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Bioorg Med Chem. 2007 Feb 1;15(3):1394-408. Epub 2006 Nov 9.

Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B.

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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.


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.

[Indexed for MEDLINE]

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