New Derivatives of 4-Piperidinylphenyl-Linked Thiazoles as VEGFR2 Inhibitors with Potential Cytotoxicity Against Renal Cancer

Abstract

Herein, a novel series of 4-piperidinylphenyl-linked thiazoles was synthesized as VEGFR2 inhibitors with potential cytotoxic activity against renal cancer. Most of the target compounds inhibited VEGFR2 enzyme at sub-micromolar IC₅₀ values. Compounds <b>7c</b> (IC₅₀ = 0.073 ± 0.002 µM), <b>9b</b> (IC₅₀ = 0.049 ± 0.002 µM), and <b>9c</b> (IC₅₀ = 0.093 ± 0.003 µM) were the most potent, showing VEGFR2 inhibition superior to that of sunitinib (IC₅₀ = 0.118 ± 0.003 µM). Furthermore, compounds <b>7c</b>, <b>9b</b>, and <b>9c</b> effectively inhibited the growth of A498 renal cancer cells, with compound <b>7c</b> being the most potent showing a one-digit IC₅₀ value of 7.866 ± 0.27 µM. In addition, compound <b>7c</b> revealed a potentially improved safety profile against non-cancerous normal cells, relative to sunitinib. The treatment of A498 renal cancer cells with compound <b>7c</b> led to an apparent cell cycle arrest and a significant induction of apoptosis. A docking study was also conducted and revealed a proper orientation of compound <b>7c</b> into the active site of VEGFR2.