Rational design and synthesis of highly potent anti-acetylcholinesterase activity huperzine A derivatives.
By targeting multi-active sites of acetylcholinesterase (AChE), a series of huperzine A (Hup A) derivatives with various aromatic ring groups were designed and synthesized by Schiff reaction. They were evaluated as AChE and butyrylcholinesterase (BChE) inhibitors. Results showed very significant specificity that the group of imine derivatives could inhibit TcAChE and hAChE, but no inhibitory effect on hBChE was detected. The experiment was explained by a docking study. In the docking model, we confirmed that aromatic ring of Hup A derivatives played the pi-pi stacking against aminophenol residues of AChE, and the structure-activity relationship (SAR) was discussed.
Yan
Jian
J
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, The Chinese Academy of Sciences, Kunming 650204, PR China. yanjian@scbg.ac.cn
Sun
Lirong
L
Wu
Guisheng
G
Yi
Ping
P
Yang
Fumei
F
Zhou
Lin
L
Zhang
Xianmin
X
Li
Zhongrong
Z
Yang
Xiaosheng
X
Luo
Huairong
H
Qiu
Minghua
M
D000110:Acetylcholinesterase; D000470:Alkaloids; D002091:Butyrylcholinesterase; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D018696:Neuroprotective Agents / Q000138:chemical synthesis; D011485:Protein Binding; D012545:Schiff Bases / Q000737:chemistry; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000470:Alkaloids; D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D012545:Schiff Bases; D012717:Sesquiterpenes; C050426:huperzine A; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase