Design, synthesis, and apoptotic antiproliferative action of new 1,2,3-triazole/1,2,4-oxadiazole hybrids as dual EGFR/VEGFR-2 inhibitors

Abstract

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids (<b>7a</b>-<b>o</b>) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds <b>7a</b>-<b>o</b> were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI₅₀ values ranging from 28 to 104 nM, compared to Erlotinib (GI₅₀ = 33 nM), and compounds <b>7i</b>-<b>m</b> were the most potent. Compounds <b>7h</b>, <b>7i</b>, <b>7j</b>, <b>7k</b>, and <b>7l</b> were evaluated as dual EGFR/VEGFR-2 inhibitors. These <i>in vitro</i> experiments demonstrated that compounds <b>7j</b>, <b>7k</b>, and <b>7l</b> are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds <b>7j</b>, <b>7k</b>, and <b>7l</b> were evaluated for their apoptotic potential activity, where findings indicated that compounds <b>7j</b>, <b>7k,</b> and <b>7l</b> promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.