Design,Synthesis And Biological Activity Evaluation Of Novel Pyrazole Sulfonamide And Sulfide Derivatives

Crop diseases caused by plant pathogenic fungi lead to about 20%annual crop reduction in the world,which seriously threatens food security.Among them,botrytis cinerea can harm thousands of plants and cause huge economic losses to crops,and it is listed as the second most dangerous plant pathogenic fungi in the world.Sclerotinia sclerotiorum caused by Sclerotinia sclerotiorum leads to the annual yield reduction of rapeseed in China by about 10-80%.The existing fungicides have some practical problems,such as aging dosage forms,shortage of new dosage forms,few original targets,and increased drug resistance of fungi.Therefore,under the dual pressures of carbon reduction and pesticide reduction and efficiency increase in China’s agricultural development,it is of great theoretical and practical significance to find original skeletons and new molecular targets and create high-efficiency and low-risk small molecular fungicides in addition to improving the use of existing antifungal agents and discovering new technologies to deal with resistant fungal pathogens.In this thesis pyrazole was modified by splicing of drug active fragments.By introducing different active fragments,40 sulfonamide derivatives containing pyrazole groups were designed and synthesized（Work A,Chapter 2）and 20 oxadiazole/thiadiazole thioether derivatives containing pyrazole groups（Work B,Chapter 3）.The structures of the compounds were verified by means of ¹HNMR,¹³CNMR and X-ray single crystal diffraction.In vitro antifungal experiments,in vivo antifungal experiments,scanning electron microscopy and transmission electron microscopy were carried out.In work A,we designed and synthesized a series of pyrazole sulfonamide derivatives by introducing active drug fragments such as sulfanilamide into pyrazole amine structure,and evaluated their antifungal activities against 10 plant pathogenic fungi.The results of bioassay showed that most of the target compounds showed excellent antifungal activity in vitro,especially the inhibitory effect of compound C25(EC₅₀=0.246 mg/L)on Sclerotinia sclerotiorum was better than that of commercial drug boscalid(EC₅₀=1.826 mg/L),and the inhibitory effect of compound C22(EC₅₀=0.567 mg/L)on botrytis cinerea was better than boscalid.At the same time,compound C22 has excellent inhibitory effect on eight plant pathogens,such as apple rot fungus,Sclerotinia sclerotiorum and Trichoderma viride,and all of them are better than boscalid.Therefore,these compounds can be further studied as potential broad-spectrum antifungal agents.B The method to optimize the structure of pyrazole amine is to introduce oxadiazole/thiadiazole heterocyclic ring at position 4 of pyrazole ring,design and synthesize 20 oxadiazole/thiadiazole sulfide derivatives containing pyrazole groups,and test their antifungal activities against 10 agricultural pathogenic fungi.The inhibitory effect of compound E14(EC₅₀=0.783 mg/L)on Sclerotinia sclerotiorum was better than that of boscalid(EC₅₀=1.826 mg/L).In addition,the inhibitory effect of compound E8(EC₅₀=1.892 mg/L)on apple rot fungi was better than that of boscalid(EC₅₀=18.755 mg/L).The experimental results show that the antifungal activity of the compound is greatly improved after the introduction of thiadiazole heterocyclic ring,so the introduction of different types of heterocyclic ring can be used as an effective means to modify the structure of the compound.To sum up,two series of 60 compounds were synthesized in this thesis most of which sulfonamides and thiadiazoles have good antifungal activities.This kind of structure provides a new chemical entity for finding new fungicides.