新型噻喃并吲哚衍生物的设计合成及其抗耐药菌和结核杆菌作用研究

Bacterial resistance to the available antibiotics has been becoming increasingly serious. Seeking novel antibacterial drugs has become one of the hotspots of antimicrobial research today, especially the discovery of new lead compounds and novel targets. In our previous study, we found that chuangxinmycin, the first brand new antibiotics of our country with a substituted thiopyranoindole skeleton, showed antibacterial activity on drug-resistant bacteria and mycobacterium tuberculosis. IMB-CV2, a chuangxinmycin derivative we synthesized, showed similar or better in vitro antibacterial activity as tigecycline. The antibacterial activity of IMB-CV2 is much better than that of chuangxinmycin on drug-resistant bacteria and mycobacterium tuberculosis. Thiopyranoindole skeleton is different from the drugs used in clinic, and substituted thiopyranoindole derivatives have the potential to be developed as novel antibacterial drugs. Through the synthesis of novel chuangxinmycin analogues with optimization on substituted groups，the synthesis of different prodrugs of chuangxinmycin and its analogues, the study of their antibacterial activity on drug-resistant bacteria, we expect to obtain valuable structure-activity relationship. Moreover, we expect to discover one or two lead compounds with good antibacterial activity on drug-resistant bacteria.

随着细菌耐药性的日益严重，寻找新先导结构、发现新抗菌靶点，成为当今研发全新抗菌药物的热点。具有噻喃并吲哚结构的创新霉素是课题承担单位自主研发的我国第一个全新抗生素，其抗菌靶点与常用抗菌药物不同。前期工作中我们发现其具有抗耐药菌和抗结核杆菌活性。我们对创新霉素进行结构改造，其衍生物IMB-CV2的体外抗MRSA、MRSE、MSSA、MSSE、肺炎链球菌的活性相当于或优于替加环素，其抗耐药菌活性和结核杆菌活性比创新霉素有了显著提高。噻喃并吲哚结构母核与现在临床上的药物结构不同，具有发展成为抗菌药物新结构母核的潜力。本课题将以创新霉素为先导，进行不同取代基团的结构优化合成，进行创新霉素及其衍生物不同类型前药的合成，研究新衍生物的抗耐药菌作用，初步阐明此类结构的构效关系，争取发现1-2 个具有良好抗耐药菌活性的候选化合物，为进一步寻找新型抗菌药物打下基础。

本课题设计合成了46个目标衍生物并测定了它们的抗菌活性，其中化合物CV1、CV2、CV3、CV8、CV10、ZJT3、ZJT21等7个化合物的体外抗表皮葡萄球菌（MRSE 12-8）活性MIC（ug/ml）强于或相当于阳性对照药左氧氟沙星；化合物CV2、CV3、CV8、CV11、CV12 、CV13等6个化合物体现了较强的抗不同表皮葡萄球菌柱和金黄色葡萄球菌柱活性；化合物 CV1、CV5、CV7、CV15、ZJT1、ZJT2 和 ZJT3 等7个化合物体现了中等的抗表皮葡萄球菌和金黄色葡萄球菌活性；化合物CV1、CV2、CV3、CV5、CV7、CV8、CV11、CV12 、CV13 、CV15、ZJT1、ZJT2 和 ZJT3 等13个化合物体现了中等的抗铜绿假单胞菌活性。. 完成了IMB-CV2的体内药效学和毒性的初步研究，ICR小鼠灌胃给药IMB-CV2的 LD50 大于1.5g/kg，KM小鼠腹腔注射给药IMB-CV2的LD50大于633.5mg/kg。IMB-CV2口服灌胃给药昆明小鼠的体内疗效较对照药替加环素弱，IMB-CV2对所试金葡菌MSSA12-4感染小鼠的ED50为72.65mg/kg，替加环素对所试金葡菌MSSA12-4感染小鼠的ED50为35.35 mg/kg。同时已经合成得到了IMB-CV2的其他类似物，下一步会继续进行其他类似物的体内抗菌活性研究，为进一步寻找新型抗菌药物打下基础。. 课题有1篇SCI论文已撰写完毕，还有2篇国内核心期刊论文在撰写中。