Submitted by PPG Medicina e Ci?ncias da Sa?de (medicina-pg@pucrs.br) on 2018-03-16T19:55:06Z No. of bitstreams: 1 THA?S_CRISTINA_MURAD?S_DIS.pdf: 883340 bytes, checksum: 6481cc56bc005f400fcfc1ae75cea11e (MD5) / Approved for entry into archive by Tatiana Lopes (tatiana.lopes@pucrs.br) on 2018-03-28T13:57:53Z (GMT) No. of bitstreams: 1 THA?S_CRISTINA_MURAD?S_DIS.pdf: 883340 bytes, checksum: 6481cc56bc005f400fcfc1ae75cea11e (MD5) / Made available in DSpace on 2018-03-28T14:01:44Z (GMT). No. of bitstreams: 1 THA?S_CRISTINA_MURAD?S_DIS.pdf: 883340 bytes, checksum: 6481cc56bc005f400fcfc1ae75cea11e (MD5) Previous issue date: 2017-12-19 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / New effective compounds for tuberculosis (TB) treatment are currently needed. This study analyzed the anti-TB activity of a series of 16 quinoxaline-derived chalcones. From an initial in vitro screening, six molecules, namely N5, N9, N10, N15, N16, and N23 inhibited the growth of the M. tuberculosis H37Rv laboratory strain. The three compounds (N9, N15 and N23) with the lowest MIC values (3.13, 6.25, 5 ?g/mL, respectively) were further tested against clinical isolates and laboratory strains harboring mutations in katG or inhA genes. From these experimental set, N9 was selected as the lead compound for further investigations. This chalcone displayed a synergistic effect when combined with moxifloxacin, according to assessment in a checkerboard assay. Noteworthy, the anti-TB effects of N9 did not rely on inhibition of mycolic acids or non-hydroxylated fatty acids synthesis, circumventing important mechanisms of resistance in mycobacteria. Considering the safety of the tested chalcones, all the compounds behaved as substrates or inhibitors of at least one cytochrome P450 isoform, as indicated by in silico evaluation. Most compounds lacked tumorigenic, mutagenic, irritant, or reproductive effects, except N3 and N7, as shown by DataWarrior program. The chalcone N9 did not elicit any toxic alteration in doses up to 2000 mg/kg, in female mice. Based on the present results, N9 can be considered a potential candidate for development of a new anti-TB therapeutic choice. / Atualmente, s?o necess?rios novos compostos eficazes para o tratamento da tuberculose (TB). Este estudo analisou a atividade anti-TB de uma s?rie de 16 chalconas derivadas da quinoxalina. A partir de uma triagem inicial in vitro, seis mol?culas, nomeadas N5, N9, N10, N15, N16 e N23 inibiram o crescimento da cepa laboratorial de M. tuberculosis H37Rv. Os tr?s compostos (N9, N15 e N23) com os valores de MIC mais baixos (3.13, 6.25, 5 ?g/mL, respectivamente) foram testados adicionalmente contra isolados cl?nicos e cepas laboratoriais com muta??es nos genes katG ou inhA. A partir deste conjunto experimental, a chalcona quinoxal?nica N9 foi selecionada como composto principal para novas investiga??es. Esta chalcona mostrou um efeito sin?rgico quando combinada com moxifloxacino, de acordo com a avalia??o em ensaio checkerboard. Destaca-se que os efeitos anti-TB de N9 n?o dependeram da inibi??o de ?cidos mic?licos ou da s?ntese de ?cidos graxos n?o hidroxilados, envolvidos em importantes mecanismos de resist?ncia em micobact?rias. Considerando a seguran?a toxicol?gica das chalconas quinoxal?nicas testadas, todos os compostos comportaram-se como substratos ou inibidores de pelo menos uma isoforma do citocromo P450, conforme indicado pela avalia??o in silico. A maioria dos compostos n?o possui efeitos tumorig?nicos, mutag?nicos, irritantes ou reprodutivos, exceto N3 e N7, conforme demonstrado pelo programa DataWarrior. A chalcona quinoxal?nica N9 n?o provocou qualquer altera??o t?xica em doses de at? 2000 mg/kg, em camundongos f?meas. Com base nos resultados atuais, N9 pode ser considerada como potencial candidata para o desenvolvimento de uma nova escolha terap?utica anti-TB.