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Previous issue date: 2016-03-31 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / Tuberculosis (TB) is an infectious disease caused mainly by Mycobacterium tuberculosis and is one of the most devastating public health problems worldwide. Furthermore, MDR-TB and XDR-TB treatments are limited and recommended medicines are often not available revealing an urgent need for new anti-TB alternatives. In the present study, a series of 2-(quinolin-4-yloxy)acetamides were synthesized for further evaluation of minimum inhibitory concentration (MIC) against Mycobacterium tuberculosis (Mtb) strains. Moreover, a preliminary structure-activity relationship (SAR) study was also performed. The synthesized compounds were evaluated in a whole-cell assay against M. tuberculosis H37Rv and drug-resistant clinical isolate. The most active molecules against M. tuberculosis H37Rv (MIC <1?M) were selected for cytotoxicity study in Vero cells. The results showed that the molecular volume and hydrophobicity at the N-arylamide portion, the effect hydrogen bond donor on the acetamide moiety and an H-bond acceptor at 4-position of the quinoline ring represent three pharmacophoric groups important for antimycobacterial action. Further, the synthesized compounds 6a, 6h, 12d-f, and 12i-n were active against drug-resistant strains (MICs ? 0,001?M) with devoid of apparent cytotoxicity to Vero (IC50s ? 20 ?M). Therefore, these data indicate that this class of compounds may furnish candidates for future development, and to provide drug alternatives for tuberculosis treatment / A tuberculose (TB) ? uma doen?a infecciosa causada principalmente por Mycobacterium tuberculosis e ? um dos problemas de sa?de p?blica mais devastadores no mundo. Al?m disso, tratamentos de XDR-TB e MDR-TB s?o limitados e os medicamentos recomendados frequentemente n?o est?o dispon?veis, ressaltando uma necessidade urgente de novas alternativas anti-TB. No presente estudo, uma s?rie de 2-(quinolin-4-iloxi)acetamidas foi sintetizada para posterior avalia??o da concentra??o inibit?ria m?nima (MIC) frente a cepas de Mycobacterium tuberculosis (Mtb). Al?m disso, um estudo preliminar da rela??o estrutura-atividade (SAR) tamb?m foi realizado. Os compostos sintetizados foram avaliados no ensaio in vitro frente ao M. tuberculosis cepas H37Rv e isolado cl?nico resistente a f?rmacos. Os compostos mais ativos frente ao M. tuberculosis H37Rv (MIC < 1?M) foram selecionados para estudos de viabilidade em c?lulas Vero. Os resultados mostraram que o volume molecular e a hidrofobicidade na por??o N-arilamida, o efeito doador liga??o de hidrog?nio na por??o acetamida e o receptor na posi??o 4 do anel quinol?nico representam tr?s grupos farmacof?ricos importantes para a a??o antimicobacteriana. Al?m disso, os compostos sintetizados 6a, 6h, 12d-f, e 12i-n foram ativos frente a cepa resistente aos medicamentos (MIC ? 0,001?M) com desprovida citotoxicidade aparente para Vero (IC50 ? 20 ?M). Portanto, estes dados indicam que esta classe de compostos pode apresentar candidatos para o desenvolvimento futuro, e oferecer alternativas de medicamentos para o tratamento da tuberculose.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/6981 |
| Date | 31 March 2016 |
| Creators | Giacobbo, Bruno Couto |
| Contributors | Machado, Pablo |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Biologia Celular e Molecular, PUCRS, Brasil, Faculdade de Bioci?ncias |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 8198246930096637360, 600, 600, 600, 600, 36528317262667714, -1634559385931244697, 2075167498588264571 |
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