Trypanosoma cruzi: inhibition of alpha-hydroxyacid dehydrogenase isozyme II by N-allyl and N-propyl oxamates and their effects on intact epimastigotes

Chena, Miguel A.; Elizondo-Jiménez, Silvia; Rodrı́guez-Páez, Lorena; Nogueda‐Torres, Benjamín; Baeza-Ramírez, Isabel; Wong-Ramírez, Carlos

doi:10.1590/s0074-02762004000800009

Cited by 7 publications

(24 citation statements)

References 29 publications

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“…Similar results were obtained with homogenates of the five tested T. cruzi strains (results not shown). Previously, we had demonstrated that the esters (EtNAOx and Et-NPOx) were not inhibitors for the purified HADH-isozyme II [5].…”

Section: Resultsmentioning

confidence: 96%

“…It has been established that HADH-isozyme II is actually integrated into metabolic pathways supplying energy for the motility of flagellum and survival of the parasites [10], because this isozyme participates in the reoxidation of NADH during glycolysis [17], and in a shuttle system transferring reducing equivalents (NADH) from cytosol into the mitochondria [10]. Consequently, an inhibitor of HADH-isozyme II will not only inhibit glycolysis but will also inhibit the shuttle system, and therefore, it has been proposed that inhibitors of this isozyme could reduce the motility and survival of this parasite [5,19,20,21].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, we synthesized NAOx and NPOx and found that these oxamates were indeed competitive and selective inhibitors of this isozyme, rather than as general inhibitors of dehydrogenases [5].…”

Section: Discussionmentioning

confidence: 99%

“…Benznidazole (N-benzyl-2-nitro-1-imidazol-1-acetamide) was from Roche-México and Nifurtimox (tetrahydro-3-methyl-4-[(5-nitro-furfurilidene) amine]-2-methyl-tetrahydro-1,4-thiazine-4,4 0 -dioxide was from Bayer-México. NAOx and NPOx and the corresponding esters, Et-NAOx and Et-NPOx, were synthesized according to the methods reported elsewhere [5].…”

Section: Chemicalsmentioning

confidence: 99%

“…In previous investigations we designed and synthesized N-allyl oxamate (NAOx) and N-propyl oxamate (NPOx) as possible inhibitors of the T. cruzi a-hydroxyacid dehydrogenase (HADH)-isozyme II and we found that these oxamates were indeed competitive and selective inhibitors of this isozyme [5].…”

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confidence: 99%

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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

Aguirre-Alvarado

Zaragoza-Martínez

Rodrı́guez-Páez³

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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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.

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Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

“…Thus, we synthesized NAOx and NPOx and found that these oxamates were indeed competitive and selective inhibitors of this isozyme, rather than as general inhibitors of dehydrogenases [5].…”

Section: Discussionmentioning

confidence: 99%

Section: Chemicalsmentioning

confidence: 99%

mentioning

confidence: 99%

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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

Aguirre-Alvarado

Zaragoza-Martínez

Rodrı́guez-Páez³

et al. 2007

Journal of Enzyme Inhibition and Medicinal Chemistry

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New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

Oliveira¹,

Mendes²,

Almeida³

et al. 2014

CRJ

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Abstract:Chagas disease is an infectious illness with a broad distribution throughout the South American and African continents, importantly influencing human morbidity and mortality and a controversial relationship with the onset of cancers, especially of the gastrointestinal tract system. In addition, it is listed by the World Health Organization (WHO) as one ofthe most neglected tropical diseases. Although Chagas disease (CD) was discovered more than 100 years ago, the existing therapies show low efficacy and serious side effects and developing safer and more effective drugs remains a hard challenge. Thus, this review highlights the main, novel and promising treatments against Trypanosoma cruzi, including biomacromolecules, natural products, vaccines, and metabolic pathway targets and highlights a worsening of esophageal cancer prognosis in chagasic patients. Moreover, we also discuss the perspectives of obtaining original optimized drugs that take advantage of organic and inorganic medicinal chemistry advances, as well as molecular modeling and biotechnology.

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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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Trypanosoma cruzi: inhibition of alpha-hydroxyacid dehydrogenase isozyme II by N-allyl and N-propyl oxamates and their effects on intact epimastigotes

Abstract: N-allyl (NAOx) and N-propyl (NPOx) N-allyl (Et-NAOx) and N-propyl (Et-NPOx) oxamates were tested as a possible trypanocidal prodrugs, in comparison with nifurtimox and benznidazole, the expected trypanocidal effects were obtained.

Cited by 7 publications

References 29 publications

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

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

New Treatments for Chagas Disease and the Relationship between Chagasic Patients and Cancers

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

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