Design and Synthesis of New Dihydropyrimidine Derivatives with a Cytotoxic Effect as Dual EGFR/VEGFR-2 Inhibitors.

We developed and synthesized tetrahydropyrimidine derivatives as possible cytotoxic agents to inhibit EGFR and VEGFR-2 in the present study. Our study completely assesses the cytotoxic efficiency of pyrimidine-based derivatives 4-15 against various cancer cell lines, revealing derivatives 12 and 15 for their remarkable activity with GI 50 values of 37 and 35 nM, respectively, when compared to the reference erlotinib (33 nM). In vitro enzyme assays showed that target compounds, particularly 12 , 14 , and 15 , effectively inhibited EGFR and VEGFR-2. In vitro enzyme testing revealed that compound 15 was the most promising, with IC 50 values of 84 and 3.50 nM for EGFR and VEGFR-2, respectively. Additionally, an in vitro assessment of the novel targets' apoptotic potential revealed that both pro-apoptotic and antiapoptotic behaviors were promising, indicating that the apoptotic induction pathway is a strongly proposed action method for the newly developed targets. Finally, molecular docking experiments are elaborately discussed to corroborate the exact binding interactions of the most active hybrids 12 and 15 with the EGFR and VEGFR-2 active sites.