Rhodanine-3-acetic acid derivatives as inhibitors of fungal protein mannosyl transferase 1 (PMT1).
The first inhibitors of fungal protein: mannosyl transferase 1 (PMT1) are described. They are based upon rhodanine-3-acetic acid and several compounds have been identified, for example, 5-[[3-(1-phenylethoxy)-4-(2-phenylethoxy)phenyl]methylene]-4-oxo-2-thioxo-3-thiazolidineacetic acid (5a), which inhibit Candida albicans PMT1 with IC(50)s in the range 0.2-0.5 microM. Members of the series are effective in inducing changes in morphology of C. albicans in vitro that have previously been associated with loss of the transferase activity. These compounds could serve as useful tools for studying the effects of protein O-mannosylation and its relevance in the search for novel antifungal agents.
Orchard
Michael G
MG
Department of Medicinal Chemistry, 4-10 The Quadrant, Abingdon Science Park, Abingdon, Oxfordshire OX14 4YS, UK. mike.orchard@celltechgroup.com
Neuss
Judi C
JC
Galley
Carl M S
CM
Carr
Andrew
A
Porter
David W
DW
Smith
Phillip
P
Scopes
David I C
DI
Haydon
David
D
Vousden
Katherine
K
Stubberfield
Colin R
CR
Young
Kate
K
Page
Martin
M
D002176:Candida albicans / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005658:Fungi / Q000187:drug effects / Q000201:enzymology; D008364:Mannosyltransferases / Q000037:antagonists & inhibitors*; D008826:Microbial Sensitivity Tests; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D012236:Rhodanine; D008364:Mannosyltransferases; C082696:protein O-mannosyltransferase