Citation: 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. doi: 10.6023/cjoc201903072 shu

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

Corresponding author: Li Jiaming, lijiaming2004@sina.com
Received Date: 29 March 2019
Revised Date: 17 June 2019
Available Online: 1 December 2019
Fund Project: the National Health Commission of "Major New Drug Creation" Scientific and Technological Major Project 2018zx09739-001Project supported by the National Health Commission of "Major New Drug Creation" Scientific and Technological Major Project (No. 2018zx09739-001)

Figures(5)

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.
- Alzheimer's disease,
- tacrine,
- 3-n-butylphthalide,
- cholinesterase,
- ROS levels
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