Antiprotozoal Activity of Benzoylthiourea Derivatives against <i>Trypanosoma cruzi</i>: Insights into Mechanism of Action
Patrícia Morais Lopes Pereira,
Bruna Terci Fernandes,
Vitória Ribeiro dos Santos,
Weslei Roberto Correia Cabral,
Maria Isabel Lovo-Martins,
Lais Alonso,
César Armando Contreras Lancheros,
Jéssica Carreira de Paula,
Priscila Goes Camargo,
Helena Tiemi Suzukawa,
Antônio Alonso,
Fernando Macedo,
Celso Vataru Nakamura,
Eliandro Reis Tavares,
Marcelle de Lima Ferreira Bispo,
Lucy Megumi Yamauchi,
Phileno Pinge-Filho,
Sueli Fumie Yamada-Ogatta
Affiliations
Patrícia Morais Lopes Pereira
Graduate Program in Microbiology, Department of Microbiology, State University of Londrina, Londrina 86057-970, Brazil
Bruna Terci Fernandes
Graduate Program in Microbiology, Department of Microbiology, State University of Londrina, Londrina 86057-970, Brazil
Vitória Ribeiro dos Santos
Laboratory of Molecular Biology of Microorganisms, Department of Microbiology, State University of Londrina, Londrina 86057-970, Brazil
Weslei Roberto Correia Cabral
Graduate Program in Microbiology, Department of Microbiology, State University of Londrina, Londrina 86057-970, Brazil
Maria Isabel Lovo-Martins
Laboratory of Experimental Immunopathology, Department of Immunology, Parasitology and General Pathology, State University of Londrina, Londrina 86057-970, Brazil
Lais Alonso
Institute of Physics, Federal University of Goiás, Goiania 74690-900, Brazil
César Armando Contreras Lancheros
Center for Human, Biological, Social and Educational Sciences, State University of Paraná, Paranagua 83203-560, Brazil
Jéssica Carreira de Paula
Department of Parasitology, University of Granada, 18071 Granada, Spain
Priscila Goes Camargo
Laboratory of Medicinal Molecules Synthesis, Department of Chemistry, State University of Londrina, Londrina 86057-970, Brazil
Helena Tiemi Suzukawa
Graduate Program in Microbiology, Department of Microbiology, State University of Londrina, Londrina 86057-970, Brazil
Antônio Alonso
Institute of Physics, Federal University of Goiás, Goiania 74690-900, Brazil
Fernando Macedo
Laboratory of Medicinal Molecules Synthesis, Department of Chemistry, State University of Londrina, Londrina 86057-970, Brazil
Celso Vataru Nakamura
Laboratory of Technological Innovation in the Development of Drugs and Cosmetics, Department of Basic Health Sciences, State University of Maringá, Maringa 87020-900, Brazil
Eliandro Reis Tavares
Laboratory of Molecular Biology of Microorganisms, Department of Microbiology, State University of Londrina, Londrina 86057-970, Brazil
Marcelle de Lima Ferreira Bispo
Laboratory of Medicinal Molecules Synthesis, Department of Chemistry, State University of Londrina, Londrina 86057-970, Brazil
Lucy Megumi Yamauchi
Graduate Program in Microbiology, Department of Microbiology, State University of Londrina, Londrina 86057-970, Brazil
Phileno Pinge-Filho
Graduate Program in Microbiology, Department of Microbiology, State University of Londrina, Londrina 86057-970, Brazil
Sueli Fumie Yamada-Ogatta
Graduate Program in Microbiology, Department of Microbiology, State University of Londrina, Londrina 86057-970, Brazil
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.
