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Huperzine A (HupA), a natural Lycopodium alkaloid, is a potent acetylcholinesterase (AChE) inhibitor for AD treatment. In this study, HupA derivatives, huperzil, <jats:italic>N<\/jats:italic>\u2010hippurylhuperzine A, pyrrolhuperzine A, maleicamide\u2010huperzine A and phthaleicamide\u2010huperzine A, were synthesized and their in silico computation as the central nervous system (CNS) drug was performed. All derivatives exhibited lower anti\u2010AChE activity than HupA. However, we found other non\u2010cholinergic functions in AD\u2010mimicking models using differentiated SH\u2010SY5Y. HupA and derivatives significantly suppressed the A\u03b2<jats:sub>25\u201035<\/jats:sub> cytotoxicity and showed recovery effects against arsenic\u2010 induced AD pathologies including reactive oxygen species generation, neurite outgrowth shortening, amyloid precursor protein suppression and the elevation of <jats:italic>\u03b2<\/jats:italic>\u2010secretase, endogenous A\u03b2 peptide, and Tau and neurofilament light proteins. In summary, we prepared three potential compounds with dual\u2010AChE cholinergic and non\u2010cholinergic functions. Further development of these compounds will be beneficial for the future use as an alternate compound against AD.<\/jats:p>","DOI":"10.1002\/asia.202401950","type":"journal-article","created":{"date-parts":[[2025,4,8]],"date-time":"2025-04-08T05:36:12Z","timestamp":1744090572000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis, Biological Evaluation, Molecular Docking, and In Silico ADME Predictions of Huperzine: A Derivative for the Novel Protective Application Against Neurodegenerations"],"prefix":"10.1002","volume":"20","author":[{"given":"Benjaporn","family":"Homkajorn","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology Chulabhorn Research Institute  Bangkok 10210 Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thanasan","family":"Nilsu","sequence":"additional","affiliation":[{"name":"Applied Biological Sciences Program Chulabhorn Graduate Institute  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