Synthesis and biological evaluation of new 2-arylcarbonyl-3-trifluoromethylquinoxaline 1,4-di-N-oxide derivatives and their reduced analogues

Abstract

As a continuation of our research in the quinoxaline 1,4-di-N-oxide new series of 2-arylcarbonyl-3-trifluoromethylquinoxaline, 1,4-di-N-oxide derivatives have been synthesized and evaluated in a full panel of 60 human tumor cell lines. Selective reductions were carried out on two compounds which allowed us to determine the compound structures by comparison of the 1H NMR spectra. In general, all the di-N-oxidized compounds showed good cytotoxic parameters. The best activity was observed in derivatives with electron-withdrawing groups in position 6 or 7 on the quinoxaline ring and in the unsubstituted analogues, whereas loss of one or two oxygens reduced the cytotoxicity. The best five compounds were selected for evaluation for the in vivo hollow fiber assays. In vitro studies reveal that compound 5h efficiently generates reactive oxygen species via redox cycling in the presence of the NADPH/cytochrome P450 enzyme system, providing a plausible molecular mechanism for the observed aerobic cytotoxicity of these quinoxaline N-oxides.