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

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.