| As the five-membered nitrogen-containing heterocycles,pyrrolidinediones have attracted great attention from chemists and pharmacologists because of their unique and complex molecular structures and broad-spectrum biological activities.Many novel pyrrolidinedione derivatives with good fungicidal activity have been synthesized.Pyrazoles are also the important nitrogen-containing heterocycles.Pyrazole fungicides have unique action mechanism and are widely used in crop disease control.Introducing pyrazole into the molecular structures of target compounds in the discovery of novel fungicides can often improve biological activity.Diphenyl ether and hydrazine groups are seldom used in the field of fungicides,but many compounds containing diphenyl ether or hydrazine groups show significant fungicidal activity,which is of great significance for the development of new fungicides with different mechanisms of action.In this paper,diphenyl ether and substituted hydrazine groups were introduced at 1-position and 3-position of pyrrolidine ring respectively to design and synthesize two series of twenty-four hydrazinyl pyrrolidinedione derivatives containing diphenyl ether group.Meanwhile,twenty derivatives of pyrazole carbohydrazide containing diphenyl ether group were designed and synthesized by introducing diphenyl ether group into 4-position of substituted pyrazole ring through the carbohydrazide structure.The fungicidal activities of the synthesized target compounds were also determined.Two intermediates 1-(4-phenoxyphenyl)-3-(1-hydroxyethylidene)pyrrolidine-2,4-diones were synthesized from phenoxyaniline and ethyl bromoacetate by substitution,acylation and cyclization.They were refluxed respectively with substituted hydrazines in ethanol to synthesize twelve 1-(4-phenoxyphenyl)-3-(1-(substituted hydrazinyl)ethylidene)pyrrolidine-2,4-diones A1-A12 and twelve 1-(4-(4-chlorophenoxy)phenyl)phenyl)-3-(1-(substituted hydrazinyl)ethylidene)pyrrolidine-2,4-diones B1-B12.At the same time,substituted pyrazole-4-carboxylic acids were synthesized from the raw materials ethyl acetoacetate,triethyl orthoformate,methyl hydrazine or hydrazine hydrate by substitution and cyclization.The phenoxyanilines were reacted with sodium nitrite to get the diazonium salt solutions,which were reduced with stannous chloride to give phenoxyphenyl hydrazines.Then,seventeen N’-phenoxyphenyl-1Hpyrazole-4-carbohydrazide derivatives C1-C6,D1-D6 and E1-E5 were synthesized by the reaction of phenoxyphenyl hydrazine with pyrazole-4-carboxylic acid.In addition,three N-phenoxyphenyl-1H-pyrazole-4-carbohydrazide F1-F3 were synthesized from the reaction of pyrazole-4-carbonyl chloride with phenoxyphenyl hydrazine.The structures of forty-four target compounds were confirmed by IR,1H NMR,13C NMR and HR-MS.Four representative plant pathogenic fungi,Fusarium graminearum,Botrytis cinerea,Rhizoctonia solani and Alternaria solani,were selected for bioactivity determination by mycelial growth rate method.For two series of compounds A and B at the concentration of 50 ug/mL,they had obvious inhibitory activity against Rhizoctonia solani.And the inhibitory rates of fifteen compounds exceeded 70%.The EC50 values of compounds A4,A5,A8,A10,A12,B8 and B10 were lower than that of the control fungicide,boscalid(2.21 μg/mL).Among them,A8 and A10 were the most active compounds in A series with the EC50 values of 0.39 μg/mL and 0.50 μg/mL,respectively.B8 and B10 were the most active compounds in B series,and EC50 values were 1.01 μg/mL and 0.97 μg/mL,respectively.For the pyrazole carbohydrazide derivatives C-F containing diphenyl ether group,most of the compounds exhibited significant inhibitory activities against Rhizoctonia solani,Botrytis cinerea and Fusarium graminearum at the concentration of 10 μg/mL.There were ten compounds showing the inhibition rates of 80%above against Rhizoctonia solani,six compounds showing the inhibition rates of over 70%against Botrytis cinerea,and all the D and E series of compounds showing the inhibition rates of more than 80%against Fusarium graminearum.The EC50 values of some compounds were determined.The EC50 values of compounds D1,D2,D4,D5,E2,E3,E4 and E5 against Rhizoctonia solani were all lower than that of carbendazim(0.34 μg/mL).The EC50 value of compound D1 against Botrytis cinerea was 0.52 μg/mL,which was better than that of boscalid(0.54 μ/mL).And compounds E1,D2 and E5 had the EC50 values of 0.27 μg/mL,0.32 μg/mL and 0.46 μ/mL against Fusarium graminearum,respectively,which were superior to that of carbendazim(0.57 μg/mL).It is worth noting that the EC50 values of compounds D1 and E5 against three pathogenic fungi were below 1.0 μg/mL,showing prominent fungicidal activity.The in vivo experiments showed that the protective effect against Rhizoctonia solani of compound E3 at 200 ug/mL was 73.25%in rice leaf test,better than that of carbendazim(59.81%),and 61.11%in rice pot culture test.The preliminary analysis of structure-activity relationship showed that the introduction of substituted phenylhydrazine group at the 3 position of pyrrolidine ring was more beneficial to improve the fungicidal activity than introduction of hydrazine or methylhydrazine group for the A and B series of compounds,and the introduction of 4-Cl and 4-Br at benzene ring of phenylhydrazine led the highest fungicidal activity.For the C-F series of compounds,introducing phenoxyphenyl at N’-position of hydrazine group was better than introducing phenoxyphenyl at N-position,and introducing 4-(4-chlorophenoxy)phenyl at N’-position of hydrazine group was most conducive to improving the fungicidal activity. |
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