In vitro and in vivo trypanocidal activity of the ethyl esters of N-allyl and N-propyl oxamates using different Trypanosoma cruzi strains

Aguirre-Alvarado, Charmina; Zaragoza-Martínez, Fabiola; Rodrı́guez-Páez, Lorena; Nogueda, Benjamín; Baeza, Isabel; Wong, Carlos

doi:10.1080/14756360601051233

Cited by 8 publications

(6 citation statements)

References 23 publications

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“…Encouraging results were also obtained on the a-hydroxyacid dehydrogenase (HADH) of Trypanosoma cruzi, which shows similarities with the human LDH-C. Simple derivatives of oxamic acid such as N-isopropyl and N-propyl oxamate were found more active in inhibiting HADH in vitro than the parent compound and their ethyl-ester prodrugs orally administered to T. cruzi-infected mice also demonstrated therapeutic efficacy in vivo [101]. To our knowledge, no oxamic acid derivative with anticancer potential has been identified with this approach.…”

Section: Modification Of Already Known Inhibitorsmentioning

confidence: 83%

Inhibition of Lactate Dehydrogenase Activity as an Approach to Cancer Therapy

et al. 2014

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In the attempt of developing innovative anticancer treatments, growing interest has recently focused on the peculiar metabolic properties of cancer cells. In this context, LDH, which converts pyruvate to lactate at the end of glycolysis, is emerging as one of the most interesting molecular targets for the development of new inhibitors. In fact, because LDH activity is not needed for pyruvate metabolism through the TCA cycle, inhibitors of this enzyme should spare glucose metabolism of normal non-proliferating cells, which usually completely degrade the glucose molecule to CO2. This review is aimed at summarizing the available data on LDH biology in normal and neoplastic cells, which support the anticancer therapeutic approach based on LDH inhibition. These data encouraged pharmaceutical industries and academic institutions in the search of small-molecule inhibitors and promising candidates have recently been identified. The availability of inhibitors with drug-like properties will allow the evaluation in the near future of the real potential of LDH inhibition in anticancer treatment, also making the identification of the most responsive neoplastic conditions possible.

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Section: Modification Of Already Known Inhibitorsmentioning

confidence: 83%

Inhibition of Lactate Dehydrogenase Activity as an Approach to Cancer Therapy

et al. 2014

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“…Unfortunately, however, NPOx is a very polar molecule and can therefore not penetrate intact epimastigotes, because cellular membranes are hydrophobic barriers that block the diffusion of polar substances. In contrast, the hydrophobic compound Et-NPOx has been reported to enter intact epimastigotes and exhibit trypanocidal activity [24,27]. …”

Section: Discussionmentioning

confidence: 99%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

Wong-Baeza

Nogueda‐Torres

Serna

et al. 2015

BMC Pharmacol Toxicol

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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.

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“…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: 99%

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

Aguirre-Alvarado

Zaragoza-Martínez

Rodrı́guez-Páez

et al. 2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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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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In vitro and in vivo trypanocidal activity of the ethyl esters of N-allyl and N-propyl oxamates using different Trypanosoma cruzi strains

Cited by 8 publications

References 23 publications

Inhibition of Lactate Dehydrogenase Activity as an Approach to Cancer Therapy

Inhibition of Lactate Dehydrogenase Activity as an Approach to Cancer Therapy

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

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

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