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 (IC(50) = 0.39 mu M for EGFR and IC(50) = 1.53 mu M 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 IC(50) value of 1.26 mu g/mL for A549 and 0.35 mu g/mL for B16-F10. Docking simulation was further performed to position compound 12 into the EGFR active site to determine the probable binding model. (C) 2011 Elsevier Ltd. All rights reserved.