Trypanocidal Activity of Quinoxaline 1,4 Di-N-oxide Derivatives as Trypanothione Reductase Inhibitors

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.

Facile Synthesis of a Series of Non-Symmetric Thioethers Including a Benzothiazole Moiety and Their Use as Efficient In Vitro anti-Trypanosoma cruzi Agents

“…Improving selectivity in drug design is a must. Thus, from the series of BTA’s compounds attained, it was important to determine whether their biological activity was a consequence of being selective or due to their general toxicity [23]. Thus, results from the experiments showed that in the case of compounds 3f and 3g their trypanocidal effect is due to toxicity and not to selectivity.…”

“…The quantification of bloodstream trypomastigotes was performed by the Brener-Pizzi method, 5 μL of blood was deposited between a slide and a coverslip (18 × 18 mm), and all bloodstream trypomastigotes present in 20 fields were quantified in an optical microscope at 40×. The amount of trypomastigotes from each sample was compared to the negative control and the percentage of lysis was determined; finally, the lytic concentration of 50% parasites (LC 50 ) were calculated for each compound and converted to micromolar data [23].…”

Quantitative proteome and phosphoproteome analyses highlight the adherent population during Trypanosoma cruzi metacyclogenesis

“…Trypanothione reductase, an example of a sulphur-modulated protein in the St phase, was found to have its activity inhibited for propyl and isopropyl quinoxaline-derivatives, as was recently established in T . cruzi , making it a potential drug target 18 . Another sulphur-modulated protein is thiol-dependent reductase 1, which is implicated in deglutathionylation and activation of the antimonial drugs used for treating leishmaniasis 19 .…”

Anti-Mycobacterium tuberculosis Activity of Esters of Quinoxaline 1,4-Di-N-Oxide

“…All compounds from the methyl, ethyl, isopropyl, and n-propyl ester series of quinoxaline 1,4- N -oxide were obtained following the procedure previously reported by Gomez-Caro et al [ 20 ]. These compounds were analyzed by IR, 1 H-NMR and elemental analysis and have been previously reported [ 21 , 22 , 23 , 24 ].…”