Synthesis, Biological Evaluation, Molecular Docking, and In Silico ADME Predictions of Huperzine: A Derivative for the Novel Protective Application Against Neurodegenerations.

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 Aβ25‐35 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 β‐secretase, endogenous Aβ 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. [ABSTRACT FROM AUTHOR]