含哌啶基苯并噻嗪酮类衍生物的设计、合成与抗结核活性评价。
Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety.
机构信息
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China; Institute of Molecular Design and Synthesis, School of Pharmaceutical Science & Technology, Tianjin University, 92 Weijin Road, Nankai District, Tianjin, 300072, China.
出版信息
Eur J Med Chem. 2018 May 10;151:1-8. doi: 10.1016/j.ejmech.2018.03.060. Epub 2018 Mar 23.
We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way.
我们在此报告了苯并噻嗪酮类化合物的设计和合成，这些化合物含有哌啶部分，是基于我们实验室发现的 IMB-ZR-1 的结构特征设计的新型抗结核药物。其中一些化合物对药敏结核分枝杆菌 H37RV 株具有良好的体外活性（MIC<1μg/mL）。经过两轮修饰，化合物 2i 显示出与 PBTZ169 相当的体外抗结核活性（MIC<0.016μg/mL），对敏感和耐药结核分枝杆菌菌株均有效。化合物 2i 还表现出可接受的 PK 特征。目前正在进行研究以确定 2i 在肺部的 PK 特征和体内疗效。
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