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 4a–d, substituted isatins 5a–f, or heterocycles 6a–b. 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 4b, 4d, 5d, and 6b had the most potent antiproliferative activity, with IC50 values ranging from 2.14 to 19.34 µM, compared to the reference drugs, doxorubicin and sunitinib. Compound 6b revealed a remarkably broad antitumor activity pattern against HepG2 (IC50 6.83 µM), MCF-7 (IC50 3.64 µM), MDA-MB-231 (IC50 2.14 µM), and HeLa (IC50 5.18 µM). In addition, compound 6b showed potent inhibitory activities against EGFR, HER2, VEGFR2, and the CDK2 protein kinase enzymes, with IC50 values of 0.279, 0.224, 0.565, and 0.886 µM, respectively. Moreover, compound 6b induced caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Finally, a molecular docking simulation was performed for compound 6b to predict the potential ligand–protein interactions with the active sites of the EGFR, HER2, and VEGFR2 proteins.