Abstract:The trypanocidal activity of N-isopropyl oxamate (NIPOx) and the ethyl ester of N-isopropyl oxamate (Et-NIPOx) were tested on cultured epimastigotes (in vitro) and on murine trypanosomiasis (in vivo) using five different T. cruzi strains. When benznidazole and nifurtimox, used for comparison, were tested we found that only three of these T. cruzi strains were affected, whereas the other two strains, Miguz and Compostela, were resistant to the in vitro and the in vivo trypanocidal activity of these substances. … Show more
“…The parasitemia induced by the Miguz and Compostela strains of T. cruzi was detectable 25–30 days after infection and reached its peak at 40–45 days, before becoming non-detectable after 55 days of infection. In contrast, the parasitemia induced by the Nayarit and INC-5 strains of T. cruzi was detectable 5 days after infection and reached its peak at 15–20 days before becoming non-detectable after 30 days of infection, as previously described [28]. Figure 3B-NPOx led to a greater reduction in the parasitemia in infected mice than Et-NPOX, Bz or Nx.…”
Section: Resultssupporting
confidence: 78%
“…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].…”
BackgroundChagas disease, which is caused by Trypanosoma cruzi, is a major health problem in Latin America, and there are currently no drugs for the effective treatment of this disease. The energy metabolism of T. cruzi is an attractive target for drug design, and we previously reported that inhibitors of α-hydroxy acid dehydrogenase (HADH)-isozyme II exhibit trypanocidal activity. N-Propyl oxamate (NPOx) is an inhibitor of HADH-isozyme II, and its non-polar ethyl ester (Et-NPOx) is cytotoxic to T. cruzi. A new derivative of NPOx has been developed in this study with higher trypanocidal activity, which could be used for the treatment of Chagas disease.MethodsThe benzyl ester of NPOx (B-NPOx) was synthesized and its activity evaluated towards epimastigotes and bloodstream trypomastigotes (in vitro), as well as mice infected with T. cruzi (in vivo). The activity of B-NPOx was also compared with those of Et-NPOx, benznidazole (Bz) and nifurtimox (Nx). NINOA, Miguz, Compostela, Nayarit and INC-5 T. cruzi strains were used in this study.ResultsPolar NPOx did not penetrate the parasites and exhibited no trypanocidal activity. In contrast, the hydrophobic ester B-NPOx exhibited trypanocidal activity in vitro and in vivo. B-NPOx exhibited higher trypanocidal activity than Et-NPOx, Bz and Nx towards all five of the T. cruzi strains. The increased activity of B-NPOx was attributed to its hydrolysis inside the parasites to give NPOx and benzyl alcohol, which is an antimicrobial compound with trypanocidal effects. B-NPOx was also effective against two strains of T. cruzi that are resistant to Bz and Nx.ConclusionB-NPOx exhibited higher in vitro (2- to 14.8-fold) and in vivo (2.2- to 4.5-fold) trypanocidal activity towards T. cruzi than Et-NPOx. B-NPOx also exhibited higher in vitro (2- to 24-fold) and in vivo (1.9- to 15-fold) trypanocidal activity than Bz and Nx. B-NPOx is more lipophilic than Et-NPOx, allowing for better penetration into T. cruzi parasites, where the enzymatic cleavage of B-NPOx would give NPOx and benzyl alcohol, which are potent trypanocidal agents. Taken together with its low toxicity, these results suggest that B-NPOx could be used as a potent prodrug for the treatment of Chagas disease.
“…The parasitemia induced by the Miguz and Compostela strains of T. cruzi was detectable 25–30 days after infection and reached its peak at 40–45 days, before becoming non-detectable after 55 days of infection. In contrast, the parasitemia induced by the Nayarit and INC-5 strains of T. cruzi was detectable 5 days after infection and reached its peak at 15–20 days before becoming non-detectable after 30 days of infection, as previously described [28]. Figure 3B-NPOx led to a greater reduction in the parasitemia in infected mice than Et-NPOX, Bz or Nx.…”
Section: Resultssupporting
confidence: 78%
“…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].…”
BackgroundChagas disease, which is caused by Trypanosoma cruzi, is a major health problem in Latin America, and there are currently no drugs for the effective treatment of this disease. The energy metabolism of T. cruzi is an attractive target for drug design, and we previously reported that inhibitors of α-hydroxy acid dehydrogenase (HADH)-isozyme II exhibit trypanocidal activity. N-Propyl oxamate (NPOx) is an inhibitor of HADH-isozyme II, and its non-polar ethyl ester (Et-NPOx) is cytotoxic to T. cruzi. A new derivative of NPOx has been developed in this study with higher trypanocidal activity, which could be used for the treatment of Chagas disease.MethodsThe benzyl ester of NPOx (B-NPOx) was synthesized and its activity evaluated towards epimastigotes and bloodstream trypomastigotes (in vitro), as well as mice infected with T. cruzi (in vivo). The activity of B-NPOx was also compared with those of Et-NPOx, benznidazole (Bz) and nifurtimox (Nx). NINOA, Miguz, Compostela, Nayarit and INC-5 T. cruzi strains were used in this study.ResultsPolar NPOx did not penetrate the parasites and exhibited no trypanocidal activity. In contrast, the hydrophobic ester B-NPOx exhibited trypanocidal activity in vitro and in vivo. B-NPOx exhibited higher trypanocidal activity than Et-NPOx, Bz and Nx towards all five of the T. cruzi strains. The increased activity of B-NPOx was attributed to its hydrolysis inside the parasites to give NPOx and benzyl alcohol, which is an antimicrobial compound with trypanocidal effects. B-NPOx was also effective against two strains of T. cruzi that are resistant to Bz and Nx.ConclusionB-NPOx exhibited higher in vitro (2- to 14.8-fold) and in vivo (2.2- to 4.5-fold) trypanocidal activity towards T. cruzi than Et-NPOx. B-NPOx also exhibited higher in vitro (2- to 24-fold) and in vivo (1.9- to 15-fold) trypanocidal activity than Bz and Nx. B-NPOx is more lipophilic than Et-NPOx, allowing for better penetration into T. cruzi parasites, where the enzymatic cleavage of B-NPOx would give NPOx and benzyl alcohol, which are potent trypanocidal agents. Taken together with its low toxicity, these results suggest that B-NPOx could be used as a potent prodrug for the treatment of Chagas disease.
“…In previous experiments, the parasitaemia induced by different T. cruzi strains was followed with time and we found that the peaks of maximum parasitaemia were: 40 days for Miguz and Compostela strains, 28 days for V2R strain, 18 days for Parra strain and 14 days for Nayarit strain [13]. To test the trypanocidal activity of drugs (Bz, Nx, NPOx, NAOx, Et-NPOx and EtNAOx), at the peak of maximum parasitaemia, a single dose of 500 mg/kg of a drug was given by the oral route and the parasitaemia was determined, before, 2, 4, and 6 h after drug administration, according to the method proposed by Filardy and Brener [14].…”
Section: Trypanocidal Effect Of Drugs On Mice Parasitaemia Induced Bymentioning
The trypanocidal activity of N-allyl (NAOx) and N-propyl (NPOx) oxamates and that of the ethyl esters of N-allyl (Et-NAOx) and N-propyl (Et-NPOx) oxamates were tested on cultured epimastigotes (in vitro) and murine trypanosomiasis (in vivo) using five different T. cruzi strains. NAOx and NPOx did not penetrate intact epimastigotes and therefore we were not able to detect any trypanocidal effect with these oxamates. Whereas the ethyl esters (Et-NAOx and Et-NPOx), acting as prodrugs, exhibited in vitro and in vivo trypanocidal activity on the five tested T. cruzi strains. On the contrary, when Nifurtimox and Benznidazole used as reference drugs were tested, we found that only three of the five tested T. cruzi strains were affected, whereas the other two strains, Miguz and Compostela, were resistant to the in vitro and in vivo trypanocidal activity of these compounds.
“…In contrast, the corresponding ethyl esters (Et-NPOX and Et-NIPOX), acting as prodrugs, exhibited trypanocidal activity on cultured epimastigotes (in vitro) and murine trypanosomiasis (in vivo) in all the tested T. cruzi strains 8,14,15 . The increased effectiveness of Et-NPOX and Et-NIPOX resulted from their better absorption by this parasite and their efficient hydrolysis inside T. cruzi by its carboxylesterases 16,17 , generating the active HADH-isozyme II inhibitors and NIPOX in situ 14,15 . Accordingly, in the present investigation we studied the possible trypanocidal activity of the ethyl esters of N-propyl and N-isopropyl oxamates on bloodstream trypomastigotes and intracellular amastigotes of Trypanosoma cruzi acute infected mice.…”
Section: Introductionmentioning
confidence: 92%
“…Nifurtimox (tetrahydro-3-methyl-4-[5-nitro-furfurilidene)amine]-2-methyl-tetrahydro-1,4-thiazine-4,4-dioxide was from Bayer, Mexico. NPOX, NIPOX, and the corresponding esters, Et-NPOX and Et-NIPOX, were synthesized according to methods reported elsewhere 7,14 .…”
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.
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