title: Design, synthesis and structure-bactericidal activity relationships of novel 9-oxime ketolides and reductive epimers of acylides.
abstract: Erythromycin was long viewed as a bacteriostatic agent. The erythromycin derivatives, 9-oxime ketolides have a species-specific bactericidal profile. Among them, the 3'-allyl version of the 9-oxime ketolide 1 (Ar=3-quinolyl; 17a) is bactericidal against Streptococcus pneumoniae and Streptococcus pyogenes. In contrast, the 2-fluoro analogs of 1, 13a (Ar=6-quinolyl), 13b (Ar=3-quinolyl) and 24a (Ar=4-isoquinolyl), show bactericidal activities against S. pneumoniae, Staphylococcus aureus and Moraxella catarrhalis, while the 2-fluoro analogs 13c (Ar=3-aminopyridyl) and 24b (Ar=3-carbamoylpyridyl) are only bactericidal against S. pneumoniae and Haemophilus influenzae. Reduction of the ketolides led to novel epiacylides, the 3-O-epimers of the acylides. Alteration of linker length (30b vs. 30a), 2-fluorination (33 vs. 30a) and incorporation of additional spacers at the 9-oxime or 6-OH (35, 40 vs. 30a) did not restore the epiacylides back to be as active as the acylide 31. Molecular docking suggested that epimerization at the 3-position reshapes the orientation of the 3-O-sidechain and leads to considerably weaker binding with bacterial ribosomes.
authors.affiliation: School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
authors.forename: Jing-Chao
authors.initials: JC
authors.lastname: Tian
authors.affiliation: School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, 47907, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Lv
authors.affiliation: School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
authors.forename: Ya-Xin
authors.initials: YX
authors.lastname: Li
authors.affiliation: Biomedical School, Beijing City University, Beijing 100094, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Life Science, Beijing Institute of Technology, Beijing 100081, China.
authors.forename: Bing-Zhi
authors.initials: BZ
authors.lastname: Fan
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, 47907, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
authors.affiliation: School of Life Science, Beijing Institute of Technology, Beijing 100081, China. Electronic address: ljhbit@bit.edu.cn.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Liang
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D048628:Ketolides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012270:Ribosomes / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D048628:Ketolides; D010091:Oximes
keywords: Acylide; Bactericidal activity; Community-acquired bacterial pneumonia; Epimer; Erythromycin; Ketolide