title: Novel azalides derived from 16-membered macrolides. Part II: Isolation of the linear 9-formylcarboxylic acid and its sequential macrocyclization with an amino alcohol or an azidoamine.
abstract: The design and synthesis of novel 14- to 16-membered 11-azalides starting from 16-membered macrolides are reported. A linear 9-formylcarboxylic acid was isolated via a mobile dialdehyde previously reported. Sequential macrocyclization of the formylcarboxylic acid with amino alcohol followed by deprotection afforded corresponding 14- to 16-membered azalides. On the other hand, reductive amination of the formylcarboxylic acid with an azidoamine followed by macrolactam formation with an amine generated from the azide gave 14- to 16-membered azalactams. Among these derivatives, 15-membered azalactams and 16-membered azalides exhibited characteristic in vitro antibacterial activities. Although optimization of 15-membered azalactams including demycarosyl analogues did not provide remarkably promising molecules, SAR studies of 16-membered azalides disclosed that substitution at the 15 position was very important for identification of a clinical candidate.
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. tomoaki_miura@meiji.co.jp
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Miura
authors.forename: Kenichi
authors.initials: K
authors.lastname: Kanemoto
authors.forename: Satomi
authors.initials: S
authors.lastname: Natsume
authors.forename: Kunio
authors.initials: K
authors.lastname: Atsumi
authors.forename: Hideki
authors.initials: H
authors.lastname: Fushimi
authors.forename: Takuji
authors.initials: T
authors.lastname: Yoshida
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ajito
mesh_terms: D000605:Amino Alcohols / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017963:Azithromycin / Q000031:analogs & derivatives / Q000494:pharmacology; D002264:Carboxylic Acids / Q000737:chemistry; D015939:Kitasamycin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
chemical_list: D000605:Amino Alcohols; D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D002264:Carboxylic Acids; D018942:Macrolides; D015939:Kitasamycin; D017963:Azithromycin