Caracterização farmacológica e toxicológica de chalconas quinoxalínicas como candidatas a fármacos anti-tuberculose

• Ano de defesa: 2017
• Autor(a) principal: Muradás, Thaís Cristina
• Orientador(a): Basso, Luiz Augusto
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Pontifícia Universidade Católica do Rio Grande do Sul
• Programa de Pós-Graduação: Programa de Pós-Graduação em Medicina e Ciências da Saúde
• Departamento: Escola de Medicina
• País: Brasil
• Palavras-chave em Português: Chalconas; Tuberculose; Desenvolvimento de Fármacos; Estudos Pré-Clínicos
• Área do conhecimento CNPq: CIENCIAS DA SAUDE::MEDICINA
• Link de acesso: http://tede2.pucrs.br/tede2/handle/tede/7908

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 µg/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.