Orally active cephalosporins. Part 3: synthesis, structure-activity relationships and oral absorption of novel C-3 heteroarylmethylthio cephalosporins.
A series of 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-(heteroarytmethylthio)cephalosporins was designed, synthesized and evaluated for antibacterial activity and oral absorption in rats. Antibacterial activity was markedly influenced by the structure of the heteroaromatic ring moiety. Oral absorption was influenced by the heteroaromatic ring moiety as well as by the arrangement of heteroatoms. Among these compounds, FK041 (2o), having a 4-pyrazolylmethylthio moiety, showed potent antibacterial activity against both gram-positive and gram-negative bacteria including Haemophilus influenzae. Further, it showed higher oral absorption than CFDN.
Yamamoto
H
H
Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Terasawa
T
T
Nakamura
A
A
Kawabata
K
K
Takasugi
H
H
Tanaka
H
H
Matsumoto
S
S
Matsumoto
Y
Y
Tawara
S
S
D000284:Administration, Oral; D000818:Animals; D001646:Bile / Q000737:chemistry; D002511:Cephalosporins / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006193:Haemophilus influenzae / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014556:Urine / Q000737:chemistry
D002511:Cephalosporins; C114137:FK 041; D006571:Heterocyclic Compounds