Synthesis and antibacterial evaluation of novel 11,4″-disubstituted azithromycin analogs with greatly improved activity against erythromycin-resistant bacteria

A series of novel 11,4″-disubstituted azithromycin analogs were synthesized and evaluated for their antibacterial activity. All the 11,4″-disubstituted analogs exhibited excellent activity (0.03–0.12 μg/ml) against erythromycin-susceptible Streptococcus pneumoniae, and significantly improved activity against three phenotypes of erythromycin-resistant S. pneumoniae compared with erythromycin A, clarithromycin or azithromycin. Among them, compounds 26–28 showed the most potent activity (0.25, 0.03 and 2 μg/ml) against S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, respectively. In addition, compound 28 was the most effective (0.03 and 0.12 μg/ml) against erythromycin-susceptible S. pneumoniae and Staphylococcus aureus as well. It is noteworthy that the most active compounds described above possess the same terminal 3,5-dinitrophenyl groups on their C-4″ bisamide side chains.

The 11,4″-disubstituted analogs synthesized from azithromycin exhibited excellent activity against erythromycin-susceptible and -resistant Streptococcus pneumoniae.Figure optionsDownload as PowerPoint slideHighlights
► Novel 11,4″-disubstituted azithromycin analogs were synthesized and evaluated.
► These analogs had excellent activity against erythromycin-susceptible strains.
► Antibacterial activity was improved against some erythromycin-resistant strains.
► The best compounds had the terminal 3,5-dinitrophenyl group on the C-4″ side chain.