Design, Synthesis, and Biological Evaluation of 2-Mercaptobenzoxazole Derivatives as Potential Multi-Kinase Inhibitors

A series of 12 compounds was designed and synthesized, based on 2-mercaptobenzoxazole derivatives containing either the substituted benzenes - , substituted isatins - , or heterocycles - . The in vitro antiproliferative activity of the compounds was evaluated against hepatocellular carcinoma (HepG2), mammary gland cancer (MCF-7), breast cancer (MDA-MB-231), and the epithelioid cervix carcinoma (HeLa) cancer cell lines. Compounds , , , and had the most potent antiproliferative activity, with IC values ranging from 2.14 to 19.34 µM, compared to the reference drugs, doxorubicin and sunitinib. Compound revealed a remarkably broad antitumor activity pattern against HepG2 (IC 6.83 µM), MCF-7 (IC 3.64 µM), MDA-MB-231 (IC 2.14 µM), and HeLa (IC 5.18 µM). In addition, compound showed potent inhibitory activities against EGFR, HER2, VEGFR2, and the CDK2 protein kinase enzymes, with IC values of 0.279, 0.224, 0.565, and 0.886 µM, respectively. Moreover, compound induced caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Finally, a molecular docking simulation was performed for compound to predict the potential ligand-protein interactions with the active sites of the EGFR, HER2, and VEGFR2 proteins.