title: A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether: synthesis and structure-activity relationships.
abstract: A new type of ketolide bearing an N-aryl-alkyl acetamide moiety at the C-9 iminoether and its analogues were prepared, and their antibacterial activities and pharmacokinetic properties were evaluated. We found that the introduction of an (R)-alkyl group between the amide and iminoether groups could improve the pharmacokinetic properties while maintaining the activity against erythromycin-resistant Streptococcus pneumoniae. Among the ketolides prepared with the (R)-alkyl group, compound 5p with an N-(3-quinoxalin-6-yl-propyl)-propionamide moiety was found to have in vivo efficacy comparable to CAM with potent in vitro antibacterial activities against the key respiratory pathogens including Haemophilus influenzae and erythromycin-resistant S. pneumoniae.
authors.affiliation: Discovery Research Laboratories, Shionogi & Co., Ltd, 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan. takashi.nomura@shionogi.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Iwaki
authors.forename: Yukitoshi
authors.initials: Y
authors.lastname: Narukawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Uotani
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hori
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miwa
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004917:Erythromycin / Q000494:pharmacology; D004987:Ethers / Q000737:chemistry*; D006193:Haemophilus influenzae / Q000187:drug effects; D007097:Imines / Q000737:chemistry; D066298:In Vitro Techniques; D048628:Ketolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013237:Stereoisomerism; D013296:Streptococcus pneumoniae / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D004987:Ethers; D007097:Imines; D048628:Ketolides; D004917:Erythromycin