Coumarin-based hybrid anticancer agents: Recent advances in rational design, structure-activity relationships, and biological mechanisms.

Molecular hybridization has expanded coumarin from a synthetically tractable scaffold into a versatile platform for the development of structurally diverse anticancer agents. This review critically compares coumarin hybrids incorporating chalcone, triazole, pyrazole, thiazole, pyrimidine, hydroxamate, organochalcogen, carbonic anhydrase-targeted, benzimidazole, oxadiazole, and related pharmacophores, with emphasis on comparative structure-activity relationships, molecular targets, computational studies, and biological evidence reported since 2020. Across these scaffold classes, improved biological activity generally arises from optimization of the complete hybrid framework rather than the coumarin nucleus alone. Comparative SAR analysis demonstrates that the influence of electronic effects, steric complementarity, linker architecture, and conformational flexibility varies substantially among scaffold classes and biological targets, indicating that no universal substitution strategy can be applied to coumarin-based hybrids. EGFR, VEGFR-2, PI3K/AKT, CDKs, c-MET/STAT-3, JNK, thioredoxin reductase, HDACs, carbonic anhydrase IX/XII, and tubulin emerged among the principal molecular targets, although the level of mechanistic validation differs considerably among the reported studies. While computational approaches have supported lead optimization, several proposed mechanisms remain based primarily on molecular docking or molecular dynamics simulations without corresponding biochemical confirmation. Most published evidence remains at the in vitro or early preclinical stage, with experimental pharmacokinetic characterization particularly limited. Further scaffold-specific optimization and rigorous experimental validation will be required to improve the translational potential of coumarin-based hybrid anticancer agents.