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Activity profile of two 5-nitroindazole derivatives over the moderately drug-resistant Trypanosoma cruzi Y strain (DTU TcII): in vitro and in vivo studies

Published online by Cambridge University Press:  12 June 2020

Cristina Fonseca-Berzal Open the ORCID record for Cristina Fonseca-Berzal [Opens in a new window] ,
Cristiane França da Silva ,
Denise da Gama Jaen Batista ,
Gabriel Melo de Oliveira ,
José Cumella ,
Marcos Meuser Batista ,
Raiza Brandão Peres ,
Aline Silva da Gama Nefertiti ,
José A. Escario  and
Alicia Gómez-Barrio
...Show all authors
Cristina Fonseca-Berzal*
Affiliation:
Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040Madrid, Spain
Cristiane França da Silva
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
Denise da Gama Jaen Batista
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
Gabriel Melo de Oliveira
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
José Cumella
Affiliation:
Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/ Juan de la Cierva 3, 28006Madrid, Spain
Marcos Meuser Batista
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
Raiza Brandão Peres
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
Aline Silva da Gama Nefertiti
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
José A. Escario
Affiliation:
Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040Madrid, Spain
Alicia Gómez-Barrio
Affiliation:
Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040Madrid, Spain
Vicente J. Arán
Affiliation:
Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/ Juan de la Cierva 3, 28006Madrid, Spain
Maria de Nazaré Correia Soeiro
Affiliation:
Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil
*
Author for correspondence: Cristina Fonseca-Berzal, E-mail: crfonseca@pdi.ucm.es
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Abstract

In previous studies, we have identified several families of 5-nitroindazole derivatives as promising antichagasic prototypes. Among them, 1-(2-aminoethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one, (hydrochloride) and 1-(2-acetoxyethyl)-2-benzyl-5-nitro-1,2-dihydro-3H-indazol-3-one (compounds 16 and 24, respectively) have recently shown outstanding activity in vitro over the drug-sensitive Trypanosoma cruzi CL strain (DTU TcVI). Here, we explored the activity of these derivatives against the moderately drug-resistant Y strain (DTU TcII), in vitro and in vivo. The outcomes confirmed their activity over replicative forms, showing IC50 values of 0.49 (16) and 5.75 μm (24) towards epimastigotes, 0.41 (16) and 1.17 μm (24) against intracellular amastigotes. These results, supported by the lack of toxicity on cardiac cells, led to better selectivities than benznidazole (BZ). Otherwise, they were not as active as BZ in vitro against the non-replicative form of the parasite, i.e. bloodstream trypomastigotes. In vivo, acute toxicity assays revealed the absence of toxic events when administered to mice. Moreover, different therapeutic schemes pointed to their capability for decreasing the parasitaemia of T. cruzi Y acute infected mice, reaching up to 60% of reduction at the peak day as monotherapy (16), 79.24 and 91.11% when 16 and 24 were co-administered with BZ. These combined therapies had also a positive impact over the mortality, yielding survivals of 83.33 and 66.67%, respectively, while untreated animals reached a cumulative mortality of 100%. These findings confirm the 5-nitroindazole scaffold as a putative prototype for developing novel drugs potentially applicable to the treatment of Chagas disease and introduce their suitability to act in combination with the reference drug.

Keywords

5-nitroindazoleChagas diseasechemotherapyin vitroin vivo
Type
Research Article
Information
Parasitology , Volume 147 , Issue 11 , September 2020 , pp. 1216 - 1228
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Copyright © The Author(s), 2020. Published by Cambridge University Press

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