A novel series of parenteral cephalosporins exhibiting potent activities against Pseudomonas aeruginosa and other Gram-negative pathogens: synthesis and structure-activity relationships.
A series of 7beta-[2-(2-aminothiazol-4-yl)-2-(Z)-(carboxymethoxyimino)acetamido]cephalosporins bearing a 1-(substituted)-1H-pyrrolo[3,2-b]pyridinium group at C-3' position was synthesized and their in vitro antibacterial activities against Pseudomonas aeruginosa and other Gram-negative pathogens were evaluated. Among the cephalosporins prepared, 7beta-[2-(2-amino-5-chlorothiazol-4yl)-2(Z)-((S)-1-carboxyethoxyimino)acetamido]cephalosporins (42d) showed potent antibacterial activities against P. aeruginosa and other Gram-negative pathogens including the strains which produce class C beta-lactamase and extended spectrum beta-lactamase (ESBL). These results imply that both the Cl atom on the C-7 aminothiazole moiety and the alpha-substituent at the iminoether moiety are essential for the stability against beta-lactamase and the potent activity against Gram-negative bacteria including P. aeruginosa.
Yamawaki
Kenji
K
Discovery Research Laboratories, Shionogi & Co Ltd, 12-4, Sagisu 5-Chome, Osaka, Japan. kenji.yamawaki@shionogi.co.jp
Nomura
Takashi
T
Yasukata
Tatsuro
T
Uotani
Koichi
K
Miwa
Hideaki
H
Takeda
Kei
K
Nishitani
Yasuhiro
Y
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002511:Cephalosporins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004333:Drug Administration Routes; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006801:Humans; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D002511:Cephalosporins