004 [2]河南大学天然药物与免疫工程重点实验室,河南开封475004 [3]河南大学药学院,河南开封475004

出　　处：《药学学报》2024年第3期651-660,共10页Acta Pharmaceutica Sinica

基　　金：河南省医学科技攻关计划项目(LHGJ20230429);河南省重点研发与推广专项(212102311030).

摘　　要：本文设计合成了一系列邻苯二甲酰亚胺−多奈哌齐杂合物(5a~e,6a~l)作为选择性的乙酰胆碱酯酶(AChE)抑制剂。结果表明,部分化合物具有较强的AChE抑制活性,半数抑制浓度(IC50)达到纳摩尔范围,优于对照药物加兰他敏和他克林,与多奈哌齐相近。其中6k对AChE的抑制活性最强,IC50值为0.13μmol·L^(-1)。酶动力学及分子对接结果表明化合物6k能够同时作用于AChE的催化活性位点和外周结合位点。部分化合物能够抑制AChE诱导的β-淀粉样蛋白聚集。另外,吸收、分布、代谢和排泄预测结果显示化合物6k符合Lipinski类药五规则且具有较高的油水分配系数。这些化合物特别是6k可以作为双功能的先导物进行更加深入的活性研究。A series of phthalimide-donepezil(PTA-DPZ)hybrids(5a−e,6a−l)were designed,synthesized and evaluated as selective inhibitors of acetylcholinesterase(AChE).The results showed that some hybrids had strong AChE inhibitory activity with half maximal inhibitory concentration(IC50)at nanomolar range,which was better than the control drugs galanthamine and tacrine,and equivalent to DPZ.Compound 6k exhibited the strongest inhibition to AChE with an IC50 value of 0.13μmol·L^(-1).Kinetic and molecular modeling studies showed that 6k targeted both catalytic active site and peripheral anionic site of AChE.Moreover,some compounds could inhibit AChE-inducedβ-amyloid(Aβ)aggregation.In addition,absorption,distribution,metabolism and excretion prediction results showed 6k conforms to the Lipinski's rule of five and had high partition coefficient P value.These compounds,especially 6k,may be considered as a dual-functional lead compound for in-depth research.

关 键 词：邻苯二甲酰亚胺 多奈哌齐 胆碱酯酶 Β-淀粉样蛋白 阿尔茨海默症 

分 类 号：R284[医药卫生—中药学]