A novel series of parenteral cephalosporins exhibiting potent activities against Pseudomonas aeruginosa and other Gram-negative pathogens: Synthesis and structure–activity relationships

• Published in: Bioorganic & medicinal chemistry 2007-11, Vol.15 (21), p.6716-6732
• Main Authors: Yamawaki, Kenji, Nomura, Takashi, Yasukata, Tatsuro, Uotani, Koichi, Miwa, Hideaki, Takeda, Kei, Nishitani, Yasuhiro
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Cephalosporin; Cephalosporins - chemical synthesis; Cephalosporins - chemistry; Cephalosporins - pharmacology; Drug Administration Routes; Extended spectrum β-lactamase; Gram-Negative Bacteria - drug effects; Gram-negative bacterium; Humans; Medical sciences; Pharmacology. Drug treatments; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Resistant; Structure-Activity Relationship; β-Lactamase
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.08.001

A novel series of cephalosporins bearing a chlorominothiazole and a carboxymethoxyimino moiety at the C-7 side chain was prepared, and their antibacterial activities were evaluated. A series of 7β-[2-(2-aminothiazol-4-yl)-2-( Z)-(carboxymethoxyimino)acetamido]cephalosporins bearing a 1-(substituted)-1 H-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, 7β-[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 β-lactamase and extended spectrum β-lactamase (ESBL). These results imply that both the Cl atom on the C-7 aminothiazole moiety and the α-substituent at the iminoether moiety are essential for the stability against β-lactamase and the potent activity against Gram-negative bacteria including P. aeruginosa.