title: Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B.
abstract: Natural (-)-huperzine B (HupB), isolated from Chinese medicinal herb, displayed moderate inhibitory activity of acetylcholinesterase (AChE). Based on the active dual-site of AChE, a series of novel derivatives of bis- and bifunctional HupB were designed and synthesized. The AChE inhibition potency of most derivatives of HupB was enhanced about 2-3 orders of magnitude as compared with the parental HupB. Among bis-HupB derivatives, 12h exhibited the most potent in the AChE inhibition and has been evaluated for its pharmacological actions in vivo on ChE inhibition, cognitive enhancement, and neuroprotection. The docking study on the bis-HupB derivatives 12 series with TcAChE has demonstrated that the ligands bound to the dual-site of the enzyme in different level.
authors.affiliation: State Key Laboratory of Drug Research, Department of Synthetic Drugs, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Zhangjiang Hi-Tech Park, Shanghai 201203, China. hexuchan@mail.shcnc.ac.cn
authors.forename: Xu-Chang
authors.initials: XC
authors.lastname: He
authors.forename: Song
authors.initials: S
authors.lastname: Feng
authors.forename: Zhi-Fei
authors.initials: ZF
authors.lastname: Wang
authors.forename: Yufang
authors.initials: Y
authors.lastname: Shi
authors.forename: Suxin
authors.initials: S
authors.lastname: Zheng
authors.forename: Yu
authors.initials: Y
authors.lastname: Xia
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.forename: Xi-can
authors.initials: XC
authors.lastname: Tang
authors.forename: Donglu
authors.initials: D
authors.lastname: Bai
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D002091:Butyrylcholinesterase / Q000097:blood / Q000737:chemistry*; D002540:Cerebral Cortex / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000470:Alkaloids; D002800:Cholinesterase Inhibitors; C053016:huperzine B; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase