含有7-肟基-3,6-二氮杂双环[3.1.1] 庚烷片段的新喹诺酮的合成与抗Ｇ＋耐药菌/结核作用研究

Quinolones are the second largest broad-spectrum antibacterial agents for the treatment of bacterial infections after the cephalosporins. Because of the significant increase in prevalence of antibiotic resistance of pathogens, especially Gram-positive bacteria and Mycobacterium tuberculosis (MTB), it becomes very urgent to develop novel quinolones with potential antibacterial activity. .We have been specialized in anti-infection drug research for over 30 years, two quinolone candidates IMB-031124 and IMB-070593 discovered by our research group was licensed for the Clinical Phase II study and is currently in the late-stage of preclinical development, respectively. Novel 7-oximido-3,6-diazabicyclo[3.1.1]heptanes will be built, based on the structural characteristics of the substituent groups at the C-7 positions of IMB-070593 and the potencial candidate IMB-1204, and then two series of quinolones (about 40 target compounds ) containing a 7-oximido-3,6-diazabicyclo[3.1.1]heptane moiety will be designed, synthesized and evaluated for their biological activities in this work. The aim of the research is to discover 1-2 lead compounds with good activity against drug-resistant Gram-positive bacteria and M. tuberculosis, to provide base and support to our further research.

喹诺酮是目前仅次于头孢菌素的第二大类抗感染化疗药物，但致病菌（尤其是革兰阳性菌）和结核分支杆菌（MTB）的耐药性逐年增加, 故克服喹诺酮的耐药性已成为本领域必须尽快解决的关键科学问题。在30余年喹诺酮研发工作的基础上，近年由我们课题组自主研制的1.1类喹诺酮候选物IMB-031124和IMB-070593已分别获得II期临床试验批件和处于临床前后期研究阶段。本研究将结合IMB-070593和另一个有苗头的喹诺酮化合物IMB-1204的7-位侧链的结构特点，构建出全新的7-肟基-3,6-二氮杂双环[3.1.1] 庚烷，通过两种方式与母核化合物缩合，合成两个不同系列约40个喹诺酮目标物。力争发现1-2个对革兰阳性耐药菌和/或MTB具有良好体外活性的目标物, 为本课题组今后的进一步研究提供先导物。

喹诺酮是目前仅次于头孢菌素的第二大类抗感染化疗药物，但致病菌（尤其是革兰阳性菌.和结核分支杆菌（MTB）的耐药性逐年增加, 故克服喹诺酮的耐药性已成为本领域必须尽快.解决的关键科学问题。在30余年喹诺酮研发工作的基础上，近年由我们课题组自主研制的1.1类喹诺酮候选物IMB-031124和IMB-070593已分别获得II期临床试验批件和处于临床前后期研究阶段。本研究将结合IMB-070593和另一个有苗头的喹诺酮化合物IMB-1204的7-位侧链的结构特点，探索7-肟基-3,6-二氮杂双环[3.1.1] 庚烷片段的合成，同时借鉴第三代大环内酯类抗生素Telithromycin等的特点，在氟代环丙沙星以及8-甲氧基环丙沙星喹诺酮母核的7-位引入不同的芳杂环结构片段，共合成72个目标化合物并进行体外抗菌活性测定。多数目标物对革兰阳性菌和革兰阴性菌表现出优秀的体外广谱活性（见相关SCI）。这些化合物均值得深入研究。