3-羟基-6-O-甲基红霉素-9-O-取代肟衍生物的合成及抗菌活性

[Synthesis and antibacterial activity of 3-hydroxy-6-O-methylerythromycin-9-O-substituted oxime derivatives].

作者信息

Chen S X, Xu X D, Yu L X

机构信息

Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

出版信息

Yao Xue Xue Bao. 2001 Aug;36(8):581-4.

PMID:12579933

Abstract

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 NH2OH.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 H2 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 microgram.mL-1) and 6 (MIC = 1 microgram.mL-1) showed significant activity against Staphylococcus epidermidis 26,069 compared with erythromycin (MIC = 4 micrograms.mL-1). Compounds 5 (MIC = 16, 4 micrograms.mL-1), 7 (MIC = 32, 64 micrograms.mL-1) and 8 (MIC = 64, 32 micrograms.mL-1) showed better activity against Streptococcus pneumoniae 64 and Staphylococcus aureus 9525 than erythromycin (MIC > 128, 128 micrograms.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.

摘要

目的

为研究3-羟基-6-O-甲基红霉素-9-O-取代肟衍生物对耐红霉素菌株的抗菌活性，设计了一条6步的新合成路线。

方法

起始原料红霉素A（1）与盐酸羟胺反应得到2，2再与苯甲酰溴反应得到3。用碘甲烷对C-6羟基进行选择性甲基化得到4，4经水解失去3-克拉定糖得到5。化合物5用氢气还原得到6，6再与取代苄基氯反应得到7和8。

结果

合成了4个未见报道的化合物（5 - 8）。对新化合物的抗菌活性进行了体外测试，测试对象包括对红霉素敏感和耐药的菌株。与红霉素（MIC = 4微克·mL-1）相比，化合物5（MIC = 1微克·mL-1）和6（MIC = 1微克·mL-1）对表皮葡萄球菌26069显示出显著活性。化合物5（MIC = 16、4微克·mL-1）、7（MIC = 32、64微克·mL-1）和8（MIC = 64、32微克·mL-1）对肺炎链球菌64和金黄色葡萄球菌9525的活性比红霉素（MIC > 128、128微克·mL-1）更好。