Design,Synthesis And Fungicidal Activity Of Novel Pyrazol-5-yl-benzamide Derivatives

Pyrazol-4-amide derivatives,as an important member of succinate dehydrogenase class of inhibitors,exhibit excellent pharmacological properties and extremely high biological activities in the field of fungicides.In this thesis,a series of novel pyrazol-5-yl-benzamide derivatives were designed,synthesized by hopping and inversion of amide groups of pyrazole-4-carboxamides.Thirty two compounds were evaluated for biological activity by the mycelial growth rate method and in vitro leaf method,and the results showed that at a concentration of 50mg/L,the target compounds showed different inhibitory activities against Sclerotinia sclerotiorum,Physalospora piricola,Valsa mali,Fusarium graminearum and Botrytis cinerea.The bioassay data revealed that compound 5IIc exhibited an excellent in vitro activity against Sclerotinia sclerotiorum with EC₅₀ value of 0.20 mg/L,closed to that of commercial fungicide.For Valsa mali,compound 5IIc(EC₅₀=3.68 mg/L)showed a significantly higher activity than Fluxapyroxad(EC₅₀=12.67 mg/L).In addition,in vivo experiments proved that compound 5IIc has an excellent protective fungicidal activity with an inhibitory rate of 97.1%against Sclerotinia sclerotiorum at 50 mg/L,while the positive control Fluxapyroxad showed a 98.6%inhibitory effect.The antifungal mechanism of the target compounds was initially explored by observation of hyphal morphology,SDH enzymatic inhibition assay and molecular docking.SEM revealed that compound 5IIc could cause a significant shrinkage on the mycelial surface of Sclerotinia sclerotiorum,and this compound may have some effect on the morphological structure of the hyphae.The results of SDH enzyme activity assay showed that compound 5IIc had the same inhibitory activity as Fluxapyroxad,a succinate dehydrogenase inhibitor;Molecular docking simulation showed that compound 5IIc interacted TRP 173,SER 39 and ARG 43 of the succinate dehydrogenase（SDH）through hydrogen bond and p-πinteraction,verifying that this compound may act on this target and that its antifungal activity may be related to inhibition of succinate dehydrogenase activity.In this thesis,a series of novel pyrazol-5-yl-benzamide derivatives were synthesized,and the lead compound 5IIc with high antifungal activity was found through biological activity screening.The preliminary mechanism showed that the compound acted on succinate dehydrogenase,which is very important for further development of novel succinate dehydrogenase inhibitors.