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PAGES: DOI: 10.1590/0074-02760170267 Full paper
Looking for combination of benznidazole and Trypanosoma cruzi-triosephosphate isomerase inhibitors for Chagas disease treatment

Elena Aguilera1, Javier Varela1, Elva Serna2, Susana Torres2, Gloria Yaluff2, Ninfa Vera de Bilbao2, Hugo Cerecetto1,3, Guzmán Alvarez1,4, Mercedes González1,+

1Universidad de la República, Facultad de Ciencias, Grupo de Química Medicinal, Montevideo, Uruguay
2Universidad Nacional de Asunción, Instituto de Investigaciones en Ciencias de la Salud, Departamento de Medicina Tropical, Asunción, Paraguay
3Universidad de la República, Facultad de Ciencias, Centro de Investigaciones Nucleares, Área de Radiofarmacia, Montevideo, Uruguay
4Universidad de la República, Centro Universitario Regional Litoral Norte, Laboratorio de Moléculas Bioactivas, Paysandú, Uruguay


BACKGROUND The current chemotherapy for Chagas disease is based on monopharmacology with low efficacy and drug tolerance. Polypharmacology is one of the strategies to overcome these limitations.

OBJECTIVES Study the anti-Trypanosoma cruzi activity of associations of benznidazole (Bnz) with three new synthetic T. cruzi-triosephosphate isomerase inhibitors, 2, 3, and 4, in order to potentiate their actions.

METHODS The in vitro effect of the drug combinations were determined constructing the corresponding isobolograms. In vivo activities were assessed using an acute murine model of Chagas disease evaluating parasitaemias, mortalities and IgG anti-T. cruzi antibodies.

FINDINGS The effect of Bnz combined with each of these compounds, on the growth of epimastigotes, indicated an additive action or a synergic action, when combining it with 2 or 3, respectively, and an antagonic action when combining it with 4. In vivo studies, for the two chosen combinations, 2 or 3 plus one fifth equivalent of Bnz, showed that Bnz can also potentiate the in vivo therapeutic effects. For both combinations a decrease in the number of trypomastigote and lower levels of anti-T. cruzi IgG-antibodies were detected, as well clear protection against death.

MAIN CONCLUSIONS These results suggest the studied combinations could be used in the treatment of Chagas disease.

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Financial support: Comisión Sectorial de Investigación Científica (CSIC)-Universidad de la República (CSIC No 661).
EA was supported by Agencia Nacional de Investigación e Innovación (ANII, POS_NAC_2014_1_102490, Uruguay).
+ Corresponding author: This e-mail address is being protected from spambots. You need JavaScript enabled to view it.
Received 7 July 2017
Accepted 25 October 2017