Synthesis and structure-activity relationships of novel 8a-aza-8a-homoerythromycin A ketolides.
A series of novel 6-O-substituted 8a-aza-8a-homoerythromycin A ketolides was synthesized and evaluated for in vitro antibacterial activity. Key strategic elements of the synthesis include the base-induced E-Z isomerization of 3-O-descladinosyl-6-O-allylerythromycin A 9(E)-oxime followed by ring-expanding reaction of the resulting 9(Z)-oxime via Beckmann rearrangement. The ketolides showed potent activity against a variety of erythromycin-susceptible and macrolide-lincosamide-streptogramin B (MLS(B)) resistant Gram-positive and fastidious Gram-negative pathogens. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens and display in vitro activity comparable to telithromycin and cethromycin.
Pavlović
Drazen
D
Pliva Research Institute, Prilaz baruna Filipovica 29, 10000 Zagreb, Croatia. dpavlovic@enscbp.fr
Mutak
Stjepan
S
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D048628:Ketolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C551962:6-(2''-hydroxy-3''-(2-(quinolin-6-ylamino)ethylamino)propoxy)-3-oxo-8a-aza-8a-homoerythromycin A; C544242:8a-aza-8a-homoerythromycin; D000900:Anti-Bacterial Agents; D048628:Ketolides; D004917:Erythromycin