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Título:

Preclinical studies and drug combination of low-cost molecules for Chagas disease

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Autor:

Aguilera, Elena
Sánchez, Carina
Cruces, María Eugenia
Dávila Saralegui, Belén
Minini Rivas, Lucía
Mosquillo, María Florencia
Pérez-Díaz, Leticia
Serna, Elva
Torres, Susana
Schini, Alicia
Sanabria, Luis
Vera de Bilbao, N.I.
Yaluff, Gloria
Zolessi, Flavio R.
Ceilas, Luis Fabian
Cerecetto, Hugo
Álvarez, Guzmán

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Tipo de documento:

Artículo

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Palabras clave:

Chagas disease
Pre-clinically studied
Drug combination
RMN metabolomics

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Año de publicación:

2023

Contenido:

Resumen:

Chagas disease is caused by the protozoan Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America and is spreading worldwide, affecting over 10 million people. Hundreds of new compounds with trypanosomicidal action have been identified from different sources such as synthetic or natural molecules, but they have been deficient in several stages of drug development (toxicology, scaling-up, and pharmacokinetics). Previously, we described a series of compounds with simple structures, low cost, and environmentally friendly production with potent trypanosomicidal activity in vitro and in vivo. These molecules are from three different families: thiazolidenehydrazines, diarylideneketones, and steroids. From this collection, we explored their capacity to inhibit the triosephosphate isomerase and cruzipain of T. cruzi. Then, the mechanism of action was explored using NMR metabolomics and computational molecular dynamics. Moreover, the mechanism of death was studied by flow cytometry. Consequently, five compounds, 314, 793, 1018, 1019, and 1260, were pre-clinically studied and their pharmacologic profiles indicated low unspecific toxicity. Interestingly, synergetic effects of diarylideneketones 793 plus 1018 and 793 plus 1019 were evidenced in vitro and in vivo. In vivo, the combination of compounds 793 plus 1018 induced a reduction of more than 90% of the peak of parasitemia in the acute murine model of Chagas disease.

Descripción:

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MDPI

EN:

Pharmaceuticals, 2023, 16(1): 20.

Financiadores:

ANII: POS_NAC_2016_1_129945

Citación:

Aguilera, E, Sánchez, C, Cruces, M [y otros autores]. "Preclinical studies and drug combination of low-cost molecules for Chagas disease". Pharmaceuticals. [en línea] 2023, 16(1): 20. 23 h. DOI: 10.3390/ph16010020.

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ISSN:

1424-8247

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Licencia:

Licencia Creative Commons Atribución (CC - By 4.0)

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Publicaciones académicas y científicas
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