New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules

Detalhes bibliográficos
Autor(a) principal: Boechat, Núbia
Data de Publicação: 2012
Outros Autores: Pinheiro, Luiz C. S., Silva, Thiago S., Aguiar, Anna Caroline Campos, Carvalho, Alcione Silva de, Bastos, Monica M., Costa, Carolina C. P., Pinheiro, Sergio, Pinto, Angelo da Cunha, Mendonça, Jorge S., Dutra, Karen D. B., Valverde, Alessandra Leda, Santos Filho, Osvaldo A., Cerávolo, Isabela Penna, Krettli, Antoniana Ursine
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/7379
Resumo: Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, Brazil
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spelling Boechat, NúbiaPinheiro, Luiz C. S.Silva, Thiago S.Aguiar, Anna Caroline CamposCarvalho, Alcione Silva deBastos, Monica M.Costa, Carolina C. P.Pinheiro, SergioPinto, Angelo da CunhaMendonça, Jorge S.Dutra, Karen D. B.Valverde, Alessandra LedaSantos Filho, Osvaldo A.Cerávolo, Isabela PennaKrettli, Antoniana Ursine2014-03-06T19:21:51Z2014-03-06T19:21:51Z2012BOECHAT, Núbia et al. New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules. 2012, vol.17, pp. 8285-8302.1420-3049https://www.arca.fiocruz.br/handle/icict/737910.3390/molecules17078285engMDPI AGNew trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Moleculesinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleFundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, BrazilFundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, BrazilFundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, Brazil/Universidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Orgânica. Rio de Janeiro, RJ BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, Brazil/Universidade Federal de Minas Gerais. Faculdade de Medicina. Programa de Pós Graduação em Medicina Molecular. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, BrazilFundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, BrazilFundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, BrazilUniversidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, BrasilUniversidade Federal do Rio de Janeiro. Instituto de Química. Departamento de Química Orgânica. Rio de Janeiro, RJ BrazilFundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, BrazilFundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, Brazil/Universidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, BrasilUniversidade Federal Fluminense. Instituto de Química. Departamento de Química Orgânica. Niterói, RJ, BrasilFundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, BrazilFundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Laboratório de Malária. Belo Horizonte, MG, Brazil/ Universidade Federal de Minas Gerais. Faculdade de Medicina. Programa de Pós Graduação em Medicina Molecular. Belo Horizonte, MG, BrazilAccording to the World Health Organization, half of the World’s population, approximately 3.3 billion people, is at risk for developing malaria. Nearly 700,000 deaths each year are associated with the disease. Control of the disease in humans still relies on chemotherapy. Drug resistance is a limiting factor, and the search for new drugs is important. We have designed and synthesized new 2-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyrimidine derivatives based on bioisosteric replacement of functional groups on the anti-malarial compounds mefloquine and amodiaquine. This approach enabled us to investigate the impact of: (i) ring bioisosteric replacement; (ii) a CF3 group substituted at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine scaffold and (iii) a range of amines as substituents at the 7-position of the of heterocyclic ring; on in vitro activity against Plasmodium falciparum. According to docking simulations, the synthesized compounds are able to interact with P. falciparum dihydroorotate dehydrogenase (PfDHODH) through strong hydrogen bonds. The presence of a trifluoromethyl group at the 2-position of the [1,2,4]triazolo[1,5-a]pyrimidine ring led to increased drug activity. Thirteen compounds were found to be active, with IC50 values ranging from 0.023 to 20 µM in the anti-HRP2 and hypoxanthine assays. The selectivity index (SI) of the most active derivatives 5, 8, 11 and 16 was found to vary from 1,003 to 18,478.triazolopyrimidinetrifluoromethylmalariaP. falciparum; PfDHODHinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZORIGINALNew Trifluoromethyl Triazolopyrimidines as Anti-Plasmodium falciparum Agents.pdfNew Trifluoromethyl Triazolopyrimidines as Anti-Plasmodium falciparum Agents.pdfapplication/pdf382026https://www.arca.fiocruz.br/bitstream/icict/7379/1/New%20Trifluoromethyl%20Triazolopyrimidines%20as%20Anti-Plasmodium%20falciparum%20Agents.pdfea502f37247c0ba9ea04596383ea178eMD51LICENSElicense.txtlicense.txttext/plain; charset=utf-81914https://www.arca.fiocruz.br/bitstream/icict/7379/2/license.txt7d48279ffeed55da8dfe2f8e81f3b81fMD52TEXTNew Trifluoromethyl Triazolopyrimidines as Anti-Plasmodium falciparum Agents.pdf.txtNew Trifluoromethyl Triazolopyrimidines as Anti-Plasmodium falciparum Agents.pdf.txtExtracted texttext/plain53480https://www.arca.fiocruz.br/bitstream/icict/7379/5/New%20Trifluoromethyl%20Triazolopyrimidines%20as%20Anti-Plasmodium%20falciparum%20Agents.pdf.txt006d0883f9c526559e14f45fd278c0d9MD55THUMBNAILNew Trifluoromethyl Triazolopyrimidines as Anti-Plasmodium falciparum Agents.pdf.jpgNew Trifluoromethyl Triazolopyrimidines as Anti-Plasmodium falciparum Agents.pdf.jpgGenerated Thumbnailimage/jpeg2387https://www.arca.fiocruz.br/bitstream/icict/7379/4/New%20Trifluoromethyl%20Triazolopyrimidines%20as%20Anti-Plasmodium%20falciparum%20Agents.pdf.jpg5c882762d514394b5da038b0f66efd5aMD54icict/73792018-04-06 08:43:55.566oai:www.arca.fiocruz.br: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ório InstitucionalPUBhttps://www.arca.fiocruz.br/oai/requestrepositorio.arca@fiocruz.bropendoar:21352018-04-06T11:43:55Repositório Institucional da FIOCRUZ (ARCA) - Fundação Oswaldo Cruz (FIOCRUZ)false
dc.title.pt_BR.fl_str_mv New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules
title New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules
spellingShingle New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules
Boechat, Núbia
triazolopyrimidine
trifluoromethyl
malaria
P. falciparum; PfDHODH
title_short New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules
title_full New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules
title_fullStr New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules
title_full_unstemmed New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules
title_sort New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules
author Boechat, Núbia
author_facet Boechat, Núbia
Pinheiro, Luiz C. S.
Silva, Thiago S.
Aguiar, Anna Caroline Campos
Carvalho, Alcione Silva de
Bastos, Monica M.
Costa, Carolina C. P.
Pinheiro, Sergio
Pinto, Angelo da Cunha
Mendonça, Jorge S.
Dutra, Karen D. B.
Valverde, Alessandra Leda
Santos Filho, Osvaldo A.
Cerávolo, Isabela Penna
Krettli, Antoniana Ursine
author_role author
author2 Pinheiro, Luiz C. S.
Silva, Thiago S.
Aguiar, Anna Caroline Campos
Carvalho, Alcione Silva de
Bastos, Monica M.
Costa, Carolina C. P.
Pinheiro, Sergio
Pinto, Angelo da Cunha
Mendonça, Jorge S.
Dutra, Karen D. B.
Valverde, Alessandra Leda
Santos Filho, Osvaldo A.
Cerávolo, Isabela Penna
Krettli, Antoniana Ursine
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.author.fl_str_mv Boechat, Núbia
Pinheiro, Luiz C. S.
Silva, Thiago S.
Aguiar, Anna Caroline Campos
Carvalho, Alcione Silva de
Bastos, Monica M.
Costa, Carolina C. P.
Pinheiro, Sergio
Pinto, Angelo da Cunha
Mendonça, Jorge S.
Dutra, Karen D. B.
Valverde, Alessandra Leda
Santos Filho, Osvaldo A.
Cerávolo, Isabela Penna
Krettli, Antoniana Ursine
dc.subject.en.pt_BR.fl_str_mv triazolopyrimidine
trifluoromethyl
malaria
P. falciparum; PfDHODH
topic triazolopyrimidine
trifluoromethyl
malaria
P. falciparum; PfDHODH
description Fundação Oswaldo Cruz. Instituto de Tecnologia em Fármacos-Farmanguinhos. Departamento de Síntese Orgânica. Rio de Janeiro, RJ, Brazil
publishDate 2012
dc.date.issued.fl_str_mv 2012
dc.date.accessioned.fl_str_mv 2014-03-06T19:21:51Z
dc.date.available.fl_str_mv 2014-03-06T19:21:51Z
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 BOECHAT, Núbia et al. New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules. 2012, vol.17, pp. 8285-8302.
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/7379
dc.identifier.issn.none.fl_str_mv 1420-3049
dc.identifier.doi.none.fl_str_mv 10.3390/molecules17078285
identifier_str_mv BOECHAT, Núbia et al. New trifluoromethyl triazolopyrimidines as anti-Plasmodium falciparum agents. Molecules. 2012, vol.17, pp. 8285-8302.
1420-3049
10.3390/molecules17078285
url https://www.arca.fiocruz.br/handle/icict/7379
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 MDPI AG
publisher.none.fl_str_mv MDPI AG
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/7379/1/New%20Trifluoromethyl%20Triazolopyrimidines%20as%20Anti-Plasmodium%20falciparum%20Agents.pdf
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