Planejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculose
Ano de defesa: | 2022 |
---|---|
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 Medicina e Ci?ncias da Sa?de
|
Departamento: |
Escola de Medicina
|
País: |
Brasil
|
Palavras-chave em Português: | |
Palavras-chave em Inglês: | |
Área do conhecimento CNPq: | |
Link de acesso: | https://tede2.pucrs.br/tede2/handle/tede/10548 |
Resumo: | Tuberculosis is an infectious disease contracted through contact with Mycobacterium tuberculosis (Mtb), its main causal agent in humans. It is currently the one of the leading causes of death worldwide and one of the leading causes of death due to a single pathogen, ahead of HIV infection (human immunodeficiency virus). Recently, due to efforts accomplished by health system to contain the pandemic caused by the SARS-CoV-2 virus, there has been a significant decrease in case reports, decrease in adequate treatment and public investments to contain the disease. Despite existing pharmacological treatment being relatively effective, the therapeutic regimen has low adherence and considered adverse effects. In addition, the emergence of Mtb strains resistant to existing drugs has made clinical management difficult and contributed to the maintenance of mortality rates attributed to the disease. Interestingly, the 21st century has seen the approval of new drugs for the treatment of conditions caused by resistant strains of Mtb. Bedaquiline (2012), Delamanid (2014) and Pretomanid (2019) are now novel alternatives for the tuberculosis treatment. However, possible adverse events and the report of the emergence of infections resistant to these drugs demonstrate that research to obtain innovative structures for the treatment of the disease must still be a priority. In this context, the present work followed the study of the class of 2-(quinolin-4-yloxy)acetamides as a possible therapeutic alternative for the treatment of tuberculosis. The first part of the work proposed the removal of the acetamide function in order to increase the metabolic stability of the compounds and maintain the antimycobacterial activity at submicromolar range. The molecules were synthesized in 13?97% yields. The results obtained showed that molecular simplification, with the absence of the acetamide group, can, in some cases, increase metabolic stability. However, the Minimum Inhibitory Concentration (MIC) values of these structures against the Mtb H37Rv strain were reduced. The MICs of the most effective compounds in this series ranged from 0.3 ?M to 1.9 ?M. The second part of the work developed a method using ultrasound energy for the synthesis of 4-alkoxy-6-methoxy-2-methylquinolines. Such compounds come from the molecular simplification proposed in the first part of the work. The new synthetic protocol provided a simple procedure (15 min) using an open vessel system that provided the products with yields ranging from 45?84% and purities ? 95%. The fast and accessible methodology facilitated the determination of the structure-activity relationship of the series of molecules with a reduced environmental and operational cost compared to the conventional method (18 h, 25 ?C). Since the maintenance of the acetamide function linked to the quinoline ring proved to be necessary to potent activity against the bacillus, the third part of the work proposed structures containing electron-donating groups linked to this function. These groups would reduce the electrophilicity of the amide carbonyl and, concomitantly, would increase the stability of the chemical function in relation to hydrolysis reactions. The molecules were obtained in 44?88% yields. This strategy led to a structure with MIC value of 0.09 ?M against the Mtb H37Rv strain. In addition, the compound showed the ability to inhibit the bacillus intracellularly and exhibited satisfactory pharmacokinetic exposure after gavage administration to mice (F = 51%). The fourth part of the present work expanded the structure-activity relationship of the designed molecules using molecular simplification (first part). Once again, the acetamide group gave way to the ketone or alkoxy group at the 4-position of the quinoline ring. The structures were obtained in 63?95% yields after stirring the alkylating agent and the heterocycle for 18 h at 25 ?C. The MICs of these compounds against the Mtb H37Rv strain ranged from 0.8 ?M to 16 ?M. Finally, the fifth and last step synthesized quinolines containing substituents with a hydrophobic character attached to the piperidine substituent in order to increase the interaction with the possible molecular target (bC1 complex). Furthermore, the presence of benzene rings substituted in this position allowed us to evaluate the bioisosterism between the quinoline ring and the imidazo[1,2-a]pyridine ring present in the clinical candidate Telacebec. The structures were obtained in 36-96% yields and were able to inhibit the bacillus with MIC values as low as 0.02 ?M. These compounds were the most effective so far obtained by the research group and comprise a select group of molecules with MIC in the nanomolar range. Therefore, the data denote that the class of quinoline compounds may provide drug candidates for the tuberculosis treatment. The results of bacillus inhibition, action against strains resistant to available drugs, selectivity, chemical and metabolic stability, solubility and permeability are promising. Thus, new results are expected to confirm that these molecules or their congeners can effectively contribute as a new alternative for the treatment of this disease. |
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Basso, Luiz Augustohttp://lattes.cnpq.br/3431777523511296http://lattes.cnpq.br/1066691081798646Borsoi, Ana Fl?via2022-11-11T19:36:05Z2022-08-25https://tede2.pucrs.br/tede2/handle/tede/10548Tuberculosis is an infectious disease contracted through contact with Mycobacterium tuberculosis (Mtb), its main causal agent in humans. It is currently the one of the leading causes of death worldwide and one of the leading causes of death due to a single pathogen, ahead of HIV infection (human immunodeficiency virus). Recently, due to efforts accomplished by health system to contain the pandemic caused by the SARS-CoV-2 virus, there has been a significant decrease in case reports, decrease in adequate treatment and public investments to contain the disease. Despite existing pharmacological treatment being relatively effective, the therapeutic regimen has low adherence and considered adverse effects. In addition, the emergence of Mtb strains resistant to existing drugs has made clinical management difficult and contributed to the maintenance of mortality rates attributed to the disease. Interestingly, the 21st century has seen the approval of new drugs for the treatment of conditions caused by resistant strains of Mtb. Bedaquiline (2012), Delamanid (2014) and Pretomanid (2019) are now novel alternatives for the tuberculosis treatment. However, possible adverse events and the report of the emergence of infections resistant to these drugs demonstrate that research to obtain innovative structures for the treatment of the disease must still be a priority. In this context, the present work followed the study of the class of 2-(quinolin-4-yloxy)acetamides as a possible therapeutic alternative for the treatment of tuberculosis. The first part of the work proposed the removal of the acetamide function in order to increase the metabolic stability of the compounds and maintain the antimycobacterial activity at submicromolar range. The molecules were synthesized in 13?97% yields. The results obtained showed that molecular simplification, with the absence of the acetamide group, can, in some cases, increase metabolic stability. However, the Minimum Inhibitory Concentration (MIC) values of these structures against the Mtb H37Rv strain were reduced. The MICs of the most effective compounds in this series ranged from 0.3 ?M to 1.9 ?M. The second part of the work developed a method using ultrasound energy for the synthesis of 4-alkoxy-6-methoxy-2-methylquinolines. Such compounds come from the molecular simplification proposed in the first part of the work. The new synthetic protocol provided a simple procedure (15 min) using an open vessel system that provided the products with yields ranging from 45?84% and purities ? 95%. The fast and accessible methodology facilitated the determination of the structure-activity relationship of the series of molecules with a reduced environmental and operational cost compared to the conventional method (18 h, 25 ?C). Since the maintenance of the acetamide function linked to the quinoline ring proved to be necessary to potent activity against the bacillus, the third part of the work proposed structures containing electron-donating groups linked to this function. These groups would reduce the electrophilicity of the amide carbonyl and, concomitantly, would increase the stability of the chemical function in relation to hydrolysis reactions. The molecules were obtained in 44?88% yields. This strategy led to a structure with MIC value of 0.09 ?M against the Mtb H37Rv strain. In addition, the compound showed the ability to inhibit the bacillus intracellularly and exhibited satisfactory pharmacokinetic exposure after gavage administration to mice (F = 51%). The fourth part of the present work expanded the structure-activity relationship of the designed molecules using molecular simplification (first part). Once again, the acetamide group gave way to the ketone or alkoxy group at the 4-position of the quinoline ring. The structures were obtained in 63?95% yields after stirring the alkylating agent and the heterocycle for 18 h at 25 ?C. The MICs of these compounds against the Mtb H37Rv strain ranged from 0.8 ?M to 16 ?M. Finally, the fifth and last step synthesized quinolines containing substituents with a hydrophobic character attached to the piperidine substituent in order to increase the interaction with the possible molecular target (bC1 complex). Furthermore, the presence of benzene rings substituted in this position allowed us to evaluate the bioisosterism between the quinoline ring and the imidazo[1,2-a]pyridine ring present in the clinical candidate Telacebec. The structures were obtained in 36-96% yields and were able to inhibit the bacillus with MIC values as low as 0.02 ?M. These compounds were the most effective so far obtained by the research group and comprise a select group of molecules with MIC in the nanomolar range. Therefore, the data denote that the class of quinoline compounds may provide drug candidates for the tuberculosis treatment. The results of bacillus inhibition, action against strains resistant to available drugs, selectivity, chemical and metabolic stability, solubility and permeability are promising. Thus, new results are expected to confirm that these molecules or their congeners can effectively contribute as a new alternative for the treatment of this disease.A tuberculose ? uma doen?a infectocontagiosa contra?da atrav?s do contato com o Mycobacterium tuberculosis (Mtb), seu principal agente causal em humanos. Atualmente, est? entre as principais de morte em todo o mundo e ? descrita como umas das principais causas de morte devido a um ?nico pat?geno, ficando ? frente da infec??o pelo HIV (v?rus da imunodefici?ncia humana). Recentemente, em virtude dos esfor?os do sistema de sa?de para conter a pandemia ocasionada pelo v?rus SARS-CoV-2, houve uma significante diminui??o nas notifica??es de casos, no tratamento adequado e nos investimentos p?blicos para conten??o da doen?a. Apesar do tratamento farmacol?gico existente ser relativamente efetivo, o regime terap?utico possui baixa ades?o e efeitos adversos considerados. Al?m disso, o surgimento de cepas de Mtb resistente aos f?rmacos existentes tem dificultado o manejo cl?nico e colaborado para manuten??o das taxas de mortalidade atribu?das ? doen?a. Interessantemente, o s?culo XXI tem presenciado a aprova??o de novos f?rmacos para o tratamento de quadros ocasionados por cepas resistentes de Mtb. Bedaquilina (2012), Delamanid (2014) e Pretomanid (2019) s?o agora novas alternativas para o tratamento da tuberculose. Entretanto, poss?veis eventos adversos e o relato do surgimento de infec??es resistentes a esses f?rmacos demonstram que as pesquisas para obten??o de estruturas inovadoras para o tratamento da doen?a devem ser ainda uma prioridade. Nesse contexto, o presente trabalho seguiu o estudo da classe das 2-(quinolin-4-iloxi)acetamidas como uma poss?vel alternativa terap?utica para o tratamento da tuberculose. A primeira parte do trabalho prop?s a retirada da fun??o acetamida no intuito de aumentar a estabilidade metab?lica dos compostos e manter a atividade antimicobacteriana em valores de submicromolares. As mol?culas foram sintetizadas em rendimentos que variaram entre 13?97%. Os resultados obtidos demonstraram que a simplifica??o molecular, com a aus?ncia do grupo acetamida, pode, em alguns casos, aumentar a estabilidade metab?lica. Entretanto, os valores da Concentra??o Inibit?ria M?nima (MIC) dessas estruturas contra a cepa H37Rv de Mtb foram aumentados. Os MICs dos compostos mais efetivos dessa s?rie variaram entre 0,3 ?M e 1,9 ?M, resultados acima dos apresentados por compostos contendo a fun??o amida. A segunda parte do trabalho desenvolveu um m?todo utilizando a energia proveniente do ultrassom para a s?ntese das 4-alcoxi-6-metoxi-2-metilquinolinas. Tais compostos s?o oriundos da simplifica??o molecular proposta na primeira parte do trabalho. O novo protocolo sint?tico forneceu um procedimento simples (15 min) utilizando um sistema aberto que forneceu os produtos com rendimentos variando entre 45?84% e purezas ? 95%. A metodologia r?pida e acess?vel facilitou a determina??o da rela??o estrutura-atividade da s?rie de mol?culas com um custo ambiental e operacional reduzido em compara??o ao m?todo convencional (18 h, 25 ?C). Uma vez que a manuten??o da fun??o acetamida ligada ao anel quinol?nico demonstrou ser necess?ria para que essa classe qu?mica apresentasse atividade potente contra o bacilo, a terceira parte do trabalho prop?s estruturas contendo grupos doadores de el?trons ligados nessa fun??o. Esses grupos reduziriam a eletrofilicidade da carbonila am?dica e, concomitantemente, poderiam aumentar a estabilidade da fun??o qu?mica em rela??o a rea??es de hidr?lise. As mol?culas foram obtidas em rendimentos de 44?88%. Essa estrat?gia conduziu a uma estrutura com MIC de 0,09 ?M contra a cepa H37Rv de Mtb. Al?m disso, o composto apresentou capacidade de inibir o bacilo intracelularmente e exibiu exposi??o farmacocin?tica satisfat?ria ap?s administra??o por gavagem em camundongos (F = 51%). A quarta parte do presente trabalho expandiu a rela??o estrutura-atividade das mol?culas planejadas utilizando a simplifica??o molecular (primeira parte). Uma vez mais, o grupo acetamida deu lugar ao grupo cetona ou alcoxi na posi??o 4 do anel quinol?nico. As estruturas foram obtidas em rendimentos que variaram entre 63?95% ap?s agita??o do agente alquilante e do heterociclo por 18 h em temperatura de 25 ?C. Os MICs desses compostos contra a cepa H37Rv de Mtb variaram entre 0,8 ?M e 16 ?M. Finalmente, a quinta e ?ltima etapa sintetizou quinolinas contendo substituintes com car?ter hidrof?bico ligado no substituinte piperid?nico com intuito de aventar um aumento da intera??o com o poss?vel alvo molecular (complexo bC1). Al?m disso, a presen?a de an?is benz?nicos substitu?dos nessa posi??o permitiu avaliar o bioisosterismo existente entre o anel quinol?nico e o anel imidazo[1,2-a]piridina presente no candidato cl?nico Telacebec. As estruturas foram obtidas em rendimentos que variaram entre 36-96% e foram capazes de inibir o bacilo com valores de MIC t?o baixos quanto 0,02 ?M. Esses compostos foram os mais efetivos at? ent?o obtidos pelo grupo de pesquisa e comp?em um seleto grupo de mol?culas com MIC na faixa nanomolar. Por conseguinte, os dados denotam que a classe de compostos quinol?nicos pode fornecer candidatos a f?rmacos para o tratamento da tuberculose. Os resultados de inibi??o do bacilo, de a??o contra cepas resistentes aos f?rmacos dispon?veis, seletividade, estabilidade qu?mica e metab?lica, solubilidade e permeabilidade s?o promissores. Assim, s?o esperados que novos resultados confirmem que essas mol?culas ou suas cong?neres apresentam condi??es de contribuir efetivamente como uma alternativa nova para o tratamento dessa doen?a.Submitted by PPG Medicina e Ci?ncias da Sa?de (medicina-pg@pucrs.br) on 2022-11-10T12:06:21Z No. of bitstreams: 1 TESE_ANAFLAVIA.pdf: 16302803 bytes, checksum: 2247e353245a0cbbe476a99c865e0f0b (MD5)Approved for entry into archive by Sheila Dias (sheila.dias@pucrs.br) on 2022-11-11T19:23:21Z (GMT) No. of bitstreams: 1 TESE_ANAFLAVIA.pdf: 16302803 bytes, checksum: 2247e353245a0cbbe476a99c865e0f0b (MD5)Made available in DSpace on 2022-11-11T19:36:05Z (GMT). No. of bitstreams: 1 TESE_ANAFLAVIA.pdf: 16302803 bytes, checksum: 2247e353245a0cbbe476a99c865e0f0b (MD5) Previous issue date: 2022-08-25Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPESapplication/pdfhttps://tede2.pucrs.br/tede2/retrieve/185940/TES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdf.jpgporPontif?cia Universidade Cat?lica do Rio Grande do SulPrograma de P?s-Gradua??o em Medicina e Ci?ncias da Sa?dePUCRSBrasilEscola de MedicinaMycobacterium TuberculosisCepas MultirresistentesQu?mica MedicinalRela??o Estrutura-AtividadeMycobacterium TuberculosisMultidrug-Resistant StrainsMedicinal ChemistryStructure-Activity RelationshipCIENCIAS DA SAUDE::MEDICINAPlanejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculoseinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisTrabalho ser? publicado como artigo ou livro60 meses11/11/2027-721401722658532398500500500600-224747486637135387-9693694523087866273590462550136975366info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da PUC_RSinstname:Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)instacron:PUC_RSTHUMBNAILTES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdf.jpgTES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdf.jpgimage/jpeg4121https://tede2.pucrs.br/tede2/bitstream/tede/10548/4/TES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdf.jpgf616069d4dee1d5d7eec87d0add1c756MD54TEXTTES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdf.txtTES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdf.txttext/plain1751https://tede2.pucrs.br/tede2/bitstream/tede/10548/3/TES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdf.txt784c61bc082eb0083de9416bbbb59a80MD53ORIGINALTES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdfTES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdfapplication/pdf278896https://tede2.pucrs.br/tede2/bitstream/tede/10548/2/TES_ANA_FLAVIA_BORSOI_CONFIDENCIAL.pdff7c465c8e6d07d88b84fd0429d5d154fMD52LICENSElicense.txtlicense.txttext/plain; charset=utf-8590https://tede2.pucrs.br/tede2/bitstream/tede/10548/1/license.txt220e11f2d3ba5354f917c7035aadef24MD51tede/105482022-11-12 20:00:13.933oai: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:2022-11-12T22:00:13Biblioteca Digital de Teses e Dissertações da PUC_RS - Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS)false |
dc.title.por.fl_str_mv |
Planejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculose |
title |
Planejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculose |
spellingShingle |
Planejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculose Borsoi, Ana Fl?via Mycobacterium Tuberculosis Cepas Multirresistentes Qu?mica Medicinal Rela??o Estrutura-Atividade Mycobacterium Tuberculosis Multidrug-Resistant Strains Medicinal Chemistry Structure-Activity Relationship CIENCIAS DA SAUDE::MEDICINA |
title_short |
Planejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculose |
title_full |
Planejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculose |
title_fullStr |
Planejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculose |
title_full_unstemmed |
Planejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculose |
title_sort |
Planejamento, s?ntese e avalia??o de compostos quinol?nicos como candidatos a f?rmacos para o tratamento da tuberculose |
author |
Borsoi, Ana Fl?via |
author_facet |
Borsoi, Ana Fl?via |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Basso, Luiz Augusto |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/3431777523511296 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1066691081798646 |
dc.contributor.author.fl_str_mv |
Borsoi, Ana Fl?via |
contributor_str_mv |
Basso, Luiz Augusto |
dc.subject.por.fl_str_mv |
Mycobacterium Tuberculosis Cepas Multirresistentes Qu?mica Medicinal Rela??o Estrutura-Atividade |
topic |
Mycobacterium Tuberculosis Cepas Multirresistentes Qu?mica Medicinal Rela??o Estrutura-Atividade Mycobacterium Tuberculosis Multidrug-Resistant Strains Medicinal Chemistry Structure-Activity Relationship CIENCIAS DA SAUDE::MEDICINA |
dc.subject.eng.fl_str_mv |
Mycobacterium Tuberculosis Multidrug-Resistant Strains Medicinal Chemistry Structure-Activity Relationship |
dc.subject.cnpq.fl_str_mv |
CIENCIAS DA SAUDE::MEDICINA |
description |
Tuberculosis is an infectious disease contracted through contact with Mycobacterium tuberculosis (Mtb), its main causal agent in humans. It is currently the one of the leading causes of death worldwide and one of the leading causes of death due to a single pathogen, ahead of HIV infection (human immunodeficiency virus). Recently, due to efforts accomplished by health system to contain the pandemic caused by the SARS-CoV-2 virus, there has been a significant decrease in case reports, decrease in adequate treatment and public investments to contain the disease. Despite existing pharmacological treatment being relatively effective, the therapeutic regimen has low adherence and considered adverse effects. In addition, the emergence of Mtb strains resistant to existing drugs has made clinical management difficult and contributed to the maintenance of mortality rates attributed to the disease. Interestingly, the 21st century has seen the approval of new drugs for the treatment of conditions caused by resistant strains of Mtb. Bedaquiline (2012), Delamanid (2014) and Pretomanid (2019) are now novel alternatives for the tuberculosis treatment. However, possible adverse events and the report of the emergence of infections resistant to these drugs demonstrate that research to obtain innovative structures for the treatment of the disease must still be a priority. In this context, the present work followed the study of the class of 2-(quinolin-4-yloxy)acetamides as a possible therapeutic alternative for the treatment of tuberculosis. The first part of the work proposed the removal of the acetamide function in order to increase the metabolic stability of the compounds and maintain the antimycobacterial activity at submicromolar range. The molecules were synthesized in 13?97% yields. The results obtained showed that molecular simplification, with the absence of the acetamide group, can, in some cases, increase metabolic stability. However, the Minimum Inhibitory Concentration (MIC) values of these structures against the Mtb H37Rv strain were reduced. The MICs of the most effective compounds in this series ranged from 0.3 ?M to 1.9 ?M. The second part of the work developed a method using ultrasound energy for the synthesis of 4-alkoxy-6-methoxy-2-methylquinolines. Such compounds come from the molecular simplification proposed in the first part of the work. The new synthetic protocol provided a simple procedure (15 min) using an open vessel system that provided the products with yields ranging from 45?84% and purities ? 95%. The fast and accessible methodology facilitated the determination of the structure-activity relationship of the series of molecules with a reduced environmental and operational cost compared to the conventional method (18 h, 25 ?C). Since the maintenance of the acetamide function linked to the quinoline ring proved to be necessary to potent activity against the bacillus, the third part of the work proposed structures containing electron-donating groups linked to this function. These groups would reduce the electrophilicity of the amide carbonyl and, concomitantly, would increase the stability of the chemical function in relation to hydrolysis reactions. The molecules were obtained in 44?88% yields. This strategy led to a structure with MIC value of 0.09 ?M against the Mtb H37Rv strain. In addition, the compound showed the ability to inhibit the bacillus intracellularly and exhibited satisfactory pharmacokinetic exposure after gavage administration to mice (F = 51%). The fourth part of the present work expanded the structure-activity relationship of the designed molecules using molecular simplification (first part). Once again, the acetamide group gave way to the ketone or alkoxy group at the 4-position of the quinoline ring. The structures were obtained in 63?95% yields after stirring the alkylating agent and the heterocycle for 18 h at 25 ?C. The MICs of these compounds against the Mtb H37Rv strain ranged from 0.8 ?M to 16 ?M. Finally, the fifth and last step synthesized quinolines containing substituents with a hydrophobic character attached to the piperidine substituent in order to increase the interaction with the possible molecular target (bC1 complex). Furthermore, the presence of benzene rings substituted in this position allowed us to evaluate the bioisosterism between the quinoline ring and the imidazo[1,2-a]pyridine ring present in the clinical candidate Telacebec. The structures were obtained in 36-96% yields and were able to inhibit the bacillus with MIC values as low as 0.02 ?M. These compounds were the most effective so far obtained by the research group and comprise a select group of molecules with MIC in the nanomolar range. Therefore, the data denote that the class of quinoline compounds may provide drug candidates for the tuberculosis treatment. The results of bacillus inhibition, action against strains resistant to available drugs, selectivity, chemical and metabolic stability, solubility and permeability are promising. Thus, new results are expected to confirm that these molecules or their congeners can effectively contribute as a new alternative for the treatment of this disease. |
publishDate |
2022 |
dc.date.accessioned.fl_str_mv |
2022-11-11T19:36:05Z |
dc.date.issued.fl_str_mv |
2022-08-25 |
dc.type.status.fl_str_mv |
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doctoralThesis |
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por |
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Pontif?cia Universidade Cat?lica do Rio Grande do Sul |
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Programa de P?s-Gradua??o em Medicina e Ci?ncias da Sa?de |
dc.publisher.initials.fl_str_mv |
PUCRS |
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Brasil |
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Escola de Medicina |
publisher.none.fl_str_mv |
Pontif?cia Universidade Cat?lica do Rio Grande do Sul |
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PUC_RS |
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