ANHYDROLIDE MACROLIDES - 1 - SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF 2,3-ANHYDRO-6-O-METHYL 11,12-CARBAMATE ERYTHROMYCIN-A ANALOGS

A series of 3-descladinosyl-2,3-anhydro-6-O-methylerythromycin A 11,12 -carbamate analogues have been synthesized and evaluated for antibacte rial activity. These compounds were found to be potent antibacterial a gents against Gram-positive organisms in vitro, many having MIC values below 1 mu g/mL for the macrolide-susceptible Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae, as well as impro ved activity compared to erythromycin A against the inducibly MLS (mac rolide, lincosamide, and streptogramin B)-resistant organisms. Structu re-activity studies revealed that arylalkyl carbamates with two and fo ur carbon atoms between the aromatic moiety and carbamate nitrogen hav e the best in vitro activity. All of the C-10 epi analogues evaluated were found to have substantially less activity than the corresponding natural C-10 isomer. Several analogues demonstrated moderate antibacte rial activity against the constitutively resistant S. aureus A-5278, S . pneumoniae 5979, and S. pyogenes 930. However, despite potent in vit ro activity, these analogues showed only moderate in vivo activity in mouse protection studies.