Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/18022
Title: Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi
Authors: Silva, M. R. Simões
Nefertiti, A. S. G.
Araújo, J. S. de
Batista, M. M.
Silva, P. B. da
Bahia, M. T.
Menna-Barreto, R. S.
Pavão, B. P.
Green, J.
Farahat, A. A.
Kumar, A.
Boykin, D. W.
Soeiro, M. N. C.
Affilliation: Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Universidade Federal de Ouro Preto. Escola de Medicina & Núcleo de Pesquisas em Ciências Biológicas. Laboratório de Doenças Parasitárias. Ouro Preto, MG, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Georgia State University. Department of Chemistry. Atlanta, Georgia, USA.
Georgia State University. Department of Chemistry. Atlanta, Georgia, USA / Mansoura University. Faculty of Pharmacy. Department of Pharmaceutical Organic Chemistry. Amnsoura, Egypt.
Georgia State University. Department of Chemistry. Atlanta, Georgia, USA.
Georgia State University. Department of Chemistry. Atlanta, Georgia, USA.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.
Abstract: The current treatment of Chagas disease (CD), based on nifurtimox and benznidazole (Bz), is unsatisfactory. In this context, we performed the phenotypic in vitro screening of novel mono- and diamidines and drug interaction assays with selected compounds. Ten novel amidines were tested for their activities against bloodstream trypomastigote (BT) and amastigote forms of Trypanosoma cruzi (Y and Tulahuen strains) and their toxicities for mammalian host cells (L929 cells and cardiac cells). Seven of 10 molecules were more active than Bz against BT, with the most active compound being the diamidine DB2267 (50% effective concentration [EC50] = 0.23 μM; selectivity index = 417), which was 28-fold more active and about 3 times more selective than the standard drug. Five of the six monoamidines were also more active than Bz. The combination of DB2267 and DB2236 in fixed-ratio proportions showed an additive effect (sum of fractional inhibitory concentrations < 4) on BT. Interestingly, when intracellular forms were exposed to DB2267, its activity was dependent on the parasite strain, being effective (EC50 = 0.87 ± 0.05 μM) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles (β-cyclodextrin and dimethyl sulfoxide) were used. The intrinsic fluorescence of several diamidines allowed their uptake to be studied. Testing of the uptake of DB2236 (inactive) and DB2267 (active) by amastigotes of the Y strain showed that the two compounds were localized intracellularly in different compartments: DB2236 in the cytoplasm and DB2267 in the nucleus. Our present data encourage further studies regarding the activities of amidines and provide information which will help with the identification of novel agents for the treatment of CD.
Keywords: Chagas disease
Trypanosoma cruzi
Amidines
Treatment
Phenotypic Screening
In Vitro
keywords: Doença de Chagas
Amidinas
Trypanosoma cruzi
Tratamento
Triagem Fenotípica
In Vitro
Issue Date: 2016
Publisher: American Society for Microbiology
Citation: SILVA, M. R. Simões; et al. Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, v.60, n.8, p.4701-4707, Aug. 2016.
DOI: 10.1128/AAC.01788-15
ISSN: 0066-4804
Copyright: open access
Appears in Collections:IOC - Artigos de Periódicos

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