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


CONCLUSIONS
3-hydroxy-6-O-methylerythromycin-9-O-substituted oxime derivatives have stronger antibacterial activity against some erythromycin-resistant organisms than erythromycin A.
Chen
S X
SX
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. chenshengxi@sina.com
Xu
X D
XD
Yu
L X
LX
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects; D013212:Staphylococcus epidermidis / Q000187:drug effects*; D013296:Streptococcus pneumoniae / Q000187:drug effects
D000900:Anti-Bacterial Agents; D004917:Erythromycin