Biosynthesis, total synthesis, and pharmacological activities of galanthamine and its analogues

Galanthamine (GAL), an isoquinoline alkaloid characterized by a unique tetracyclic skeleton bearing three chiral centers, is a potent and selective acetylcholinesterase inhibitor with established therapeutic significance. Extensive pharmacological and clinical investigations over decades have conclusively demonstrated its efficacy and favorable safety profile as an anti-Alzheimer's agent. While the yield of GAL obtained from plant sources remains insufficient to meet current demands, recent advances in both biosynthesis and chemical synthesis offer promising avenues to overcome these supply constraints. This review systematically summarizes and evaluates recent progress in three central domains: (1) elucidation and engineering of biosynthetic pathways; (2) novel strategies for the total synthesis of GAL; and (3) pharmacological profiles of GAL and its structural analogues. By synthesizing knowledge across these disciplines, this work aims to identify persistent gaps in current understanding and highlight emerging opportunities for future research. Particular focus is given to the mechanistic insights into GAL biosynthesis, which may inform the design of high-efficiency microbial or enzymatic production platforms capable of supporting the growing clinical demand for this valuable plant-derived therapeutic.