Synthesis and antibacterial activity of isomeric 15-membered azalides.
A series of 3-keto and 3-O-acyl derivatives of both 6-O-alkyl-8a-aza-8a-homoerythromycin A and 6-O-alkyl-9a-aza-9a-homo-erythromycin A were synthesised and tested against Gram-positive and Gram-negative bacteria. Derivatives of 8a-aza-8a-homoerythromycin A have potent antibacterial activity against not only azithromycin-susceptible strains, but also efflux (M) and inducible macrolide-lincosamide-streptogramin (iMLSB) resistant Gram-positive pathogens, while the corresponding 9a-isomers were less active. Introduction of an additional ring such as 11,12-cyclic carbonate reduced antibacterial activity of both series. 3-Keto and 3-O-(4-nitrophenyl)-acetyl derivatives of 6-O-methyl-8a-aza-8a-homo-erythromycin A show typical macrolide pharmacokinetics in preliminary in vivo studies in mice, and their in vivo efficacy is demonstrated.
Alihodzic
Sulejman
S
GSK Research Centre Zagreb Ltd., Prilaz baruna Filipovica 29, 10000 Zagreb, Croatia.
Fajdetic
Andrea
A
Kobrehel
Gabrijela
G
Lazarevski
Gorjana
G
Mutak
Stjepan
S
Pavlovic
Drazen
D
Stimac
Vlado
V
Cipcic
Hana
H
Kramaric
Miroslava Dominis
MD
Erakovic
Vesna
V
Hasenöhrl
Andreja
A
Marsic
Natasa
N
Schoenfeld
Wolfgang
W
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001424:Bacterial Infections / Q000188:drug therapy; D018942:Macrolides / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D018942:Macrolides