Design,Synthesis And Biological Activity Of Novel Triketone HPPD Inhibitors

4-Hydroxyphenylpyruvate dioxygenase(HPPD),is an Fe(II)-containing non-heme oxygenase that catalyzes the second reaction in the catabolism of tyrosine in various aerobic bodies,the oxidative decarboxylation and rearrangement of p-hydroxyphenylpyruvate acid(HPPA)into homogentic acid(HGA).In plants the product HGA is a key precursor in the biosynthesis of plastoquinone and tocopherol.The depletion of plastoquinone results in a reduction of the carotenoid level,further photosynthesis process of the plant will be hindered,leading to bleaching symptoms.Inhibitors targeting the plant HPPD enzyme,such as β-triketones(cyclohexanedione),pyrazolones and isoxazoles(prodrugs)are widely used as herbicides.HPPD herbicides have become a research hotspot for researchers in the agrochemical industry because of their excellent crop selectivity,low application rates,and broad-spectrum weed control,benign environmental effects and not susceptible to resistance.The development of new and novel HPPD inhibitors have important research significance and potential application prospects.Based on a comprehensive understanding of the structure and physiological functions of HPPD,the mechanism of action of HPPD inhibitors,as well as integrative literature review,in this thesis,we have designed and synthesized triketone based quinazolinone and quinoxaline hybrids Ⅰ-Ⅳ(total of 37 target compounds).All compounds were characterized by 1H NMR,13C NMR and HRMS analysis.In addition,we explored the structure-activity relationship between the study of the kinetics of enzyme inhibition of the target molecule and the screening of the herbicidal activity.The main contents of this thesis were listed as follows:1.Using the molecular hybridization approach(hybridization of different compounds with known biological activity),a series of triketone-quinazolinone hybrids I(I-9a-1-9h)were designed and synthesized.The in vitro AtHPPD enzyme inhibitory activity test results showed that the triketone derivatives containing quinazolinone fragment had an overall unsatisfactory inhibitory activity against the AtHPPD enzyme and the inhibition rate was below 50%,compared with the commercial herbicide mesotrione(95%),there was still a big gap between them.The green house herbicidal activity screening(150 g ai/ha dose)results showed that most of the compounds showed no significant herbicidal effect,and only a few compounds had slight whitening on leek.The result of living activity was basically consistent with the result of enzyme activity.The change of R1 on cyclohexanedione greatly affected the activity.The introduction of dimethyl(at R1)was also not conducive to its activity in vivo.2.Further,we designed triketone-quinoxaline hybrids Ⅱ(Ⅱ-7a-Ⅱ-71);and Ⅲ(Ⅲ-9a-Ⅲ-9j)and synthesized using molecular hybridization approach.The Ⅱ-7 series(X=H,unsubstituted phenyl ring)had comparable enzyme inhibitory activity to the control mesotrione,but the in vivo inhibitory activities were unsatisfactory;But the Ⅲ-9 series(X=CH3,the methyl group was introduced in the ortho-position to carbonyl group on the benzene ring)compounds showed no significant inhibitory effect both in vitro and in vivo.3.On the basis of structure Ⅱ,we designed and synthesized triketone-quinoxaline hybrids Ⅳ(Ⅳ-7a-7g)by incorporating a flexible oxygen atom(or phenoxy ring)into the quinoxaline structure.The in vitro activity levels of this series of compounds is comparable to mesotrione,but the herbicidal effect of the same compound is not obvious.4.This thesis systematically summarizes the relationship between AtHPPD inhibitory activity and structure,and the relationship between herbicidal activity and structure of the three major compounds synthesized.This study also provides ideas for the molecular design of the later HPPD inhibitors,and has certain appraisal value.