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

Carlos Wong-Baeza,Carlos Wong,Manuel Serna,Benjamín Nogueda-Torres,Sergio Meza-Toledo,Isabel Baeza

doi:10.1186/s40360-015-0010-4

Carlos Wong-Baeza, Carlos Wong + Show 4 more

Open Access

https://doi.org/10.1186/s40360-015-0010-4

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Abstract

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.

Highlights

Chagas 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
We have shown that N-allyl oxamate (NAOx), N-propyl oxamate (NPOx) and N-isopropyl oxamate (NIPOx) are selective inhibitors of hydroxy acid dehydrogenase (HADH)-isozyme II, based on the chemical structures of the compounds being similar to those of the isozyme II substrates, α-ketocaproate and α-ketoisocaproate
B-N-Propyl oxamate (NPOx) inhibits the activity of α-hydroxy acid dehydrogenase-isozyme II in homogenates from T. cruzi strains benzyl ester of NPOx (B-NPOx) did not inhibit the activity of purified HADHisozyme II (Figure 1A), and the same effect was reported previously for Ethyl ester of NPOx (Et-NPOx) [24]

Summary

Introduction

Chagas 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. Chagas disease causes about 50,000 deaths per year in Latin America, and approximately 25% of the population is at risk of acquiring the disease [1,2,3]. There are currently very few drugs available for the treatment of Chagas disease, which is considered to be a “neglected” disease. The drugs currently available for the treatment of Chagas disease, including benznidazole (Bz) and nifurtimox (Nx), are only weakly efficacious against this disease and generally fail to restore patients to full health [4]. The heart, esophagus, colon and peripheral nervous system can be irreversibly damaged during the chronic phase of Chagas disease, and the majority of patients usually die from heart failure [5,6]

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