喹诺酮-噁唑烷酮杂合体的设计、合成与抗革兰阳性耐药菌/抗结核作用研究

Quinolones have become the second largest classes of chemotherapeutic drugs used in the clinic after the cephalosporins. However, quinolone resistance has increased in almost all pathogens (especially Gram-positive strains) and Mycobacterium tuberculosis (MTB). Linezolid, the first and only oxazolidinone drug, was approved in 2000 by the FDA for the treatment of resistant Gram-positive bacterial infections. However, linezolid-resistant strains of Staphylococcus aureus and Enterococcus faecium began to appear in the clinic recently. Therefore, it urgently calls for the development of new strategies that can address the problem of growing bacterial resistance. We have been specialized in quinolone research for over 30 years, and several quinolone-containing hybrids discovered in our lab recently, were found to possess considerable activities against resistant Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), or multidrug resistant MTB (MDR-MTB). In this work, a series of novel quinolone-oxazolidinone hybrids will be designed and synthesized based on the structural features of the above hybrids in our lab. Our primary object is to discover 1-2 candidates with potent activities against resistant Gram-positive bacteria and/or MDR-MTB, which can provides base and support to the enrichment of this field in china and development of new hybrid drugs with own intellectual property rights.

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。适应证为革兰阳性耐药菌感染的利奈唑胺（唯一上市的噁唑烷酮类药物）已有细菌（金葡菌，屎肠球菌）耐药性的报道。因此，克服这两类抗菌药的耐药性已成为国际抗生素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，近期我们发现了一些新的喹诺酮杂合体，它们对耐甲氧西林金葡菌（MRSA）和耐甲氧西林表葡菌（MRSE）等革兰阳性耐药菌或MTB[包括耐多药MTB(MDR-MTB) ]显示优秀的抗菌活性。本研究将以这些杂合体为先导物，设计合成一系列新型结构的喹诺酮-噁唑烷酮杂合体，力争发现1-2个对革兰阳性耐药菌和/或MTB（尤其是MDR-MTB）高度有效的候选化合物，为开拓我国在杂合药物领域的研究并最终研发出拥有自主知识产权的喹诺酮杂合体药物奠定坚实的知识基础。

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。适应证为革兰阳性耐药菌感染的利奈唑胺（唯一上市的噁唑烷酮类药物）已有细菌（金葡菌，屎肠球菌）耐药性的报道。本研究设计合成了一系列新型结构的喹诺酮-噁唑烷酮杂合体以期克服该耐药性问题。然而，所合成的目标化合物对代表性革兰阳性菌和革兰阴性菌的体外活性均很差。为此，我们对本课题的研究方向及时进行了调整。基于多年来我们在喹诺酮领域的研究心得及喹诺酮杂合体的最新进展，我们设计合成了另外三类基于喹诺酮的杂合体（8-甲氧基环丙沙星杂合体，喹诺酮-三氮唑硫酮杂合体，含有肟片段的喹诺酮杂合体）。通过以上四个方面的工作，我们迄今共合成喹诺酮杂合体180个（其中，喹诺酮-噁唑烷酮杂合体和喹诺酮-三氮唑硫酮杂合体的其余目标物仍在合成中）。测定了它们的体外抗菌和/或抗MTB活性，还评价了其中2个目标物的体内抗菌作用。结果发现，除喹诺酮-噁唑烷酮杂合体外，另外三个系列中的多个目标物的体外抗菌（包括MRSE和MRSA）和/或抗MTB活性优于母药喹诺酮，其中某些化合物对喹诺酮或万古霉素耐药的革兰阳性菌和/或MDR-MTB仍表现出良好活性。例如，在喹诺酮-三氮唑硫酮杂合体（65个）系列中，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，尤其是其中16个目标物（MIC: ug/mL）对3株万古霉素耐药的粪肠球菌非常敏感（MIC: ug/mL）。此外，6个杂合体对临床分离株MDR-MTB显示优秀的体外活性（MIC: ug/mL）（见相关SCI）。这些化合物均值得深入研究。