Metronidazole acid acyl sulfonamide: A novel class of anticancer agents and potential EGFR tyrosine kinase inhibitors

A series of novel metronidazole derivatives were recently reported as potent anticancer agents targeting EGFR and HER-2 by our group [Qian, Y.; Zhang, H. J.; Zhang, H.; Xu, C.; Zhao, J.; Zhu, H. L. Bioorg. Med. Chem.2010, 18, 4991]. Based on the previous results, we designed and synthesized a new series of metronidazole acid acyl sulfonamide derivatives and a new series of phenylacetyl benzenesulfonamide derivatives and their anticancer activities were evaluated as potential EGFR and HER-2 kinase inhibitors. Among all the compounds, compound 12 displayed the most potent inhibitory activity EGFR and HER-2 (IC50 = 0.39 μM for EGFR and IC50 = 1.53 μM for HER-2) and it also showed the most potent growth inhibitory activity against A549 and B16-F10 cancer cell line in vitro, with an IC50 value of 1.26 μg/mL for A549 and 0.35 μg/mL for B16-F10. Docking simulation was further performed to position compound 12 into the EGFR active site to determine the probable binding model.

Two series of benzenesulfonamide derivatives have been designed and synthesized, and their biological activities were also evaluated for EGFR inhibitory activity. Compound 12 possessed the most potent enzyme inhibition activities (IC50 = 0.39 μM for EGFR and IC50 = 1.53 μM for HER-2) and anticancer activities (IC50 = 1.26 μg/mL for A549 and IC50 = 0.35 μg/mL for B16-F10). Docking simulation was performed to explore the binding model of compound 12 with EGFR.Figure optionsDownload as PowerPoint slide