Vanillin Derivatives in Drug Design: Structure–Activity Relationship (SAR) Hotspots and Synthetic Pathways for Enhanced Pharmacological Activity

Drug discovery often uses privileged molecular scaffolds, such as vanillin, which are naturally found in plants for drug design and synthesis. Incorporating vanillin into standard chemical structures and synthesizing novel derivatives with active scaffolds are vital for developing effective therapeutic candidates. The aromatic ring of vanillin contains functional groups such as aldehyde, hydroxyl, and ether, which facilitate its modification and the generation of various resultant derivatives with promising biological activities. Consequently, numerous strategies have been developed and incorporated into synthetic pathways to produce biologically potent vanillin derivatives. Vanillin-based compounds have demonstrated effectiveness against a wide range of emerging infectious diseases. This review focuses on the key structure-activity relationship hotspots within vanillin derivatives that influence their biological activity. By examining the synthetic pathways developed over the past decade (2014-2025), we highlight how targeted modifications at specific SAR hotspots can enhance the therapeutic potential of these compounds, such as antitubercular, antioxidant, antimalarial, anticancer, and anti-inflammatory properties.