ABSTRACT
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.
Subject(s)
Cephalosporins/chemical synthesis , Cephalosporins/pharmacology , Animals , Cephalosporins/chemistry , Mice , Microbial Sensitivity Tests , Staphylococcal Infections/drug therapy , Staphylococcus aureus/drug effects , Structure-Activity RelationshipABSTRACT
An improved synthesis and in vitro activity of cephalosporins with a (4-carboxy-3-hydroxy-5-isothiazolyl)thiomethyl group at the 3-position and its application to the preparation of new derivatives are described. These compounds showed excellent activity against Gram-negative bacteria including beta-lactamase producing strains. Among them, 2f was the most interesting because of its broad spectrum of antibacterial activity, including Gram-positive bacteria, and its outstanding inhibitory potency against Pseudomonas aeruginosa.
