Design, synthesis and anti-Alzheimer's disease activity evaluation of C-3 arylated huperzine A derivatives.

A series of C-3 arylated huperzine A (HPA) derivatives (1-30) were designed and synthesized in good yields via palladium-catalyzed Suzuki cross-coupling reaction. Cholinesterase inhibitory and neuroprotective activities of all 30 derivatives were evaluated. Cholinesterase inhibition results revealed that derivatives 2 and 15 exhibited dual inhibitory activity against both acetylcholinesterase (AChE inhibition: 2, IC50 = 1.205 ± 0.395 μM; 15, IC50 = 0.225 ± 0.062 μM) and butyrylcholinesterase (BChE inhibition: 2, IC50 = 8.598 ± 3.605 μM; 15, IC50 = 4.013 ± 0.068 μM), a feature not observed in huperzine A. Molecular docking results indicated that the introduction of aryl groups enhanced the affinity of the derivatives for the acyl-binding pocket of BChE, thereby limiting the hydrolysis of acetyl choline. However, these derivatives exhibited poor performance in cytotoxicity and neuroprotection assays.