Action of flavonoids against Trypanosoma cruzi epimastigotes

CIFUENTE DA; BARRERA P; LOZANO E; CANO R; SOSA MA

Buenos Aires

Congreso; Drug Discovery for Neglected Diseases International Congress 2018. 4th Scientific Meeting of ResNet NPND; 2018

Instituto de la Química y Metabolismo del Fármaco.Consejo Nacional de Investigaciones Científicas y Técnicas Facultad de Farmacia y Bioquímica ? Universidad de Buenos Aires

Action of flavonoids against Trypanosoma cruzi epimastigotesTrypanosoma cruzi is the causal etiologic agent of Chagas disease. It is estimated that around 8-10 million people are infected worldwide, being an endemic disease in Latin America. In cultures this parasite is mainly found in the epimastigote form and a low percentage in the infective form, trypomastigote. At present, chemotherapy against T. cruzi is insufficient because the available drugs, nifurtimox and benznidazole, have limited activity, and show toxic side effects in patients. Therefore, the ?screening? of purified molecules from plant sources, mainly plant leaves has become an important tool for the fight against Chagas disease. Many natural compounds, extracted from plants native to Argentina, have been shown to be effective against the parasite [2, 3, 4, 5]. Among them, flavonoids are an important family of molecules that have been widely studied. In this work we analyze the effect of the flavonoids xantomicrol (XML) and salvigenin (SVG) isolated from Baccharis scandens and apigenin (AGN) isolated from Larrea divaricata, on the growth of T. cruzi. We used epimastigotes of T. cruzi (strain Dm28c) in axenic culture, grown in theabsence or presence of different concentrations of the compounds. We evaluated both the stability of the compounds and the reversibility of their effects. In addition, we evaluated the effect of these flavonoids on the mitochondrialactivity of the parasites through the MTT assay and the production of reactive oxygen species (ROS), by using the 2?, 7?-diclocrofluorescein diacetate (H2DCFDA) probe. All the compounds showed an antiproliferative effect on epimastigotes, even at low concentrations. In addition, this effect was irreversible even in the short term (1 h) of exposure to the compounds. We observed that SVG significantly decreases the mitochondrial activity of the parasites, at all the concentrations tested (1, 2, 5 and 10 μg/ml). In contrast, AGN only decreased mitochondrial activity at concentrations of 10 μg/ml andXML affected the mitochondrial activity of epimastigotes at concentrations of5 and 10μg/ml. These alterations are related to ROS production observed with each treatment. From these results it is necessary to identify the moleculartargets of the parasites for the action of these drugs and to determine how they affect the life cycle of T cruzi.References1. World Health Organization, 2015. Tropical Disease Research, Program for research and training tropical disease (TDR), Fact sheet Nu340, Updated March 2015.2. Barrera P. et al. 2008. Natural sesquiterpene lactones are active against Leishmania mexicana possible by multiple effects. The Journal of Parasitology. 94:1143?9.3. Lozano E., et al. 2012a. The effect of the diterpene 5-epi-icetexone on the cell cycle of Trypanosoma cruzi. Parasitol Int 61: 275?279.4. Lozano E., et al. 2012b. Sesquiterpene lactones and the diterpene 5-epi-icetexone affect the intracellular and extracellular stages of Trypanosoma cruzi. Parasitol Int 61: 628?633.5. Lozano E.S., et al. 2015. An abietane diterpene from Salvia cuspidata and some new derivatives are active against Trypanosoma cruzi. Bioorg Med Chem Lett 25: 5481?5484Keywords: Trypanosoma cruzi; Natural compounds; Flavonoids.