A novel series of parenteral cephalosporins exhibiting potent activities against both Pseudomonas aeruginosa and other gram-negative pathogens. Part 2: Synthesis and structure-activity relationships.
A novel series of 7beta-[2-(2-amino-5-chloro-thiazol-4-yl)-2(Z)-((S)-1-carboxyethoxyimino)acetamido]cephalosporins bearing various pyridinium groups at the C-3' position were synthesized and their in vitro antibacterial activities against gram-negative pathogens including Pseudomonas aeruginosa and several gram-positive pathogens were evaluated. Among the cephalosporins prepared, we found that a cephalosporin bearing the 2-amino-1-(3-methylamino-propyl)-1H-imidazo[4,5-b]pyridinium group at the C-3' position (8a) showed potent and well-balanced 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). Compound 8a also showed efficacious in vivo activity and high stability against AmpC beta-lactamase. These findings indicate that 2-aminoimidazopyridinium having an aminoalkyl group at the 1-position as a C-3' side chain is suitable for cephalosporins bearing an aminochlorothiazolyl moiety and a carboxyethoxyimino moiety on the C-7 side chain.
Yamawaki
Kenji
K
Discovery Research Laboratories, Shionogi & Co., Ltd., 12-4, Sagisu 5-chome, Fukushima-ku, Osaka 553-0002, Japan. kenji.yamawaki@shionogi.co.jp
Nomura
Takashi
T
Yasukata
Tatsuro
T
Tanimoto
Norihiko
N
Uotani
Koichi
K
Miwa
Hideaki
H
Yamano
Yoshinori
Y
Takeda
Kei
K
Nishitani
Yasuhiro
Y
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis*; D002511:Cephalosporins / Q000138:chemical synthesis / Q000737:chemistry*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D011725:Pyridines; D013329:Structure-Activity Relationship; D001618:beta-Lactamases
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D011725:Pyridines; D001618:beta-Lactamases; C023666:pyridine