Design, synthesis, in vitro and in vivo evaluation of tacrine-cinnamic acid hybrids as multi-target acetyl-and butyrylcholinesterase inhibitors against Alzheimer's disease

被引：36

作者：

Chen, Yao ^{[1
,2
,3
]}

Lin, Hongzhi ^{[5
]}

Zhu, Jie ^{[5
]}

Gu, Kai ^{[5
]}

Li, Qi ^{[5
]}

He, Siyu ^{[5
]}

Lu, Xin ^{[5
]}

Tan, Renxiang ^{[2
]}

Pei, Yuqiong ^{[1
]}

Wu, Liang ^{[2
]}

Bian, Yaoyao ^{[4
]}

Sun, Haopeng ^{[5
]}

机构：

[1] Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210023, Jiangsu, Peoples R China

[2] Nanjing Univ Chinese Med, State Key Lab Cultivat Base TCM Qual & Efficacy, Nanjing 210023, Jiangsu, Peoples R China

[3] Nanjing Univ Chinese Med, Jiangsu Key Lab Funct Subst Chinese Med, Nanjing 210023, Jiangsu, Peoples R China

[4] Nanjing Univ Chinese Med, Sch Nursing, Nanjing 210023, Jiangsu, Peoples R China

[5] China Pharmaceut Univ, Dept Med Chem, Nanjing 210009, Peoples R China

来源：

RSC ADVANCES | 2017年 / 7卷 / 54期

基金：

中国国家自然科学基金;

关键词：

BETA-AMYLOID AGGREGATION; TARGET-DIRECTED LIGANDS; MULTIFUNCTIONAL AGENTS; OXIDATIVE STRESS; HUMAN ACETYLCHOLINESTERASE; CHOLINESTERASE-INHIBITORS; CHOLINERGIC HYPOTHESIS; DRUGS; DERIVATIVES; NEURODEGENERATION;

D O I：

10.1039/c7ra04385f

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

Previously, we have reported tacrine-ferulic acid hybrids as multi-target cholinesterase inhibitors against Alzheimer's disease. However, the detailed structure-activity relationship (SAR), especially regarding the ferulic acid moiety, has yet to be elucidated. Herein we report the structural modification of the ferulic acid moiety, which is replaced by cinnamic acid with different substitutions. The target compounds are synthesized and evaluated for their in vitro cholinesterase inhibitory activities, inhibition of amyloid beta-protein self-aggregation, cyto-protective effects against hydrogen peroxide and antiproliferative activity in PC-12 cells. The optimal compounds 35 and 36 are subsequently selected for in vivo assays. 36 shows much better performance in ameliorating the scopolamine-induced cognition impairment and less hepatotoxicity than tacrine. The compound serves as a good lead compound for further optimization.

引用

页码：33851 / 33867

页数：17

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