Novel broad-spectrum and long-acting parenteral cephalosporins having an acyl cyanamide moiety at the C-3 terminal: Synthesis and structure-activity relationships

• Published in: European journal of medicinal chemistry Vol. 124; pp. 698 - 712
• Main Authors: Yokoo, Katsuki, Yamawaki, Kenji, Yoshida, Yutaka, Yonezawa, Shuji, Yamano, Yoshinori, Tsuji, Masakatsu, Hori, Toshihiko, Nakamura, Rio, Ishikura, Koji
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 29.11.2016; Elsevier
• Subjects: Acyl cyanamide; Animals; Anti-Infective Agents - chemistry; Anti-Infective Agents - pharmacokinetics; Anti-Infective Agents - pharmacology; Bacteria - drug effects; BLNAR; Cephalosporin; Cephalosporins - chemistry; Cephalosporins - pharmacokinetics; Cephalosporins - pharmacology; Chemistry, Medicinal; Cyanamide - chemistry; Cyanamide - pharmacokinetics; Cyanamide - pharmacology; Disease Models, Animal; Half-Life; Haplorhini - metabolism; Life Sciences & Biomedicine; Long acting; Male; Mice; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; PRSP; Science & Technology; Structure-Activity Relationship; BLNAR; Long acting; PRSP; Acyl cyanamide; Cephalosporin; ANTIMICROBIAL SUSCEPTIBILITY; RO 13-9904
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2016.09.015

A series of novel 7β-[2-(2-aminothiazole-4-yl)-2-(Z)-(alkoxyimino)acetamido]-cephalosporins having pyridinium-linked acyl cyanamide at the C-3 position were prepared and their antibacterial activities and pharmacokinetics profiles were evaluated. Most of the compounds exhibited potent antibacterial activities against penicillin-resistant Streptococcus pneumoniae (PRSP) and β-lactamase non-producing penicillin-resistant Haemophilus influenzae (BLNAR). Introduction of a propenyl group between the cephalospoin core and the side chains at the C-3 position improved the pharmacokinetics profile. Among these compounds, 7β-[2-(2-aminothiazole-4-yl)-2-(Z)- (alkoxyimino)acetamido]-3-(pyridin-1-ium-1-yl)prop-1-en-1-yl)cephalosporins (32j) showed well-balanced antibacterial activity against S. pneumoniae and H. influenzae which included resistant strains and also other Gram-positive or Gram-negative pathogens. Furthermore, 32j showed a long half-life comparable to that of Ceftriaxone in mice and monkeys. [Display omitted] •New cephalosporin compounds having acyl cyanamide group were synthesized.•Most of them showed good antibacterial activity against PRSP and BLNAR.•In particular, the compounds introduced propenyl group as a linker showed long acting feature.