title: Computational design of novel inhibitors to overcome weed resistance associated with acetohydroxyacid synthase (AHAS) P197L mutant.
abstract: BACKGROUND
  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 of AHAS 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 derivatives were designed through fragment-based drug discovery. Fortunately, the newly synthesized compounds showed good inhibitory activity against both wild-type and P197L mutant. Some compounds not only had 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.
  
  
  CONCLUSIONS
  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. © 2016 Society of Chemical Industry.
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, People's Republic of China.
authors.forename: Ren-Yu
authors.initials: RY
authors.lastname: Qu
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, People's Republic of China.
authors.forename: Jing-Fang
authors.initials: JF
authors.lastname: Yang
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, People's Republic of China.
authors.forename: Yu-Chao
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, People's Republic of China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, People's Republic of China.
authors.forename: Ge-Fei
authors.initials: GF
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, People's Republic of China.
authors.forename: Cong-Wei
authors.initials: CW
authors.lastname: Niu
authors.affiliation: State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, People's Republic of China.|Collaborative Innovation Center of Chemical Science and Engineering, Tianjing, 300071, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xi
authors.affiliation: Key Laboratory of Pesticide and Chemical Biology of Ministry of Education, College of Chemistry, Central China Normal University, Wuhan, 430079, People's Republic of China.|Collaborative Innovation Center of Chemical Science and Engineering, Tianjing, 300071, People's Republic of China.
authors.forename: Guang-Fu
authors.initials: GF
authors.lastname: Yang
mesh_terms: D000095:Acetolactate Synthase / Q000037:antagonists & inhibitors*; D019607:Brassicaceae / Q000201:enzymology / Q000235:genetics*; D019295:Computational Biology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D053209:Herbicide Resistance; D006540:Herbicides / Q000737:chemistry*; D009154:Mutation; D013329:Structure-Activity Relationship; D058728:Weed Control
chemical_list: D004791:Enzyme Inhibitors; D006540:Herbicides; D000095:Acetolactate Synthase
keywords: acetohydroxyacid synthase; fragment-based drug discovery; herbicide; pyrimidinyl salicylic acid; weed resistance