Synthesis And Fungicidal Activity Of 2-Pyrazolamide Cyclohexane Sulfonamide

In the previous work,the laboratory conducted structural optimization studies with cyclohexamethyldithiocarbamate as the lead compound and obtained esters,amides,benzylamines and other derivatives.Based on the study of its structure-activity relationship,combined with the characteristics of hot amide compounds in recent years,a series of novel N-substituted-2-pyrazole amide cyclohexane sulfonamides were designed and synthesized.First,the lead compound N-（2-trifluoromethyl-4-chlorophenyl）-2-oxocyclohexane sulfonamide（cyclohexafluzamide）was synthesized by sulfonation and sulfonamidolysis,and then by reducingammonia.ThereactiongivesN-（2-trifluoromethyl-4-chlorophenyl）-2-aminocyclohexane sulfonamide and 18 4-pyrazole carboxylic acids（III）via EDCI/HOBt amide.A series of 18 novel N-（2-trifluoromethyl-4-chlorophenyl）-2-pyrazolecarboxamido cyclohexanesulfonamides（IV-1^IV-18）were synthesized by the reaction.Eighteen compounds were tested for their bioactivity using mycelial growth rate method,spore germination method,and potted plant method.The results showed that:most of the compounds exhibited good bactericidal activity on the mycelial growth rate test for Botrytis cinerea（strain number:KZ-9）,with EC₅₀ of 6 compounds below 20μg/mL,and EC₅₀ of compounds IV-1,IV-7,and IV-17 were 4.28,10.08,and 2.37μg/m L which close to the control agent boscalid.In the spore germination test,most compounds inhibited the spore germination of Botrytis cinerea from 70%to 90%,and the inhibitory rates of compounds IV-7 and IV-12were 91%and 90%,respectively,higher than the control agent boscalid（90%）.In the potted tomato test,11 compounds showed better bioactivity than the control agents boscalid（59.7%）and procymidone（44.9%）.The control effect of Botrytis cinerea on tomato flowers surpassed the control agents boscalid（53.1%）and procymidone（38.0%）,and the overall control effect on the leaves was better than that of the flowers.After comprehensively studying the structure-activity relationship of the above 18 compounds,compounds IV-1 and IV-7 were selected as active compounds,and the structure of active pyrazole carboxylic acid was determined to be 1-methyl-3-difluoromethyl-lH-4-pyrazolecarboxylic acid（III-1）and 1-（3-fluorophenyl）-5-trifluoromethyl-4-pyrazolecarboxylic acid（III-7）.Subsequently,10 2-oxocyclohexanesulfonamide compounds I were synthesized,and 10novel 2-aminocyclohexanesulfonamide compounds II were synthesized by reductive amination reaction.The second and third series of pyrazole amides IV-19^IV-36 were synthesized by amidation of oxazole carboxylic acids III-1 and III-7.In the mycelial growth rate test for Botrytis cinerea（KZ-9）,the EC₅₀ of 3 compounds in the second series was lower than 10.00μg/m L,and the EC₅₀ of 5 compounds in the third series was lower than 1.00μg/mL,where Compound IV-28(EC₅₀=0.06μg/m L),IV-30(EC₅₀=0.42μg/m L),IV-32(EC₅₀=0.16μg/mL)exhibited excellent bactericidal activity.In the spore germination test,the inhibitory rate of 6out of the 18 amide compounds in the second and third series exceeded that of the control agent procymidone（68%）,and the inhibitory rate of the compound IV-22（98%）exceeded the agent boscalid of control（95%）.In tomato live pot test,9 out of 18 amide compounds of the second and third series had more control effect on Botrytis cinerea invasion on tomato leaves than control agent procymidone（44.2%）and boscalid（82.0%）,it is worth mentioning that the control effect of compound IV-23 reached 100%,and it was more prominent in the live test.After that,we determined the bactericidal activity of the target compounds IV-1^IV-36against the other three pathogenic fungi.At 50μg/m L,with carbendazim as the control agent,compounds IV-13 and IV-34 showed the highest inhibition rates against Phytophthora capsici,49.0%and 48.1%,respectively,and had the highest inhibition rate against Rhizoctonia solani which the compounds were 73.6%of IV-23 and 70.7%of IV-27.The compound with the highest inhibition rate against Pyricularia was 66.7%of IV-30.The structure-activity relationship study shows that in the first series of compounds,when the substituent R¹ in the 1-position of the pyrazole ring is a fluorophenyl group,the compound tends to exhibit high bactericidal activity,and the highest activity of the compound is the substituent 3-fluorophenyl.In the second and third series of compounds,when the substituent R⁴ on the sulfonamide is fluorophenyl or bromophenyl,the bactericidal activity of the compound is generally higher.Laterally comparing the bactericidal activity of the second and third series of compounds,the third series was superior to the second series in the ex vivo and in vivo test results.In summary,when the substituent R¹ is 3-fluorophenyl and R⁴ is fluorophenyl or bromophenyl,the bactericidal activity of the N-substituted-2-pyrazoleamide cyclohexane sulfonamide compounds（IV）are more excellent.In this paper,through the synthesis,bioassay and structure-activity relationship study of N-substituted-2-pyrazole amide cyclohexane sulfonamides,new compounds with high activity were screened out,which laid the foundation for further structural optimization.