Synthesis and structure-activity relationships of new cephalosporins with aminoimidazoles at C-7. Effect of the pKa of the C-7 aminoimidazole on antibacterial spectrum and beta-lactamase stability.
Cephalosporins with new aminoimidazole heterocycles at C-7 have been synthesized by reaction of anti-alpha-aminooximes with C-7 dihaloisocyanocephalosporins esters or by direct condensation of 2-fluoroimidazoles with C-7 aminocephalosporins esters. These compounds combine a broad spectrum of antibacterial activity, including Gram-negative and Gram-positive organisms with a good beta-lactamase stability. Activity is discussed in terms of its relationship to the pKa of the C-7 aminoimidazole heterocycle, basic C-7 aminoimidazole residues gave cephalosporins with the best beta-lactamase stability but the poorest activity against Gram-positive organisms. An additional interesting property of the C-7 imidazolylaminocephalosporins is the oral activity present in some compounds of this series.
Jung
F
F
ZENECA Pharma, Centre de Recherches, Zone Industrielle La Pompelle, REIMS, France.
Boucherot
D
D
Delvare
C
C
Olivier
A
A
Davies
G M
GM
Betts
M J
MJ
Brown
R
R
Stevenson
R
R
Joseph
M
M
Kingston
J F
JF
D000818:Animals; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000494:pharmacology*; D004795:Enzyme Stability / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000737:chemistry* / Q000187:drug effects
D002511:Cephalosporins; D007093:Imidazoles; D001618:beta-Lactamases