Design, Synthesis and Evaluation of Novel Tacrine-3-n-butylphthalide Hybrids as Multifunctional Cholinesterase Inhibitors

doi:10.6023/cjoc201903072

Chinese Journal of Organic Chemistry ›› 2019, Vol. 39 ›› Issue (12): 3505-3515.DOI: 10.6023/cjoc201903072 Previous Articles Next Articles

新型他克林-丁苯酞杂合物作为多靶点胆碱酯酶抑制剂的设计合成及活性评价

刘万冬^a,b, 杨雨^a,b, 李家明^a,b, 郭燕燕^a,b, 金凡^a,b, 张斌^a,b

a 安徽中医药大学药学院合肥 230012;
b 安徽省中医药科学院药物化学研究所合肥 230012

收稿日期:2019-03-29 修回日期:2019-06-17 发布日期:2019-08-01
通讯作者: 李家明 E-mail:lijiaming2004@sina.com
基金资助:
国家卫生健康委员会“重大新药创制”科技重大专项（No.2018zx09739-001）资助项目.

Design, Synthesis and Evaluation of Novel Tacrine-3-n-butylphthalide Hybrids as Multifunctional Cholinesterase Inhibitors

Liu Wandong^a,b, Yang Yu^a,b, Li Jiaming^a,b, Guo Yanyan^a,b, Jin Fan^a,b, Zhang Bin^a,b

a College of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012;
b Deparment of Medicinal Chemistry, Anhui Academy of Chinese Medicine, Hefei 230012

Received:2019-03-29 Revised:2019-06-17 Published:2019-08-01
Supported by:
Project supported by the National Health Commission of "Major New Drug Creation" Scientific and Technological Major Project (No. 2018zx09739-001).

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Abstract

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

Cite this article

Liu Wandong, Yang Yu, Li Jiaming, Guo Yanyan, Jin Fan, Zhang Bin. Design, Synthesis and Evaluation of Novel Tacrine-3-n-butylphthalide Hybrids as Multifunctional Cholinesterase Inhibitors[J]. Chinese Journal of Organic Chemistry, 2019, 39(12): 3505-3515.

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新型他克林-丁苯酞杂合物作为多靶点胆碱酯酶抑制剂的设计合成及活性评价

Design, Synthesis and Evaluation of Novel Tacrine-3-n-butylphthalide Hybrids as Multifunctional Cholinesterase Inhibitors

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