Abstract
Chagas disease or American trypanosomiasis is a worldwide public health problem. In this work, we evaluated 26 new propyl and isopropyl quinoxaline-7-carboxylate 1,4-di-N-oxide derivatives as potential trypanocidal agents. Additionally, molecular docking and enzymatic assays on trypanothione reductase (TR) were performed to provide a basis for their potential mechanism of action. Seven compounds showed better trypanocidal activity on epimastigotes than the reference drugs, and only four displayed activity on trypomastigotes; T-085 was the lead compound with an IC50 = 59.9 and 73.02 µM on NINOA and INC-5 strain, respectively. An in silico analysis proposed compound T-085 as a potential TR inhibitor with better affinity than the natural substrate. Enzymatic analysis revealed that T-085 inhibits parasite TR non-competitively. Compound T-085 carries a carbonyl, a CF3, and an isopropyl carboxylate group at 2-, 3- and 7-position, respectively. These results suggest the chemical structure of this compound as a good starting point for the design and synthesis of novel trypanocidal derivatives with higher TR inhibitory potency and lower toxicity.
Highlights
American trypanosomiasis or Chagas disease is a neglected tropical disease caused by the parasitic protozoa Trypanosoma cruzi [1]
The effect on trypanocidal activity between the methyl and ethyl ester group at 7-position on quinoxaline 1,4-di-N-oxide in analogue compounds was not conclusive [23]; in this study, the results showed that the change from a propyl to an isopropyl group does not confer an advantage on biological activity
Based on previous reports [23] and previous docking analysis, we suggested that quinoxaline-7-carboxylate-1,4-di-N-oxide derivatives could bind and inhibit trypanothione reductase (TR)
Summary
American trypanosomiasis or Chagas disease is a neglected tropical disease caused by the parasitic protozoa Trypanosoma cruzi [1]. The infection is transmitted to humans by blood-sucking triatomine bugs, which excrete the parasite in their feces near the bite site during feeding. Other modes of transmission are blood transfusion, congenital transmission, organ transplantation or less frequently, Molecules 2017, 22, 220; doi:10.3390/molecules22020220 www.mdpi.com/journal/molecules. Chagas disease starts with an acute phase that is frequently asymptomatic, characterized by high parasitemia that progresses to a chronic phase. In this phase, the infection may remain silent for decades and about 30% of infected individuals can develop cardiac and intestinal complications [5]
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