School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane 4072, Queensland, Australia.
J Med Chem. 2013 Jan 10;56(1):210-9. doi: 10.1021/jm301501k. Epub 2012 Dec 31.
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.
磺酰脲类除草剂通过抑制植物乙酰羟酸合酶（AHAS）发挥作用，AHAS 是支链氨基酸生物合成途径中的第一个酶。先前的研究表明，如果 Candida albicans 中的 AHAS 基因缺失，则会减弱其毒力，这表明 AHAS 是一种抗真菌药物靶标。本文中，我们克隆、表达并纯化了 C. albicans AHAS，并证实了几种磺酰脲类化合物是该酶的抑制剂，具有抗真菌活性。其中最有效的化合物是乙基 2-（N-（（4-碘-6-甲氧基嘧啶-2-基）氨基甲酰基）磺酰基）苯甲酸酯（10c），其对 C. albicans AHAS 的 K(i) 值为 3.8 nM，在细胞测定中对该真菌的 MIC₉₀为 0.7 μg/mL。对于测试的磺酰脲类化合物，它们对 C. albicans AHAS 的抑制活性与杀菌活性之间存在很强的相关性，这支持了 AHAS 是其在细胞内抑制活性的靶标的假设。
