Chagas disease is caused by Trypanosoma cruzi (T. cruzi) and affects millions of people worldwide, mostly in Latin America. Despite its sanitary importance, there are currently only two drugs available for its treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects on patients. In order to complete its life cycle, T. cruzi faces extreme environmental conditions ?i.e. oxidative stress- as it propagates from an insect vector to a mammalian host, driving the transition from non-infective epimastigote to the infective form trypomastigote. It is known that the antioxidant defense system in the trypanosomatids is different from that in mammalian cells since the parasites have exclusive molecules and reducing enzymes. Because of this, the parasite redox machinery is an attractive target for antiparasitic therapies. The sesquiterpene lactone dehydroleucodine (DhL), is a trypanocidal molecule containing an alpha-methylene group that could react with sulfhydryl groups of key redox enzymes. This study was focused on elucidating the DhL mechanism of action and extended to ten DhL derivatives (DC-X1 to DC-X10) obtained by chemical substitutions on the methylene group. We firstly confirmed an antiproliferative effect of DhL and its chemical derivatives, being DC- X6 one of the most active. The effect of DhL and DC-X6 was blocked by reduced glutathione, suggesting that compounds are reactive to sulfhydryl groups of certain molecules. Moreover, parasites overexpressing reducing enzymes, such as Tc-CPX, showed a protective effect against these STLs. Consistent with these results, both STLs increased ROS concentration in the wild type parasites. These results indicate that STLs induce oxidative stress on the parasites, possibly by affecting some crucial enzymes of the redox system.Fil: Gomez, Jessica Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales. Departamento de Biología; ArgentinaFil: Guarise, C.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; ArgentinaFil: Tello Faral, P.. Instituto Pasteur de Montevideo; UruguayFil: Robello, Carlos. Instituto Pasteur de Montevideo; UruguayFil: Caballero, P.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; ArgentinaFil: Cifuente, Diego Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Investigaciones en Tecnología Química. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Investigaciones en Tecnología Química; ArgentinaFil: Sosa, M. A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Barrera, Patricia Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Histología y Embriología D/mend Dr.m.burgos; Argentina. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales; ArgentinaXXXVII Reunión Científica Anual de la Sociedad de Biología de CuyoSan LuisArgentinaSociedad de Biología de Cuy
