新型截短侧耳素衍生物的合成及抗菌活性研究  

Synthesis and biological evaluation of novel pleuromutilin derivatives with nitrogen-containing heterocycles as antibacterial agents

作　　者：王新杨[1,2] 陈敏[1] 王铎[3,4] 陈向东[3] 凌勇[1,2] 王晓丽[1,2] 汪辉[3] 

机构地区：[1]南通大学药学院,江苏南通226001 [2]江苏省炎症与分子药靶重点实验室,江苏南通226001 [3]中国药科大学生命与科学技术学院,江苏南京210009 [4]南京师范大学附属中学,江苏南京210009

出　　处：《药学学报》2015年第10期1297-1304,共8页Acta Pharmaceutica Sinica

基　　金：江苏省自然科学基金资助项目(BK2011389);南通市科技局科技项目(BK2012093);南通大学自然科学基金资助项目(07Z086)

摘　　要：通过将含氮杂环与WL001的2-氨基噻唑侧链相连,设计合成了一系列新的截短侧耳素衍生物。用革兰阳性和革兰阴性菌对该系列化合物进行体外抗菌活性测定,合成的大多数化合物不仅在药物敏感菌株中表现出抗菌活性,而且在耐药菌株中也有相同效果。特别值得注意的是具有饱和氮杂环的化合物表现出显著的抗菌活性（0.062 5～8μg·m L-1）,优于或类似于阿莫西林、泰妙菌素和左氧氟沙星。此外,15a和15b含有哌啶或吗啉的化合物同样能够有效的抑制革兰阴性菌。本研究为相关截短侧耳素衍生物的设计提供了一个新视野,为进一步研究治疗耐药性致病菌奠定了基础。A series of new pleuromutilins derivatives were designed and synthesized through coupling 2-aminothiazole ring of WL001 with different nitrogen-containing substituted heterocycles in the side chain. Their biological activities were evaluated against both Gram-positive and Gram-negative clinical bacteria in vitro Most new compounds displayed specificity to certain strain of bacteria. Particularly, compounds with saturated nitrogen-containing heterocycles exhibited significant antibacterial activities （0.062 5-8 μg·mL-1） superior or similar to those of amoxicillin, tiamulin and levofloxcin. Furthermore, treatment with 15a and 15b having piperidine or morpholine residues also could effectively inhibit Gram-negative bacteria. Therefore, our novel findings may provide a new insight into the design of novel pleuromutilin derivatives and lay the basis for further studies on the treatment of drug-resistance of pathogenic bacteria

关 键 词：截短侧耳素衍生物 抗菌活性 含氮杂环化合物 耐药的革兰阳性病原体 

分 类 号：R916[医药卫生—药学]