Homkajorn_2025_Chem.Asian.J__e202401950

To date, there has been no effective treatment available for the Alzheimer's disease (AD); hence, novel compounds with AD inhibitory effects are highly desirable. Huperzine A (HupA), a natural Lycopodium alkaloid, is a potent acetylcholinesterase (AChE) inhibitor for AD treatment. In this study, HupA derivatives, huperzil, N-hippurylhuperzine A, pyrrolhuperzine A, maleicamide-huperzine A and phthaleicamide-huperzine A, were synthesized and their in silico computation as the central nervous system (CNS) drug was performed. All derivatives exhibited lower anti-AChE activity than HupA. However, we found other non-cholinergic functions in AD-mimicking models using differentiated SH-SY5Y. HupA and derivatives significantly suppressed the Abeta(25-35) cytotoxicity and showed recovery effects against arsenic- induced AD pathologies including reactive oxygen species generation, neurite outgrowth shortening, amyloid precursor protein suppression and the elevation of beta-secretase, endogenous Abeta peptide, and Tau and neurofilament light proteins. In summary, we prepared three potential compounds with dual-AChE cholinergic and non-cholinergic functions. Further development of these compounds will be beneficial for the future use as an alternate compound against AD.