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2-(phenylthio)ethylidene derivatives as anti-Trypanosoma cruzi compounds: Structural design, synthesis and antiparasitic activity

2019; Elsevier BV; Volume: 180; Linguagem: Inglês

10.1016/j.ejmech.2019.07.018

1768-3254

Marcos Veríssimo de Oliveira Cardoso, Gevânio Bezerra de Oliveira Filho, Lucianna Râbelo Pessôa de Siqueira, José Wanderlan Pontes Espíndola, Elany Barbosa da Silva, Andresa Pereira de Oliveira Mendes, Valéria Rêgo Alves Pereira, Maria Carolina Accioly Brelaz de Castro, Rafaela Salgado Ferreira, Filipe Silva Villela, Francielly Morais Rodrigues da Costa, Cássio Santana Meira, Diogo Rodrigo Magalhães Moreira, Milena Botelho Pereira Soares, Ana Cristina Lima Leite,

Synthesis and Biological Evaluation

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi. The current chemotherapy is based on benznidazole, and, in some countries, Nifurtimox, which is effective in the acute phase of the disease, but its efficacy in the chronic phase remains controversial. It can also cause serious side effects that lead sufferers to abandon treatment. In the present work, is reported the synthesis and trypanocidal activity of new 2-(phenylthio)ethylidene thiosemicarbazones (4-15) and 1,3-thiazoles (16–26). The cyclization of thiosemicarbazones into 1,3-thiazoles presents an improvement in the cytotoxic profile for T. cruzi parasite, denoting selective compounds. Compound 18 was identified as the most promising of all compounds tested, showing an IC50 of 2.6 μM for the trypomastigote form and a non-cytotoxic effect on mouse spleen cells, reaching a selective index of 95.1. Among the 22 compounds tested, six compounds present a better trypanocidal activity, and five compounds have an equipotent activity compared to benznidazole. Flow cytometry and ultrastructural analysis were performed and indicate that compound 18 causes parasite cell death through apoptosis and acts via an autophagic pathway.