S?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculose
Ano de defesa: | 2021 |
---|---|
Autor(a) principal: | |
Orientador(a): | |
Banca de defesa: | |
Tipo de documento: | Tese |
Tipo de acesso: | Acesso aberto |
Idioma: | por |
Instituição de defesa: |
Pontif?cia Universidade Cat?lica do Rio Grande do Sul
|
Programa de Pós-Graduação: |
Programa de P?s-Gradua??o em Biologia Celular e Molecular
|
Departamento: |
Escola de Ci?ncias
|
País: |
Brasil
|
Palavras-chave em Português: | |
Área do conhecimento CNPq: | |
Link de acesso: | http://tede2.pucrs.br/tede2/handle/tede/9924 |
Resumo: | Pulmonary tuberculosis occurs through airborne transmission and shows diversity in clinical manifestations. The extent of the infection depends on the host's immune response, culminate in cure, progression to the latent or active form of the disease. In 2019, it was estimated at 10 million (8.9 - 11.0 million) the number of new tuberculosis (TB) cases in the world. In Brazil, about 4,500 deaths from the disease were reported. In 1993, WHO established tuberculosis as a public health emergency and a therapeutic strategy of Directly Observed Treatment Short-course (DOTS) was fundamental to progress in combating the disease. Although the total number of deaths has decreased, tuberculosis has prolonged as one of the ten leading causes of death in the world, mainly aggravated by co-infection with HIV, the growing number of cases of resistant strains and, recently, by the COVID-19 pandemic. Despite the existence of a vaccine, such as BCG, pharmacotherapy is the most effective way of tuberculosis treatment. To achieve control of this TB epidemic, there is an urgent need for new anti-TB drugs and among the desired characteristics for these structures are low cost and easy administration, to ensure wide accessibility and adherence to treatment. Within this scenario, heterocycle chemistry is one of the most valuable sources of new compounds with diverse pharmacological activity, mainly because of the unique ability of constituted compounds to mimic the structure of peptides and reversibly bind to proteins. Almost limitless combinations of fused heterocyclic structures can be designed, updated into molecules with diverse physical-bonded, steric and electronic properties. Among the structures, the indole ring is one of the most studied compounds as a component of biologically active products. Due to its wide range of pharmacological activities, it is a privileged structure in medicinal chemistry. In this work, 3-aryl-1H-indoles were synthesized and their antimycobacterial activity determined. The compounds demonstrated activity against M. tuberculosis H37Rv strain and, the hit compounds, demonstrated activity against clinical MDR isolates. One of the hit compounds did not significantly affect the viability of the cell lines tested and did not produce DNA damage. To assess the dynamics of antimycobacterial activity, was performed a time-kill curve of compound 3r, combined with mathematical modeling to predict its pharmacodynamic characteristics. The minimum bactericidal concentration obtained was 2X MIC and the demonstrated kill kinetics were time-dependent, with characteristics similar to rifampicin. The results obtained in this work suggest that this class of molecules is promising and may lead to new anti-TB drug candidates. |
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Machado, Pablohttp://lattes.cnpq.br/3319303431365448http://lattes.cnpq.br/1313252756923111Etchart, Renata Jardim2021-10-22T20:22:16Z2021-08-26http://tede2.pucrs.br/tede2/handle/tede/9924Pulmonary tuberculosis occurs through airborne transmission and shows diversity in clinical manifestations. The extent of the infection depends on the host's immune response, culminate in cure, progression to the latent or active form of the disease. In 2019, it was estimated at 10 million (8.9 - 11.0 million) the number of new tuberculosis (TB) cases in the world. In Brazil, about 4,500 deaths from the disease were reported. In 1993, WHO established tuberculosis as a public health emergency and a therapeutic strategy of Directly Observed Treatment Short-course (DOTS) was fundamental to progress in combating the disease. Although the total number of deaths has decreased, tuberculosis has prolonged as one of the ten leading causes of death in the world, mainly aggravated by co-infection with HIV, the growing number of cases of resistant strains and, recently, by the COVID-19 pandemic. Despite the existence of a vaccine, such as BCG, pharmacotherapy is the most effective way of tuberculosis treatment. To achieve control of this TB epidemic, there is an urgent need for new anti-TB drugs and among the desired characteristics for these structures are low cost and easy administration, to ensure wide accessibility and adherence to treatment. Within this scenario, heterocycle chemistry is one of the most valuable sources of new compounds with diverse pharmacological activity, mainly because of the unique ability of constituted compounds to mimic the structure of peptides and reversibly bind to proteins. Almost limitless combinations of fused heterocyclic structures can be designed, updated into molecules with diverse physical-bonded, steric and electronic properties. Among the structures, the indole ring is one of the most studied compounds as a component of biologically active products. Due to its wide range of pharmacological activities, it is a privileged structure in medicinal chemistry. In this work, 3-aryl-1H-indoles were synthesized and their antimycobacterial activity determined. The compounds demonstrated activity against M. tuberculosis H37Rv strain and, the hit compounds, demonstrated activity against clinical MDR isolates. One of the hit compounds did not significantly affect the viability of the cell lines tested and did not produce DNA damage. To assess the dynamics of antimycobacterial activity, was performed a time-kill curve of compound 3r, combined with mathematical modeling to predict its pharmacodynamic characteristics. The minimum bactericidal concentration obtained was 2X MIC and the demonstrated kill kinetics were time-dependent, with characteristics similar to rifampicin. The results obtained in this work suggest that this class of molecules is promising and may lead to new anti-TB drug candidates.A tuberculose pulmonar ocorre por meio da transmiss?o a?rea e apresenta diversidade nas manifesta??es cl?nicas. A extens?o da infec??o depende da resposta imune do hospedeiro, resultando na cura, progress?o para forma latente ou ativa da doen?a. Em 2019, foi estimado em 10 milh?es (8,9 ? 11,0 milh?es) o n?mero de novos casos de tuberculose (TB) no mundo. No Brasil, foram notificados cerca de 4,5 mil ?bitos pela doen?a. Em 1993, a OMS declarou a tuberculose como uma emerg?ncia de sa?de p?blica e a estrat?gia terap?utica do Tratamento Diretamente Supervisionado de Curta Dura??o (DOTS) foi fundamental para o progresso no combate da doen?a. Apesar do n?mero total de mortes ter diminu?do, a TB permanece como uma das dez causas principais de morte no mundo, principalmente agravada pela coinfec??o com HIV, crescente n?mero de casos de cepas resistentes e, recentemente, pela pandemia da COVID-19. Apesar da exist?ncia de vacina, como a BCG, a farmacoterapia ? a forma mais efetiva de tratamento da tuberculose. Para alcan?ar o controle desta epidemia de TB, h? a necessidade urgente de novos f?rmacos anti-TB e dentre as caracter?sticas desejadas para essas estruturas est?o baixo custo e f?cil administra??o, para garantir ampla acessibilidade e ades?o ao tratamento. Diante deste cen?rio, a qu?mica de heterociclos ? uma das fontes mais valiosas de compostos novos com atividade farmacol?gica diversa, principalmente por causa da capacidade ?nica dos compostos resultantes de mimetizar a estrutura dos pept?deos e se ligar reversivelmente ?s prote?nas. Combina??es quase ilimitadas de estruturas heteroc?clicas fundidas podem ser projetadas, resultando em mol?culas com propriedades f?sicoqu?micas, est?ricas e eletr?nicas diversas. Dentre as estruturas, o anel ind?lico ? um dos compostos mais estudado como componente de produtos biologicamente ativos. Por sua ampla gama de atividades farmacol?gicas, ? uma estrutura privilegiada em qu?mica medicinal. Neste trabalho foram sintetizados compostos da classe 3-aril-1H-ind?is que tiveram sua atividade antimicobacteriana avaliada. Os compostos demonstraram atividade contra cepa laboratorial H37Rv e as mol?culas mais efetivas contra essa cepa (hits) demonstraram tamb?m atividade contra isolados cl?nicos resistentes a f?rmacos. Um desses hits n?o afetou de maneira significativa a viabilidade das linhagens celulares testadas e n?o produziu danos ao significativos ao DNA de c?lulas HepG2. Para avaliar a din?mica da atividade antimicobacteriana, foi realizada a curva de morte celular do composto 3r, aliado a uma modelagem matem?tica para predizer suas caracter?sticas farmacodin?micas. A concentra??o bactericida m?nima obtida foi de 2X MIC e a cin?tica de morte demonstrada foi dependente do tempo, com caracter?sticas semelhantes ? rifampicina. Os resultados obtidos neste trabalho sugerem que esta classe qu?mica ? promissora e pode originar candidatos a novos f?rmacos anti-TB.Submitted by PPG Biologia Celular e Molecular (bcm@pucrs.br) on 2021-10-21T20:07:39Z No. of bitstreams: 1 RENATA JARDIM ETCHART_TES.pdf: 15156720 bytes, checksum: b868751400fd4333ac7b3cfaa38abfa9 (MD5)Approved for entry into archive by Sarajane Pan (sarajane.pan@pucrs.br) on 2021-10-22T20:15:52Z (GMT) No. of bitstreams: 1 RENATA JARDIM ETCHART_TES.pdf: 15156720 bytes, checksum: b868751400fd4333ac7b3cfaa38abfa9 (MD5)Made available in DSpace on 2021-10-22T20:22:16Z (GMT). No. of bitstreams: 1 RENATA JARDIM ETCHART_TES.pdf: 15156720 bytes, checksum: b868751400fd4333ac7b3cfaa38abfa9 (MD5) Previous issue date: 2021-08-26Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPESapplication/pdfhttp://tede2.pucrs.br:80/tede2/retrieve/182358/RENATA%20JARDIM%20ETCHART_TES.pdf.jpgporPontif?cia Universidade Cat?lica do Rio Grande do SulPrograma de P?s-Gradua??o em Biologia Celular e MolecularPUCRSBrasilEscola de Ci?nciasTuberculoseMycobacterium TuberculosisDesenvolvimento de F?rmacos3-aril-1-H-ind?isCIENCIAS BIOLOGICAS::BIOLOGIA GERALS?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculoseinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisTrabalho n?o apresenta restri??o para publica??o3463594373552466096500500600-16345593859312446973590462550136975366info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da PUC_RSinstname:Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)instacron:PUC_RSTHUMBNAILRENATA JARDIM ETCHART_TES.pdf.jpgRENATA JARDIM ETCHART_TES.pdf.jpgimage/jpeg5940http://tede2.pucrs.br/tede2/bitstream/tede/9924/4/RENATA+JARDIM+ETCHART_TES.pdf.jpgea00a95f6b2cd9f07394acb06338883cMD54TEXTRENATA JARDIM ETCHART_TES.pdf.txtRENATA JARDIM ETCHART_TES.pdf.txttext/plain62325http://tede2.pucrs.br/tede2/bitstream/tede/9924/3/RENATA+JARDIM+ETCHART_TES.pdf.txt46637aae50f1c97763e3a75809607e70MD53ORIGINALRENATA JARDIM ETCHART_TES.pdfRENATA JARDIM ETCHART_TES.pdfapplication/pdf15156720http://tede2.pucrs.br/tede2/bitstream/tede/9924/2/RENATA+JARDIM+ETCHART_TES.pdfb868751400fd4333ac7b3cfaa38abfa9MD52LICENSElicense.txtlicense.txttext/plain; charset=utf-8590http://tede2.pucrs.br/tede2/bitstream/tede/9924/1/license.txt220e11f2d3ba5354f917c7035aadef24MD51tede/99242021-10-22 21:00:22.962oai:tede2.pucrs.br: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Biblioteca Digital de Teses e Dissertaçõeshttp://tede2.pucrs.br/tede2/PRIhttps://tede2.pucrs.br/oai/requestbiblioteca.central@pucrs.br||opendoar:2021-10-22T23:00:22Biblioteca Digital de Teses e Dissertações da PUC_RS - Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)false |
dc.title.por.fl_str_mv |
S?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculose |
title |
S?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculose |
spellingShingle |
S?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculose Etchart, Renata Jardim Tuberculose Mycobacterium Tuberculosis Desenvolvimento de F?rmacos 3-aril-1-H-ind?is CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
title_short |
S?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculose |
title_full |
S?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculose |
title_fullStr |
S?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculose |
title_full_unstemmed |
S?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculose |
title_sort |
S?ntese e avalia??o da atividade antimicobacteriana de 3-Aril-1-H-ind?is : prot?tipos para o desenvolvimento de candidatos ? f?rmacos para o tratamento da tuberculose |
author |
Etchart, Renata Jardim |
author_facet |
Etchart, Renata Jardim |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Machado, Pablo |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/3319303431365448 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1313252756923111 |
dc.contributor.author.fl_str_mv |
Etchart, Renata Jardim |
contributor_str_mv |
Machado, Pablo |
dc.subject.por.fl_str_mv |
Tuberculose Mycobacterium Tuberculosis Desenvolvimento de F?rmacos 3-aril-1-H-ind?is |
topic |
Tuberculose Mycobacterium Tuberculosis Desenvolvimento de F?rmacos 3-aril-1-H-ind?is CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
dc.subject.cnpq.fl_str_mv |
CIENCIAS BIOLOGICAS::BIOLOGIA GERAL |
description |
Pulmonary tuberculosis occurs through airborne transmission and shows diversity in clinical manifestations. The extent of the infection depends on the host's immune response, culminate in cure, progression to the latent or active form of the disease. In 2019, it was estimated at 10 million (8.9 - 11.0 million) the number of new tuberculosis (TB) cases in the world. In Brazil, about 4,500 deaths from the disease were reported. In 1993, WHO established tuberculosis as a public health emergency and a therapeutic strategy of Directly Observed Treatment Short-course (DOTS) was fundamental to progress in combating the disease. Although the total number of deaths has decreased, tuberculosis has prolonged as one of the ten leading causes of death in the world, mainly aggravated by co-infection with HIV, the growing number of cases of resistant strains and, recently, by the COVID-19 pandemic. Despite the existence of a vaccine, such as BCG, pharmacotherapy is the most effective way of tuberculosis treatment. To achieve control of this TB epidemic, there is an urgent need for new anti-TB drugs and among the desired characteristics for these structures are low cost and easy administration, to ensure wide accessibility and adherence to treatment. Within this scenario, heterocycle chemistry is one of the most valuable sources of new compounds with diverse pharmacological activity, mainly because of the unique ability of constituted compounds to mimic the structure of peptides and reversibly bind to proteins. Almost limitless combinations of fused heterocyclic structures can be designed, updated into molecules with diverse physical-bonded, steric and electronic properties. Among the structures, the indole ring is one of the most studied compounds as a component of biologically active products. Due to its wide range of pharmacological activities, it is a privileged structure in medicinal chemistry. In this work, 3-aryl-1H-indoles were synthesized and their antimycobacterial activity determined. The compounds demonstrated activity against M. tuberculosis H37Rv strain and, the hit compounds, demonstrated activity against clinical MDR isolates. One of the hit compounds did not significantly affect the viability of the cell lines tested and did not produce DNA damage. To assess the dynamics of antimycobacterial activity, was performed a time-kill curve of compound 3r, combined with mathematical modeling to predict its pharmacodynamic characteristics. The minimum bactericidal concentration obtained was 2X MIC and the demonstrated kill kinetics were time-dependent, with characteristics similar to rifampicin. The results obtained in this work suggest that this class of molecules is promising and may lead to new anti-TB drug candidates. |
publishDate |
2021 |
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2021-10-22T20:22:16Z |
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2021-08-26 |
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