Commentary on the Obtention of Semi-Synthetic Derivatives from Natural Products for Medicinal Applications: Advances, Challenges, and Perspectives

Plants have historically been a primary source of medicines due to their diversemolecular and structural composition. Plant metabolism, comprising primary and secondary processes, produces primary metabolites crucial for growth and secondary metabolites, or natural products (NPs), with specific biological functions. These small moleculesare instrumental in pharmacology for their ability to penetrate biological barriers and interact with intracellular targets. The structural complexity and limited availability of NPshave led to research focusing on enhancing their diversity through semi-synthesis. In thiscommentary, examples of various semisynthetic derivatives of NPs obtained through different synthetic strategies, such as organic semi-synthesis or combinatorial chemistry, arecited. Additionally, the importance of developing hybrid molecules based on the combination of two or more distinct pharmacophores is emphasized. This strategy has been widelyimplemented to obtain new multitarget drugs applicable to the treatment of multifactorialneurodegenerative diseases, where stimulating the cholinergic system by modulating different therapeutic targets is crucial. However, challenges, such as structural complexity,raw material availability, and the need for precise synthetic methods, persist. Innovationsin synthetic routes, sustainable harvesting, and biotechnological advances are critical toovercoming these barriers. The integration of omics technologies, green chemistry principles, and global collaboration is essential to maximize the potential of NPs in drug development, ensuring sustainable and efficient production of new therapeutics.