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A Fluorinated Phenylbenzothiazole Arrests the Trypanosoma cruzi Cell Cycle and Diminishes the Infection of Mammalian Host Cells

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Cuevas-Hernandez, I, Roberto ; Girard, Richard M. B. M. [1] ; Martinez-Ceron, Sarai [2] ; Santos da Silva, Marcelo [3, 4] ; Elias, Maria Carolina [3, 4] ; Crispim, Marcell [1] ; Trujillo-Ferrara, Jose G. [2] ; Silber, Ariel Mariano [1]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Cuevas-Hernandez, Roberto, I, Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Lab Biochem Tryps LaBTryps, Sao Paulo - Brazil
[2] Cuevas-Hernandez, Roberto, I, Inst Politecn Nacl, Lab Biochem Res, Escuela Super Med, Mexico Plan San Luis & Diaz Miron S-N, Mexico City, DF - Mexico
[3] Butantan Inst, Special Lab Cell Cycle, Sao Paulo - Brazil
[4] Ctr Toxins Immune Response & Cell Signalling CeTI, Butantan Inst, Sao Paulo - Brazil
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: Antimicrobial Agents and Chemotherapy; v. 64, n. 2 FEB 2020.
Citações Web of Science: 0

Chagas disease (CD) is a human infection caused by Trypanosoma cruzi. CD was traditionally endemic to the Americas; however, due to migration it has spread to countries where it is not endemic. The current chemotherapy to treat CD induces several side effects, and its effectiveness in the chronic phase of the disease is controversial. In this contribution, substituted phenylbenzothiazole derivatives were synthesized and biologically evaluated as trypanocidal agents against Trypanosoma cruzi. The trypanocidal activities of the most promising compounds were determined through systematic in vitro screening, and their modes of action were determined as well. The physicochemical-structural characteristics responsible for the trypanocidal effects were identified, and their possible therapeutic application in Chagas disease is discussed. Our results show that the fluorinated compound 2-methoxy-4-{[}5-(trifluoromethyl)-1,3-benzothiazol-2-yl] phenol (BT10) has the ability to inhibit the proliferation of epimastigotes {[}IC50(Epi) = 23.1 +/- 1.75 mu M] and intracellular forms of trypomastigotes {[}IC50(Tryp) = 8.5 +/- 2.9 mu M] and diminishes the infection index by more than 80%. In addition, BT10 has the ability to selectively fragment 68% of the kinetoplastid DNA compared with 5% of nucleus DNA. The mode of action for BT10 on T. cruzi suggests that the development of fluorinated phenyl-benzothiazole with electron-withdrawing substituent is a promising strategy for the design of trypanocidal drugs. (AU)

Processo FAPESP: 16/06034-2 - O papel biológico de aminoácidos e seus metabólitos derivados em Trypanosoma cruzi
Beneficiário:Ariel Mariano Silber
Linha de fomento: Auxílio à Pesquisa - Temático