Design, Synthesis And Biological Activities Of Novel Anti-resistant AHAS Inhibitors

Acetohydroxyacid synthase (AHAS), which is the key enzyme for the biosynthesis of branched amino acids in plants, has attracted much attention for many years as a potential target to be used as hebicides. Moreover, It also has been recognized as the most widely used all over the world because of its high efficacy, limited environmental effect, low mammalian toxicity and relatively low application rares. Despite the great success of commercial AHAS inhibitors over the past decades, drug resistance has become one of the most serious problems to overcome.According to this phenomenon, a series of new AHAS inhibitors has been designed and synthesized with the aim of discovery of new herbicides with higher activity and overcome the drug resistance. Based on literatures and our previous work, resistance to AHAS-inhibiting products has been shown to be caused by an alteration in the AHAS enzyme itself. Single point mutations that confer resistance to AHAS inhibitors include Ala122、Pro197、Ala205、Asp376、Trp574、Ser653、 Gly654 (Arabidopsis AHAS residue numbering). We also discovered that oxygen bridge in the herbicides can improve the flexibility of the ligand in the binding pocket and that should result in a higher binding affinity against the mutant enzyme.1. Based on this, for the most prominent mutation P197L and W574L, we have designed and synthesized three series of 2-aroxyl-heterocycles (108 new compounds) as conformationally flexible AHAS inhibitors successfully. The Ki values of compounds in mutant system have been found to keep in the same order of magnitude with that in wild model. The 2-Aroxyl-triazolopyrimidine derivatives (Ⅲ-4, Ⅲ-5) reveal high inhibitory activity against the wild-type AHAS and its W574L mutant simultaneously. For example, the Ki; values of Y10058 against wide-type and W574L AHAS were determined to be 3.21±0.98×10-6 M and 3.46±0.52×10-6 M, respectively. So, it could be used as new leads for the further discovery of novel anti-resistance herbicides. However, It is a great progress for combating herbicide resistance.2. We have successfully designed and synthesized a series of 2-aroxyl-4,6-dimethoxypyrimidine derivatives as conformationally flexible AHAS inhibitors. Bioassay indicated that some compounds displayed promising herbicidal activities. Almost all the V-6 compounds displayed promising and broad-spectrum post-emergence herbicidal activities as flumetsulam. Especially, compound Y11149 displayed over 80% inhibition activity against either wild weeds or mutant weeds, such as D. Sophia(M),D. Sophia(K), D. Sophia(GK), A. Arenaria, C. Iria L even at a dosage as low as of 0.24 g a.i./ha.3. We also have developed a convenient method for the synthesis of functionalized benzoicacids and their derivatives from aryl iodide by using microwave-assisted Suzuki cross-coupling reactions. The reactions has a wide range of substrate scope and can be used to produce a variety of densely functionalized functionalized benzoicacids and their derivatives in good to excellent yields within a very short time. Moreover, This progress is the foundation of our follow-up work.4. The summary of structure-activity relationship of target compounds and give important direction for further study of anti-resistance AHAS-inhibiting herbicides.