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Effect of B-NIPOx in Experimental Trypanosoma cruzi Infection in Mice

Chagas disease is caused by Trypanosoma cruzi and represents a major public health problem, which is endemic in Latin America and emerging in the rest of the world. The two drugs that are currently available for its treatment, Benznidazole and Nifurtimox, are partially effective in the chronic phase...

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Detalles Bibliográficos
Autores principales: Reséndiz-Mora, Albany, Barrera-Aveleida, Giovanna, Sotelo-Rodríguez, Anahi, Galarce-Sosa, Iván, Nevárez-Lechuga, Irene, Santiago-Hernández, Juan Carlos, Nogueda-Torres, Benjamín, Meza-Toledo, Sergio, Gómez-Manzo, Saúl, Wong-Baeza, Isabel, Baeza, Isabel, Wong-Baeza, Carlos
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9820238/
https://www.ncbi.nlm.nih.gov/pubmed/36613783
http://dx.doi.org/10.3390/ijms24010333
Descripción
Sumario:Chagas disease is caused by Trypanosoma cruzi and represents a major public health problem, which is endemic in Latin America and emerging in the rest of the world. The two drugs that are currently available for its treatment, Benznidazole and Nifurtimox, are partially effective in the chronic phase of the disease. In this study, we designed and synthesized the benzyl ester of N-isopropyl oxamic acid (B-NIPOx), which is a non-polar molecule that crosses cell membranes. B-NIPOx is cleaved inside the parasite by carboxylesterases, releasing benzyl alcohol (a molecule with antimicrobial activity), and NIPOx, which is an inhibitor of α-hydroxy acid dehydrogenase isozyme II (HADH-II), a key enzyme in T. cruzi metabolism. We evaluated B-NIPOx cytotoxicity, its toxicity in mice, and its inhibitory activity on purified HADH-II and on T. cruzi homogenates. We then evaluated the trypanocidal activity of B-NIPOx in vitro and in vivo and its effect in the intestine of T. cruzi-infected mice. We found that B-NIPOx had higher trypanocidal activity on epimastigotes and trypomastigotes than Benznidazole and Nifurtimox, that it was more effective to reduce blood parasitemia and amastigote nests in infected mice, and that, in contrast to the reference drugs, it prevented the development of Chagasic enteropathy.