Wang Jian-Guo, Li Zheng-Ming, Ma Ning, Wang Bao-Lei, Jiang Lin, Pang Siew Siew, Lee Yu-Ting, Guddat Luke W, Duggleby Ronald G
Elemento-Organic Chemistry Institute, State Key Laboratory of Elemento-Organic Chemistry, National Pesticide Engineering Research Center, Nankai University, 300071, Tianjin , PR China.
J Comput Aided Mol Des. 2005 Nov;19(11):801-20. doi: 10.1007/s10822-005-9028-9. Epub 2005 Dec 23.
Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) catalyzes the first common step in branched-chain amino acid biosynthesis. The enzyme is inhibited by several chemical classes of compounds and this inhibition is the basis of action of the sulfonylurea and imidazolinone herbicides. The commercial sulfonylureas contain a pyrimidine or a triazine ring that is substituted at both meta positions, thus obeying the initial rules proposed by Levitt. Here we assess the activity of 69 monosubstituted sulfonylurea analogs and related compounds as inhibitors of pure recombinant Arabidopsis thaliana AHAS and show that disubstitution is not absolutely essential as exemplified by our novel herbicide, monosulfuron (2-nitro-N-(4'-methyl-pyrimidin-2'-yl) phenyl-sulfonylurea), which has a pyrimidine ring with a single meta substituent. A subset of these compounds was tested for herbicidal activity and it was shown that their effect in vivo correlates well with their potency in vitro as AHAS inhibitors. Three-dimensional quantitative structure-activity relationships were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. For the latter, the best result was obtained when steric, electrostatic, hydrophobic and H-bond acceptor factors were taken into consideration. The resulting fields were mapped on to the published crystal structure of the yeast enzyme and it was shown that the steric and hydrophobic fields are in good agreement with sulfonylurea-AHAS interaction geometry.
乙酰羟酸合酶（AHAS；EC 2.2.1.6）催化支链氨基酸生物合成的第一步共同反应。该酶受到几类化合物的抑制，这种抑制作用是磺酰脲类和咪唑啉酮类除草剂作用的基础。商业磺酰脲类化合物含有一个嘧啶环或三嗪环，且在两个间位均有取代，因此符合莱维特提出的最初规则。在此，我们评估了69种单取代磺酰脲类似物及相关化合物作为纯重组拟南芥AHAS抑制剂的活性，并表明双取代并非绝对必要，我们的新型除草剂单嘧磺隆（2-硝基-N-(4'-甲基-嘧啶-2'-基)苯基-磺酰脲）就是例证，它有一个仅在间位有单个取代基的嘧啶环。对这些化合物的一个子集进行了除草活性测试，结果表明它们在体内的作用与其作为AHAS抑制剂在体外的效力密切相关。使用比较分子场分析和比较分子相似性指数分析建立了三维定量构效关系。对于后者，当考虑空间、静电、疏水和氢键受体因素时获得了最佳结果。将所得场映射到已发表的酵母酶晶体结构上，结果表明空间场和疏水场与磺酰脲-AHAS相互作用几何结构吻合良好。
