Synthesis and structure-activity relationship of new cephalosporins with amino heterocycles at C-7. Dependence of the antibacterial spectrum and beta-lactamase stability on the pKa of the C-7 heterocycle.
Cephalosporins with new aminobenzimidazole and aminoimidazoline heterocycles at C-7 have been synthesized starting with versatile C-7 isocyanide dihalide synthons. The aminobenzimidazoles have a broad spectrum of antibacterial activity, including Gram-positive and Gram-negative organisms, but possess limited beta-lactamase stability. In contrast, the aminoimidazolines have a narrow spectrum of antibacterial activity, limited to Gram-negative strains only, but possess outstanding beta-lactamase stability. Structure-activity relationships are discussed in terms of their dependence on the pKa of the C-7 amino heterocycle, basic C-7 residues giving cephalosporins with exceptional beta-lactamase stability.
Jung
F
F
I.C.I. Pharma, Centre de Recherches, Zone Industrielle La Pompelle, Reims, France.
Delvare
C
C
Boucherot
D
D
Hamon
A
A
Ackerley
N
N
Betts
M J
MJ
D001419:Bacteria / Q000187:drug effects*; D002511:Cephalosporins / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006571:Heterocyclic Compounds; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D001618:beta-Lactamases / Q000378:metabolism*
D002511:Cephalosporins; D006571:Heterocyclic Compounds; D007093:Imidazoles; D001618:beta-Lactamases