3-羟基-6-O-甲基红霉素-9-肟基衍生物的合成及体外抗菌活性

SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF 3-HYDROXY-6-O-METHYLERYTHROMYCIN-9-O-SUBSTITUTED OXIME DERIVATIVES

目的 寻找并合成抗耐药菌活性的 3位羟基红霉素衍生物。方法 以红霉素A为原料 ,经 9位酮基肟化 ,9位肟羟基 ,2′位羟基和 3′位二甲胺基同时苄基化 ,6位羟基甲基化 ,水解去 3位克拉定糖 ,氢化还原脱苄基 ,对甲基苄基或邻氯苄基取代 9位肟羟基等 6步反应 ,制得 3 羟基 6 O 甲基红霉素 9 肟基衍生物 ,其结构经1 3 CNMR ,FAB MS确证。结果 共制得 7个化合物 ,对其中 4个 (5 - 8)未见报道的化合物进行了体外抗菌活性测定。结论 5 ,7。

AIM To study the antibacterial activity against erythromycin resistant organisms of 3 hydroxy 6 O methylerythromycin 9 O substituted oxime derivatives, a new route of synthesis with 6 steps was designed. METHODS The starting material, erythromycin A (1), was reacted with NH 2OH·HCI to give 2, which reacted with BzBr to give 3. Selective methylation of C 6 hydroxy group using iodomethane afforded 4, which was hydrolyzed with loss of the 3 cladinosyl to give 5. Compound 5 was reduced by H 2 to provide 6, which was treated with substituted benzyl chlorides to provide 7 and 8. RESULTS Four unreported compounds (5-8) were synthesized. The antibacterial activity of the new compounds were tested in vitro against both erythromycin susceptible and erythromycin resistant organisms. The compounds 5 (MIC=1 μg·mL -1 ) and 6 (MIC=1 μg·mL -1 ) showed significant activity against Staphylococcus epidermidis 26069 compared with erythromycin (MIC=4 μg·mL -1 ). Compounds 5 (MIC=16, 4 μg·mL -1 ), 7 (MIC=32, 64 μg·mL -1 ) and 8 (MIC=64, 32 μg·mL -1 ) showed better activity against Streptococcus pneumoniae 64 and Staphylococcus aureus 9525 than erythromycin (MIC>128, 128 μg·mL -1 ). CONCLUSION 3 hydroxy 6 O methylerythromycin 9 O substituted oxime derivatives have stronger antibacterial activity against some erythromycin resistant organisms than erythromycin A.