Hybrid Pharmacophores in Cancer Treatment: Emphasis on Coumarinbased Scaffolds and Their Multi-target Mechanisms

Hybrid molecules have emerged as a promising strategy in anti-cancer drug discovery, offering the ability to simultaneously modulate multiple molecular targets and overcome limitations associated with conventional chemotherapeutics. This review presents an updated and systematically organized overview of recent advancements (2013-2025) in the design, synthesis, and biological evaluation of coumarin-based hybrid molecules with anti-cancer potential. Coumarin, owing to its structural versatility, natural abundance, and broad spectrum of pharmacological profiles, has become a valuable scaffold for generating hybrid pharmacophores with enhanced potency, selectivity, and reduced off-target toxicity. We summarize major classes of coumarin-integrated hybrids, including sulfonamide, thiazole, triazole, indole, quinoline, pyridine, chalcone, pyrazole, and selenophene conjugates, highlighting representative molecules, their cytotoxic profiles, and mechanistic insights into their modes of action. Additionally, the mechanistic section elucidates how hybrid entities exert anti-cancer effects either by coordinated modulation of multiple nodes within key signaling pathways (such as PI3K/Akt/mTOR, MAPK/ERK, NF-κB, and apoptotic networks) or by synergistic interaction at different sites of the same molecular target. Collectively, the evidence underscores molecular hybridization as a robust medicinal chemistry approach and positions coumarinbased hybrids as promising candidates for future anti-cancer drug development.