Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2016 |
| Outros Autores: | , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Institucional da FIOCRUZ (ARCA) |
| Texto Completo: | https://www.arca.fiocruz.br/handle/icict/18022 |
Resumo: | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil. |
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Silva, M. R. SimõesNefertiti, A. S. G.Araújo, J. S. deBatista, M. M.Silva, P. B. daBahia, M. T.Menna-Barreto, R. S.Pavão, B. P.Green, J.Farahat, A. A.Kumar, A.Boykin, D. W.Soeiro, M. N. C.2017-03-13T16:36:41Z2017-03-13T16:36:41Z2016SILVA, 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. 2016.0066-4804https://www.arca.fiocruz.br/handle/icict/1802210.1128/AAC.01788-151098-6596engAmerican Society for MicrobiologyDoença de ChagasAmidinasTrypanosoma cruziTratamentoTriagem FenotípicaIn VitroChagas diseaseTrypanosoma cruziAmidinesTreatmentPhenotypic ScreeningIn VitroPhenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruziinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação 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.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.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/18022/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALmrsimoes_silva_etal_IOC_2016.pdfmrsimoes_silva_etal_IOC_2016.pdfapplication/pdf1065472https://www.arca.fiocruz.br/bitstream/icict/18022/2/mrsimoes_silva_etal_IOC_2016.pdfd530bbd01dd3e793b8c912cfb16e3734MD52TEXTmrsimoes_silva_etal_IOC_2016.pdf.txtmrsimoes_silva_etal_IOC_2016.pdf.txtExtracted texttext/plain38603https://www.arca.fiocruz.br/bitstream/icict/18022/3/mrsimoes_silva_etal_IOC_2016.pdf.txt29267f7c56c630951a1a8bce29bc6ba6MD53icict/180222018-08-15 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| dc.title.pt_BR.fl_str_mv |
Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi |
| title |
Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi |
| spellingShingle |
Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi Silva, M. R. Simões Doença de Chagas Amidinas Trypanosoma cruzi Tratamento Triagem Fenotípica In Vitro Chagas disease Trypanosoma cruzi Amidines Treatment Phenotypic Screening In Vitro |
| title_short |
Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi |
| title_full |
Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi |
| title_fullStr |
Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi |
| title_full_unstemmed |
Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi |
| title_sort |
Phenotypic Screening In Vitro of Novel Aromatic Amidines against Trypanosoma cruzi |
| author |
Silva, M. R. Simões |
| author_facet |
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. |
| author_role |
author |
| author2 |
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. |
| author2_role |
author author author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
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. |
| dc.subject.other.pt_BR.fl_str_mv |
Doença de Chagas Amidinas Trypanosoma cruzi Tratamento Triagem Fenotípica In Vitro |
| topic |
Doença de Chagas Amidinas Trypanosoma cruzi Tratamento Triagem Fenotípica In Vitro Chagas disease Trypanosoma cruzi Amidines Treatment Phenotypic Screening In Vitro |
| dc.subject.en.pt_BR.fl_str_mv |
Chagas disease Trypanosoma cruzi Amidines Treatment Phenotypic Screening In Vitro |
| description |
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil. |
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2016 |
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2016 |
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2017-03-13T16:36:41Z |
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2017-03-13T16:36:41Z |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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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. |
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https://www.arca.fiocruz.br/handle/icict/18022 |
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0066-4804 |
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10.1128/AAC.01788-15 |
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1098-6596 |
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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. 0066-4804 10.1128/AAC.01788-15 1098-6596 |
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American Society for Microbiology |
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American Society for Microbiology |
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