Synthesis and antibacterial activity of novel 4''-O-carbamoyl erythromycin-A derivatives.

Novel 4''-O-carbamoyl erythromycin-A derivatives were designed, synthesized, and evaluated for their in-vitro antibacterial activities. All of the 4''-O-carbamoyl derivatives showed excellent activity against erythromycin-susceptible Staphylococcus aureus ATCC25923, Streptococcus pyogenes, and Streptococcus pneumoniae ATCC49619. Most of the 4''-O-arylalkylcarbamoyl derivatives displayed potent activity against erythromycin-resistant S. pneumoniae encoded by the mef gene and greatly improved activity against erythromycin-resistant S. pneumoniae encoded by the erm gene or the erm and mef genes. In particular, the 4''-O-arylalkyl derivatives 4c-4e and 4g were found to possess the most potent activity against all the tested erythromycin-susceptible strains, which were comparable to those of erythromycin, clarithromycin, or azithromycin. 4''-O-Arylalkyl derivatives 4e and 4g were the most effective against erythromycin-resistant S. pneumoniae encoded by the mef gene (0.25 and 0.25 microg/mL). 4''-O-Arylalkyl derivatives 4a and 4b exhibited significantly improved activity against erythromycin-resistant S. pneumoniae encoded by the erm gene. In contrast, the 4''-O-alkylcarbamoyl derivatives hardly showed improved activity against all the tested erythromycin-resistant strains.