【作者】 张存彦；

【导师】 赵康；

【作者基本信息】 天津大学 ， 应用化学， 2008， 博士

【摘要】 当前,对抗耐药菌制剂的需求是一个全球性的问题。人们越来越关注具有多重耐药性的革兰氏阳性菌所导致的感染。具有多重耐药性的革兰氏阳性菌的菌种包括:耐甲氧苯青霉素金黄色葡萄球菌(Methicillin-resistant Staphylococcus aureus, MRSA)、耐甲氧苯青霉素表皮葡萄球菌(Methicillin-resistant Staphylococcus epidermidis , MRSE)、耐万古霉素粪肠球菌(Vancomycin-resistant Enterococcus faecalis and Enterococcus faecium, VREF)和耐青霉素与头孢菌素的肺炎链球菌。上述病原体直接影响医院和社区发病率和死亡率。噁唑烷酮类化合物是一类新型的具有良好发展前景的抗菌药,其代表药物是利奈唑酮(PNU-100766,商品名Zyvox)。近来,利奈唑酮在国外被用于治疗由革兰氏阳性菌所造成的感染。噁唑烷酮类化合物可以选择性的与50S核糖体亚基的23SRNA部分结合,阻止功能性的70S起始因子的形成,从而阻断蛋白质合成的初始阶段。鉴于其独特的作用机理,噁唑烷酮类抗菌剂很少与其它类抗菌剂产生交叉耐药性。有关噁唑烷酮类化合物构效关系研究的文献报道,异噁唑环是噁唑烷酮环的生物电子等排体之一。同时,含有异噁唑环的化合物中有些被用来开发作为除菌剂。根据拼合原理,本文合成了45个新化合物,并且对这些化合物药理活性进行了体外活性测试,其中有7个抑菌活性比较好的化合物。这几个化合物的体内抑菌活性还需要进行广泛测试,其药物代谢、药物毒理学方面的安全性问题还需要进一步的考察。更多还原

【Abstract】 The development of bacterial resistance to currently available antibacterial agents is a growing global health problem. Of particular concern are infections caused by multidrug-resistant Gram-positive pathogens. Principal players among these problematic organisms are isolates of methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE), vancomycinresistant Enterococcus faecalis and Enterococcus faecium (VREF), and also penicillin and cephalosporin resistant Streptococcus pneumoniae. These pathogens are responsible for significant morbidity and mortality in both the hospital and community setting. A new and promising group of antibacterial agents, collectively known as the oxazolidinones and exemplified by linezolid (PNU-100766, marketed as Zyvox), have recently emerged as important new therapeutic agents for the treatment of infections caused by Gram positive bacteria. The oxazolidinone class of antibacterial agents selectively binds to the 23S RNA component of the 50S ribosomal subunit and prevents the formation of a functional 70S initiation complex, inhibiting protein synthesis at the early stage. Due to its unique mechanism of action, there are fewer cross-resistances between the oxazolidinones and other families of antibacterial agents. Previous literature on the structure-activity relationships for the oxazolidinones has demonstrated that the oxazolidinone ring and the isoxazoline ring are bioisosteres. Furthermore, the compounds carrying isoxazoline ring can be used for the protection of plant from diseases, and fungicidal against phytophthora infestation on tomatoes. About 45 compounds were synthesized according to the combination principles.The antibacterial activity of the new compounds has been tested. Fortunately, some of the compounds have novel antibacterial activity. Studies to establish their in vivo efficacy and safety are being planned for further development.更多还原