In vitro tripanocidal effect of 1,8-dioxooctahydroxanthenes (xanthenodiones) and tetraketones and improvement of cardiac parameters in vivo

• Main Authors: Ana Paula de Jesus Menezes, Milene Lopes da Silva, Wagner Luiz Pereira, Guilherme de Paula Costa, Aline Luciano Horta, Andréa Aparecida Santos Mendonça, Ana Claudia Alvarenga Carneiro, Debora Maria Soares de Souza, Rômulo Dias Novaes, Róbson Ricardo Teixeira, André Talvani
• Format: Article
• Language: English
• Published: Elsevier 2020-09-01
• Series: Journal of Global Antimicrobial Resistance
• Subjects: Trypanosoma cruzi; Xanthenodiones; Tetraketones; Inflammation; Heart damage; Benznidazole
• Online Access: http://www.sciencedirect.com/science/article/pii/S2213716520300977

Objective: Trypanosoma cruzi infection affects millions of people worldwide, and the drugs available for its treatment have limited efficacy. 1,8-Dioxooctahydroxanthenes and tetraketones are compounds with important biological applications. The aim of this study was to assess the trypanocidal and inflammatory activities of nine 1,8-dioxooctahydroxanthenes (1–9) and three tetraketones (10–12). Methods and results: By in vitro killing assay, three compounds were able to eliminate CL TdTomato expressing strain of T. cruzi, 9 (IC50 = 30.65 μM), 10 (IC50 = 14.11 μM), and 11 (IC50 = 26.43 μM). However, only 9 was not toxic to Vero cells. Next, to evaluate the in vivo antitrypanosomal and immunological efficacy of 9, Swiss mice were infected with the Y and CL strains of T. cruzi and treated for 10 days with 50 mg/kg of 9. This compound reduced the cardiac inflammatory infiltration in animals infected with both strains. Rank's ligand (RankL), CCL2, and interferon (IFN)-γ were measured in the cardiac tissue homogenate of the Y-strain-infected animals, and no interference of 9 was observed. However, compound 9 increased the RankL and interleukin (IL)-10 levels in CL-infected mice. No hepatic and renal toxicity was observed. Conclusion: Our findings showed that 1,8-dioxooctahydroxanthene has antiparasitic effect and ameliorates the cardiac inflammatory parameters related to T. cruzi infection.