Design,Synthesis,and Antifungal Activity Of Novel Monofluoroolefin Succinate Dehydrogenase Inhibitors

As a big agricultural country,food security is related to the stability of national development.However,plant pathogenic fungi have caused huge losses to grain production.Among them,succinate dehydrogenase inhibition is an important class of fungicides,showing good fungicides activity in pesticide fungicides,and the structure of pyrazole formamide is often an important structural unit of succinate dehydrogenase inhibitors.In this paper,pyrazole carboxylate formamide is used as the parent structure,and monofluorolefin is introduced in the hydrophobic tail.A total of 58 novel compounds containing monofluoroolefins succinate dehydrogenase inhibitors were synthesized.1.In order to introduce monofluorinated olefin fragments into the hydrophobic tail of succinate dehydrogenase inhibitors,the reaction route was designed by the method of inverse synthesis analysis.The key step was to introduce monofluorinated olefin fragments into the target compounds.Then the monofluoroolefin fragment was successfully introduced into the hydrophobic tail of succinate dehydrogenase inhibitor by Suzuki coupling catalyzed by metal palladium.In this study,we first synthesized 42target compounds,and then further explored the influence of fluoroolefin substitution on biological activity,and synthesized 4 target molecules.In addition,we also modified the benzene ring directly connected with amide in order to obtain compounds with better biological activity.12 kinds of modified target products were synthesized.The structure of 58 compounds was characterized by ¹H NMR,¹³C NMR,¹⁹F NMR and ESI-MS.Compound 31 was selected for single crystal derivatization to determine the Z-configuration of fluoroolefins.2.We used mycelium growth rate method and in vitro leaves（fruits）to determine the bioactivity of 58 compounds newly synthesized.The experimental results showed that.At a concentration of 200μmol/L,the target compounds have inhibition effect on8 pathogenic fungi（Sclerotinia sclerotiorum,Rhizoctonia solani,Botrytis cinerea,Fusarium graminearum,Altermaria alternata,Monilinia fructicola,Cochliobolus heterostrophus,Pestalotiopsis）to various degrees,and the target compounds have strong antifungal activity on Rhizoctonia solani,Sclerotinia sclerotiorum,Botrytis cinerea,and Monilinia fructicola,In particular,Rhizoctonia solani has strong antifungal activity,The EC₅₀ of target compound 41 was 0.05μmol/L,which was better than that of commercial fungicide Fluxapyroxad(EC₅₀=0.21μmol/L)and far better than that of commercial fungicide Boscalid(EC₅₀=2.7μmol/L).In addition,compound 41 was tested in vitro on rape leaves and tomato fruits,and the results showed that it had certain therapeutic activity.By scanning electron microscope observation,it was found that the bacteria were damaged and wrinkled after being treated with the target compound 41.The enzyme activity of succinate dehydrogenase was determined,and the inhibition of succinate dehydrogenase was much higher than that of Fluxapyroxad.Finally,the molecular docking experiment showed that the binding pattern of compound 41 with Fluxapyroxad was similar,and there was p-πconjugation and hydrogen bond interaction with the target protein.It was verified that the target compound is bound to succinate dehydrogenase,and its antibacterial activity is closely related to succinate dehydrogenase.It has a profound reference significance for further research and development of novel succinate dehydrogenase inhibitors.