Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi.
Autor(a) principal: | |
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Data de Publicação: | 2016 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UFOP |
Texto Completo: | http://www.repositorio.ufop.br/handle/123456789/9225 https://aac.asm.org/content/60/8/4701.long https://doi.org/10.1128/AAC.01788-15 |
Resumo: | 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 M; 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 M) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles ( -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. |
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Silva, Marianne Rocha SimõesGama, Aline Nefertiti Silva daAraújo, Julianna Siciliano deBatista, Marcos MeuserSilva, Patrícia Bernardino daBahia, Maria TerezinhaBarreto, Rubem Figueiredo Sadok MennaPavão., Beatriz PhilotGreen, JuliusFarahay, Abdelbaset AKumar, ArvindBoykin, David WilsonSoeiro, Maria de Nazaré Correia2017-12-20T15:08:01Z2017-12-20T15:08:01Z2016SILVA, M. R. S. et al. Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, v. 60, p. 4701-4707, 2016. Disponível em: <http://aac.asm.org/content/60/8/4701.long>. Acesso em: 15 set. 2017.1098-6596http://www.repositorio.ufop.br/handle/123456789/9225https://aac.asm.org/content/60/8/4701.longhttps://doi.org/10.1128/AAC.01788-15The 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 M; 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 M) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles ( -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.Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi.info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccessengreponame:Repositório Institucional da UFOPinstname:Universidade Federal de Ouro Preto (UFOP)instacron:UFOPLICENSElicense.txtlicense.txttext/plain; charset=utf-8924http://www.repositorio.ufop.br/bitstream/123456789/9225/2/license.txt62604f8d955274beb56c80ce1ee5dcaeMD52ORIGINALARTIGO_PhenotyoicScreeningVitro.pdfARTIGO_PhenotyoicScreeningVitro.pdfapplication/pdf1062965http://www.repositorio.ufop.br/bitstream/123456789/9225/1/ARTIGO_PhenotyoicScreeningVitro.pdfe3dc6df466070edbedb7f288e81b0ea2MD51123456789/92252020-04-09 17:11:28.451oai:localhost: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ório InstitucionalPUBhttp://www.repositorio.ufop.br/oai/requestrepositorio@ufop.edu.bropendoar:32332020-04-09T21:11:28Repositório Institucional da UFOP - Universidade Federal de Ouro Preto (UFOP)false |
dc.title.pt_BR.fl_str_mv |
Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. |
title |
Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. |
spellingShingle |
Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. Silva, Marianne Rocha Simões |
title_short |
Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. |
title_full |
Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. |
title_fullStr |
Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. |
title_full_unstemmed |
Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. |
title_sort |
Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. |
author |
Silva, Marianne Rocha Simões |
author_facet |
Silva, Marianne Rocha Simões Gama, Aline Nefertiti Silva da Araújo, Julianna Siciliano de Batista, Marcos Meuser Silva, Patrícia Bernardino da Bahia, Maria Terezinha Barreto, Rubem Figueiredo Sadok Menna Pavão., Beatriz Philot Green, Julius Farahay, Abdelbaset A Kumar, Arvind Boykin, David Wilson Soeiro, Maria de Nazaré Correia |
author_role |
author |
author2 |
Gama, Aline Nefertiti Silva da Araújo, Julianna Siciliano de Batista, Marcos Meuser Silva, Patrícia Bernardino da Bahia, Maria Terezinha Barreto, Rubem Figueiredo Sadok Menna Pavão., Beatriz Philot Green, Julius Farahay, Abdelbaset A Kumar, Arvind Boykin, David Wilson Soeiro, Maria de Nazaré Correia |
author2_role |
author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Silva, Marianne Rocha Simões Gama, Aline Nefertiti Silva da Araújo, Julianna Siciliano de Batista, Marcos Meuser Silva, Patrícia Bernardino da Bahia, Maria Terezinha Barreto, Rubem Figueiredo Sadok Menna Pavão., Beatriz Philot Green, Julius Farahay, Abdelbaset A Kumar, Arvind Boykin, David Wilson Soeiro, Maria de Nazaré Correia |
description |
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 M; 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 M) against a discrete typing unit (DTU) II strain (strain Y) but not against a representative DTU VI strain (strain Tulahuen) even when different vehicles ( -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. |
publishDate |
2016 |
dc.date.issued.fl_str_mv |
2016 |
dc.date.accessioned.fl_str_mv |
2017-12-20T15:08:01Z |
dc.date.available.fl_str_mv |
2017-12-20T15:08:01Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.citation.fl_str_mv |
SILVA, M. R. S. et al. Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, v. 60, p. 4701-4707, 2016. Disponível em: <http://aac.asm.org/content/60/8/4701.long>. Acesso em: 15 set. 2017. |
dc.identifier.uri.fl_str_mv |
http://www.repositorio.ufop.br/handle/123456789/9225 |
dc.identifier.issn.none.fl_str_mv |
1098-6596 |
dc.identifier.uri2.none.fl_str_mv |
https://aac.asm.org/content/60/8/4701.long |
dc.identifier.doi.none.fl_str_mv |
https://doi.org/10.1128/AAC.01788-15 |
identifier_str_mv |
SILVA, M. R. S. et al. Phenotypic screening of novel aromatic amidines against Trypanosoma cruzi. Antimicrobial Agents and Chemotherapy, v. 60, p. 4701-4707, 2016. Disponível em: <http://aac.asm.org/content/60/8/4701.long>. Acesso em: 15 set. 2017. 1098-6596 |
url |
http://www.repositorio.ufop.br/handle/123456789/9225 https://aac.asm.org/content/60/8/4701.long https://doi.org/10.1128/AAC.01788-15 |
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eng |
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