title: 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.
abstract: 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, IC50of 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.
authors: a College of Pharmacy , Hu'nan University of Chinese Medicine , Changsha , PR China.
authors: Xiao-Hui
authors: XH
authors: Gao
authors: b College of Chemistry and Chemical Engineering , Hu'nan University , Changsha , PR China.
authors: Chao
authors: C
authors: Zhou
authors: b College of Chemistry and Chemical Engineering , Hu'nan University , Changsha , PR China.
authors: Hao-Ran
authors: HR
authors: Liu
authors: b College of Chemistry and Chemical Engineering , Hu'nan University , Changsha , PR China.
authors: Lin-Bo
authors: LB
authors: Liu
authors: b College of Chemistry and Chemical Engineering , Hu'nan University , Changsha , PR China.
authors: Jing-Jing
authors: JJ
authors: Tang
authors: a College of Pharmacy , Hu'nan University of Chinese Medicine , Changsha , PR China.
authors: Xin-Hua
authors: XH
authors: Xia
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism*; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D002713:Chlorine / Q000737:chemistry* / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D047188:Chalcones; D002800:Cholinesterase Inhibitors; D007659:Ketones; D002713:Chlorine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase
keywords: Acetylcholinesterase inhibitors; Alzheimer’s disease; chlorochalcones; pyrazoline; structure–activity relationship