Synthesis and structure-activity relationships of novel 8a-aza-8a-homoerythromycin A ketolides
Drazen Pavlović1, Stjepan Mutak
1Pliva Research Institute, Prilaz baruna Filipovica 29, 10000 Zagreb, Croatia. dpavlovic@enscbp.fr
Abstract:
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.
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