Design, Synthesis, and Characterization of N‑Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity

Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.由结核分枝杆菌（Mycobacterium tuberculosis, Mtb）引发的结核病，是全球致死人数最多的传染性疾病。本研究共合成22种新型含N-氧化物类化合物，并针对其抗结核分枝杆菌活性开展了体外与体内评价。研究发现化合物8是最具开发前景的候选化合物，其对活跃增殖型与非复制持留型结核分枝杆菌的90%最低抑菌浓度（MIC90）分别为1.10 μM与6.62 μM。此外，本研究通过体内实验验证了化合物8的安全性与有效性：该化合物具备良好的口服生物利用度，且抗菌活性极强，在感染小鼠模型中可将结核分枝杆菌载量降至无法检出的水平。基于基因芯片（microarray）的作用机制初步研究显示，化合物8可阻断蛋白质翻译过程。综上，上述研究结果表明，苯并呋咱（benzofuroxan）衍生物8是一类新型抗结核药物化学骨架的极具开发潜力的先导化合物。