Computational design of novel inhibitors to overcome weed resistance associated with acetohydroxyacid synthase (AHAS) P197L mutant
Computational design of novel inhibitors to overcome weed resistance associated with acetohydroxyacid synthase (AHAS) P197L mutant
复制标题
克服与乙酰羟酸合酶（AHAS）P197L突变体相关的杂草抗性的新型抑制剂的计算设计
DOI：
10.1002/ps.4460
复制
发表时间：
2017-07-01
影响因子：
4.1
通讯作者：
Yang, Guang-Fu
中科院分区：
文献类型：
--
作者：
Qu, Ren-Yu;Yang, Jing-Fang;Yang, Guang-Fu
背景：乙酰羟酸合成酶(AHAS；EC 2.2.1.6)是植物和多种微生物体内支链氨基酸生物合成途径中的第一个常见酶。随着AHAS类除草剂的长期广泛应用，杂草抗性已成为一个全球性的问题，迫切需要新型的拮抗野生型和抗性AHAS的除草剂。结果：嘧啶水杨酸衍生物作为一类主要的商品化AHAs除草剂，对野生型和P197L突变体表现出潜在的抗药性生物活性。在本工作中，通过基于片段的药物发现，设计了一系列新型的2-苯甲酰氧基-6-嘧啶水杨酸衍生物。幸运的是，新合成的化合物对野生型和P197L突变体都表现出良好的抑制活性。有些菌株具有较低的抗性因子值，但对野生型AHAs和突变体P197L也表现出良好的抑制活性。此外，温室实验表明，化合物11M在150g a.i.剂量下对野生型和高抗播娘菊均表现出近100%的抑制作用。HA(-1)。结论：2-苯甲酰氧基-6-嘧啶水杨酸模体具有进一步优化的价值。此外，化合物11M还可作为一种潜在的抗药性AHAs除草剂，有待于进一步研究。(三)2016年化学工业学会
BACKGOUND: Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is the first common enzyme in the biosynthetic pathway leading to the branched-chain amino acids in plants and a wide range of microorganisms. With the long-term and wide application ofAHAS inhibitors, weed resistance is becoming a global problem, which leads to an urgent demand for novel inhibitors to antagonize both wild-type and resistant AHAS.RESULTS: Pyrimidinyl salicylic acid derivatives, as one of the main classes of commercial AHAS herbicides, show potential anti-resistant bioactivity to wild-type and P197L mutant. In current work, a series of novel 2-benzoyloxy-6-pyrimidinyl salicylic acid derivativesweredesigned throughfragment-baseddrugdiscovery. Fortunately, the newly synthesizedcompoundsshowed goodinhibitory activity against both wild-type andP197Lmutant. Somecompoundsnotonlyhad a lower resistance factor value but also showed excellent inhibitory activity against wild-type AHAS and P197L mutant. Furthermore, greenhouse experiments showed compound 11m displayed almost 100% inhibition against both wild-type and high-resistant Descurainia sophia at a dosage of 150 g a.i. ha(-1).CONCLUSION: The present work indicated that the 2-benzoyloxy-6-pyrimidinyl salicylic acid motif was well worth further optimization. Also, compound 11m could be used as a potential anti-resistant AHAS herbicide, which requires further research. (C) 2016 Society of Chemical Industry