Synthesis And Structure-activity Relationship Of β-carboline Derivatives With Antifungal Activity

Natural products have broad prospects in the development of novel green pesticides due to the advantages of easy degradation,low toxicity and low resistance.β-carboline alkaloids are natural products from a wide range of sources and have significant biological activities.The green pesticides derived from plants developed withβ-carboline alkaloids as lead compounds have great potential.Based on a large number of previous work of our research group,this thesis uses tetrahydro-β-carboline skeleton as the lead compound,draws on the active structure-activity relationship of tetrahydro-β-carboline alkaloids revealed in the previous study,and uses the active substructure pharmacodynamic assembly principle to introduce a potentially bioactive nicotine group on the tetrahydro-β-carboline parent ring structure.Twenty-one tetrahydro-β-carboline derivatives were designed and synthesized.The antifungal activity and structure-activity relationship analysis of the prepared new compounds were performed,and the new compounds with significant activity and environmentally friendly characteristics were screened out,which will enrich the compound library of antifungal drugs and provide theoretical basis for the development of novel plant-derived pesticides.Composite part:In this thesis,D-tryptophan was used as the starting material,the key tetrahydro-β-carboline skeleton was obtained by Pictet-Spengler reaction,and then sulfone chloride was used as the chlorine agent for esterification in methanol solution.Under the action of acid-binding agent-triethylamine,the obtained intermediate was acylated with nicoacyl chloride at N-2 position.Twenty-one new tetrahydro-β-carbine derivatives were synthesized and the structures of all the target compounds were confirmed by ¹H NMR,¹³C NMR and ESI-MI.Biological activity test:In this thesis,carbendazim fluazolylhydroxylamine,dipyridylinoamide,flupilamide,prothiazole and pyrazole was used as positive controls,and the antifungal activities of the target compounds against 13 plant fungi at concentration of100 mg/L and 30 mg/L was tested by mycelium growth rate method.The preliminary screening results showed that all compounds showed certain antifungal activity,and the compounds W6,W11,W16,W17 and W20 showed significant inhibitory effects on the tested strains.The determination of half of the effective concentration(EC₅₀)showed that the inhibition rate of compounds W6,W16 and W20 against Sclerotinia sclerotiorum were greater than 60%,and the EC₅₀ values were 16.43 mg/L,12.71 mg/L and 12.72 mg/L,respectively.The EC₅₀ values of compounds W11,W16 and W20 for Botrytis cinerea were41.13 mg/L,12.71 mg/L and 18.76 mg/L,respectively.The inhibition rate of compound W20against Alternaria sonali was 62.76%,and its EC₅₀ value was 35.95 mg/L.The inhibition rates of compounds W11 and W17 against Curvularia lunata reached 72.23%and 60.28%,and EC₅₀ was 32.46 mg/L and 41.13 mg/L.Structure-activity relationship analysis:The antifungal activity of the compounds was generally higher when a nitrogen-containing heterocycle was introduced at the N-2 position of the tetrahydro-β-carboline skeleton and the nitrogen atom was at the C-3 position,with the compounds substituted at C-2 by a fluorine atom（W17）and without any substituent group（W11）showing the highest antifungal activity.In addition,the antifungal activity decreased as the number of nitrogen atoms in the nitrogen-containing heterocycle increased.When the benzene ring substituent was introduced,the electron-absorbing group at the C-4 position showed better antifungal activity than the electron-donating group,and the stronger the electron-absorbing ability,the higher the antifungal activity.