Biological Activities And Structure-Activity Relationship Of Novel N-[4-(1,2,4-oxadiazole)Benzyl]-Pyrazole-5-Carboxamides

Pyrazolecarboxamides are found to show a variety of bioactivities, including insecticidal, acaricidal, fungicidal and herbicidal activities. Since the1940s, lots of pyrazolecarboxamides have been developed to pesticides, such as Tebufenpyrad, Tolfenpyrad, Furametpyr etc. So much more attention has been paid to pyrazolecarboxamide pesticides for their outstanding advantages. The QSAR model was constructed for the Quantitative Structure-activity Relationship of a group of compounds with similar structures and activities when the receptor structure is unknown, to decorate the structure of leading compound and predict new compounds with higher bioactivities. So far, few receptor sturctures in pesticide field are known, so the QSAR method is widely applied.Firstly, the synthesis of the N-[4-(1,2,4-oxadiazole)benzyl]-pyrazole-5-carboxa-mides was researched. By cyclization, halogenation, hydrolysis, acyl chlorination reactions with the raw materials alkyl-2-ketone and diethyl oxalate, pyrazole-5-carboxamides were prepared, then reacting with the1,2,4-oxdiazole benzylamine which was prepared by condensation, cyclization, reduction with the initial material4-cyanobenzaldehyde to give5N-[4-(1,2,4-oxadiazole)benzyl]-pyrazole-5-carboxamides with yields over80%. The structures of all the compounds were confirmed by1H NMR, IR and MS.Biological activities, including insecticidal, fungicidal and herbicidal activities, of23N-[4-(1,2,4-oxadiazole)benzyl]-pyrazole-5-carboxamides(18of them were supplied by Jiangsu Pesticide Research Institute Co. Ltd) were evaluated. The results showed that the title compounds have excellent insecticidal activities, weak fungicidal and herbicidal activities, the LC50were between8.08and307.53μg/mL, which was assayed by feeding dipped-leaf method against the third instar larvae of Plutella xylostell. Activities of11title compounds were higher than Tolfenpxrad (LC50=37.47 μg/mL).The2D and3D QSAR were researched by Hyperchem, Sybyl molecular simulation and SPSS statistical software with the dependent of-igLC50.2D Hansh Equation is-lgLC50=0.1681ogP+0.2171ogP3,4-0.003MR2+0.585MR-1.368σ4,5-30.312, N=15, S=0.198, R=0.869, F=5.567. Results indicated that the bioactivity can be in increased by increasing the hydrophobicity of3,4-positions of pyrazole and the total molecular. The relationship between the bioactivity and the steric parameter MR is consistent with quadratic parabola, the optimum MR is97.5. The increasing of electronegativity in4-position of pyrazole and5-position of oxadiazole can increase the bioactivity of the title compounds.The3D coefficient contour maps of CoMFA and CoMSIA model showed that the increasing the volume and the hydrophobicity in3-position of pyrazole, the hydrophobicity in.4-position of pyrazole and the electronegativity in5-position of oxadiazole can increase the bioactivity. The results agree with the Hansh equation of2D-QSAR. Futhermore, decreasing the volume, increasing the hydrophilicity in5-position of oxadiazole, reducing the hydrogen-bond acceptor groups in oxadiazole, the introduction of hydrogen bond acceptor and reduction of hydrophobicity in benzene, the introduction of hydrogen bond donor in1-position of pyrazole can increase the bioactivity of the title compounds.