Synthesis And Fungicidal Activity Of Acetamide And Acetohydrazide Derivatives Containing Pyrrolidinedione Or Pyrazole Moiety

Nitrogen-containing heterocycles are widely used as intermediates of medicines,pesticides,pigments,photosensitizers,dyes,energy storage,conductive and biomimetic materials and other fine chemical products,so the related research has been very active.Pyrrolidinedione is a common nitrogen-containing heterocycle in some natural products.Natural or synthetic derivatives containing pyrrolidinedione group have extensive biological activities.Pyrazole is an important active group in pesticide structures.There are many kinds of pyrazole pesticides,which have the characteristics of high efficiency,broad spectrum and environmental friendliness.Pyrazole fungicides are widely used in the control of crop diseases.Amide and hydrazide structures are often used as bridging groups in pesticide structures to link other groups into active molecular skeletons,which has attracted wide attention in the development of new fungicides.In this paper,substituted acetamides and substituted acetohydrazides were introduced into the structures of two nitrogen-containing heterocycles of pyrrolidinediones and pyrazoles to design and synthesiz two series of sixty-six new acetamides and acetohydrazideamides containing pyrrolidinediones or pyrazoles.Their inhibitory activities against plant pathogenic fungi were determined and their structure-activity relationships were analyzed.The intermediate 2-(4-(1-hydroxyethylidene)-3,5-dioxapyrrolidine-2-yl)acetic acid was synthesized from L-aspartic acid by esterification,N-acylation,cyclization and hydrolysis.It was condensated with substituted aniline or substituted phenylhydrazine to synthesize four 2-(4-(1-(substituted phenyl)amino)ethylidene)-3,5-dioxapyrrolidin-2-yl)acetamides A1-A4,eight 2-(4-(1-(substituted phenyl)amino)ethylidene)-3,5dioxapyrrolidin-2-yl)acetohydrazides A5-A12,four 2-(3,5-dioxy-4-(1-(substituted phenyl)hydrazinyl)ethylidene)pyrrolidin-2-yl)acetamides A13-A16,and eight 2-(4-(1(substituted phenyl)hydrazinyl)ethylidene-3,5-dioxapyrrolidin-2-hydrazine)acetohydrazides A17-A24.Meanwhile,two other intermediates 2-(5-hydroxy-1-methyl-3(trifluoromethyl)-1 H-pyrazol-4-yl)acetic acid 3 and 2-(5-ethoxy-1-methyl-3(trifluoromethyl)-1H-pyrazol-4-yl)acetic acid 6 were synthesized from ethyl trifluoroacetoacetate by substitution,cyclization,hydrolysis and esterification.They was reacted respectively with substituted aniline or substituted phenylhydrazine to synthesize six 2-(5-hydroxy-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)acetamides B1-B6,twelve 2-(5-hydroxy-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)acetohydrazides B7-B18,twelve 2-(5-ethoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)acetamides C1-C12,and twelve 2-(5-ethoxy-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-yl)acetohydrazides C13-C24.The molecular structures of the target compounds were confirmed by FT-IR,1H NMR,13C NMR and HR-MS.The antifungal activities of the target compounds against three plant pathogens,Rhizoctonia solani,Fusarium graminearum and Botrytis cinerea,were determined by mycelial growth rate method.Firstly,the inhibition rates were determined at the concentration of 10 or 50 μg/mL.It was found that some of the target compounds exhibited certain fungicidal activity.Among them,the fungicidal activity against Rhizoctonia solani was more prominent.Subsequently,the EC50 values of compounds with higher inhibition rates were determined.Among the compounds of A1-A24 series,the EC50 values of fourteen compounds tagainst Rhizoctonia solani were less than 1 μg/mL.The EC50 values of compounds A12,A13,A14,A17,A18,A19 and A20 were 0.1567,0.1490,0.1562,0.1722,0.1692,0.1052 and 0.1367 μg/mL,respectively,which were better than that of carbendazim(0.2804 ug/mL).The EC50 values of seven target compounds against Fusarium graminearum were less than 1 ug/mL,and the EC50 values of compounds A13 and A17 were 0.3190 ug/mL and 0.2710 ug/mL,respectively,which were better than that of carbendazim(0.3192 μg/mL).Among the compounds B1-B18 and C1-C24,compounds B8,B9,B11,B12,B13,B15,B16 and B17 had significant inhibitory activities against Rhizoctonia solani.The EC50 values of compounds B12 and B15 were less than 1 μg/mL,and the EC50 values of compounds B12 and B15 were 0.2539 and 0.2662 μg/mL respectively,lower than that of carbendazim(0.2804 μg/mL).The control effect experiments of compound B15 against Rhizoctonia solani on detached rice leaves and rice plants in pot culture were studied.Compound B15 showed 75.02%efficacy against Rhizoctonia solani in potted rice at 200 μg/mL.The analysis of structure-activity relationship shows the following rules.For A1-A24 series of compounds,the introduction of substituted phenylhydrazine group into the ethylidene group at the 3-position of pyrrolidinedione is beneficial to the enhancement of fungicidal activity.When the ethylidene group at the 3-position of pyrrolidinedione is substituted with aniline group,the introduction of hydrazide group at the 5-position of pyrrolidinedione is beneficial to the improvement of the fungicidal activity against Rhizoctonia solani.The 3D-QSAR between the molecular structures of target compounds B7-B18 and C13-C24 and their inhibition of the fungicidal activity against Rhizoctonia solani was studied.The CoMFA model(q2=0.890,r2=0.996)and CoMSIA model(q2=0.800,r2=0.967)had good robustness and internal prediction ability.The analysis showed that the introduction of large hydrophobic group at the 4-positions of benzene ring can significantly improve the fungicidal activity of the compounds against Rhizoctonia solani.