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

Abstract

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 <b>4-15</b> against various cancer cell lines, revealing derivatives <b>12</b> and <b>15</b> for their remarkable activity with GI₅₀ values of 37 and 35 nM, respectively, when compared to the reference erlotinib (33 nM). In vitro enzyme assays showed that target compounds, particularly <b>12</b>, <b>14</b>, and <b>15</b>, effectively inhibited EGFR and VEGFR-2. <i>In vitro</i> enzyme testing revealed that compound <b>15</b> was the most promising, with IC₅₀ values of 84 and 3.50 nM for EGFR and VEGFR-2, respectively. Additionally, an <i>in vitro</i> 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 <b>12</b> and <b>15</b> with the EGFR and VEGFR-2 active sites.