Synthesis of deoxygenated alpha(1-->5)-linked arabinofuranose disaccharides as substrates and inhibitors of arabinosyltransferases of Mycobacterium tuberculosis.
Arabinosyltransferases (AraTs) play a critical role in mycobacterial cell wall biosynthesis and are potential drug targets for the treatment of tuberculosis, especially multi-drug resistant forms of M. tuberculosis (MTB). Herein, we report the synthesis and acceptor/inhibitory activity of Araf alpha(1-->5) Araf disaccharides possessing deoxygenation at the reducing sugar of the disaccharide. Deoxygenation at either the C-2 or C-3 position of Araf was achieved via a free radical procedure using xanthate derivatives of the hydroxyl group. The alpha(1-->5)-linked disaccharides were produced by coupling n-octyl alpha-Araf 2-/3-deoxy, 2-fluoro glycosyl acceptors with an Araf thioglycosyl donor. The target disaccharides were tested in a cell free mycobacterial AraTs assay as well as an in vitro assay against MTB H(37)Ra and M. avium complex strains.
Pathak
Ashish K
AK
Drug Discovery Division, Southern Research Institute, PO Box 55305, Birmingham, AL 35255, USA.
Pathak
Vibha
V
Suling
William J
WJ
Riordan
James R
JR
Gurcha
Sudagar S
SS
Besra
Gurdyal S
GS
Reynolds
Robert C
RC
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001089:Arabinose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004187:Disaccharides / Q000138:chemical synthesis* / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010430:Pentosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity
D000900:Anti-Bacterial Agents; D004187:Disaccharides; C431714:arabinofuranose; D001089:Arabinose; D010430:Pentosyltransferases; C101967:arabinosyltransferase