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 diverse molecular 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 molecules are instrumental in pharmacology for their ability to penetrate biological barriers and interact with intracellular targets. The structural complexity and limited availability of NPs have led to research focusing on enhancing their diversity through semi-synthesis. In this commentary, examples of various semisynthetic derivatives of NPs obtained through different synthetic strategies, such as organic semi-synthesis or combinatorial chemistry, are cited. Additionally, the importance of developing hybrid molecules based on the combination of two or more distinct pharmacophores is emphasized. This strategy has been widely implemented to obtain new multitarget drugs applicable to the treatment of multifactorial neurodegenerative 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. Innovations in synthetic routes, sustainable harvesting, and biotechnological advances are critical to overcoming 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.