Medicinal chemistry perspective on quinazoline derivatives: Sustainable synthetic routes, anticancer evaluation, and SAR analysis.

Cancer remains a leading cause of global mortality, demanding safer and more effective therapies. Quinazoline and its derivatives have gained significant interest due to their versatile biological activity and ability to modulate multiple oncogenic pathways. Among these, EGFR and VEGFR are the primary targets, with many quinazoline derivatives showing strong inhibition at nanomolar IC levels through hydrogen bonding and hydrophobic interactions within ATP-binding pockets. FDA-approved drugs like Gefitinib, Erlotinib, Afatinib, Dacomitinib, and Vandetanib validate the therapeutic significance of the quinazoline framework in modulating different cancer pathways. Additionally, derivatives acting on BRAF, HER2, PARP-1, COX-2, and PI3K/Akt/mTOR pathways have shown notable cytotoxic and apoptosis-inducing effects. Different synthetic strategies, including metal-catalysed, microwave-assisted, and solvent mediated methods, have been used to develop diverse quinazoline frameworks fused with rings like triazole, thiazole, oxadiazole, and pyrimidine. Structure activity relationship (SAR) analyses reveal that adding halogen, methoxy, or heteroaryl groups at specific ring positions enhance kinase affinity and cytotoxic efficacy. Overall, this review highlights recent progress linking synthetic design, molecular docking, and biological response, establishing quinazoline derivatives as promising multitargeted scaffolds for the design of next-generation anticancer agents.