Design, synthesis and biological evaluation of pyrazolyl-nitroimidazole derivatives as potential EGFR/HER-2 kinase inhibitors

A series of novel pyrazole-nitroimidazole derivatives had been arranged and evaluated for their EGFR/HER-2 tyrosine kinase inhibitory activity as well as their antiproliferative properties on four kinds of cancer cell lines (MCF-7, Hela, HepG2, B16-F10). The bioassay results showed most of the designed compounds exhibited potential antiproliferation activity, with the IC50 values ranging from 0.13 mu M to 128.06 mu M in four tumor cell lines. Among them, compound 5c exhibited remarkable inhibitory activity against EGFR/HER-2 tyrosine kinase with IC50 value of 0.26 mu M/0.51 mu M, respectively, comparable to the positive control erlotinib (IC50 = 0.41 mu M for HER-2 and IC50 = 0.20 mu M for EGFR) and lapatinib (IC50 = 0.54 mu M for HER-2 and IC50 = 0.28 mu M for EGFR). Molecular modeling simulation studies were performed in order to predict the biological activity of the proposed compounds and activity relationship (SAR) of these pyrazole-nitroimidazole derivatives. (C) 2015 Elsevier Ltd. All rights reserved.