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Chagas disease is caused by the parasite Trypanosoma cruzi (T. cruzi). It remains the major parasitic disease in Latin America, despite recent advances in the control of its vector-borne and transfusion mediated transmission. Moreover, migration of infected people has spread the disease to non-endemic areas, presenting a new worldwide challenge. The chemotherapy employed to control the parasitic infection is based on two drugs: Nifurtimox (Nfx) and Benznidazole (Bnz), requiring long-term treatment that can give rise to severe side effects. They are not active against all T. cruzi strains, exhibit low efficiency in long-term chronic infections, and are mutagenic. The search of new drugs is an urgent need. In this work, we used three symmetrical diarylideneketones containing thiophene and furane ((1E,3E,6E,8E)-1,9-Di(furan-2-yl)nona-1,3,6,8-tetraen-5-one (1), (2E,6E)-2,6-Bis((E)-3-(furan-2-yl)allylidene)cyclohexanone (2) and (2E,5E)-2,5-Bis[3-(thiophen-2-yl)allyliden]cyclopentanone (3)). These molecules showed good to excellent trypanosomicidal activity and selectivity to the parasite, affected cruzipain, a proteolytic enzyme of the parasite, and the glycolytic enzyme, triosephosphate isomerase of T. cruzi (TcTIM) without affecting human´s TIM and showing effectiveness in protecting infected mice and without toxic effects in vivo. In addition, these could be obtained by a simple and economic green synthetic route, which is an important feature in the research and development of future drugs for neglected diseases. The type of T. cruzi death caused is an important feature to determine, because it could govern inflammation events unbeneficial in the elimination of the parasite. We studied the mechanism of T. cruzi death using Annexin V and propidium iodide followed by flow cytometry analysis of epimastigote treated with the arylideneketones (1, 2, and 3). The arylideneketones along with Nfx and Bnz were evaluated at 24 h post- incubation with the parasite at 5X, 10X and 20X IC50. Arylidenketones 1 and 2 causes after 24 h late apoptosis/necrosis at a concentration of 20 times the value of its IC50 (approximately 80% of late apoptosis/necrosis) as Nfx. This necrotic effect of Nfx was also observed in our previous study by TUNNEL and 1H NMR. It should be studied what happens with compound 3 since no death is observed by apoptosis or necrosis at a dose of 20 times the value of their IC50 as Bnz. Probably, an autophagy process could be ongoing. Currently, we are performing studies in this sense. Acknowledgments: This work was supported by CSIC, PEDECIBA and Elena Aguilera is recipient of a ANII doctoral fellowship.