Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection
| Autor(a) principal: | |
|---|---|
| Data de Publicação: | 2017 |
| 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/20080 |
Resumo: | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil. |
| id |
CRUZ_d34104cabda5285ed025d3f2a8ccf2fb |
|---|---|
| oai_identifier_str |
oai:www.arca.fiocruz.br:icict/20080 |
| network_acronym_str |
CRUZ |
| network_name_str |
Repositório Institucional da FIOCRUZ (ARCA) |
| repository_id_str |
2135 |
| spelling |
Silva, Cristiane França daBatista, Denise da Gama JaénAraújo, Julianna Sicilano deCunha Junior, Edézio FerreiraStephens, Chad E.Banerjee, MoloyFarahat, Abdelbasset A.Akay, SenolFisher, Mary K,Boykin, David W.Soeiro, Maria de Nazaré Correia2017-07-13T17:00:16Z2017-07-13T17:00:16Z2017SILVA, Cristiana França da; et al Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection. Drug Design, Development and Therapy, v.11, p.1095-1105, 2017.1177-8881https://www.arca.fiocruz.br/handle/icict/20080engDove Medical PressDoença de ChagasQuimioterapia experimentalEnsaios in vivoArilimidamidasChagas diseasearylimidamidesexperimental chemotherapyin vivo assaysPhenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infectioninfo: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 Bioquímica de Tripanossomatídeos. Rio de Janeiro, RJ. Brasil.Augusta University. Department of Chemistry and Physics. Augusta, USA.Georgia State University. Department of Chemistry. Atlanta, GA, USA.Georgia State University. Department of Chemistry. Atlanta, GA, USA / Mansoura University. Faculty of Pharmacy. Department of Pharmaceutical Organic Chemistry. Mansoura, Egypt.Georgia State University. Department of Chemistry. Atlanta, GA, USA.Augusta University. Department of Chemistry and Physics. Augusta, USA.Georgia State University. Department of Chemistry. Atlanta, GA, USA.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil.Abstract: Arylimidamides (AIAs), previously termed as reversed amidines, present a broad spectrum of activity against intracellular microorganisms. In the present study, three novel AIAs were evaluated in a mouse model of Trypanosoma cruzi infection, which is the causative agent of Chagas disease. The bis-AIAs DB1957, DB1959 and DB1890 were chosen based on a previous screening of their scaffolds that revealed a very promising trypanocidal effect at nanomolar range against both the bloodstream trypomastigotes (BTs) and the intracellular forms of the parasite. This study focused on both mesylate salts DB1957 and DB1959 besides the hydrochloride salt DB1890. Our current data validate the high activity of these bis-AIA scaffolds that exhibited EC50 (drug concentration that reduces 50% of the number of the treated parasites) values ranging from 14 to 78 nM and 190 to 1,090 nM against bloodstream and intracellular forms, respectively, also presenting reasonable selectivity indexes and no mutagenicity profile predicted by in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET). Acute toxicity studies using murine models revealed that these AIAs presented only mild toxic effects such as reversible abdominal contractions and ruffled fur. Efficacy assays performed with Swiss mice infected with the Y strain revealed that the administration of DB1957 for 5 consecutive days, with the first dose given at parasitemia onset, reduced the number of BTs at the peak, ranging between 21 and 31% of decrease. DB1957 was able to provide 100% of animal survival, while untreated animals showed 70% of mortality rates. DB1959 and DB1890B did not reduce circulating parasitism but yielded .80% of survival rates.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/20080/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALcristiana_silva_etal_IOC_2017.pdfcristiana_silva_etal_IOC_2017.pdfapplication/pdf757102https://www.arca.fiocruz.br/bitstream/icict/20080/2/cristiana_silva_etal_IOC_2017.pdfc6e1b124c629b18cadf5c0a3ada29ee8MD52TEXTcristiana_silva_etal_IOC_2017.pdf.txtcristiana_silva_etal_IOC_2017.pdf.txtExtracted texttext/plain50315https://www.arca.fiocruz.br/bitstream/icict/20080/3/cristiana_silva_etal_IOC_2017.pdf.txtaef31a04bfe02c3eedc9538f87e43c84MD53icict/200802018-08-15 03:15:13.762oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352018-08-15T06:15:13Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false |
| dc.title.pt_BR.fl_str_mv |
Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection |
| title |
Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection |
| spellingShingle |
Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection Silva, Cristiane França da Doença de Chagas Quimioterapia experimental Ensaios in vivo Arilimidamidas Chagas disease arylimidamides experimental chemotherapy in vivo assays |
| title_short |
Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection |
| title_full |
Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection |
| title_fullStr |
Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection |
| title_full_unstemmed |
Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection |
| title_sort |
Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection |
| author |
Silva, Cristiane França da |
| author_facet |
Silva, Cristiane França da Batista, Denise da Gama Jaén Araújo, Julianna Sicilano de Cunha Junior, Edézio Ferreira Stephens, Chad E. Banerjee, Moloy Farahat, Abdelbasset A. Akay, Senol Fisher, Mary K, Boykin, David W. Soeiro, Maria de Nazaré Correia |
| author_role |
author |
| author2 |
Batista, Denise da Gama Jaén Araújo, Julianna Sicilano de Cunha Junior, Edézio Ferreira Stephens, Chad E. Banerjee, Moloy Farahat, Abdelbasset A. Akay, Senol Fisher, Mary K, Boykin, David W. Soeiro, Maria de Nazaré Correia |
| author2_role |
author author author author author author author author author author |
| dc.contributor.author.fl_str_mv |
Silva, Cristiane França da Batista, Denise da Gama Jaén Araújo, Julianna Sicilano de Cunha Junior, Edézio Ferreira Stephens, Chad E. Banerjee, Moloy Farahat, Abdelbasset A. Akay, Senol Fisher, Mary K, Boykin, David W. Soeiro, Maria de Nazaré Correia |
| dc.subject.other.pt_BR.fl_str_mv |
Doença de Chagas Quimioterapia experimental Ensaios in vivo Arilimidamidas |
| topic |
Doença de Chagas Quimioterapia experimental Ensaios in vivo Arilimidamidas Chagas disease arylimidamides experimental chemotherapy in vivo assays |
| dc.subject.en.pt_BR.fl_str_mv |
Chagas disease arylimidamides experimental chemotherapy in vivo assays |
| description |
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Celular. Rio de Janeiro, RJ. Brasil. |
| publishDate |
2017 |
| dc.date.accessioned.fl_str_mv |
2017-07-13T17:00:16Z |
| dc.date.available.fl_str_mv |
2017-07-13T17:00:16Z |
| dc.date.issued.fl_str_mv |
2017 |
| 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, Cristiana França da; et al Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection. Drug Design, Development and Therapy, v.11, p.1095-1105, 2017. |
| dc.identifier.uri.fl_str_mv |
https://www.arca.fiocruz.br/handle/icict/20080 |
| dc.identifier.issn.pt_BR.fl_str_mv |
1177-8881 |
| identifier_str_mv |
SILVA, Cristiana França da; et al Phenotypic evaluation and in silico ADMET properties of novel arylimidamides in acute mouse models of Trypanosoma cruzi infection. Drug Design, Development and Therapy, v.11, p.1095-1105, 2017. 1177-8881 |
| url |
https://www.arca.fiocruz.br/handle/icict/20080 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
Dove Medical Press |
| publisher.none.fl_str_mv |
Dove Medical Press |
| dc.source.none.fl_str_mv |
reponame:Repositório Institucional da FIOCRUZ (ARCA) instname:Fundação Oswaldo Cruz (FIOCRUZ) instacron:FIOCRUZ |
| instname_str |
Fundação Oswaldo Cruz (FIOCRUZ) |
| instacron_str |
FIOCRUZ |
| institution |
FIOCRUZ |
| reponame_str |
Repositório Institucional da FIOCRUZ (ARCA) |
| collection |
Repositório Institucional da FIOCRUZ (ARCA) |
| bitstream.url.fl_str_mv |
https://www.arca.fiocruz.br/bitstream/icict/20080/1/license.txt https://www.arca.fiocruz.br/bitstream/icict/20080/2/cristiana_silva_etal_IOC_2017.pdf https://www.arca.fiocruz.br/bitstream/icict/20080/3/cristiana_silva_etal_IOC_2017.pdf.txt |
| bitstream.checksum.fl_str_mv |
5a560609d32a3863062d77ff32785d58 c6e1b124c629b18cadf5c0a3ada29ee8 aef31a04bfe02c3eedc9538f87e43c84 |
| bitstream.checksumAlgorithm.fl_str_mv |
MD5 MD5 MD5 |
| repository.name.fl_str_mv |
Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ) |
| repository.mail.fl_str_mv |
repositorio.arca@fiocruz.br |
| _version_ |
1813008847955034112 |