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.
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.
Miura
Tomoaki
T
Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd, 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. tomoaki_miura@meiji.co.jp
Kanemoto
Kenichi
K
Natsume
Satomi
S
Atsumi
Kunio
K
Fushimi
Hideki
H
Yoshida
Takuji
T
Ajito
Keiichi
K
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
D000605:Amino Alcohols; D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D002264:Carboxylic Acids; D018942:Macrolides; D015939:Kitasamycin; D017963:Azithromycin