| It has been reported that the pyrazole compounds often show good agricultural antifungal activity.Many new pyrazole fungicides have been commercialized and applied to plant disease control.The pyrazole fungicides have become an important type of heterocyclic fungicides.Among them,the most prominent is pyrazole carboxamides fungicides,which belong to SDH inhibitors and have the characteristics of low toxicity,high efficiency and broad spectrum.Currently,the research of pyrazole fungicides is one of the hot directions in the field of new pesticide development,especially for the new SDHI fungicides.Hydrazine group is an important structural unit of pesticide compounds.It has attracted extensive attention in the field of research and application of insecticides,herbicides and fungicides.Studies have shown that linking the hydrazine group and acyl group to form acylhydrazine including sulfonohydrazine can usually improve the biological activity.There are few reports on the inhibition of antifungal activity about the sulfonohydrazine derivatives,but their structures are relatively novel,and they are still important active groups to be considered when designing the molecular structure of new fungicidal active compounds.In order to screen new compounds with high antifungal activity and provide the basis for the development of new fungicides.The sulfonyl hydrazine group was introduced at the pyrazole structure according to the active group splicing principle in this paper to design and synthesize fifty-nine novel pyrazole sulfonyl hydrazine derivatives.The fungicidal activities of these target compounds were preliminarily evaluated,and the structure-activity relationship analysis of 3D-QSAR was carried out.A series of methylpyrazoles were synthesized first by cyclization of acetylacetone with hydrazine hydrate or methylhydrazine,and then reacted with chlorosulfonic acid to produce corresponding methylpyrazol sulfonyl chlorides.These sulfonyl chlorides were reacted respectively with substituted phenylhydrazines with pyridine as acid binding agent to prepare thirty-eight N’-(substituted phenyl)-1Hpyrazole-4-sulfonohydrazides A1-A10,B1-B12,C1-C6,D1-D6 and E1-E4,and five N-(substituted phenyl)-1H-pyrazole-4-sulfonohydrazides F1-F2 and G1-G3.At the same time,two trifluoromethylpyrazoles were synthesized by cyclization of trifluoroacetone with hydrazine hydrate or methylhydrazine,and then reacted with chlorosulfonic acid to produce corresponding trifluoromethylpyrazol sulfonyl chlorides,which were reacted respectively with substituted phenylhydrazine to prepare sixteen N’-(substituted phenyl)-3-(trifluoromethyl-1H-pyrazole-4sulfonohydrazides H1-H2,11-I3 and J1-J11.The structures of fifty-nine target compounds were all confirmed by IR,1H NMR,13C NMR and HR-MS spectra.The bioactivity activity of compounds A-J was determinated by mycelia growth rate method.The phytopathogenic fungi Rhizoctonia solani(R.s.),Fusarium graminearum(F.g.),Botrytis cinerea(B.c.)and Alternaria solani(A.s.)were used as the test fungi.Firstly,at the concentration of 10 μg/mL,the inhibition rates against four fungi were determined.Thirty-four compounds showed more than 80%inhibition rates against Rhizoctonia solani,among which twelve compounds A4、B4、B5、D1-D4、H1、H2 and J4-J6 even showed 100%inhibition rates,which were much higher than that of the control drug fluxapyroxad(82.13%).At the same time,the inhibition rates of fifteen compounds against Fusarium graminearum were over 80%,among which the inhibition rates of compounds D1 and D2 reached 100%,and the inhibition activity was significantly higher than that of fluxapyroxad(22.88%).In addition,the inhibition rates of five compounds against Botrytis cinerea were more than 80%,and the inhibition rate of compound C2 was the highest,which was 90.86%,slightly higher than that of the specific drug boscalid(86.35%).The inhibition rates of the target compounds to Alternaria solani were relatively low,and only C5 had the inhibition rate of more than 80%,but 90.00%of the inhibition rate was significantly higher than that of fluxapyroxad(69.82%)and boscalid(37.86%).Then the growth inhibition rates were measured at 1 μg/mL.The inhibition rate of compound D1 to Rhizoctonia solani was still 81.68%,slightly better than that of fluxapyroxad(78.22%).In addition,the EC50 values against Rhizoctonia solani were determined for all target compounds.The results showed that the EC50 values of thirty-seven compounds were lower than 1 μg/mL,and those of twenty-two compounds were lower than 0.5 μg/mL.Compounds A8,A10,D1,E4,F2,J9 and J11 exhibited outstanding fungicidal activity.Their EC50 values were 0.3165 μg/mL,0.3057 μg/mL,0.2897 μg/mL,0.3195 μg/mL,0.3130 μg/mL,0.2344 μg/mL and 0.2914 μg/mL,respectively.By analyzing the structure-activity relationship of compounds A-G,it can be found that the substituent R4 at the benzene ring has obvious influence on the fungicidal activity.When R4 was 2-F,3-F,2-Cl,3-Cl,4-Cl,2,4-Cl2 or 4-Br,the fungicidal activity of corresponding compound was higher,especially the 2-F substituted compound.When R4 was methyl or 2,4,6-Cl3,the fungicidal activity of the corresponding compound was significantly reduced.At the same time,the substituents on pyrazole ring also affect the fungicidal activity.The fungicidal activity of D series compounds containing 1,3-dimethyl substituents at pyrazole ring was better than that of other series of compounds on the whole.In addition,for H-J compounds,introducing trifluoromethyl group in the third position of the pyrozole ring is not present certain regularity for fungicidal activity.The 3D-QSAR between the molecular structures of the target compounds A-E and their fungicidal activities against Rhizoctonia solani was studied.The CoMFA and CoMSIA models were established.It was found that the introduction of hydrophobic groups with strong electronegativity at 2-position of the benzene ring or hydrophobic groups with large volume at 4-position of the benzene ring could improve the fungicidal activity of the compounds against Rhizoctonia solani. |
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