Analogues of the mycobacterial arabinogalactan linkage disaccharide as cell wall biosynthesis inhibitors.
The mycobacterial arabinogalactan linkage disaccharide [alpha-L-Rha-(1-->3)-alpha-D-GlcNAc] provides a basis for the design of new antitubercular drugs, since it supports a key skeletal structure in the bacterial cell wall. A series of analogues of the linker was synthesized by coupling appropriate thiorhamnosyl donors modified at their 4-positions, with an N-acetyl glucosamine acceptor. In a cell-free enzyme inhibition assay, three analogues inhibited the activity of the galactosyltransferase that adds a Galf residue to the linkage disaccharide. Although the compounds were modest inhibitors, these data confirm the viability of this approach to anti-mycobacterial agents. It is especially significant that the three effective compounds are modified at the site of the acceptor atom in the natural substrate.
Wen
Xianghui
X
Department of Chemistry, University of Manitoba, R3T 2N2, Winnipeg, MB, Canada.
Crick
Dean C
DC
Brennan
Patrick J
PJ
Hultin
Philip G
PG
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002236:Carbohydrate Conformation; D002473:Cell Wall / Q000187:drug effects / Q000378:metabolism; D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005685:Galactans / Q000737:chemistry* / Q000494:pharmacology*; D009161:Mycobacterium / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D011134:Polysaccharides / Q000138:chemical synthesis
D000995:Antitubercular Agents; D004187:Disaccharides; D004791:Enzyme Inhibitors; D005685:Galactans; D011134:Polysaccharides; C005653:arabinogalactan