Tertiary amine derivatives of chlorochalcone as acetylcholinesterase (AChE) and buthylcholinesterase (BuChE) inhibitors: the influence of chlorine, alkyl amine side chain and α,β-unsaturated ketone group

摘要

Xiao-hui Gao a , Chao Zhou b , Hao-ran Liu b* , Lin-bo Liu b , Jing-jing Tang b & Xin-hua Xia a* a College of Pharmacy , Hu’nan University of Chinese Medicine , Changsha , PR China ; b College of Chemistry and Chemical Engineering , Hu’nan University , Changsha , PR China Supplemental data for this article can be accessed here CONTACT Hao-ran Liu pharmaliu@126. com College of Chemistry and Chemical Engineering , Hu’nan University , Changsha , PR China ; Xin-hua Xia xiaxinhua001@163. com College of Pharmacy , Hu'nan University of Chinese Medicine , Changsha , PR China A new series of tertiary amine derivatives of chlorochalcone ( 4a～4l ) were designed, synthesized and evaluated for the effect on acetylcholinesterase (AChE) and buthylcholinesterase (BuChE). The results indicated that all compounds revealed moderate or potent inhibitory activity against AChE, and some possessed high selectivity for AChE over BuChE. The structure–activity investigation showed that the substituted position of chlorine significantly influenced the activity and selectivity. The alteration of tertiary amine group also leads to obvious change in bioactivity. Among them, IC₅₀ of compound 4l against AChE was 0.17?±?0.06?μmol/L, and the selectivity was 667.2 fold for AChE over BuChE. Molecular docking and enzyme kinetic study on compound 4l suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Further study showed that the pyrazoline derivatives synthesized from chlorochalcones had weaker activity and lower selectivity in inhibiting AChE compared to that of chlorochalcone derivatives.