Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea.
Chem Biol Drug Des. 2012 Sep;80(3):388-97. doi: 10.1111/j.1747-0285.2012.01404.x. Epub 2012 Jun 27.
We synthesized a series of oxazolidinone-type antibacterials in which morpholine C-ring of linezolid has been modified by substituted 3-azabicyclo[3.3.0]octanyl rings. Acetamide or 1,2,3-triazole heterocycle was used as C-5 side chain of oxazolidinone. The resulting series of compounds was then screened in vitro against panel of susceptible and resistant Gram-positive, Gram-negative bacteria, and Mycobacterium tuberculosis (Mtb). Several analogs in this series exhibited potent in vitro antibacterial activity comparable or superior to linezolid against the tested bacteria. Compounds 10a, 10b, 11a, and 15a displayed highly potent activity against M. tuberculosis. Selected compound 10b showed good human microsomal stability and CYP-profile, and showed low activity against hERG channel.
我们合成了一系列噁唑烷酮类抗菌药物,其中利奈唑胺的吗啡啉 C 环被取代的 3-氮杂双环[3.3.0]辛基环修饰。乙酰胺或 1,2,3-三唑杂环被用作噁唑烷酮的 C-5 侧链。然后将所得系列化合物在体外对一系列敏感和耐药的革兰氏阳性、革兰氏阴性细菌和结核分枝杆菌(Mtb)进行筛选。该系列中的几种类似物具有很强的体外抗菌活性,与测试的细菌相比,其活性与利奈唑胺相当或优于利奈唑胺。化合物 10a、10b、11a 和 15a 对结核分枝杆菌显示出高度有效的活性。选定的化合物 10b 表现出良好的人微粒体稳定性和 CYP 特征,对 hERG 通道的活性较低。