Pure and Applied Chemistry

Abstract: Recent studies have proved that huperzine A (HupA) possesses different pharmacological actions other than the inhibition of hydrolysis of ACh. These noncholinergic roles, for instance, the antagonist effect on NMDA receptor, the protection of neuronal cells against β-amyloid, free radicals, and hypoxia-ischemia-induced injury, could be important too in Alzheimer's disease (AD) treatment. The therapeutic effects of HupA are probably based on a multitarget mechanism. By targeting dual active sites of AChE, a series of bis- and bifunctional HupB compounds with various lengths of tether were designed, synthesized, and tested for the inhibition and selectivity of AChE. The most potent bis-HupB compound exhibited increase by three orders of magnitude in AChE inhibition and two orders of magnitude in selectivity for AChE than its parent HupB.