Antiprotozoal Activity of Benzoylthiourea Derivatives against ITrypanosoma cruzi/I: Insights into Mechanism of Action

For decades, only two nitroheterocyclic drugs have been used as therapeutic agents for Chagas disease. However, these drugs present limited effectiveness during the chronic phase, possess unfavorable pharmacokinetic properties, and induce severe adverse effects, resulting in low treatment adherence....

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Published inPathogens (Basel) Vol. 12; no. 8
Main Authors Pereira, Patrícia Morais Lopes, Fernandes, Bruna Terci, dos Santos, Vitória Ribeiro, Cabral, Weslei Roberto Correia, Lovo-Ma, Alonso, Lais, Lancheros, César Armando Contreras, de Paula, Jéssica Carreira, Camargo, Priscila Goes, Suzukawa, Helena Tiemi, Alonso, Antônio, Macedo, Fernando, Nakamura, Celso Vataru, Tavares, Eliandro Reis, de Lima Ferreira Bispo, Marcelle, Yamauchi, Lucy Megumi, Pinge-Filho, Phileno, Yamada-Ogatta, Sueli Fumie
Format Journal Article
LanguageEnglish
Published MDPI AG 01.08.2023
Subjects
Chagas' disease
Drug therapy
Organosulfur compounds
Physiological aspects
Testing
Trypanosoma cruzi
Brazil
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Summary:For decades, only two nitroheterocyclic drugs have been used as therapeutic agents for Chagas disease. However, these drugs present limited effectiveness during the chronic phase, possess unfavorable pharmacokinetic properties, and induce severe adverse effects, resulting in low treatment adherence. A previous study reported that N-(cyclohexylcarbamothioyl) benzamide (BTU-1), N-(tert-butylcarbamothioyl) benzamide (BTU-2), and (4-bromo-N-(3-nitrophenyl) carbamothioyl benzamide (BTU-3) present selective antiprotozoal activity against all developmental forms of Trypanosoma cruzi Y strain. In this study, we investigated the mechanism of action of these compounds through microscopy and biochemical analyses. Transmission electron microscopy analysis showed nuclear disorganization, changes in the plasma membrane with the appearance of blebs and extracellular arrangements, intense vacuolization, mitochondrial swelling, and formation of myelin-like structures. Biochemical results showed changes in the mitochondrial membrane potential, reactive oxygen species content, lipid peroxidation, and plasma membrane fluidity. In addition, the formation of autophagic vacuoles was observed. These findings indicate that BTU-1, BTU-2, and BTU-3 induced profound morphological, ultrastructural, and biochemical alterations in epimastigote forms, triggering an autophagic-dependent cell death pathway.
ISSN:2076-0817
2076-0817
DOI:10.3390/pathogens12081012