Studies on macrolide antibiotics I. Synthesis and antibacterial activity of erythromycin A 9-O-substituted oxime ether derivatives against Mycobacterium avium complex.
A series of erythromycin A 9-O-substituted oxime ether derivatives have been synthesized and evaluated for antibacterial activity against Mycobacterium avium complex (MAC) and Staphylococcus aureus. These compounds possessed stronger in vitro activity against MAC including macrolide-resistant strains than clarithromycin (2), although in vitro antibacterial activities of these compounds were less than that of 2 against Staphylococcus aureus. Our studies found that several factors contribute to the antibacterial activity against MAC. The length and spatial orientation of the substituent at 9-position were found to significantly influenced the anti-MAC activity, especially against macrolide-resistant strains. Of all the compounds prepared, erythromycin A 9-[O-(4-phenylbutyl)oxime] (12q) and erythromycin A 9-[O-(3-phenoxypropyl)oxime] (12t) possessed 16 times stronger antibacterial activity than 2 against clarithromycin-resistant strains. Surprisingly, the minimum inhibitory concentrations (MICs) of 12q and 12t against the resistant strains were almost same as those against the susceptible strains. These results suggest that the erythromycin A 9-O-substituted oxime ether derivatives would be promising macrolide antibiotics.
Nishimoto
A
A
Research and Development Headquaters, Hokuriku Seiyaku Co., Ltd., Katsuyama, Fukui, Japan. organ-hs@mitene.or.jp
Narita
K
K
Ohmoto
S
S
Takahashi
Y
Y
Yoshizumi
S
S
Yoshida
T
T
Kado
N
N
Okezaki
E
E
Kato
H
H
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D053938:DNA Fragmentation; D004917:Erythromycin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015269:Mycobacterium avium Complex / Q000187:drug effects*; D010091:Oximes / Q000138:chemical synthesis / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D012329:RNA, Bacterial / Q000187:drug effects; D012335:RNA, Ribosomal / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects
D000900:Anti-Bacterial Agents; D010091:Oximes; D012329:RNA, Bacterial; D012335:RNA, Ribosomal; D004917:Erythromycin