Synthesis And Fungalcidal Activity Of 2,4-disubsituted-5-pyrimidine Carboxamides

Succinate dehydrogenase inhibitors?SDHI?play an important role in protecting plants from many pathogenic fungi.Due to their unique mode of action,they have no cross-resistance with other chemical classes and are excellent candidates for managing the development of drug resistance and optimizing disease control.Pyrimidine is an important six-membered heterocyclic ring containing two nitrogen atoms.Many pyrimidine-based compounds play important roles in the field of pesticides because of their high activity and low toxicity.In this study,we used bioelectronic isobaric and substructure connection methods to introduce active groups from the pyrimidine ring as the parent,thereby synthesizing 17 new pyrimidinecarboxamide compounds,and the compounds were tested for biological activity.The main research contents are as follows.1.Condensation and cyclization reactions using ethyl acetoacetate,triethyl orthoformate and S-methylisothiourea sulfate as raw materials afforded 2,4-disubstituted pyrimidine esters,followed by hydrolysis to obtain 4-methyl-2-methylthiopyrimidine-5-carboxylic acid.The intermediate N²-phenylpyridine-2,3-diamines was prepared by two-step reaction of 2-chloro-3-nitropyridine and substituted aniline through substitution and addition.Finally,the pyrimidinecarboxylic acid and N²-phenylpyridine-2,3-diamine were subjected to a condensation reaction offered the target product?Ia-Ig?.2.Cyclizatiopn reaction of ethoxymethylenemalonate with S-methylisothiourea sulfate gave ethyl 4-hydroxy-2-methylthiopyrimidine-5-carboxylic ester.Then,4-methoxy-2-methyl-thiopyrimidine-5-carboxylic acid was prepared by chlorination,methanol methoxylation and hydrolysis reaction.Lastly,the condensation of the pyrimidine-5-carboxylic acid with N²-phenylpyridine-2,3-diamine the target product?Ih-Iq?.3.The structures of the synthesized compounds were confirmed by IR,¹H NMR,¹³C NMR,MALDI-TOF-MS,and the physical and spectral properties of the compounds were analyzed in detail.4.Using strawberry Botrytis cinerea and cucumber Sclerotinia sclerotiorum as test strains,the synthesized target compounds?Ia-Iq?were tested for their fungicidal activity by using the mycelial growth rate method.Boscali was used as a positive control.The results showed that the target compounds Ia-Iq showed moderate activity against strawberry Botrytis cinerea in the test of Botrytis cinerea,and the inhibitory rates of Ia-Ig and Ip were between70%-84%at a dose of 50?g/mL.In the meantime,the EC₅₀ values of I_b and I_p can reach 6.15and 6.35?g/mL,respectively,which are close to those of the control agent,Boscali?5.26?g/mL?,indicating that the two compounds have higher activity against Botrytis cinerea.For the test of the inhibitory activity of cucumber Sclerotinia sclerotiorum,at a dose of 50?g/mL,in addition to the target compound Ih,the remaining 16 compounds have a high bactericidal activity against Sclerotinia sclerotiorum,the inhibition rate is more than 90%;The compounds Ij-Il containing only one chlorine atom on the ring,and the compound Iq with one chlorine atom and methyl group have an Iq inhibition rate of 94%-97%.The EC₅₀ of In and Ip have reached 1.46 and 1.54?g/mL,but lower than Boscalid?0.29?g/mL?.From the structure of the compound,there is no obvious regularity between the methyl or methoxy substitution on the pyrimidine ring,the various substituents on the benzene ring and the fungicidal activity.5.Highly active compound Ip was molecularly docked with succinate dehydrogenase to study its mode of action.The results showed that Ip formed four hydrogen bonds with the SDH target enzyme amino acid and a cation-?interaction.