engleski

Synthesis and Antibacterial Activity of 4''-O-Substituted 8a-Aza-8a-homo-erythromycins

Starting from erythromycin and 6-O-alkyl-erythromycin, 4''-O-Acyl and 4''-O-carbamoyl derivatives of 8a-aza-8a-homoerythromycin (8a-lactams) were synthesised and tested against common gram-positive and some gram-negative bacteria, to achieve antibacterial activity against MLS-resistant strains and maintain the PK of azalides. Erythromycins were transformed with hydroxylamine into a mixture of erythromycin-9-(Z)-oximes and 9-(E)-oximes. After separation of oximes by crystallisation, Beckmann rearrangement of 9-(Z)-oximes yielded the corresponding 8a-lactams. Protection of 2’ -position and acylation of position 4'' yielded the corresponding 4''-O-acyl derivatives. Reaction with aryl-alkyl isocyanates yielded 4''-O-carbamoyl and and/or 11-O-carbamyl derivatives. The antibacterial activity (MIC) was tested by broth microdilution method. The plasma and tissue pharmacokinetics of selected compounds was characterised in mice after p.o. administration. Using in vitro antimicrobial assays some compounds showed activity comparable to azithromycin with additional activity against inducible MLS resistant S. aureus. Carbamoyl derivatives were less active than 4''-acyl derivatives. Introduction of an additional ring, such as 11, 12-cyclic carbonate or 11-carbamate, decreased antibacterial activity. Some 4''O-acyl derivatives show typical macrolide pharmacokinetics in preliminary in vivo studies in mice. 4''-O-Arylalkenyl-8a-aza-8a-homoerythromycins azalides showed better antibacterial activity than corresponding 4''-O-carbamoyl derivatives.

macrolides; 4''-O-acyl

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