| Summary: | A small set of indole-based derivatives, <b>IV</b> and <b>Va</b>–<b>I</b>, was designed and synthesized. Compounds <b>Va</b>–<b>i</b> demonstrated promising antiproliferative activity, with GI<sub>50</sub> values ranging from 26 nM to 86 nM compared to erlotinib’s 33 nM. The most potent antiproliferative derivatives—<b>Va</b>, <b>Ve</b>, <b>Vf</b>, <b>Vg</b>, and <b>Vh</b>—were tested for EGFR inhibitory activity. Compound <b>Va</b> demonstrated the highest inhibitory activity against EGFR with an IC<sub>50</sub> value of 71 ± 06 nM, which is higher than the reference erlotinib (IC<sub>50</sub> = 80 ± 05 nM). Compounds <b>Va</b>, <b>Ve</b>, <b>Vf</b>, <b>Vg</b>, and <b>Vh</b> were further tested for BRAF<sup>V600E</sup> inhibitory activity. The tested compounds inhibited BRAF<sup>V600E</sup> with IC<sub>50</sub> values ranging from 77 nM to 107 nM compared to erlotinib’s IC<sub>50</sub> value of 60 nM. The inhibitory activity of compounds <b>Va</b>, <b>Ve</b>, <b>Vf</b>, <b>Vg</b>, and <b>Vh</b> against VEGFR-2 was also determined. Finally, in silico docking experiments attempted to investigate the binding mode of compounds within the active sites of EGFR, BRAF<sup>V600E</sup>, and VEGFR-2.
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