Structure–activity relationship investigation of benzamide and picolinamide derivatives containing dimethylamine side chain as acetylcholinesterase inhibitors

Journal of Enzyme Inhibition and Medicinal Chemistry

Jing-jing Tang¹  Hao-ran Liu¹  Lu Kang¹  Lin-bo Liu¹  Peiwu Cui²  Hongnian Wu²  Jianye Yan²  Xiao-hui Gao³ 

[1] College of Chemistry and Chemical Engineering, Hu’nan University, Changsha, China;College of Pharmacy, Hu’nan University of Chinese Medicine, Changsha, Chin;Key Laboratory Breeding Base of Hu’nan Oriented Fundamental and Applied Research of Innovative Pharmaceutics, College of Pharmacy, Changsha Medical University, Changsha, China;

关键词: Cholinesterase inhibitors;    benzamide;    picolinamide;    structure–activity relationship;    Alzheimer's disease;   

DOI  :  10.1080/14756366.2017.1399885

来源: publisher

【 摘 要 】

A series of benzamide and picolinamide derivatives containing dimethylamine side chain (4a–4c and 7a–7i) were synthesised and evaluated for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity in vitro. Structure–activity relationship investigation revealed that the substituted position of dimethylamine side chain markedly influenced the inhibitory activity and selectivity against AChE and BChE. In addition, it seemed that the bioactivity of picolinamide amide derivatives was stronger than that of benzamide derivatives. Among them, compound 7a revealed the most potent AChE inhibitory activity (IC50: 2.49 ± 0.19 μM) and the highest selectivity against AChE over BChE (Ratio: 99.40). Enzyme kinetic study indicated that compound 7a show a mixed-type inhibition against AChE. The molecular docking study revealed that this compound can bind with both the catalytic site and the peripheral site of AChE.

【 授权许可】

CC BY