Orally active cephalosporins. Part 4: synthesis, structure--activity relationships and oral absorption of novel 3-(4-pyrazolylmethylthio)cephalosporins with various C-7 side chains.
A series of 3-(4-pyrazolylmethylthio)cephalosporins with various C-7 side chains was designed, synthesized and evaluated for antibacterial activity and oral absorption in rats. Antibacterial activity against Haemophilus influenzae was markedly increased by the C-7 oxime moiety. Deamination at the 2 position of, or introduction of a substituent such as halogen or methyl to, the 5 position of the (Z)-2-(2-aminothiazol-4-yl)-2-(hydroxyimino) moiety improved oral absorption. Among these compounds, FR192752 having a (Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-hydroxyiminoacetamido moiety, showed potent antibacterial activity against both Gram-positive and Gram-negative bacteria including H.influenzae and penicillin G-resistant Streptococcus pneumoniae (PRSP). Further, it showed higher oral absorption than CFDN and FK041.
Yamamoto
Hirofumi
H
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 2-1-6, Kashima, Yodogawa-ku, 532-8514, Osaka, Japan.
Eikyu
Yoshiteru
Y
Okuda
Shinya
S
Kawabata
Kohji
K
Takasugi
Hisashi
H
Tanaka
Hirokazu
H
Matsumoto
Satoru
S
Matsumoto
Yoshimi
Y
Tawara
Shuichi
S
D000284:Administration, Oral; D000818:Animals; D001646:Bile; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014556:Urine
D002511:Cephalosporins