Synthesis, antibacterial activity and docking of 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides

Article abstract of DOI:10.1016/j.ejmech.2012.10.054

A series of 9-O-(3-aryl-2-propargyl)oxime ketolides 8 was synthesized and evaluated for in vitro antibacterial activity. Among 8, 8b-8d, and 8h-8l displayed dramatically improved potency against inducibly MLS _B-resistant and efflux-resistant pathogens as compared to clarithromycin and azithromycin. Especially, 8i (Ar4-isoquinolyl) possessed an MIC of 0.064 μg/mL against constitutively MLS_B-resistant Streptococcus pneumoniae, and MICs of 0.032-0.064 μg/mL against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus hominis. The analog 10 with a propyl linker was less effective than both the corresponding 8 and 9 containing propynyl and propenyl linkers. A docking study was performed to gain insight into the binding mode of series 8 and 9 and to rationalize the disparity found in the SAR of 8 and 9.