ArticleBMC pharmacology & toxicology2015
Trypanocidal effect of the benzyl ester of N-propyl oxamate: a bi-potential prodrug for the treatment of experimental Chagas disease.
Article in BMC pharmacology & toxicology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed, 14 citations in OpenAlex.
- Molecular Docking-Based Virtual Screening of FDA-Approved Drugs Using Trypanothione Reductase Identified New Trypanocidal Agents.Molecules (Basel, Switzerland) · 2024Article
- Effect of B-NIPOx in ExperimentalInternational journal of molecular sciences · 2022Article
- Review on Experimental Treatment Strategies AgainstJournal of experimental pharmacology · 2021Review
- Experimental models in Chagas disease: a review of the methodologies applied for screening compounds against Trypanosoma cruzi.Parasitology research · 2018Review
- Dipyridamole potentiated the trypanocidal effect of nifurtimox and improved the cardiac function in NMRI mice with acute chagasic myocarditis.Memorias do Instituto Oswaldo Cruz · 2017Article
- Effects of a novel β-lapachone derivative on Trypanosoma cruzi: Parasite death involving apoptosis, autophagy and necrosis.International journal for parasitology. Drugs and drug resistance · 2016Article
- Phase Transitions of Isotropic to Anisotropic Biocompatible Lipid-Based Drug Delivery Systems Overcoming Insoluble Benznidazole Loading.International journal of molecular sciences · 2016Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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