Design,Synthesis And Antifungl Activity Evaluation Of Nitrogen-containing Heterocyclic Derivatives

In the classification list of fungicides released by FRAC（Fungicide Resistance Action Committee）in 2019,131 of the 237 fungicides have a nitrogen-containing heterocyclic structure,accounting for more than 60%.Among them,the main types of nitrogen-containing heterocycles includ thiazole,pyrazole,thiadiazole,oxadiazole,pyridine and the like.This shows the important position of nitrogen-containing heterocycles in the development of fungicides.In the research on the creation of new fungicides,bioisosterism replacement is an important strategy for lead compound structure optimization.In this paper,the widely used commercial pesticide Boscalid and the highly antifunal active compound 6ad which has been synthesized by our group were used as lead compounds.Different nitrogen-containing heterocycles were introduced into the structure of the lead compounds,resulting in a total of 73 compounds.All compounds were tested for the inhibitory activity against six common pathogenic fungi in vivo,with a view to discovering novel candidate fungicides with significant activity.Its research content is as follows:In the first part,the commercial succinate dehydrogenase inhibitors（SDHIs）Boscalid was used as a lead compound,the pyridine ring and benzene ring in its structure were replaced with oxadiazole to synthesize 4 series of compounds.The results of antifungl activity on the plate showed that oxadiazole amide derivatives（series A）had good antibacterial activity,and the EC50 value of compound Al-6 against Botrytis cinerea was 6.41 μg/mL,which was the best.The results of in vivo protective efficacy tests on Botrytis cinerea,showed that the protective effect of compound Al-6 was 51.3%,slightly weaker than 59.7%of Boscalid at a concentration of 200μg/mL.Finally,molecular docking were used by DS to study the complex of Al-6 and the target protein 2FBW,the result showed amino acid residues of recepter interacted with Al-6 by π bonding,Van der Waals forces and electronic interaction.In the second part,compound 6ad was used as a lead compound.The hydrazide skeleton was retained,and the heterocyclic part of its 1,2,3-triazole was replaced by thiazole,pyrazole,oxadiazole,thiadiazole,and pyridine.A total of 21 nitrogen-containing heterocyclic hydrazide derivatives were synthesized.The biological activity of these compounds against Fusarium graminearum,Botrytis cinerea,Rhizoctonia solani,Sclerotinia sclerotiorum and Magnaporthe oryza were determined using the mycelial growth inhibition method.The test results of the antifungl activity of the tablet showed that the compound D2-1（pyrazole hydrazide）had the lowest EC50 values against Fusarium graminearum,Sclerotinia sclerotiorum,Rhizoctonia solani and Magnaporthe oryza,respectively 0.12,0.33,0.15 and 1.45μg/mL,which were better than the lead compound 6ad.The results in vivo bioassay experiments showed that D2-1 had a protective effect against Botrytis cinerea of 48.7%at concentrations of 100 μg/mL,which were superior to the positive control Boscalid（42.8%）.When the concentration was 100 and 200 μg/mL,the protective effect of D2-1 against Rhizoctonia solani in vivo were 24.2%and 42.4%,weaker than the positive control Jinggangmycin（67.5%and 73.1%）.The above research shows that the structural modification of the lead compound through nitrogen heterocyclic ring replacement is an effective strategy for pesticide molecular design,and new molecules with good biological activity can be obtained.