2-((quinolin-4- il)oxi)-fenilacetamidas : s?ntese, caracteriza??o estrutural e atividade inibit?ria sobre o crescimento do Mycobacterium tuberculosis

• Main Author: Giacobbo, Bruno Couto
• Other Authors: Machado, Pablo
• Format: Others
• Language: Portuguese
• Published: Pontif?cia Universidade Cat?lica do Rio Grande do Sul 2016
• Subjects: TUBERCULOSE; FARMACOLOGIA; BIOLOGIA MOLECULAR; CIENCIAS BIOLOGICAS::BIOLOGIA GERAL
• Online Access: http://tede2.pucrs.br/tede2/handle/tede/6981

Submitted by Setor de Tratamento da Informa??o - BC/PUCRS ([e-mail]) on 2016-10-04T10:48:59Z No. of bitstreams: 1 DIS_BRUNO_COUTO_GIACOBBO_COMPLETO.pdf: 3325467 bytes, checksum: 539cc1eb4d805644ba436db429ede065 (MD5) === Made available in DSpace on 2016-10-04T10:48:59Z (GMT). No. of bitstreams: 1 DIS_BRUNO_COUTO_GIACOBBO_COMPLETO.pdf: 3325467 bytes, checksum: 539cc1eb4d805644ba436db429ede065 (MD5) 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.