Cephalosporins having a heterocyclic catechol in the C3 side chain. I. Enhancement of efficacy against gram-negative bacteria.
Two groups of cephalosporins substituted with a variety of heterocyclic catechols in the C3 side chain were synthesized. One is a group of 3-(heterocyclic catechol-substituted methyl)cephalosporins and another is 3-[(E)-3-heterocyclic catechol-substituted 1-propen-1-yl]cephalosporins. Cephalosporins in the latter group showed higher in vivo efficacies than those in the former group having the same heterocyclic catechol, especially against Pseudomonas aeruginosa A9843A, although there was no significant difference between their in vitro activity. Among the latter group, the 5,6-dihydroxybenzimidazole derivative (6e) and the 2,6-dihydro-7-hydroxy-6-oxo- isoquinoline derivative (6b) showed much higher activity than ceftazidime (CAZ) and imipenem (IPM) against P. aeruginosa A9843A both in in vitro and in vivo studies.
Imae
K
K
Bristol-Myers Squibb Research Institute, Bristol-Myers Squibb K.K., Tokyo, Japan.
Imura
S
S
Hasegawa
T
T
Okita
T
T
Hirano
M
M
Kamachi
H
H
Kamei
H
H
D000818:Animals; D002442:Ceftazidime / Q000494:pharmacology; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D015378:Imipenem / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000188:drug therapy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D002511:Cephalosporins; C088158:7-(2-(2-aminothiazol-4-yl)-2- (1-carboxy-1-methylethoxyimino)acetamido)-3-(3-(5,6-dihydroxybenzimidazol-1-yl)propen-1-yl)-3-cephem-4-carboxylic acid; C081747:7-(2-(2-aminothiazol-4-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido)-3-(3-(2,6-dihydro-7-hydroxy-6-oxoisoquinolin-2-yl)propen-1-yl)-3-cephem-4-carboxylic acid; D015378:Imipenem; D002442:Ceftazidime