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

Yu-Ting Lee, Chang-Jun Cui, Eve W L Chow, Nason Pue, Thierry Lonhienne, Jian-Guo Wang, James A Fraser, Luke W Guddat

School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia.

Journal of medicinal chemistry 2013 Jan 10

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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 K(i) 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.

Citation

Yu-Ting Lee, Chang-Jun Cui, Eve W L Chow, Nason Pue, Thierry Lonhienne, Jian-Guo Wang, James A Fraser, Luke W Guddat. Sulfonylureas have antifungal activity and are potent inhibitors of Candida albicans acetohydroxyacid synthase. Journal of medicinal chemistry. 2013 Jan 10;56(1):210-9