摘要
阿尔茨海默症(Alzheimer’s disease,AD)是一种神经退行性疾病,严重影响老年人的生活质量,目前治疗AD的药物主要是胆碱酯酶抑制剂,如多奈哌齐、卡巴拉汀等.本文基于多奈哌齐结构,设计合成了一系列新的萘酰亚胺衍生物并进行了活性评价.结果表明,所合成的化合物均对乙酰胆碱酯酶(AChE)有选择性抑制,其中2-((1-(3-甲氧基苄基)哌啶-4-基)甲基)-1H-苯并异喹啉-1,3(2H)-二酮(4k)的抑制活性最强,IC_(50)值为4.43μmol•L^(-1),优于对照药物卡巴拉汀.酶动力学及分子对接表明4k能够同时作用于AChE的催化活性位点和外周结合位点,并且4k对SH-SY5Y和PC12细胞毒性较低.此外,这些化合物均显示出典型的聚集诱导发光(AIE)性质,可能与萘酰亚胺分子内旋转受阻机制有关.
Alzheimer’s disease(AD)is a neurodegenerative disease characterized by impaired cognitive and memory function,which seriously affects the quality of life of the elderly.At present,the main drugs for the treatment of AD are cholinesterase inhibitors,such as donepezil and rivastigmine.In this paper,a series of novel naphthimide derivatives were designed,synthesized and evaluated based on the structure of donepezil.The results showed that all of the tested compounds were acetylcholinesterase(AChE)selective inhibitors,2-((1-(3-methoxybenzyl)piperidin-4-yl)methyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione(4k)exhibited the strongest inhibition to AChE with an IC_(50) value of 4.43μmol/L,which was better than the control rivastigmine.Kinetic and molecular modeling studies indicated that 4k targeted both the catalytic active site(CAS)and the peripheral anionic site(PAS)of AChE.In addition,4k didn’t show obvious cytotoxicity against SH-SY5Y and PC12 cell lines.Besides,these compounds exhibited typical aggregation induced emissions(AIE)properties,which might be controlled by mechanism of restriction of intramolecular rotations.
作者
赵永梅
穆叶舒
罗稳
田智勇
Zhao Yongmei;Mu Yeshu;Luo Wen;Tian Zhiyong(Pharmaceutical Engineering Department,Henan Vocational College of Applied Technology,Kaifeng,Henan 475004;Key Laboratory of Natural Medicine and Immuno-Engineering,Henan University,Kaifeng,Henan 475004;School of Pharmacy,Henan University,Kaifeng,Henan 475004)
出处
《有机化学》
SCIE
CAS
CSCD
北大核心
2022年第3期819-829,共11页
Chinese Journal of Organic Chemistry
基金
国家自然科学基金(No.U1704176)
河南省科技计划(No.212102311030)
河南应用技术职业学院(No.2020-HJ-22)资助项目.
关键词
萘酰亚胺
胆碱酯酶
聚集诱导发光
naphthalimide
cholinesterase
aggregation induced emission
