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

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.

Vascular Growth Factor Inhibition with Bevacizumab Improves Cardiac Electrical Alterations and Fibrosis in Experimental Acute Chagas Disease

“…In this study, we investigated the effect of the VEGF inhibition with bevacizumab, an antiangiogenic monoclonal antibody, in an experimental murine model of acute CD. The experimental model that was used is an important model for the study of the acute Chagas disease that gives a rapid assessment of the experimental acute infection kinetics and enables to conduct pathogenicity and chemotherapy (among others) investigations in this field [34][35][36][37]. We were the first to show that VEGF blockage significantly increased the survival of mice, reduced VEGF levels, decreased angiogenesis, and inhibited inflammation, fibrosis and alterations in cardiac electrical function.…”