Chem Biol Drug Des. 2012 Nov;80(5):781-6. doi: 10.1111/cbdd.12022. Epub 2012 Sep 10.
The screening of an in-house quinolones library against Mycobacterium tuberculosis (Mtb) H(37) Rv, followed by a first cycle of optimization, yielded 6-hydrogen-8-methyl derivatives endowed with good potency. The antitubercular activity also encompassed the bacteria in a non-replicating state (NRP-TB) with minimum inhibitory concentration values lower than those of the reference agent, moxifloxacin. Among the best compounds, 11w and 11ai, characterized by a properly substituted piperidine at the C-7 position, were active against single-drug-resistant (SDR-TB) Mtb strains, maintaining overall good potency also against ciprofloxacin-resistant Mtb. This study expands the body of SAR around antitubercular quinolones leading to reconsider the role played by the usual fluorine atom at the C-6 position. Further elaboration of the 6-hydrogen-8-methylquinolone scaffold, with a particular focus on the C-7 position, is expected to give even more potent congeners holding promise for shortening the current anti-TB regimen.
对分枝杆菌（Mtb）H（37）Rv 的内部喹诺酮文库进行筛选，然后进行第一轮优化，得到了具有良好活性的 6-氢-8-甲基衍生物。这些抗结核药物还能抑制非复制状态下的细菌（NRP-TB），其最低抑菌浓度值低于参考药物莫西沙星。在最好的化合物中，11w 和 11ai 具有在 C-7 位置适当取代的哌啶基，对单药耐药（SDR-TB）分枝杆菌菌株有效，对环丙沙星耐药的分枝杆菌也保持了总体良好的活性。这项研究扩展了抗结核喹诺酮类药物的 SAR 范围，重新考虑了通常在 C-6 位置的氟原子的作用。预计对 6-氢-8-甲基喹诺酮骨架的进一步研究，特别是对 C-7 位置的研究，将产生更有效的同系物，有望缩短目前的抗结核方案。
