Trypanocidal activity of the ethyl esters of N-propyl and N-isopropyl oxamates on intracellular amastigotes of Trypanosoma cruzi acute infected mice

Abstract

In this investigation we studied the trypanocidal activity of the ethyl esters of N-propyl (Et-NPOX) and N-isopropyl (Et-NIPOX) oxamates on bloodstream trypomastigotes and on the clinically relevant intracellular amastigotes of Trypanosoma cruzi acute infected mice. In the infected and treated mice, the levels of parasitemia were drastically reduced between days 15 and 20 of treatment and almost to zero between days 35 and 40. We also found that Et-NPOX completely eliminated amastigote nests in the myocardium of mice infected with INC-5 or NINOA T. cruzi strain, and in skeletal muscle the reduction in the number of amastigote nests was between 60 and 80% in both strains. Also, Et-NIPOX reduced by 60-80% the number of amastigote nests in the myocardium and skeletal muscle of mice infected with these T. cruzi strains. In contrast, nifurtimox, used for comparison, produced a reduction of amastigote nests of only 20-40% in the studied tissues in both strains.

Trypanocidal effect of the benzyl ester of N-propyl oxamate: a bi-potential prodrug for the treatment of experimental Chagas disease

“…Levels of parasitemia, beginning 24 h after infection, were determined every other day in a Neubauer hemocytometer using 5 μL of blood, which was collected from the tail vein of the infected mice and diluted at a ratio of 1:10 (v/v) with a saturated solution of ammonium chloride [39]. The reduction in the parasitemia was evaluated by comparing the number of trypomastigotes obtained at each time point after the administration of NPOx, Et-NPOx, B-NPOx, Bz or Nx with the number of trypomastigotes obtained at the same point in infected/untreated mice, which was taken as 100% [29]. The experimental protocols for animal care and use were reviewed and approved by the Bioethics Committee of our Institution according to the “Guide for the care and use of laboratory animals”, which was published by the US National Institute of Health [40].…”

“…Fifty randomly selected microscopic fields from at least three mice were examined to quantify the number of amastigote nests. The mean number of amastigote nests in the infected/untreated group was taken as 100% [29]. …”

“…Although these oxamates were unable to penetrate intact T. cruzi , the corresponding hydrophobic ethyl esters (i.e., Et-NAOx, Et-NPOx and Et-NIPOx) successfully penetrated intact parasites and exerted trypanocidal activity [27,28]. Et-NAOx, Et-NPOx and Et-NIPOx also exhibited inhibitory activity towards amastigote nests [29]. It was envisaged that the non-specific aliphatic and aromatic carboxyl esterases found in T. cruzi [30,31] would hydrolyze these esters after they had penetrated the T. cruzi and release the inhibitors, which would then block the activity of HADH-isozyme II and kill the T. cruzi .…”

Review on Experimental Treatment Strategies Against Trypanosoma cruzi

“…96 In addition, tetraamines were able to inhibit iron superoxide dismutase and trypanothione reductase of T. cruzi and presented activity in vitro and in vivo with low toxicity. 97 Other classes as antimicrobial peptides; 98,99 copper 100 or ruthenium [101][102][103][104] complexes, compounds that impact on purine salvage pathway, [105][106][107] oxaboroles, 56,57 oxamates, [108][109][110] quinolines, 111 sphingosine kinase inhibitor, 112 squaramides, 55,113 terpene and terpenoid derivatives 55 and proteasome inhibitors, 114,115 revealed interesting results, impacting the evolution of T. cruzi infection (Table 1), but the mechanisms are not well known. Figure 4 shows schematic representation of the main drug targets identified in T. cruzi.…”