Synthesis And Biological Activity Of Novel Ferulic Acid And Amide Derivatives

Ferulic acid,as a naturally occurring product,possesses a broad spectrum of biological activity.It has been widely studied and applied in the field of medicine.In recent years,it is reported that it also possesses good antiviral activity,therefore,ferulic acid was used as the lead compound.Based on our previous work,we found that α-aminophosphonate derivatives possess good to excellent antiviral activity.Thus,herein the active groups of α-aminophosphonates were introduced into the structure of ferulic acid and series of novel ferulic acid-amide derivatives g1-g26 bearing α-aminophosphonate moieties were firstly synthesized.Their antiviral activity against TMV and CMV were evaluated via the half-leaf method.In addition,further to study the interaction between compouds(g6,g9,g18,g24,and Ningnanmycin)and TMV CP with trace thermophoresis method(MST).The work of this thesis is summarized as follows:1.With substituted benzaldehyde,ammonia,dietyl phosphite,p-toluene sulfonic acid as raw materials,respectively go through Mannich reaction,Michael addition,salt formation and hydrolysis reaction to gain α-aminophosphonate intermediates c1-c2.Meanwhile,with ferulic acid,methanol,benzyl halides as raw materials,intermediates f1-f13 were obtained through esterification,substitution,hydrolysis reactions,sequentially.Finally using HOBt/EDCI as catalyst,DMF as solvent,intermediates f1-f13 and c1-c2 were stirring at room temperature for 6-10 h to get target compouds g1-g26,and the structures of these compounds were confirmed by 1H NMR,13 C NMR,31 P NMR,IR,and HRMS.2.The antiviral activity against TMV of compounds g1-g26 were evaluated via the half-leaf method at 500 μg/m L.Bioassays results showed that some target compounds exhibited good anti TMV activity.Based on the preliminary biological evaluation,the EC50 values of curative and protective activities against TMV of some target compounds further to been evaluated,of which compound g18 possesed remarkable curative activitiy against TMV with EC50 values of 285.42 μg/mL,approximately close to that of ningnanmycin(254.91 μg/mL).Meanwhile,compounds g5,g16,g18,and g24 showed good protection activity against TMV,the EC50 values were 190.74,191.04,180.37,and 183.16 μg/mL,respectively,well-comparative to that of Ningnanmycin(165.95 μg/mL).Preliminary structure-activity relationships analysis revealed that the the introduction of electron-withdrawing groups(F,Cl)at the 2-position or 4-position of the R2 are favorable for antiviral activity,and the introduction of large electron withdrawing group(CF3)at the 4-position of the R2 also favor of the activity against TMV.3.The antiviral activity against CMV of compounds g1-g26 were also evaluated via the half-leaf method at 500 μg/mL.Bioassays results showed that some target compounds exhibited excellent antiviral activity.Based on the preliminary biological evaluation,the EC50 values of curative and protective activities against TMV of some target compounds further to been evaluated,of which,compounds g3,g5,g8,g16,and g23 exerted comparative curative activities(with EC50 values of 332.06,342.36,347.77,323.27,and 347.89 μg/mL,respectively)against CMV compared to that of Ningnanmycin(352.08 μg/m L),distinguishingly,compounds g18 and g21 possessed obviously higher curative activities(with EC50 values of 284.67 and 296.99 μg/m L,respectively)against CMV than that of Ningnanmycin(352.08 μg/mL).Moreover,compounds g5,g16,g18,and g21 exerted more potent protective effect(with EC50 values of 254.53,236.90,216.30,and 227.04 μg/mL,respectively)against CMV than that of Ningnanmycin(262.53 μg/mL).Preliminary structure-activity relationships analysis implied that the introduction of electron-withdrawing groups(F,Cl,CF3)at the 2-position or 4-position of the R2 are favorable for antiviral activity against CMV.4.Using microscale thermophoresis(MST)to investigate the interactions between compounds with high,medium and low inactivation activity against TMV and TMV CP.The results further demonstrated that g18 and g24 exerted promising interaction with TMV CP,with binding constant(Kd)values of 9.78 and 6.83 μM,which were well-comparative to that of Ningnanmycin(6.01 μM).