Discovery of novel Quinazoline-chalcone hybrids as dual VEGFR-2/P-gp inhibitors to reverse cisplatin resistance in cervical Cancer.

To address the clinical challenge of cisplatin resistance in cervical cancer, a series of 25 novel quinazoline-chalcone derivatives (5a-5w and 10a-10b) was designed and synthesized using a dual-target strategy. Among them, lead compound 5n displayed potent antiproliferative activity against HeLa and cisplatin-resistant HeLa/DDP cells (IC50 = 1.21 μM and 1.88 μM, respectively), achieving a remarkably low resistance index (RI = 1.55) and a high selectivity index (SI = 53.0) over normal H8 cells. Mechanistic studies revealed that 5n strongly inhibited VEGFR-2 kinase (IC50 = 126.4 nM), suppressed its phosphorylation, and effectively reduced HUVEC tube formation. Furthermore, at a non-cytotoxic concentration (0.3 μM), 5n directly blocked the efflux function of P-glycoprotein (P-gp) without altering its expression levels. Notably, co-administration of 5n significantly restored HeLa/DDP cell sensitivity to cisplatin, reducing the RI of cisplatin from 6.07 to 1.49, outperforming the classical inhibitor, verapamil. Molecular dynamics simulations demonstrated that the conformational flexibility of 5n enables stable binding to the distinct active sites of VEGFR-2 and P-gp. In silico ADMET prediction revealed favorable drug-like properties. Coupled with a favorable safety profile in a zebrafish toxicity model, these findings highlight 5n as a promising dual-target lead compound for overcoming cisplatin-resistant cervical cancer.