Avaliação do efeito antiparasitário de Cloridrato de N-Geranil - 1,2 - Diaminoetano (GIB24) sobre trypanosoma cruzi

Abstract

Chagas disease, caused by the protozoan Trypanosoma cruzi, affects around 7 million people worldwide. Currently, the only drug available for treatment in Brazil is benznidazole (BZ), which has several limitations and adverse effects. The known in vitro trypanocidal activity of diamines, their supposed mechanism of action on polyamine biosynthesis, and the ease of their chemical synthesis encourage investigation of their in vivo efficacy. The objective of this work was to evaluate the effect of synthetic ethanediamine GIB24 against T. cruzi (Y strain). First, the in vitro effect against intracellular amastigote forms of T. cruzi was evaluated, whose IC50 value was less than 0.5 μM, which is 20 times more potent than BZ (IC50 = 11.4 μM). GIB24 was not cytotoxic to Vero E6 cells in active concentrations, being at least 180 times more toxic to the parasite than to the host cell (SI>180). To determine an optimal dose of GIB24 (in vivo I), BALB/c mice were infected i.p. with 104 T. cruzi blood trypomastigotes. Five days later, the 5 experimental groups were treated once a day orally (gavage) for 5 consecutive days with: GIB24 100, 50 and 20 mg / kg / day, benznidazole 100 mg/kg/day and vehicle (DMSO 5%). Based on the reduction in parasitemia, a dose of 50 mg/kg was defined for subsequent trials. To assess the trypanocidal efficacy of GIB24 (in vivo II), three groups of infected male BALB/c mice were treated by gavage with GIB24 50 mg/kg/day, BZ 50 mg/kg/day or vehicle, for a period of up to 11 consecutive days with treatment starting on the 5th dpi. The activity of GIB24 was also evaluated, under the same conditions, in a group of female Swiss mice. In vivo toxicity was also evaluated with the same treatment regimens, in uninfected animals, through the analysis of behavioral changes, weight mass and serum markers (ALT, CK and urea). A group of unhandled animals (naive) was used as a control. Our results showed that GIB24 at 50 mg/kg did not suppress the parasitemia or prevent mortality in both female and male mice, contrary to what was observed in the in vivo I assay. Administration of GIB24 for periods longer than 5 days caused apathy, weight loss, mortality and increased serum ALT levels. The toxicity observed in vivo partially corroborates the predictive results observed in silico, where GIB24 was classified in class IV (not lethal, but potentially harmful), and LD50 of 700 mg/kg. Therefore, in vitro assays showed that GIB24 was more potent than BZ. However, it was innefective and toxic in mice treated longer than 5 days.