Valproic acid as a therapeutic scaffold: Advances in structural modification and drug design

Valproic acid (VPA), a short-chain branched fatty acid with a broad pharmacological profile, remains one of the most versatile molecules in neuropsychopharmacology. Beyond its established use in epilepsy and bipolar disorder (BD), VPA functions as a histone deacetylases (HDACs) inhibitor, revealing significant potential in oncology and other therapeutic areas. However, its clinical application is limited by serious adverse effects, notably hepatotoxicity and teratogenicity. Owing to its simple and modifiable chemical structure, VPA has served as a valuable scaffold for the development of new analogues designed to enhance therapeutic efficacy while reducing toxicity. This review presents current advances in the design and biological evaluation of VPA derivatives and prodrugs, emphasizing their pharmacological potential in neurological and oncological disorders. Numerous analogues-including modified carboxylic acids, amides, esters, hydroxamates, ureas, glycine conjugates, phosphonate derivatives, and tetramethylcyclopropyl analogues-have demonstrated improved anticonvulsant, antiallodynic, and antimigraine efficacy with reduced adverse effects. In parallel, several VPA-based hybrid molecules and metal coordination complexes exhibit potent anticancer properties through HDAC inhibition, apoptosis induction, and tumor cell differentiation. Collectively, these findings underscore the continued relevance of VPA as a privileged framework for the design of novel therapeutic agents with enhanced safety and pharmacological performance.