Cephalosporins having a heterocyclic catechol in the C3 side chain. II. Improvement of pharmacokinetic profile.
7-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxy-(or hydroxy)-iminoacetamido]-3- [propen-1-yl]-cephalosporins having a variety of heterocyclic catechol in 3-position of the propenyl group were synthesized. Among them, 6,7-dihydroxyisoquinoline derivatives, 2a and 2b, showed very high and prolonged blood levels after intramuscular administration to mice and higher in vivo antibacterial activity than expected from their in vitro activity. The former cephalosporin (2a) gave well-balanced in vitro and in vivo antibacterial spectra including anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. The latter cephalosporin (2b) also showed good in vitro and in vivo activities against Gram-positive bacteria, especially against S. aureus A15036, a strain of MRSA, the in vivo activity being comparable to vancomycin but was lacking in anti-pseudomonal activity.
Iimura
S
S
Bristol-Myers Squibb Research Institute, Bristol-Myers Squibb K.K., Tokyo.
Imae
K
K
Hasegawa
T
T
Okita
T
T
Tamaoka
M
M
Murata
S
S
Kamachi
H
H
Kamei
H
H
D000818:Animals; D001424:Bacterial Infections / Q000188:drug therapy; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D006207:Half-Life; D051379:Mice; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
D002511:Cephalosporins; D002442:Ceftazidime