Design, Synthesis And Biological Activity Of 1,3,4-thiadiazole Sulfone Derivatives Containing Amide Structure

In view of the damage of crop yield and quality caused by plant pathogens,starting from the molecular structure of commercial fungicide carboxin,the lead compounds were screened by computer simulation.Based on the principle of active substructure splicing,the structure of the target compound was determined as 1,3,4-thiadiazole sulfone derivatives containing amide units.And the structure of the target compounds was determined by ¹H-NMR,¹³C-NMR and HR-MS.Meanwhile,the biological activity test and computer-aided verification were carried out to explore the relationship between structure and activity and the mechanism of action preliminarily.The work of this paper is summarized as follows:(1)Based on the structure of carboxin,the lead compound was obtained and optimized by theoretical design.Finally,we obtained the target compounds that the derivates of 1,3,4-thiadiazol sulfone with amide units.And the 23 title compounds were designed and synthesized,and the structure were confirmed by ¹H NMR,¹³C NMR and HR-MS.(2)According to the nephelometry method,bismerthiazol and thiodiazole-copper as positive control agents,the inhibition activities were tested on Xanthomonas oryzae(Xoo)and Xanthomonas citri(Xac)in vitro.The results showed:At 100?g/m L,the inhibition rate of compound 4a(86.95%),4b(83.55%),4d(81.10%),4k(91.56%),4l(96.55%),4m(99.14%),4n(60.43%),4q(95.50%),4s(99.62%),4u(81.43%)and4w(91.77%)on Xoo,and better on the bismerthiazol(60.33%)and thiodiazole-copper(54.91%);at 50?g/m L,the inhibition rate of compounds 4b(78.12%),4g(62.71%),4l(78.61%)?4m(81.77%),4n(48.43%),4p(71.41%)and 4t(70.02%)on Xoo,and better on the bismerthiazol(32.42%)and thiodiazole-copper(34.58%).Based on the biological data against Xoo,the values of effective medium concentration(EC₅₀)of some title compounds were calculated.The EC₅₀ values of compounds 4g(4.21?g/m L),4k(27.64?g/m L),4l(25.51?g/m L),4m(25.02?g/m L),4n(63.71?g/m L),4t(12.85?g/m L)and 4u(37.93?g/m L),and lower than the bismerthiazol(76.18?g/m L)and thiodiazole-copper(85.43?g/m L).(3)According to the leaf cutting inoculation method,compound 4n was tested the efficacies(protective/curative)of against Xoo in vivo,the bismerthiazol and thiodiazole-copper as positive control agents at 200?g/m L.The results showed:the protective efficacy of 4n,thiodiazole-copper and bismerthiazol was 18.47%,37.03%,34.12%respectively;the curative efficacy of 4n thiodiazole-copper and bismerthiazol was 35.91%,56.90%,56.87%respectively.(4)According to the mycelial growth rate method,hymexazol as control agent,the inhibition rate of title compounds was tested at 50?g/m L against the 6 types plant pathogens fungi in vitro.(C.gloeosporioides,P.infestans,F.oxysporum,B.cinerea,Pestalotiopsis sp and P.cinnamomic)The results showed:the inhibition rate of compound 4m was 26.55%against C.gloeosporioides,and the hymexazol was36.14%;the inhibition rate of compound 4g was 50.74%against B.cinerea,and hymexazol was 69.51%.(5)Based on the biological activity data,we have explored the relationship between the structure of target compounds and biological activity.Preliminarily analysis of SAR:introduce the unsaturated group at the site of S,based on the structure of sulfone,and the biological activity could be promoted;The model of 3D-QSAR:described the relationship of compounds'structure and inhibition activity,and the model was influenced by steric field and hydrophobic field.(6)Compound 4n was docked with the protein(FtsZ and 2FBW),and the free bind energy was calculated to verify the reliability between the small molecular ligand and protein receptor.Besides,the complex system of 4n-2FBW with molecular dynamic 100 ns were more stable than the carboxin-2FBW,and the root-mean-square deviation(RMSD)value of 4n-2FBW were in 2-3(?)since 50 ns.In another word,the energy and conformation of 4n-2FBW were in stable.