title: Synthesis, antibacterial activity and docking of 14-membered 9-O-(3-arylalkyl) oxime 11,12-cyclic carbonate ketolides.
abstract: 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 (Ar=4-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.
authors.affiliation: School of Life Science, Beijing Institute of Technology, Beijing 100081, China. ljhbit@bit.edu.cn
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Liang
authors.forename: Kun
authors.initials: K
authors.lastname: An
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.forename: Ying-Chun
authors.initials: YC
authors.lastname: Xu
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D002254:Carbonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D048628:Ketolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D062105:Molecular Docking Simulation
chemical_list: D000900:Anti-Bacterial Agents; D002254:Carbonates; D048628:Ketolides