Synthesis, antiproliferative evaluation and in silico studies of new quinazoline derivatives as VEGFR-2 inhibitors

New quinazoline derivatives were designed and synthesized to target VEGFR-2, aiming to identify potential anticancer agents. The synthesized compounds underwent in vitro screening to evaluate their cytotoxic effects across 60 cancer cells following the NCI protocol. The most promising derivatives, 3i and 3j, underwent further evaluation via a five-dose test to assess broad-spectrum anticancer activity. Their VEGFR-2 inhibitory potential was compared to sorafenib. Cell cycle analyses, annexin V-FITC, and apoptotic markers were used to examine HT-29 colon cancer cells after treatment with 3j for cell cycle arrest and apoptosis induction. Molecular docking and MD simulations explored binding interactions, while ADMET studies assessed pharmacokinetics. Compounds 3i and 3j exhibited potent to moderate cytotoxic activity, with compound 3j showing the highest activity against colon cancer cell lines (GI50 = 3.29 μM). Both compounds demonstrated promising VEGFR-2 inhibitory activity (IC50 = 0.120 and 0.197 µM, respectively), comparable to sorafenib (IC50 = 0.088 µM). Cell cycle analysis displayed G1 phase arrest and pro-apoptotic effects. Docking studies confirmed favorable VEGFR-2 binding affinity (−7.57 and −7.83 kcal/mol). ADMET profiling indicated promising drug-like properties. Compounds 3i and 3j exhibit promising VEGFR-2 inhibitory properties and significant anticancer activity, warranting further investigation.