Synthesis, Acaricidal Activities And QSAR Of Scopoletin Phenol Ether Derivatives

Scopoletin is a natural compound,which has a variety of biological activity.Studies has shown that scopoletin also has conspicuous acaricidal activity,but the toxicity of scopoletin was not good enough compared to the commercial acaricidal.It has been reported that the phenolic hydroxyl group of scopoletin has a great influence on the bioactivity of scopoletin.In order to increase the acaricidal potency,thirty scopoletin phenol ether derivatives were synthesized by modifying the structure of phenolic hydroxy group by using molecular hybridization method.And their acaricidal activities and quantitative structure-activity relationships were studied.The main results are as follows:1.Thirty kinds of scopoletin phenol ether derivatives were designed and synthesized with scopoletin as lead compound:30 kinds of phenol ether derivatives were designed and synthesized by modifying the structure of phenolic hydroxy group by using molecular hybridization method?The phenolic hydroxyl group was modified by molecular hybridization.Their structure was confirmed by infrared spectroscopy,nuclear magnetic resonance spectroscopy,carbon spectroscopy and mass spectrometry.Among them,22 compounds were not reported in the literature.2.The acaricidal activity of 30 scopoletin phenol ether derivatives against Tetranychus cinnabarinus was evaluated by slide dipping method.The acaricidal activity of most compounds was higher than scopoletin.Among them,compd.5 and compd.6 had the highest acaricidal activity.The LC₅₀ values of compd.5 and compd.6 were 171 mg/L and 185 mg/L.The virulence of this two compounds were about 6.19 and 5.72 fold than scopoletin and were about 1.95 and 1.81 fold than propargite.3.The activity of compd.5 and compd.6 against the egg,larva stage,nymph stage of Tetranychus cinnabarinus was valuated.It was found that the activity of the two compounds against the larva stage and the nymph stage were better than against the eggs.The hatching inhibition rate of compd.5 and compd.6 were 4.42%and 24.58%.After 48 h of treatment,the corrected mortality rates of compd.5 and compd.6 against the larva stage of Tetranychus cinnabarinus were 81.27%and 59.26%,against the nymph stage of Tetranychus cinnabarinu were 47.92%and 55.89%;after 72 h of treatment,the corrected mortality rates of compd.5 and compd.6 against the larva stage of Tetranychus cinnabarinu were 90.72%and 72.76%,against the nymph stage of Tetranychus cinnabarinu were67.04%and 71.95%.4.A 2D-QSAR model was established.E-dragon was used to calculate the molecular descriptors of scopoletin phenol ether derivatives.Stepwise regression analysis method was used to establish a 2D-QSAR model which was containing five descriptors.The test value F of this model was26.527.The complex correlation coefficient R value was 0.935,and the complex determination coefficiern R² was 0.875,indicating that this model can explain 87.5%of the target compounds.At the same time,through the fitting of the predicted values and experimental values obtained by the model,it was found that the predicted and experimental values of the compounds were evenly distributed on both sides of the straight line,further illustrating that the model has a good predictive ability.5.A 3D-QSAR model was established.The models of CoMFA and CoMSIA have been built.Comparative molecular field analysis?CoMFA?was applied to study of 3D-QSAR on scopoletin phenol derivatives.The reasonable model with predictive ability was obtained from the investigation:q²=0.802,r²=0.993,n=6,steric contour=70.8%,electrostatic contour=29.2%.A linear fitting was applied to the predicted and experimental values.The slope of the fitted curve was 0.9926,indicating that the model has strong stability and good predicting ability.In the comparative molecular similarity indices analysis?CoMSIA?model,q²=0.735,r²=0.965,n=6,steric contour=21.5%,electrostatic contour=28.5%,hydrophobic contour=44.9%,acceptor contour=12.6%.A fitting curve was generated based on the predicted and experimental values.The slope of this curve was 0.9653,indicating that the model has a good predictive ability.The 3D equipotential maps were established by partial least squares based on CoMFA model and CoMSIA model.In the CoMFA model,it is indicated that introducing larger volume functional groups at C3,C6 and C7,introducing negative groups at C7 and C8 can increase the acaricidal activity.In the CoMSIA model,introducing larger volume functional groups at C3,C4 and C7,negative groups at C6,hydrophobic functional groups at C3 and C4,hydrogen bond acceptor function groups at C3,C4 and C7 can improve the acaricidal activity.6.Molecular docking was used to study the mode of scopoletin phenol ether derivatives and target.The results showed that scopoletin and its phenolic ether derivatives have different binding sites and binding modes.Five key amino acids?ASP222,ASP213,GLU220,VAL224 and THR218?in the binding pocket interact with scopoletin via hydrogen bonding and hydrophobic interaction.Scopoletin formed a conventional hydrogen bond with ASP222,two unconventional hydrogen bond with ASP213,and GLU220 respectively,two pi-alkyl interactions with the VAL224,a Pi–Sigma interaction with the THR 218.In addition,acid residues GLU 214,SER 215,HIS 223,SER 221 and ARG 781 in the binding pocket interact with scopoletin via Van der Waals.Among the Derivatives?take compd.5 and compd.25 as examples?,compd.5 was interacted with Six key amino acids?GLU214,ASP222,ASP213,GLY723,ASP724 and VAL224?in the binding pocket via hydrogen bonding and hydrophobic interaction.Compd.5 formed two conventional hydrogen bond with GLU214,and ASP222,respectively,three unconventional hydrogen bond with GLY723,ASP724,and ASP213,respectively,two pi-alkyl interactions with the VAL224.Compd.5 was also surrounded by SER215,HIS223,THR218,ARG781,ASN725,GLU220 and SER221 through Van der Waals interactions.Compd.25 was interacted with seven key amino acids?GLU 214,VAL 224,THR 218,ASP 213,GLY 723,ARG 781 and LEU 217?in the binding pocket via hydrogen bonding and hydrophobic interaction.Compd.25 formed three conventional hydrogen bonds with GLU214,VAL224,and THR218,respectively,three unconventional hydrogen bonds with ASP 213,GLY 723,ARG 781,and GLU 214,respectively,two pi-alkyl interactions with the VAL 224,Alkyl–Alkyl interactions with the LEU 217.Compd.25 interacted with ILE 212,HIS 223,ASP 222,GLU 220,ASN725,ASP 724,PRO 784,SER 783 and SER 782 through Van der Waals.