Structure-activity relationships of cephalosporins having a (dimethylisoxazolidinio)vinyl moiety at their 3-position.
A series of cephalosporins having a (dimethylisoxazolidinio)vinyl group at their 3-position were synthesized to investigate their structure-activity relationships. With regard to the olefin geometry, the (E)-vinyl compound exhibited higher in vitro activity than the (Z)-compound. Regarding the C-7 substituents, the replacement of 2-aminothiazole with 5-amino-1,2,4-thiadiazole increased the anti-pseudomonal activity. Determination of the absolute configuration of the C-3 substituent is also presented. Among the compounds synthesized, we selected 7 beta-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(fluoromethoxyimi no)acetamido]-3-[(E)-2-((S)-2,2-dimethyl-5-isoxazolidinio)vinyl ]-3-cephem-4-carboxylate (YM-40220), which showed well-balanced in vitro activity and an excellent in vivo efficacy against Staphylococcus aureus Smith, as a candidate for further development.
Hara
R
R
Infectious Disease & Immunology Research Labs, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Sakamoto
K
K
Hisamichi
H
H
Nagano
N
N
D000818:Animals; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
D002511:Cephalosporins