| Autor: |
Fonseca-Berzal C; Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040Madrid, Spain., da Silva CF; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil., Batista DDGJ; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil., de Oliveira GM; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil., Cumella J; Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/ Juan de la Cierva 3, 28006Madrid, Spain., Batista MM; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil., Peres RB; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil., Silva da Gama Nefertiti A; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil., Escario JA; Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040Madrid, Spain., Gómez-Barrio A; Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), Pza. Ramón y Cajal s/n, 28040Madrid, Spain., Arán VJ; Instituto de Química Médica (IQM), Consejo Superior de Investigaciones Científicas (CSIC), c/ Juan de la Cierva 3, 28006Madrid, Spain., Soeiro MNC; Laboratório de Biologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz (FIOCRUZ), Av. Brasil 4365, 21040-900Rio de Janeiro, Brazil. |
| Abstrakt: |
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. |
