Chemical and biological analysis of 4-acyloxy-3-nitrocoumarins as trypanocidal agents

Abstract

Abstract Chagas disease is the most widespread contagious tropical disease in Latin America, being an important public health problem. Treatments against this disease are still very ineffective, presenting several side effects. Therefore, the search for alternative therapeutic solutions is urgent. In the present work, we evaluate the trypanocidal activity and the mechanism of action of a select series of synthetic 4-acyloxy-3-nitrocoumarins. All coumarin derivatives showed moderate trypanocidal activity in trypomastigotes and low cytotoxicity. However, compound 1 decreased the number of infected Vero cells in the intracellular T. cruzi model, unlike the less active compound (2) that did not decrease the number of parasites per cell and the number of infected cells. Electron spin resonance and electrochemical studies showed the formation of nitro radical anions. The Fukui index provided additional information to elucidate the proposed reduction mechanism. Furthermore, in vitro radical formation studies demonstrated the potential of these compounds to achieve higher concentrations of intracellular free radicals, proposing oxidative stress as a possible trypanocidal mechanism. Furthermore, no correlation was observed between the diffusion of these compounds, which shows that lipophilicity is not a predominant factor for activity. Elsevier Ltd. All rights reserved.