他克林-苯酚-联苯双酯杂合物的合成、胆碱酯酶抑制活性及肝毒性评价  

Synthesis,cholinesterase inhibition and hepatotoxicity of tacrine-phenol-bifendate hybrids

作　　者：洪琛 赵永梅 郭卉艳[3] 罗稳[3] HONG Chen;ZHAO Yong-mei;GUO Hui-yan;LUO Wen(Huaihe Hospital,Henan University,Kaifeng 475004,China;Pharmaceutical Engineering Department,Henan Vocational College of Applied Technology,Kaifeng 475004,China;Key Laboratory of Natural Medicine and Immuno-Engineering,Henan University,Kaifeng 475004,China)

机构地区：[1]河南大学淮河医院,河南开封475004 [2]河南应用技术职业学院制药工程学院,河南开封475004 [3]河南大学天然药物与免疫工程重点实验室,河南开封475004

出　　处：《药学学报》2022年第9期2759-2766,共8页Acta Pharmaceutica Sinica

基　　金：河南省医学科技攻关计划项目(2018020333);河南省重点研发与推广专项(212102311030);河南应用技术职业学院项目(2020-HJ-22).

摘　　要：本文设计合成了一系列他克林-苯酚-联苯双酯杂合物(7a~7e,8a~8e)作为胆碱酯酶抑制剂,并对其进行了肝毒性活性评价。结果表明,这些化合物具有较强的胆碱酯酶抑制活性,半数抑制浓度(IC_(50))值达到纳摩级,部分化合物优于对照药物他克林,其中8d对乙酰胆碱酯酶(AChE)的抑制活性最强,IC_(50)值为156.39 nmol·L^(-1),7b对丁酰胆碱酯酶的活性最强,IC_(50)值为16.33 nmol·^(L-1)。酶动力学及分子对接表明化合物8d能够同时作用于AChE的催化活性位点和外周结合位点。另外,这些化合物对肝细胞的体外毒性较低,8d没有明显增加HepG2细胞内活性氧水平。A series of tacrine-phenol-bifendate hybrids(7a-7e,8a-8e)were designed,synthesized and evaluated as inhibitors of cholinesterases(ChEs)with low hepatotoxicity.All the compounds had potent ChEs inhibitory activity with half-inhibitory concentration(IC_(50))values at the nanomolar range.Compound 8d exhibited the strongest inhibition to acetylcholinesterase(AChE)with an IC_(50)value of 156.39 nmol·L^(-1)and compound 7b showed the most potent inhibition for butyrylcholinesterase with IC_(50)value of 16.33 nmol·L^(-1).Kinetic and molecular modeling studies showed that 8d targeted both the catalytic active site and the peripheral anionic site of AChE.In addition,these compounds showed low toxicity to hepatocytes,and compound 8d did not increase the level of reactive oxygen species in HepG2 cells.

关 键 词：他克林 胆碱酯酶 肝毒性 阿尔茨海默症 

分 类 号：R914[医药卫生—药物化学]