摘要/Abstract

设计合成并评价了一系列他克林-丁苯酞杂合物作为多功能胆碱酯酶（ChE）抑制剂治疗阿尔茨海默病的活性.结果表明，他克林-丁苯酞杂合物对两种胆碱酯酶均表现出抑制活性.其中3-丁基-6-（（7-（（1，2，3，4-四氢吖啶-9-基）氨基）庚基）氧基）异苯并呋喃-1（3H）-酮（10b）显示出最优的乙酰胆碱酯酶（AChE，IC₅₀=38.65 nmol·L^-1）抑制活性，高于他克林（IC₅₀=200.70 nmol·L^-1）约5倍.3-丁基-6-（（8-（（6-氯-1，2，3，4-四氢吖啶-9-基）氨基）庚基）氧基）异苯并呋喃-1（3H）-酮（10g）显示出最好的丁酰胆碱酯酶（BuChE，IC₅₀=33.69 nmol·L^-1）抑制活性，其值与他克林（IC₅₀=27.12 nmol·L^-1）相似，高于多奈哌齐（IC₅₀=7530 nmol·L^-1）约220倍.在大鼠海马体神经元细胞Aβ诱导损伤模型中，测试化合物对大鼠海马神经元细胞（Rat hippocampal neurons）中ROS水平的影响，结果显示，大多数化合物均能对Aβ_1-42诱导的大鼠海马体神经元细胞分泌的ROS产生抑制作用.
关键词: 阿尔茨海默病, 他克林, 丁苯酞, 胆碱酯酶, ROS水平
A series of tacrine-3-n-butylphthalide hybrids have been designed, synthesized and evaluated as multifunctional cholinesterase (ChE) inhibitors against Alzheimer's disease (AD). The result showed that all the target compounds exhibited inhibitory activity on acetylcholinesterase (AChE) and butylcholinesterase (BuChE). Especially, 3-butyl-6-((7-((1,2,3,4-tetra-hydroacridin-9-yl)amino)heptyl)oxy)isobenzofuran-1(3H)-one (10b) displayed the greatest ability to inhibit AChE (IC₅₀=38.65 nmol·L^-1), which was 5-fold greater than that of tacrine (IC₅₀=200.70 nmol·L^-1). 3-Butyl-6-((8-((6-chloro-1,2,3,4-tetrahydroacridin-9-yl)amino)heptyl)oxy)isobenzofuran-1(3H)-one (10g) displayed the greatest ability to inhibit BuChE (IC₅₀=33.69 nmol·L^-1), which was close to tacrine (IC₅₀=27.12 nmol·L^-1) and 220-fold greater than that of donepezil (IC₅₀=7530 nmol·L^-1). In rat Aβ-induced injury model of hippocampal neurons, the effect of compounds on reactive oxygen species (ROS) levels in rat hippocampal have been evaluated, and the results indicated that most of these compounds had potent inhibitory activity for rat hippocampal neuronal cells secreting ROS induced by Aβ_1-42.
Key words: Alzheimer's disease, tacrine, 3-n-butylphthalide, cholinesterase, ROS levels


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