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) 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 50 = 1.205 f 0.395 mu M; 15 , IC50 50 = 0.225 f 0.062 mu M) and butyrylcholinesterase (BChE inhibition: 2 , IC50 50 = 8.598 f 3.605 mu M; 15 , IC50 50 = 4.013 f 0.068 mu M), 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.