Structure-activity Relationships of Cephalosporins Having a (Dimethylisoxazolidinio)vinyl Moiety at Their 3-Position

• Published in: Journal of antibiotics Vol. 49; no. 11; pp. 1162 - 1171
• Main Authors: HARAI, RYUICHIRO, SAKAMOTO, KENICHIRO, HISAMICHI, HIROYUKI, NAGANO, NORIAKI
• Format: Journal Article
• Language: English
• Published: TOKYO JAPAN ANTIBIOTICS RESEARCH ASSOCIATION 01.11.1996; JAPAN ANTIBIOT RES ASSN; Japan Antibiotics Research Association
• Subjects: Animals; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Biotechnology & Applied Microbiology; Cephalosporins - chemical synthesis; Cephalosporins - chemistry; Cephalosporins - pharmacology; Immunology; Life Sciences & Biomedicine; Medical sciences; Mice; Microbial Sensitivity Tests; Microbiology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Staphylococcal Infections - drug therapy; Staphylococcus aureus - drug effects; Structure-Activity Relationship; METHODOLOGY; Pseudomonadales; Enterococcus faecalis; Enterobacter cloacae; Molecular structure; Escherichia coli; Biosynthesis; Citrobacter freundii; Structure activity relation; Serratia marcescens; Bacteria; Micrococcales; Pseudomonadaceae; Pseudomonas aeruginosa; Streptococcus pyogenes; Micrococcaceae; Activity spectrum; Staphylococcus aureus; Enterobacteriaceae; Olefination; In vitro; Biological activity; Streptococcaceae; Antibiotic; Cephalosporin derivatives; Microbial origin; Antibacterial agent; Comparative study
• ISSN: 0021-8820; 1881-1469
• DOI: 10.7164/antibiotics.49.1162

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-l, 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 7β-[(Z)-2-(5-amino-l, 2, 4-thiadiazol-3-yl)-2-(fluoromethoxyimino)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.