Synthesis And Fungicidal Activity Of Substituted Pyrimidine Formamides Containing Carbamate/carboxylate Group

Pyrimidine is a nitrogen-containing heterocyclic compound.Compounds containing pyrimidine ring play an important role in the field of pesticides because of their high activity and low toxicity.In this study,two series of 30 target compounds were designed and synthesized by splicing the pyrimidine ring of pyrimidine derivative and the amide bond of amide derivative into a framework,and then splicing with carbamate or carboxylic ester group through bioelectron isoarrangement and active substructure splicing method.The structures of the target compound were confirmed by ~1H NMR,¹³C NMR,IR and HRMS,and the biological activity test and molecular docking were completed.The main research contents are as follows.1.Using triethyl orthoformate,ethyl acetoacetate and S-methyl isothiourea sulfate or formamidine acetate as raw materials,ethyl pyrimidine formate was synthesized by cyclization.The ethyl pyrimidine formate was hydrolyzed to obtain substituted pyrimidine formic acid;Then pyrimidine formic acid condenses with o-aminoacetophenone,and then reduces to obtain the intermediate N-(2-(1-hydroxyethyl)phenyl)-2,4-disubstituted pyrimidine-5-formamide.Finally,the target compounds,1-(2-(2,4-substituted pyrimidine-5-formamide)phenyl)ethyl carbamate(A1-A18)and ethyl 1-(2-(2,4-substituted pyrimidine-5-formamido)phenyl)carboxylate(B1-B12),were obtained by reacting with isocyanate or acyl chloride.The target compound was confirmed by IR,~1H NMR,¹³C NMR and HRMS.2.Five plant fungi,strawberry Botrytis cinerea,eggplant Sclerotinia sclerotiorum,Gibberella fujikuroi,Thanatephorus cucumeris and Phytophthora sojae were used as test strains.The biological activity of the target compound was tested by mycelial growth rate,and Boscalid was used as the control drug.The results show that:The target compound A1-A18 has moderate inhibitory activity against Sclerotinia sclerotiorum.Among them,A4 has the highest inhibitory activity,with the inhibitory rate of58.9%at 50 mg/L and 63.4%at 100 mg/L.The target compound B1-B12 has certain inhibitory activity against Thanatephorus cucumeris,of which B4 has the highest inhibitory activity,with an inhibitory rate of 43.0%at 50 mg/L and 55.5%at 100 mg/L.At the same time,from the structure of the compounds,the biological activity of the compounds without methylthio structure is lower than that of the compounds with methylthio structure,such as A4 and A13,B4 and B9.The inhibition rates of the former group on Sclerotinia sclerotiorum at 50 mg/L are 58.9%and 21.0%respectively,and the latter group on Thanatephorus cucumeris at 50 mg/L are 43.0%and 7.0%,respectively.The preliminary structure-activity relationship analysis showed that the inhibitory rate of compounds containing-CF₃ group and halogen on Sclerotinia sclerotiorum was higher than that of other compounds.When the benzene ring is monosubstituted,the ortho substituted compounds have higher biological activity than the meta and para substituted compounds.3.1-(2-(4-methyl-2-(methylthio)pyrimidine-5-formamino)phenyl)-2-methylphenyl-carba-mate(A4)and 1-(2-(4-methyl-2-(methylthio)pyrimidine-5-formamino)phenyl)-3-methyl butyrate(B4)with moderate inhibitory activity were selected for molecular docking with succinate dehydrogenase.The results show that the carbonyl oxygen atom of A4 pyrimidine cyclic amide bond forms a hydrogen bond with TRP-173,the oxygen atom of phenylcyclic amide bond forms a hydrogen bond with TYR-58,and there is also a cation-?bond between pyrimidine ring and ARG-43.As for B4,the oxygen atom on the amide bond carbonyl forms a hydrogen bond with TRP-173,and the oxygen atom on the carbonyl group of carboxylic acid ester group forms a hydrogen bond with TYR-58.The pyrimidine ring forms a cation-?bond with ARG-43.