Studies on anti-MRSA parenteral cephalosporins. II. Synthesis and antibacterial activity of 7beta-[2-(5-amino-1,2,4- thiadiazol-3-yl)-2(Z)-alkoxyiminoacetamido]-3-(substituted imidaz.
In an effort to discover a novel cefozopran (CZOP) derivative having excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA), we performed chemical modification of the alkoxyimino moiety and imidazo[1,2-b]pyridazinium group of CZOP. Among the prepared compounds, the cyclopentyloxyimino derivative 7beta-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-cyclopentyloxyiminoacetamido]-3-(3,6-diaminoimidazo[1,2-b]pyridazinium-1-yl)methyl-3-cephem-4-carboxylate (20 g) showed the most potent anti-MRSA activity, reflecting its high affinity (IC50 = 1.6 microg/ml) for penicillin binding protein 2' (PBP2'), although its anti-MRSA activity was slightly inferior to that of vancomycin (VCM). In experimental systemic infection in mice, however, 20 g showed activity comparable to that of VCM against MRSA. In addition, 20 g showed activity similar or slightly inferior to that of CZOP against Pseudomonas aeruginosa both in vitro and in vivo. Considering its favorable antibacterial activity profile, 20 g was considered to be the most promising CZOP derivative for further studies.
Ishikawa
T
T
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, Osaka, Japan.
Kamiyama
K
K
Matsunaga
N
N
Tawada
H
H
Iizawa
Y
Y
Okonogi
K
K
Miyake
A
A
D000818:Animals; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D016106:Methicillin Resistance; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests / Q000379:methods; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects*; D013329:Structure-Activity Relationship; D000097586:Cefozopran
D002511:Cephalosporins; D000097586:Cefozopran; C418195:7-(2-(5-amino-1,2,4-thiadiazol--3-yl)-2-cyclopentyloxyiminoacetamido)-3-(3,6-diaminoimidazo(1,2-b)pyridazinium-1-yl)methyl-3-cephem-4-carboxylate