Exploiting COX-2 engagement for amplifying anticancer potential of Quinazoline-triazole conjugates with superior EGFR/VEGFR-2 inhibition.

A novel series of quinazoline-1,2,3-triazole hybrid compounds (8-22) were synthesized and evaluated as multi-target directed ligands (MTDLs) against EGFR, VEGFR-2, and COX-2 enzymes for anticancer activity. The synthesized compounds demonstrated significant anticancer activity against four human cancer cell lines (HeLa, HepG2, HCT-116, and MCF-7), with compound 17 emerging as the most potent derivative. Compound 17 exhibited exceptional anticancer activity with IC₅₀ values of 4.93, 2.34, 6.07, and 3.35 μM against HeLa, HepG2, HCT-116, and MCF-7 cell lines, respectively, surpassing doxorubicin (DOX) against HepG2 cells (IC50 = 4.50 μΜ). Importantly, compound 17 demonstrated superior selectivity toward cancer cells over normal human lung fibroblasts (WI-38) with a selectivity index of 11.78, compared to DOX (SI = 1.61). Multi-target enzyme inhibition assays revealed that compound 17 exhibited potent EGFR inhibition (IC₅₀ = 0.0085 μM), comparable to erlotinib (IC₅₀ = 0.0078 μM), strong VEGFR-2 inhibition (IC₅₀ = 0.068 μM), approaching sorafenib's activity (IC₅₀ = 0.056 μM), and significant COX-2 inhibition (IC₅₀ = 0.158 μM), comparable to Celecoxib (IC₅₀ = 0.044 μM). Compound 13 also demonstrated multi-target activity with IC₅₀ values of 0.0323, 0.220, and 0.103 μM against EGFR, VEGFR-2, and COX-2, respectively. Mechanistic studies revealed that compound 17 induces G1-phase cell cycle arrest in MCF-7 cells. The compound triggered a 5.11-fold increase in the Bax/Bcl-2 ratio, 2.90-fold upregulation of caspase-8, and elevated caspase-9 protein levels from 139.48 to 392.53 ng/mL, confirming the intrinsic apoptotic pathway activation. Molecular docking and dynamics simulations provided structural insights into the multi-target binding modes. These findings establish quinazoline-1,2,3-triazole hybrids as promising multi-target anticancer agents, with compound 17 demonstrating exceptional therapeutic potential through the simultaneous inhibition of tumor proliferation, angiogenesis, and inflammation pathways while maintaining favorable selectivity profiles.