Design, Synthesis And Biological Activity Of Trifluoromethylpyridine Piperazine Derivative

In this paper,piperazine was introduced on the structure of trifluoromethyl pyridine,and then the diversity of the structure was derived on the piperazine.And the structures of the compounds were determined by ¹H NMR,¹³C NMR,¹⁹F NMR,HRMS and other means for structural characterization.The compounds were tested for their inhibitory activity against tobacco mosaic virus（TMV）and cucumber mosaic virus（CMV）by half leaf spot method.The results were obtained as follows.1.Novel trifluoromethylpyridine piperazine derivatives（A1-A27）were designed and synthesized.The in vivo antiviral activities were measured against TMV and CMV,and the results showed that compounds A1,A2,A3,A9,A10,A16,A17and A21 exhibited higher antiviral activity than commercialized ningnanmycin.Particularly,the in vivo antiviral activity indicated compound A16 showed the most potent protective activity toward TMV(EC₅₀=18.4μg/m L)and CMV(EC₅₀=347.8μg/m L),compared to ningnanmycin（50.2μg/m L for TMV,359.6μg/m L for CMV）.Excitingly,further studies revealed that compound A16 enhanced the defense enzyme activities of superoxide dismutase（SOD）,polyphenol oxidase（PPO）and phenylalanine aminolyase（PAL）,activated the phenylpropanoid biosynthetic pathway and enhanced the antiviral activity of tobacco.2.Twenty eight biamide trifluoromethylpyridine piperazine derivatives（S1-S28）were designed and synthesized.The results of biological activity tests showed that most compounds had good curative activity against CMV,and the EC₅₀values of compounds S1,S2,S7,S8,S10,S11,S15 and S28 were 119.6,168.9,197.6,169.1,97.9,73.9,224.4 and 125.2μg/m L,respectively,which were lower than ningnanmycin(EC₅₀=314.7μg/m L).The EC₅₀for the protective activities of S5 and S8 were 170.8 and 95.0μg/m L,respectively,which were lower than ningnanmycin(EC₅₀=171.4μg/m L).The inactivation activities of S6 and S8 at 500μg/m L were remarkably high at 66.1%and 78.3%,respectively,surpassing that of ningnanmycin（63.5%）.Additionally,their EC₅₀values were more favorable at 22.2 and 18.1μg/m L,respectively,than ningnanmycin（38.4μg/m L）.And molecular docking and molecular dynamics simulation showed compound S8 had better binding with CMV coat protein,providing a reliable explanation for the anti-CMV activity of compound S8.