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


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   

  1. 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
  • 基金资助:

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

Liu Wandonga,b, Yang Yua,b, Li Jiaminga,b, Guo Yanyana,b, Jin Fana,b, Zhang Bina,b   

  1. 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).

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 Aβ1-42.

Key words: Alzheimer's disease, tacrine, 3-n-butylphthalide, cholinesterase, ROS levels