Design and synthesis of substrate-mimic inhibitors of mycothiol-S-conjugate amidase from Mycobacterium tuberculosis.
The Staudinger reaction between a polymer-supported triphenylphosphine reagent and pseudo-disaccharide azides is successfully applied to synthesize a variety of substrate-mimic mycothiol analogs. Screening of this new group of analogs against the mycobacterial detoxification enzyme mycothiol-S-conjugate amidase (MCA) yielded several modest inhibitors (IC50 values around 50 microM) and provided additional structure-activity relationships for future optimization of inhibitors of MCA and its homologs.
Metaferia
Belhu B
BB
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Ray
Satyajit
S
Smith
Jeremy A
JA
Bewley
Carole A
CA
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006020:Glycopeptides / Q000737:chemistry / Q000378:metabolism; D006031:Glycosylation; D007294:Inositol / Q000737:chemistry / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D006020:Glycopeptides; C089265:mycothiol; D007294:Inositol; D000581:Amidohydrolases; C413523:mycothiol S-conjugate amidase; D003545:Cysteine