ABSTRACT. As a continuation of our research and with the aim of obtaining new agents against Chagas disease, an extremely neglected disease which threatens 100 million people, eighteen new quinoxaline 1,4-di-N-oxide derivatives have been synthesized following the Beirut reaction. The synthesis of the new derivatives was optimized through the use of a new and more efficient microwave-assisted organic synthetic method. The new derivatives showed excellent in vitro biological activity against Trypanosoma cruzi. Compound 17, which was substituted with 2 fluoro groups at the 6-and 7-positions of the quinoxaline ring, was the most active and selective in the cytotoxicity assay. The electrochemical study showed that the most active compounds, which were substituted by electron-withdrawing groups, possessed a greater ease of reduction of the N-oxide groups.

The electrochemical properties of 24 quinoxaline 1,4-di-N-oxide-2-ketone derivatives with varying degrees of anti-chagas activity were investigated in the aprotic solvent dimethylformamide (DMF) using cyclic voltammetry and first derivative cyclic voltammetry. For this group of compounds, the first reduction in DMF was either reversible or quasireversible and consistent with reduction of the N-oxide functionality to form the radical anion. The second reduction process for these compounds was found to be irreversible under the conditions used. The reduction potentials correlated well with molecular structure. Substitution in the 3-, 6-, and 7-positions of the quinoxaline ring by electron-withdrawing substituents directly affects the ease of reduction and improves the biological activities of these compounds, whereas substitution by electrondonating groups has the opposite effect. The results of this study when combined with previous work into their mechanism of action against chagas disease suggest that charge transfer might play a role in the mechanism of action for these compounds.