Development of novel chalcone-based quinazoline derivatives as dual VEGFR-2 and EGFR inhibitors

Abstract

As possible dual VEGFR-2/EGFR inhibitors, a new set of quinazoline-chalcone hybrid compounds (8a-h and 11a-h) was logically developed and synthesized. The synthesized compounds' chemical structures were verified by high-resolution mass spectrometry and 1H and 13C NMR. When all compounds were first tested against the MCF-7 and HepG-2 cancer cell lines at a single concentration (10 μM), several variants showed encouraging growth-inhibitory efficacy. The MTT assay was used to further assess the cytotoxic activity (IC₅₀ values) of the most active candidates (8c, 8h, 11b, 11d, and 11f). Interestingly, the investigated compounds showed low toxicity against normal WI-38 cells and specific cytotoxicity toward cancer cells. The chosen compounds demonstrated greater affinity for VEGFR-2 and efficiently inhibited both EGFR and VEGFR-2 kinases at nanomolar concentrations, as determined by enzyme inhibition studies. When compared to erlotinib (IC₅₀ = 99.5 nM against EGFR) and sorafenib (IC₅₀ = 30.7 nM against VEGFR-2), compound 8h exhibited the strongest dual inhibitory activity, with IC₅₀ values of 97.7 nM against EGFR and 27.8 nM against VEGFR-2, respectively. Molecular docking and molecular dynamics simulations were used to clarify the molecular basis of their activity, and the results confirmed stable binding interactions within both kinases' ATP-binding sites. Additionally, in silico ADME and toxicity tests demonstrated good drug-likeness, pharmacokinetic characteristics, and a satisfactory safety profile. Overall, these results show that quinazoline-chalcone hybrids are effective dual EGFR/VEGFR-2 inhibitors with strong anti-cancer potential.