Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) and Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, RS, Brazil.
Programa de Pós-Graduação em Medicina e Ciências da Saúde, PUCRS, Porto Alegre, Brazil.
PLoS One. 2018 Aug 16;13(8):e0202568. doi: 10.1371/journal.pone.0202568. eCollection 2018.
New effective compounds for tuberculosis treatment are needed. This study evaluated the effects of a series of quinoxaline-derived chalcones against laboratorial strains and clinical isolates of M. tuberculosis. Six molecules, namely N5, N9, N10, N15, N16, and N23 inhibited the growth of the M. tuberculosis H37Rv laboratorial strain. The three compounds (N9, N15 and N23) with the lowest MIC values were further tested against clinical isolates and laboratory strains with mutations in katG or inhA genes. From these data, N9 was selected as the lead compound for further investigation. Importantly, this chalcone displayed a synergistic effect when combined with moxifloxacin. Noteworthy, the anti-tubercular effects of N9 did not rely on inhibition of mycolic acids synthesis, circumventing important mechanisms of resistance. Interactions with cytochrome P450 isoforms and toxic effects were assessed in silico and in vitro. The chalcone N9 was not predicted to elicit any mutagenic, genotoxic, irritant, or reproductive effects, according to in silico analysis. Additionally, N9 did not cause mutagenicity or genotoxicity, as revealed by Salmonella/microsome and alkaline comet assays, respectively. Moreover, N9 did not inhibit the cytochrome P450 isoforms CYP3A4/5, CYP2C9, and CYP2C19. N9 can be considered a potential lead molecule for development of a new anti-tubercular therapeutic agent.
需要新的有效抗结核化合物。本研究评估了一系列喹喔啉衍生查耳酮对结核分枝杆菌实验室株和临床分离株的作用。有 6 种分子，即 N5、N9、N10、N15、N16 和 N23，抑制了结核分枝杆菌 H37Rv 实验室株的生长。三种化合物（N9、N15 和 N23）具有最低 MIC 值，进一步针对 katG 或 inhA 基因突变的临床分离株和实验室株进行了测试。从这些数据中，选择 N9 作为进一步研究的先导化合物。重要的是，这种查尔酮与莫西沙星联合使用时具有协同作用。值得注意的是，N9 的抗结核作用不依赖于抑制分枝菌酸的合成，避免了重要的耐药机制。在体内和体外评估了与细胞色素 P450 同工型的相互作用和毒性作用。根据体内分析，查尔酮 N9 预计不会引起任何诱变、遗传毒性、刺激性或生殖毒性作用。此外，N9 没有引起致突变性或遗传毒性，这分别通过沙门氏菌/微粒体和碱性彗星试验揭示。此外，N9 不抑制细胞色素 P450 同工型 CYP3A4/5、CYP2C9 和 CYP2C19。N9 可被视为开发新的抗结核治疗药物的潜在先导分子。
