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

Background: New quinazoline derivatives were designed and synthesized to target VEGFR-2, aiming to identify potential anticancer agents. Research design and methods: The synthesized compounds underwent invitro 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. Results: 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. Conclusions: Compounds 3i and 3j exhibit promising VEGFR-2 inhibitory properties and significant anticancer activity, warranting further investigation.