Design, Synthesis And Herbicidal Activity Of Novel Acetyl-coenzyme A Carboxylase And D1 Protease Inhibitors

Acetyl-CoA Carboxylase (ACCase) is the key enzyme that catalyses the plant fatty acid biosynthesis in the plant metabolism. The ACCase inhibitors are typically herbicides act through inhibition of homomeric ACCase in the gramineous grass and used for the selective, post-emergence control of grasses in broadleaf crops. Most herbicides in this class are translocated within the phloem of grasses environmentally friendly and crop safe. Design and discovery of novel ACCase-Inhibitor herbicides with high activities are still important tasks; Dl protease (CtpA) is a kind of C-terminal processing protease and catalyzes carboxyl terminal processing of the D1 protein of photosystem II, which is essential for the assembly of a manganese cluster and consequent light-mediated water oxidation. This processing is essential for photosynthesis, which is itself essential for plant growth; The inhibitors of the D1 protease that could target the photosynthetic apparatus of plant would constitute a broad spectrum herbicides. To develop new herbicides targeting Dl protease possess great potential to solve the resistance problems in agriculture.In this thesis, three series of one hundred and twenty-eight ACCase inhibitors containing pyrimidine ring and twenty-six D1 protease inhibitors with topology structure were designed and synthesized based on the bioisosterism and structure-based drug design. The molecular structures of the target compounds were characterized with'H NMR and MS spectroscopies, and some were also confirmed with IR, 13C NMR, elemental analysis and X-ray crystallography. Preliminary bioassay showed that most of title compounds showed moderate to good herbicidal activities. This dissertation maybe summarized as follows:1. In the preamble, the strategies for the discovery of new herbicides are summarized as well as the research progress of ACCase and D1 protease inhibitors are also reviewed in detail. Based on the deficiencies and problems of the research on herbicide, an outline of the research proposal in this thesis is designed and listed.2. Fifty-nine R enantiomers of aryloxyphenyloxypropionate herbicides containing pyrimidine ring were designed and synthesized according to bioisosterism. Preliminary bioassay showed that this series of compounds have good herbicidal activities against rape and barnyard grass. Interestingly, several compounds shows inhibit of barnyard grass selectively. Molecular docking of our designed pyrimidinyloxyphenoxypropionic acid into the active site of ACCase model results in the similar binding pattern as diclofop and haloxyfop in the reported crystal with comparable expected bioactivity. 3. Eighteen 5-pyrimidinyl-1,2,4-oxadiazole derivatives, which are rationally identified as potential inhibitors toward the herbicidal target ACCase, were synthesized by the reaction of substituted benzamidoxime with pyrimidinecarbonyl chloride; Another fourty-one 5-pyrimidinyl-1,2,4-oxadiazole derivatives were synthesized by the oxidative dehydrogenation of Biginelli-type products followed by chlorination and nucleophilic substitution in an efficient and versatile way. The preliminary result showed that some of the compounds have promising herbicide activity.4. On the basis of our previous work, the homology model of spinach D1 protease was built on the basis of the crystal structure of D1 protease from Scenedesmus obliquus. With the three-dimension structure of this spinach D1 protease model, virtual screening was performed by docking of small molecules from various compound libraries into the active site of three-dimension structure of spinach D1 protease model and several types of hit compounds with topology structure were identified. Totally twenty-six compounds were rationally designed and synthesized by a multiple step synthetic procedures. Preliminary bioassay shows that some of this series of compounds have good herbicide activity and R enantiomers are better than the S enantiomers.