Dados do Trabalho

Título

Molecular modifications in the berenyl structure as a strategy to obtain potent and selective anti-T. cruzi agents

Introdução

Currently, only two drugs are available for the treatment of Chagas disease, the nitroimidazole benznidazole and the nitrofuran nifurtimox. These drugs are effective in curing the acute phase of the disease, but have low efficacy in the chronic phase, have several side effects and even induction of resistant strains to these drugs. In this context, new compounds are being investigated, with the aim of increasing the therapeutic arsenal for the treatment of Chagas disease.

Objetivo (s)

Here, we investigate the action of novel compounds derived from berenyl in the treatment of Chagas disease.

Material e Métodos

The cytotoxicity of fifteen compounds was determined in cultures of macrophages of the J774 cell line and H9c2 cardiomyocytes. The trypanocidal effect was initially evaluated in Trypanosoma cruzi trypomastigotes (Y strain). The effects of the compounds alone or in combination with benznidazole on the proliferation of intracellular amastigotes were also evaluated. Transmission electron microscopy (TEM) assays were performed with trypomastigotes treated with compound 9. Lastly, the efficacy of 9 was evaluated in an acute model of T. cruzi infection.

Resultados e Conclusão

All compounds did not show cytotoxicity against J774 or H9c2 cell lines at the concentrations tested. In addition, with the exception of berenyl, all compounds were able to lyse trypomastigote forms of T. cruzi with IC50 values ranging from 0.59 to 3.58 µM. Compounds 5 and 9 showed the best anti-T. cruzi profile with IC50 values of 0.63 and 0.59 μM, respectively. Under the same conditions, benznidazole had an IC50 value of 10.61 µM. Treatment with 5 and 9 also significantly reduced amastigote proliferation. In addition, the combination index value of 0.78 associated with a concave isobologram revealed that 9 and benznidazole have synergistic effects against amastigote proliferation. Using TEM, we observed that compound 9 caused a strong swelling of the mitochondria, nuclear membrane rupture, intense vacuolization, and an intense kDNA network disruption in trypomastigotes. Finally, treatment with compound 9, at 100 mg/Kg, caused a reduction in blood parasitemia of 66.0 and 72.7%, respectively at days 10 and 12 post infection. In conclusion, we identified the berenyl derivative 9, a selective anti-T. cruzi agent, which destroys parasite cells by targeting the kDNA and acts synergistically in combination to benznidazole.

Palavras-chave

Trypanosoma cruzi; Chagas disease; Berenyl; kDNA.

Agradecimentos

CNPq and PRONEX.