Design,Synthesis And Fungicidal Activity Of Novel Pyrimidine Amides

Food security bears on people’s basic needs and social stability.The use of chemical pesticides is indispensable to ensure the output and quality of grain.Succinate dehydrogenase inhibitor fungicides due to its broad-spectrum efficient biological activity,has an important role in the field of pesticide.But the longer it’s been used,the more resistance becomes a problem,and some compounds which have similar structurally develop cross-resistance.In order to ensure the safety of agricultural production,it is urgent to develop fungicides with novel structure.In this study,we used the bioactive substructure splicing method,combined with the structural characteristics of succinate dehydrogenase inhibitor fungicides,and introduced the bioactive pyrimidine structure on the basis of retaining the amide bond skeleton to replace the original commercial fungicides and pyrazolomeamide structure that has been widely used in recent years.To explore the contribution of different positions of amide moiety to pharmacodynamics of pyrimidine ring,six series of 70 novel pyrimidine formamide compounds were designed and synthesized by the following strategies:（1）Pyrimidine 5-formamide compounds（A series）containing ether chain were designed by introducing an oxygen atom as hydrogen bond acceptor in the alkyl chain based on ortho-branched alkyl substituted benzene in the aniline structure of penflufen.On the basis of A series,2,4-dimethylpyrimidine-5-formamide compounds（B series）containing oxime ether were designed by using bioactive oxime ether fragment instead of ether chain structure.（2）Using 2-methoxy-pyrimidine-5-formamide as the carboxylic acid part and following the design strategy of a-series amine part,4-methoxy-pyrimidine-5-formamide compounds containing ether chain（C series）were designed.（3）Pyrimidine formamide compounds containing phenylthiazoles（D series）were designed according to the large volume rigid biphenyl structure of boscalid and thiazole structure of tifurofuramide.（4）Pyrimidine formamide compounds containing phenoxypyridine（E series）were designed by using pyrimidine rings with different substituents and linking modes as carboxylic acid parts and amine parts referring to the diphenyl ether structure of fluorophenoxamide,and replacing benzene ring with pyridine,a nitrogenous heterocyclic ring.（5）The pyrimidine structure of pyrimidine with bactericidal activity and the pyrazole structure of fluzomyl hydroxylamine are joined by a rotatable single bond as the carboxylic acid part of the compound.Using aniline or benzylamine with flexible structure as amine part,2-substituted pyrimidine 4-formamide compounds（F series）were designed and synthesized.The synthesized compounds was tested by mycelium growth rate method of in vitro bactericidal activity（Sclerotinia sclerotiorum,Botrytis cinerea,Rhizoctonia solani）,the results showed that most compounds except D series have certain fungicidal activity,participants strains of Rhizoctonia solani on the compounds are the most sensitive.The overall inhibitory effect of the compounds was higher than that of Sclerotinia sclerotiorum and Botrytis cinerea.Among them,2-substituted pyrimidine-4-formamide compound F7 had the best inhibitory effect on Rhizoctonia solani at 100 mg/L,reaching 85.3%.The inhibitory rate of other compounds in F series on Rhizoctonia solani was 60%-85%,which was higher than that of Sclerotinia sclerotiorum（40%-79%）and Botrytis cinerea（30%-68%）.Further experiments were carried out to obtain the semi-maximum effect concentration values(EC₅₀)of different series of compounds with better efficacy.It was found that the compounds with the best EC₅₀ for Sclerotinia sclerotiorum,Botrytis cinerea and Rhizoctonia solani were C3（30.16 mg/L）,C3（66.12 mg/L）and F14（20.98 mg/L）,respectively.Its activity was lower than that of the boscalid,the EC₅₀ value was 0.78,10.03 and 1.20 mg/L,respectively.In order to study the interaction between the ligand and target protein,Autodock4.2software was used for molecular docking of the highly active compound.Molecular docking analysis revealed that the oxygen atoms of the F7,F8 and F14 amide bonds all formed hydrogen bond with TRP-173 amino acid residue,and the amine parts was partially in the hydrophobic cavity,and the hydrophobic interaction provided partial binding force.The carboxylic acid partial pyrimidine rings have distinctπ-cation interactions with ARG-43residues.Pyrimidine rings play an important role in the binding of compound molecules to target enzymes regardless of the structural changes of amine parts.