Synthesis of 8-substituted derivatives of the 2-deoxy analog of 3-deoxy-.beta.-D-manno-2-octulopyranosonic acid (2-deoxy-.beta.-KDO) as inhibitors of 3-deoxy-D-manno-octulosonate cytidylyltransferase

• Published in: Journal of medicinal chemistry 1989-05, Vol.32 (5), p.1069-1074
• Main Authors: Pring, Brian G, Jansson, Anita M, Persson, Kerstin, Andersson, Inger, Gagner-Milchert, Ingalill, Gustafsson, Kent, Claesson, Alf
• Format: Article
• Language: English
• Subjects: 3-deoxy-manno-octulosonate cytidylyltransferase; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - pharmacology; Bacteria - drug effects; Carbohydrates with 4, 5, 6, ... C atoms, dissacharides and oligosaccharides; Carbohydrates. Nucleosides and nucleotides; Chemistry; Enzyme Inhibitors; Exact sciences and technology; Lipid A - metabolism; Nucleotidyltransferases - antagonists & inhibitors; Organic chemistry; Preparations and properties; Structure-Activity Relationship; Sugar Acids - chemical synthesis; Sugar Acids - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00125a023

The 2-deoxy analogue of 3-deoxy-beta-D-manno-2-octulopyranosonic acid (2-deoxy-beta-KDO, 2) is a potent inhibitor of the enzyme 3-deoxy-D-manno-octulosonate cytidylyltransferase, which is involved in the biosynthesis of lipopolysaccharide, an essential component of the outer membrane of Gram-negative bacteria. Since compound 2 lacks antibacterial activity, a series of 8-substituted derivatives of 2 has been synthesized in an attempt to find enzyme inhibitors suitable for modification as antibacterials. Compounds 9, 11, and 13, in which the 8-hydroxy group of 2 is replaced by F, H, and NH2, respectively, were as potent inhibitors of the enzyme as 2, but were devoid of antibacterial activity, with the exception of the amino acid 13, which showed weak activity against some strains of Salmonella typhimurium.