Chemical preparation, biological evaluation and 3D-QSAR of ethoxysulfuron derivatives as novel antifungal agents targeting acetohydroxyacid synthase
Chemical preparation, biological evaluation and 3D-QSAR of ethoxysulfuron derivatives as novel antifungal agents targeting acetohydroxyacid synthase
复制标题
乙氧基磺隆衍生物作为靶向乙酰羟酸合酶的新型抗真菌剂的化学制备、生物学评价和3D-QSAR
DOI：
10.1016/j.ejmech.2018.11.005
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发表时间：
2019-01-15
影响因子：
6.7
通讯作者：
Wang, Jian-Guo
中科院分区：
文献类型：
--
作者：
Wu, Ren-Jun;Ren, Tongtong;Wang, Jian-Guo
乙酰羟酸合成酶（AHAS）是第一个参与支链氨基酸生物合成途径的酶。小鼠模型中白色念珠菌的早期基因突变表明该酶是一个有希望的抗真菌药物靶点。最近的研究表明，一些商业AHAS抑制磺酰脲类除草剂具有良好的抗真菌活性。本文设计合成了68种新型乙氧硫隆（ethoxysulfulron，ES）衍生物，并测定了它们对C.白色念珠菌AHAS和基于细胞的最小抑制浓度（MIC）值。目标化合物5-1、5-10、5-22、5-31和5-37显示出比ES更强的AHAS抑制作用。化合物5-1对真菌AHAS的最佳Ki为6.7 nM，72 h后对白色念珠菌和近平滑念珠菌的MIC值为2.5 mg/L。本文建立了一种合适的线虫模型，并进一步评价了5-1的体内抗真菌活性。通过分子对接模拟了一种可能的结合模式，并构建了比较场分析（CoMFA）模型，以了解结构-活性关系。目前的研究表明，某些ES衍生物有望成为开发具有新生物靶点的抗真菌药物的理想选择。(C)2018年Elsevier Masson SAS。All rights reserved.
Accetohydroxyacid synthase (AHAS) is the first enzyme involved in the biosynthetic pathway of branched-chain amino acids. Earlier gene mutation of Candida albicans in a mouse model suggested that this enzyme is a promising target of antifungals. Recent studies have demonstrated that some commercial AHAS-inhibiting sulfonylurea herbicides exerted desirable antifungal activity. In this study, we have designed and synthesized 68 novel ethoxysulfulron (ES) derivatives and evaluated their inhibition constants (K-i) against C. albicans AHAS and cell based minimum inhibitory concentration (MIC) values. The target compounds 5-1, 5-10, 5-22, 5-31 and 5-37 displayed stronger AHAS inhibitions than ES did. Compound 5-1 had the best K-i of 6.7 nM against fungal AHAS and MIC values of 2.5 mg/L against Candida albicans and Candica parapsilosis after 72 h. A suitable nematode model was established here and the antifungal activity of 5-1 was further evaluated in vivo. A possible binding mode was simulated via molecular docking and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationship. The current study has indicated that some ES derivatives should be considered as promising hits to develop antifungal drugs with novel biological target. (C) 2018 Elsevier Masson SAS. All rights reserved.