Anti-proliferation evaluation of new derivatives of indole-6-carboxylate ester as receptor tyrosine kinase inhibitors

<b>Aim:</b> The main goal was to create two new groups of indole derivatives, hydrazine-1-carbothioamide (<b>4a</b> and <b>4b</b>) and oxadiazole (<b>5</b>, and <b>6a–e</b>) that target EGFR (<b>4a</b>, <b>4b</b>, <b>5</b>) or VEGFR-2 (<b>6a–e</b>). <b>Materials &amp; methods:</b> The new derivatives were characterized using various spectroscopic techniques. Docking studies were used to investigate the binding patterns to EGFR/VEGFR-2, and the anti-proliferative properties were tested <i>in vitro</i>. <b>Results:</b> Compounds <b>4a</b> (targeting EGFR) and <b>6c</b> (targeting VEGFR-2) were the most effective cytotoxic agents, arresting cancer cells in the G2/M phase and inducing the extrinsic apoptosis pathway. <b>Conclusion:</b> The results of this study show that compounds <b>4a</b> and <b>6c</b> are promising cytotoxic compounds that inhibit the tyrosine kinase activity of EGFR and VEGFR-2, respectively. Two hydrazine-1-carbothioamide derivatives (<b>4a</b> and <b>4b</b>), and oxadiazole-2-thione compound (<b>5</b>) were designed and synthesized to mimic the pharmacophoric properties of EGFR tyrosine kinase inhibitors. Several oxadiazole derivatives (<b>6a–e</b>) were designed and synthesized to mimic the pharmacophoric properties of VEGFR-2 tyrosine kinase inhibitors. Molecular docking revealed that compounds <b>4a</b> and <b>6c</b> were the best fits within the active sites of EGFR and VEGFR-2 tyrosine kinases, respectively. IC₅₀ values against HepG2, HCT-116 and A549 cancer cell lines were calculated. Compounds <b>4a</b> and <b>6c</b> were noted to be the most potent anti-proliferative compounds against cancer cells. Compound <b>4a</b> with an unsubstituted phenyl moiety (R=H) exhibited the highest EGFR enzyme inhibitory activity. Compound <b>6c</b> with a chloro group at the 4-position of the aromatic ring showed the highest VEGFR-2 enzyme inhibitory activity.