Design,Synthesis And Biological Activities Of Novel Pyrazo Le-Containing HPPD Inhibitors

Discovery of p-hydroxyphenyl pyruvate dual oxidase(HPPD)-inhibiting herbicides has bee n extensively investigated in the pesticide area due to its broad-spectrum,high efficiency,low residue,environmental compatibility,and safety for humans.HPPD is a non-heme iron dual oxidase with p-hydroxyphenyl pyruvate(HPP)as the substrate,and it is widely found in ani mals,plants,bacteria and other organisms.The catalytic reaction between plastoquinone and t ocopherols is an important process in plants,inhibition of which can result in tissue bleaching till death in green plants so as to achieve the herbicidal effect.This thesis was based on rational design of inhibitors against specific target enzymes.Wi th the benzoylpyrazole moiety in highly active commercialized HPPD inhibitors unchanged,tw o strategies were proposed and attempted.Firstly,based on the principle of combination of bi oactive substructure,134 target molecules bearing benzo-fused heterocycles were synthesized.Secondly,seven target molecules were obtained by varying substitutions on the In vitro inhibi tion activities against both human HPPD and AtHPPD and in vivo herbicidal activities have been performed.The results demonstrated that a number of compounds showed comparable ac tivities with the control herbicide,but they showed more safety against crops.Therefore,it is of great value for further structure modifications of these compounds.In this thesis,the detailed contents are as follows:1.We systematically summarized the role and the structural evolution of HPPD inhibitors.2.Four series of 141 target molecules have been designed and synthesized.All these co mpounds were characterized by 1H NMR,13C NMR and HRMS,and the structures of some r epresentative compounds were further confirmed by X-ray crystallography.3.Greenhouse herbicidal activities were studied for all the synthesized molecules,and so me of them showed good activities.Further screening and crop safety testing were then perfo rmed.The results demonstrated that some of the compounds exhibited good inhibition for bro adleaf weeds at the dose of 150 g.ai/ha.Compound Y13309 had more than 70%post-emerge nce control of abutilon theophrasti,amaranthusretroflexus and eclipta prostrate even at the dos e of 37.5 g.ai/ha;while compound Y13322,showed more than 70%post-emergence control o f abutilon theophrasti,amaranthusretroflexus and eclipta prostrate at the dose of 75 g.ai/ha;compound Y13455 showed more than 98%post-emergence control of abutilon theophras ti,amaranthusretroflexus and eclipta prostrate at the dose of 37.5 g.ai/ha;compound Y13458 showed more than 90%post-emergence control of abutilon theophrasti,amaranthusretroflexu s and eclipta prostrate at the dose of 37.5 g.ai/ha.Crop Safety testing illustrated that compou nd Y13309 is relatively safe for rice,corn,soybean and cotton at the dose of 150 g.ai/ha,so are compound Y13322 for rice,wheat,soybean and rapeseed;compounds Y13455 and Y13458 for corn,rice,and wheat;and compounds Y13496,Y13502,Y13507,Y13517,and Y13518 for corn,rice,wheat,and canola.In contrast,mesotrione,the control herbicide,is only safe for corn.4.A number of compounds showed excellent inhibition activities against Arabidopsisthali ana,and the Ki values of most compounds are lower than that of the control herbicide.For quinazolinone derivatives,compound Y13205 has a Ki value of 0.0025?M,which indicated t hat its activity is more than 5-fold as high as that of the control herbicide.For benzimidazol one derivatives,the Ki value of compound Y13457 is0.0012 ?M,which demonstrated that its activity is 10-fold higher than that of the control herbicide.Notably,for benzo-fused 2,2-diox o-thiadiazole derivatives,the Ki value of compound Y13514 is 0.88 nM,which reached the s ubnanomolar level and showed much higher activity than the control herbicide.5.Inhibition activities were studied for all the synthesized moleculesagainst human HPPD,and the selectivity ratio between AtHPPD and human HPPD were calculated.The selectivity ratio of the control herbicide is 4.For quinazolinone derivatives,the selectivity ratio for com pound Y13204 is 43,11-fold higher than that of NTBC.For benzo-fused 2,2-dioxo-thiadiazole derivatives,the selectivity ratio for compound Y13510 is 15,4-fold higher than that of NTB C.For the amine-containing series of compounds,the selectivity ratio between AtHPPD and hu man HPPD for compound Y14154 is 16,5-fold higher than that of NTBC.For benzimidazol one derivatives,the selectivity ratio between AtHPPD and hHPPD for compound Y13467 is 93,23-fold higher than that of NTBC.It is a lead compound structure of further research valu e.6.The pr eliminary structure-activity relationships for the four series of compounds have been summarized,which is of vital importance to further search and discover HPPD-inhibitin g pesticide candidates with both high activity and selectivity.