Antiprotozoal Activity of Benzoylthiourea Derivatives against Trypanosoma cruzi: Insights into Mechanism of Action
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MDPI
Materia
Autophagy-dependent pathway Cell death Chagas disease Epimastigote forms Mechanism of action Ultrastructural changes
Date
2023-08-03Referencia bibliográfica
Pereira, P.M.L.; Fernandes, B.T.; dos Santos, V.R.; Cabral,W.R.C.; Lovo-Martins, M.I.; Alonso, L.; Lancheros, C.A.C.; de Paula, J.C.; Camargo, P.G.; Suzukawa, H.T.; et al. Antiprotozoal Activity of Benzoylthiourea Derivatives against Trypanosoma cruzi: Insights into Mechanism of Action. Pathogens 2023, 12, 1012. [https://doi.org/10.3390/ pathogens12081012]
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Financial Code 01)Abstract
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-(tertbutylcarbamothioyl)
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