title: Novel broad-spectrum and long-acting parenteral cephalosporins having an acyl cyanamide moiety at the C-3 terminal: Synthesis and structure-activity relationships.
abstract: 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.
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan. Electronic address: katsuki.yokoo@shionogi.co.jp.
authors.forename: Katsuki
authors.initials: K
authors.lastname: Yokoo
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamawaki
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Yonezawa
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Yamano
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Tsuji
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Hori
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Rio
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Shionogi Pharmaceutical Research Center, Shionogi & Co., Ltd., 1-1, Futaba-cho, 3-chome, Toyonaka, Osaka 561-0825, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ishikura
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects*; D002511:Cephalosporins / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D003484:Cyanamide / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004195:Disease Models, Animal; D006207:Half-Life; D000882:Haplorhini / Q000378:metabolism; D008297:Male; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000890:Anti-Infective Agents; D002511:Cephalosporins; D003484:Cyanamide
keywords: Acyl cyanamide; BLNAR; Cephalosporin; Long acting; PRSP