Novel hybrids of 15-membered 8a- and 9a-azahomoerythromycin A ketolides and quinolones as potent antibacterials.
A series of novel 6-O-substituted and 6,12-di-O-substituted 8a-aza-8a-homoerythromycin A and 9a-aza-9a-homoerythromycin A ketolides were synthesized and evaluated for in vitro antibacterial activity against a panel of representative erythromycin-susceptible and erythromycin-resistant test strains. Another series of ketolides based on 14-membered erythromycin oxime scaffold was also synthesized and their antibacterial activity compared to those of 15-membered azahomoerythromycin analogues. In general, structure-activity studies have shown that 14-membered ketolides displayed favorable antibacterial activity in comparison to their corresponding 15-membered analogues within 9a-azahomoerythromycin series. However, within 8a-azahomoerythromycin series, some compounds incorporating a ketolide combined with either quinoline or quinolone pharmacophore substructures showed significantly potent activity against a variety of erythromycin-susceptible and macrolide-lincosamide-streptogramin B (MLS(B))-resistant Gram-positive pathogens as well as fastidious Gram-negative pathogens. The best compounds in this series overcome all types of resistance in relevant clinical Gram-positive pathogens and display hitherto unprecedented in vitro activity against the constitutively MLS(B)-resistant strain of Staphylococcus aureus. In addition, they also represent an improvement over telithromycin (2) and cethromycin (3) against fastidious Gram-negative pathogens Haemophilus influenzae and Moraxella catarrhalis.
PLIVA Research Institute, Prilaz baruna Filipovića 29, 10000 Zagreb, Croatia. dpavlovic@enscbp.fr
Dražen
D
Pavlović
Andrea
A
Fajdetić
Stjepan
S
Mutak
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D024881:Drug Resistance, Bacterial; D018432:Drug Resistance, Multiple; D004917:Erythromycin / Q000031:analogs & derivatives*; D006193:Haemophilus influenzae / Q000187:drug effects; D048628:Ketolides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D001936:Moraxella catarrhalis / Q000187:drug effects; D015363:Quinolones / Q000737:chemistry* / Q000494:pharmacology; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
C544242:8a-aza-8a-homoerythromycin; D000900:Anti-Bacterial Agents; D048628:Ketolides; D015363:Quinolones; C017547:erythromycin oxime; D004917:Erythromycin