Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.

Detalhes bibliográficos
Autor(a) principal: Trindade, Joana D'Arc da Silva
Data de Publicação: 2019
Tipo de documento: Tese
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações da UFRRJ
Texto Completo: https://rima.ufrrj.br/jspui/handle/20.500.14407/10238
Resumo: O tratamento da doença de Chagas é feito apenas por dois medicamentos, o nifurtimox (1) e o benznidazol (2). Contudo, além destes fármacos não serem eficazes em todas as fases da infecção, apresentam severos efeitos colaterais, o que justifica a busca de novas alternativas para o tratamento desta grave enfermidade. Dados da literatura descrevem a interferência de fármacos anti-inflamatórios não-esteroidais no processo de infecção por tripomastigotas de Trypanosoma cruzi, sobre células de mamíferos. O mecanismo de ação destes fármacos ocorre sobre as isoformas da enzima ciclo-oxigenase, importantes para o estabelecimento da infecção do parasito. Adicionalmente, são bem conhecidos os efeitos tóxicos de compostos nitro-aromáticos, sendo o T. cruzi bastante afetado pela ação dessas moléculas em seu equilíbrio redox. De posse destas informações, propusemos neste trabalho a investigação da atividade tripanocida do fármaco nimesulida (3), anti-inflamatório nãoesteroidal, que possui em sua estrutura o grupamento toxicofórico nitro-aromático. A abordagem de reposicionamento de fármacos, como a que apresentamos aqui visando à possível atividade tripanocida da nimesulida (3), é um recurso importante na descoberta de fármacos aplicáveis ao tratamento de doenças negligenciadas. Outra estratégia, desenvolvida em paralelo, envolveu o emprego da hibridação molecular na preparação de dois derivados da nimesulida (3) com a amida natural piperina (5). Os resultados obtidos nas avaliações biológicas realizadas evidenciaram a atividade antiparasitária da nimesulida (3) sobre as diferentes formas evolutivas do parasito. Além disso, dos dois híbridos moleculares construídos, o híbrido H1, no qual foi preservada a porção nitro aromática, apresentou ação tripanocida, enquanto que o híbrido H2 perdeu significativamente a atividade com a retirada do grupo nitro de sua estrutura, o que permitiu apontar para o grupo nitro presente na nimesulida (3) e no híbrido H1 como porção farmacofórica para a atividade tripanocida estudada, validando as hipóteses deste estudo. Os resultados obtidos na avaliação das alterações ultra-estruturais em epimastigotas de T. cruzi tratados com nimesulida mostram a desorganização da estrutura das mitocôndrias, corroborando a possível interferência do fármaco no equilíbrio redox do parasito.
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spelling Trindade, Joana D'Arc da SilvaLima, Marco Edilson Freire dehttps://orcid.org/0000-0003-0563-3483880.202.667-04http://lattes.cnpq.br/8392420706762318Lima, Debora Decote Ricardo dehttps://orcid.org/0000-0001-8761-7641875.362.007-06http://lattes.cnpq.br/3572066508469025Lima, Marco Edilson Freire dehttps://orcid.org/0000-0003-0563-3483880.202.667-04http://lattes.cnpq.br/8392420706762318Kratz, Jadel Müllerhttps://orcid.org/0000-0002-7681-8234http://lattes.cnpq.br/5657186266877840Almeida, Wanda Pereirahttp://lattes.cnpq.br/3903296396671088Soares, Deivid Costahttp://lattes.cnpq.br/7894147147292742Silva, Lúcia Helena Pinto dahttp://lattes.cnpq.br/0013386072339397https://orcid.org/0000-0002-3619-053406.711.187-2843.688.107-91http://lattes.cnpq.br/98303521295629352023-12-21T18:59:20Z2023-12-21T18:59:20Z2019-10-17TRINDADE, Joana D’Arc da Silva. Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação. 2019. 179 f. Tese. (Tese em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2019.https://rima.ufrrj.br/jspui/handle/20.500.14407/10238O tratamento da doença de Chagas é feito apenas por dois medicamentos, o nifurtimox (1) e o benznidazol (2). Contudo, além destes fármacos não serem eficazes em todas as fases da infecção, apresentam severos efeitos colaterais, o que justifica a busca de novas alternativas para o tratamento desta grave enfermidade. Dados da literatura descrevem a interferência de fármacos anti-inflamatórios não-esteroidais no processo de infecção por tripomastigotas de Trypanosoma cruzi, sobre células de mamíferos. O mecanismo de ação destes fármacos ocorre sobre as isoformas da enzima ciclo-oxigenase, importantes para o estabelecimento da infecção do parasito. Adicionalmente, são bem conhecidos os efeitos tóxicos de compostos nitro-aromáticos, sendo o T. cruzi bastante afetado pela ação dessas moléculas em seu equilíbrio redox. De posse destas informações, propusemos neste trabalho a investigação da atividade tripanocida do fármaco nimesulida (3), anti-inflamatório nãoesteroidal, que possui em sua estrutura o grupamento toxicofórico nitro-aromático. A abordagem de reposicionamento de fármacos, como a que apresentamos aqui visando à possível atividade tripanocida da nimesulida (3), é um recurso importante na descoberta de fármacos aplicáveis ao tratamento de doenças negligenciadas. Outra estratégia, desenvolvida em paralelo, envolveu o emprego da hibridação molecular na preparação de dois derivados da nimesulida (3) com a amida natural piperina (5). Os resultados obtidos nas avaliações biológicas realizadas evidenciaram a atividade antiparasitária da nimesulida (3) sobre as diferentes formas evolutivas do parasito. Além disso, dos dois híbridos moleculares construídos, o híbrido H1, no qual foi preservada a porção nitro aromática, apresentou ação tripanocida, enquanto que o híbrido H2 perdeu significativamente a atividade com a retirada do grupo nitro de sua estrutura, o que permitiu apontar para o grupo nitro presente na nimesulida (3) e no híbrido H1 como porção farmacofórica para a atividade tripanocida estudada, validando as hipóteses deste estudo. Os resultados obtidos na avaliação das alterações ultra-estruturais em epimastigotas de T. cruzi tratados com nimesulida mostram a desorganização da estrutura das mitocôndrias, corroborando a possível interferência do fármaco no equilíbrio redox do parasito.CAPESChagas disease is treated only by two drugs, nifurtimox (1) and benznidazole (2). However, in addition to these drugs not being effective in all stages of infection, they have severe side effects, which justifies the search for new alternatives for the treatment of this serious disease. Literature data describe the interference of non-steroidal anti-inflammatory drugs on Trypanosoma cruzi trypomastigote infection process on mammalian cells. The mechanism of action of these drugs occurs on the isoforms of the enzyme cyclooxygenase, important for the establishment of parasite infection. Additionally, the toxic effects of nitroaromatic compounds are well known, and T. cruzi is greatly affected by the action of these molecules in its redox equilibrium. With this information, we proposed in this work the investigation of the trypanocidal activity of the nimesulide (3), non-steroidal antiinflammatory drug, which has in its structure the nitro-aromatic toxicophoric group. The drug repositioning approach, as presented here aiming at the possible trypanocidal activity of nimesulide (3), is an important resource in the discovery of drugs applicable to the treatment of neglected diseases. Another strategy, developed in parallel, involved the use of molecular hybridization in the preparation of two nimesulide derivatives (3) withing the structure of natural amide piperine. The results obtained from the biological evaluations carried out indicated antiparasitic activity of nimesulide (3) on the different evolutionary forms of the parasite. In addition, of the two molecular hybrids constructed, the hybrid H1, in which the aromatic nitro portion was preserved, presented trypanocidal action, while the hybrid H2 significantly lost activity with the removal of the nitro group from its structure. This set of results allowed us to point to the nitro portion present both in the structures of nimesulide (3) and its hybrid H1 as pharmacophoric group for the trypanocidal activity validating the hypothesis of this study. The results obtained in the evaluation of ultrastructural changes in T. cruzi epimastigotes treated with nimesulide show the disorganization of the mitochondrial structure, corroborating the possible interference of the drug on the redox equilibrium of the parasite.application/pdfporUniversidade Federal Rural do Rio de JaneiroPrograma de Pós-Graduação em QuímicaUFRRJBrasilInstituto de Ciências ExatasTrypanosoma cruziAnti-inflamatórios não-esteroidasNitro-aromáticosFármacos antiparasitáriosPiperinaHibridação molecularTrypanosoma cruziNon-steroidal antiinflanmatory drugsNitroaromaticsAntiparasitic drugsPiperineMolecular hybridizationQuímicaEstudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.Studies in the repositioning of the drug nimesulide for the treatment of Chagas disease: synthesis of derivatives, evaluation of the tripanocidal activity and investigation on the probable mechanisms of action.info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisABRAMSON, S.B. e WEISSMAN, G. 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dc.title.por.fl_str_mv Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.
dc.title.alternative.eng.fl_str_mv Studies in the repositioning of the drug nimesulide for the treatment of Chagas disease: synthesis of derivatives, evaluation of the tripanocidal activity and investigation on the probable mechanisms of action.
title Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.
spellingShingle Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.
Trindade, Joana D'Arc da Silva
Trypanosoma cruzi
Anti-inflamatórios não-esteroidas
Nitro-aromáticos
Fármacos antiparasitários
Piperina
Hibridação molecular
Trypanosoma cruzi
Non-steroidal antiinflanmatory drugs
Nitroaromatics
Antiparasitic drugs
Piperine
Molecular hybridization
Química
title_short Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.
title_full Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.
title_fullStr Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.
title_full_unstemmed Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.
title_sort Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação.
author Trindade, Joana D'Arc da Silva
author_facet Trindade, Joana D'Arc da Silva
author_role author
dc.contributor.author.fl_str_mv Trindade, Joana D'Arc da Silva
dc.contributor.advisor1.fl_str_mv Lima, Marco Edilson Freire de
dc.contributor.advisor1ID.fl_str_mv https://orcid.org/0000-0003-0563-3483
880.202.667-04
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/8392420706762318
dc.contributor.advisor-co1.fl_str_mv Lima, Debora Decote Ricardo de
dc.contributor.advisor-co1ID.fl_str_mv https://orcid.org/0000-0001-8761-7641
875.362.007-06
dc.contributor.advisor-co1Lattes.fl_str_mv http://lattes.cnpq.br/3572066508469025
dc.contributor.referee1.fl_str_mv Lima, Marco Edilson Freire de
dc.contributor.referee1ID.fl_str_mv https://orcid.org/0000-0003-0563-3483
880.202.667-04
dc.contributor.referee1Lattes.fl_str_mv http://lattes.cnpq.br/8392420706762318
dc.contributor.referee2.fl_str_mv Kratz, Jadel Müller
dc.contributor.referee2ID.fl_str_mv https://orcid.org/0000-0002-7681-8234
dc.contributor.referee2Lattes.fl_str_mv http://lattes.cnpq.br/5657186266877840
dc.contributor.referee3.fl_str_mv Almeida, Wanda Pereira
dc.contributor.referee3Lattes.fl_str_mv http://lattes.cnpq.br/3903296396671088
dc.contributor.referee4.fl_str_mv Soares, Deivid Costa
dc.contributor.referee4Lattes.fl_str_mv http://lattes.cnpq.br/7894147147292742
dc.contributor.referee5.fl_str_mv Silva, Lúcia Helena Pinto da
dc.contributor.referee5Lattes.fl_str_mv http://lattes.cnpq.br/0013386072339397
dc.contributor.authorID.fl_str_mv https://orcid.org/0000-0002-3619-0534
06.711.187-2
843.688.107-91
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/9830352129562935
contributor_str_mv Lima, Marco Edilson Freire de
Lima, Debora Decote Ricardo de
Lima, Marco Edilson Freire de
Kratz, Jadel Müller
Almeida, Wanda Pereira
Soares, Deivid Costa
Silva, Lúcia Helena Pinto da
dc.subject.por.fl_str_mv Trypanosoma cruzi
Anti-inflamatórios não-esteroidas
Nitro-aromáticos
Fármacos antiparasitários
Piperina
Hibridação molecular
topic Trypanosoma cruzi
Anti-inflamatórios não-esteroidas
Nitro-aromáticos
Fármacos antiparasitários
Piperina
Hibridação molecular
Trypanosoma cruzi
Non-steroidal antiinflanmatory drugs
Nitroaromatics
Antiparasitic drugs
Piperine
Molecular hybridization
Química
dc.subject.eng.fl_str_mv Trypanosoma cruzi
Non-steroidal antiinflanmatory drugs
Nitroaromatics
Antiparasitic drugs
Piperine
Molecular hybridization
dc.subject.cnpq.fl_str_mv Química
description O tratamento da doença de Chagas é feito apenas por dois medicamentos, o nifurtimox (1) e o benznidazol (2). Contudo, além destes fármacos não serem eficazes em todas as fases da infecção, apresentam severos efeitos colaterais, o que justifica a busca de novas alternativas para o tratamento desta grave enfermidade. Dados da literatura descrevem a interferência de fármacos anti-inflamatórios não-esteroidais no processo de infecção por tripomastigotas de Trypanosoma cruzi, sobre células de mamíferos. O mecanismo de ação destes fármacos ocorre sobre as isoformas da enzima ciclo-oxigenase, importantes para o estabelecimento da infecção do parasito. Adicionalmente, são bem conhecidos os efeitos tóxicos de compostos nitro-aromáticos, sendo o T. cruzi bastante afetado pela ação dessas moléculas em seu equilíbrio redox. De posse destas informações, propusemos neste trabalho a investigação da atividade tripanocida do fármaco nimesulida (3), anti-inflamatório nãoesteroidal, que possui em sua estrutura o grupamento toxicofórico nitro-aromático. A abordagem de reposicionamento de fármacos, como a que apresentamos aqui visando à possível atividade tripanocida da nimesulida (3), é um recurso importante na descoberta de fármacos aplicáveis ao tratamento de doenças negligenciadas. Outra estratégia, desenvolvida em paralelo, envolveu o emprego da hibridação molecular na preparação de dois derivados da nimesulida (3) com a amida natural piperina (5). Os resultados obtidos nas avaliações biológicas realizadas evidenciaram a atividade antiparasitária da nimesulida (3) sobre as diferentes formas evolutivas do parasito. Além disso, dos dois híbridos moleculares construídos, o híbrido H1, no qual foi preservada a porção nitro aromática, apresentou ação tripanocida, enquanto que o híbrido H2 perdeu significativamente a atividade com a retirada do grupo nitro de sua estrutura, o que permitiu apontar para o grupo nitro presente na nimesulida (3) e no híbrido H1 como porção farmacofórica para a atividade tripanocida estudada, validando as hipóteses deste estudo. Os resultados obtidos na avaliação das alterações ultra-estruturais em epimastigotas de T. cruzi tratados com nimesulida mostram a desorganização da estrutura das mitocôndrias, corroborando a possível interferência do fármaco no equilíbrio redox do parasito.
publishDate 2019
dc.date.issued.fl_str_mv 2019-10-17
dc.date.accessioned.fl_str_mv 2023-12-21T18:59:20Z
dc.date.available.fl_str_mv 2023-12-21T18:59:20Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
status_str publishedVersion
dc.identifier.citation.fl_str_mv TRINDADE, Joana D’Arc da Silva. Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação. 2019. 179 f. Tese. (Tese em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2019.
dc.identifier.uri.fl_str_mv https://rima.ufrrj.br/jspui/handle/20.500.14407/10238
identifier_str_mv TRINDADE, Joana D’Arc da Silva. Estudos no reposicionamento do fármaco nimesulida para o tratamento da doença de Chagas: preparação de derivados, avaliação da atividade tripanocida e investigações sobre prováveis mecanismos de ação. 2019. 179 f. Tese. (Tese em Química) - Instituto de Química, Universidade Federal Rural do Rio de Janeiro, Seropédica, 2019.
url https://rima.ufrrj.br/jspui/handle/20.500.14407/10238
dc.language.iso.fl_str_mv por
language por
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