Synthesis of 8-substituted derivatives of the 2-deoxy analogue of 3-deoxy-beta-D-manno-2-octulopyranosonic acid (2-deoxy-beta-KDO) as inhibitors of 3-deoxy-D-manno-octulosonate cytidylyltransferase.
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.
Pring
B G
BG
Department of Antibacterial Chemotherapy, Research and Development, Astra Alab AB, Södertälje, Sweden.
Jansson
A M
AM
Persson
K
K
Andersson
I
I
Gagner-Milchert
I
I
Gustafsson
K
K
Claesson
A
A
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D004791:Enzyme Inhibitors; D008050:Lipid A / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013400:Sugar Acids / Q000138:chemical synthesis* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D008050:Lipid A; D013400:Sugar Acids; C052138:2,6-anhydro-3-deoxyoctonate; D009713:Nucleotidyltransferases; C028984:3-deoxy-manno-octulosonate cytidyltransferase