Design, synthesis, biological evaluation, and in silico study of quinazoline-based dual inhibitors targeting EGFR and VEGFR-2 for cancer therapy

Quinazoline derivatives with substitution at the N3 and C2 positions, were synthesized for targeting a dual inhibition of vascular endothelial growth factor receptor 2 (VEGFR) and epidermal growth factor receptor (EGFR) kinases. The final derivatives 4a-e were characterized using various spectroscopic techniques, and their antiproliferative activity against A-549, MDA, and HeLa cancer cell lines was evaluated in vitro. Among the compounds, 4e demonstrated the most significant cytotoxicity, with an IC₅₀ value of 0.59 ± 0.01 µM against A-549 cells. The SAR analysis suggested that the presence of the ethyl acetate fragment plays a crucial role in enhancing anticancer efficacy, while the ethyl group did not notably impact its antiproliferative activity. Further investigation of compound 4e revealed its high binding affinity to EGFR, with an IC₅₀ of 69.4 ± 1.55 nM compared to Docetaxel (IC₅₀ = 56.1±1.17 nM). Molecular docking and molecular dynamics (MD) simulations provided valuable insights into the interactions between quinazoline derivatives, EGFR, and VEGFR-2. However, these studies suggest that 4e exhibits a good binding affinity toward EGFR and VEGFR-2 with docking scores of -4.46 kcal/mol and -4.41 kcal/mol, respectively. Ligand 4e and VEGFR-2 formed a stable complex, indicating its potential as promising anticancer drug over docetaxel.