Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase

Lee, Yu-Ting, Cui, Chang-Jun, Chow, Eve W. L., Pue, Nason, Lonhienne, Thierry, Wang, Jian-Guo, Fraser, James A. and Guddat, Luke W. (2013) Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase. Journal of Medicinal Chemistry, 56 1: 210-219. doi:10.1021/jm301501k


Author Lee, Yu-Ting
Cui, Chang-Jun
Chow, Eve W. L.
Pue, Nason
Lonhienne, Thierry
Wang, Jian-Guo
Fraser, James A.
Guddat, Luke W.
Title Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2013-01-10
Year available 2012
Sub-type Article (original research)
DOI 10.1021/jm301501k
Volume 56
Issue 1
Start page 210
End page 219
Total pages 10
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2013
Language eng
Formatted abstract
The sulfonylurea herbicides exert their activity by inhibiting plant acetohydroxyacid synthase (AHAS), the first enzyme in the branched-chain amino acid biosynthesis pathway. It has previously been shown that if the gene for AHAS is deleted in Candida albicans, attenuation of virulence is achieved, suggesting AHAS as an antifungal drug target. Herein, we have cloned, expressed, and purified C. albicans AHAS and shown that several sulfonylureas are inhibitors of this enzyme and possess antifungal activity. The most potent of these compounds is ethyl 2-(N-((4-iodo-6-methoxypyrimidin-2-yl)carbamoyl) sulfamoyl)benzoate (10c), which has a Ki value of 3.8 nM for C. albicans AHAS and an MIC90 of 0.7 μg/mL for this fungus in cell-based assays. For the sulfonylureas tested there was a strong correlation between inhibitory activity toward C. albicans AHAS and fungicidal activity, supporting the hypothesis that AHAS is the target for their inhibitory activity within the cell.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online: 13 December 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 08 Feb 2013, 13:16:55 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences