Phthalimido-thiazoles as building blocks and their effects on the growth and morphology of Trypanosoma cruzi

Chagas disease is a parasitic infection caused by protozoan Trypanosoma cruzi that affects approximately 6–7 million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases; however, its efficacy during the symptomatic chronic phase is...

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Veröffentlicht in:European journal of medicinal chemistry 2016-03, Vol.111, p.46-57
Hauptverfasser: Gomes, Paulo André Teixeira de Moraes, Oliveira, Arsênio Rodrigues, Cardoso, Marcos Veríssimo de Oliveira, Santiago, Edna de Farias, Barbosa, Miria de Oliveira, de Siqueira, Lucianna Rabelo Pessoa, Moreira, Diogo Rodrigo Magalhães, Bastos, Tanira Matutino, Brayner, Fábio André, Soares, Milena Botelho Pereira, Mendes, Andresa Pereira de Oliveira, de Castro, Maria Carolina Accioly Brelaz, Pereira, Valéria Rego Alves, Leite, Ana Cristina Lima
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Sprache:eng
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Zusammenfassung:Chagas disease is a parasitic infection caused by protozoan Trypanosoma cruzi that affects approximately 6–7 million people worldwide. Benznidazole is the only drug approved for treatment during the acute and asymptomatic chronic phases; however, its efficacy during the symptomatic chronic phase is controversial. The present work reports the synthesis and anti-T. cruzi activities of a novel series of phthalimido-thiazoles. Some of these compounds showed potent inhibition of the trypomastigote form of the parasite at low cytotoxicity concentrations in spleen cells, and the resulting structure-activity relationships are discussed. We also showed that phthalimido-thiazoles induced ultrastructural alterations on morphology, flagellum shortening, chromatin condensation, mitochondria swelling, reservosomes alterations and endoplasmic reticulum dilation. Together, these data revealed, for the first time, a novel series of phthalimido-thiazoles-structure-based compounds with potential effects against T. cruzi and lead-like characteristics against Chagas disease. [Display omitted] •The anti-T. cruzi activity of 26 phthalimido-thiazoles were evaluated.•Five compounds presented better trypanocidal activity than Benznidazole.•Compound 6j was 26-fold more selective than Benznidazole.•The structural upgrade planned present positive effects on trypanocidal activity.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2016.01.010