Design,Synthesis And Biological Activity Of Double Pyrazole Derivatives Containing Amide Moiety

Heterocyclic ring play a pivotal role in the development of new pesticides.As an active branch of nitrogen-containing heterocyclic structure,pyrazole amide compounds possess broad biological activities.In addition,amide structure is an important intermediate,it also have a very wide range of pharmacological activity.The domestic and foreign research report found that two-heterocyclic compound containing a pyrazole ring tends to have a higher and more extensive biological activity,and double-containing heterocyclic compound pyrazole ring is a new and important focus of the new pesticides.In this paper,a series of novel double pyrazole derivatives containing amide moiety which SDH and TMV protein as the target has been designed and synthesized,and the specific studies are as follows: 1.Designed and synthesized of a series of novel double pyrazole derivatives containing amide moietyAfter analyzing the structure of the known pyrazole-4-amides SDHIs fungicides and combination with antiviral activity of the structure characteristics of pyrazole compounds in most previous studies at home and abroad,16 novel pyrazole amide compounds were designed and synthesized,introducing factive groups containing cyano pyrazole,using furametpyr as the master and with active structure fragments modified and docked.All the compounds were characterized by 1H-NMR?ESI-MS and elemental analysis.2.The biological activity and structure-activity relationship of the target compoundAll the target compounds were tested for their antifungal activities against three phytopathogenic fungi(Fusarium graminearum,Sclerotinia sclerotiorum,Venturia pirina)by an in vitro mycelia growth inhibitionassay.The target compounds showed different levels of antifungal activity agaist the three fungi.Especially,compounds9 i and 9k showed the a significantly inhibitionassay,with inhibition rates of 63.38% and 67.62% in the dose of 10.00 mg/L at 72 h after treatment against Sclerotinia sclerotiorum mycelium,with inhibition rates of 55.82% and 65.35% in the dose of 10.00 mg/L at 72 h after treatment against Fusarium graminearum mycelium,with inhibition rates of 43.02% and 63.62% in the dose of 10.00 mg/L at 72 h after treatment against Venturia pirina mycelium.The preliminary structure-activity relationship showed that target compounds 9a-9p's antifungal activities were higher than electron withdrawing groups when R1=4-CH3,R2=4-CH3 or-H electron-donating groups.Anti-tobacco mosaic viral activity results show that the target compounds have some antitobacco mosaic virus activity.Especially,compound 9p showed the similar vitro inhibitionassay and inactivation against tobacco mosaic virus(TMV),and the most potent protection and curative against tobacco mosaic virus(TMV)compared to ningnanmycin.3D-QSAR results indicated that introduction of a fluorine atom facilitates the adoption of a complementary shape of the designed ligands with TMV PC,and this possibly improves the anti-TMV inhibitory potency.3.Effect of target compounds against succinate dehydrogenase enzymeEffects of some target compounds on SDH activity against Fusarium graminearum and Sclerotinia sclerotiorum were measured to determine the functional targets of the target compounds from enzymatic angle.The results showed that all the mycelia of target compounds treated weighed less than those of the controlled and showed significant difference(P<5%).The all treatment group displayed inhibiting activity at a low dose of 0.2mg/L,but their effects on SDH enayme activity showed no discernible difference.However,with increasing doses of treatment,each sample liquid Group SDH inhibition of enzyme activity gradually increased,and the differences of influence on the activity of SDH significant gradually.The overall trends show that,the treatment groups showed significant dose-effect.4.Molecular dockingThe combination of target compounds and SDH enzymes was studied and the binding energy was estimated through molecular docking to furtherly verigy the functional targets of the target compounds.The results of docking showed that compound 9i interacted with the Active pocket region amino acid residues HIS 56,THR 57,GLU 397,GLY 27,LEU 414,LEU 417,ALA 29 and ALA 60.The result of molecular docking suggests that the chlorine atoms of pyrazole ring facilitates the adoption of a complementary shape of the designed ligands with SDH.For the binding model of compound 9p,an H-bond(2.49 ? and 109.02°)was established between its fluorine atom and Gin47,and it also formed a ?-cation interaction(4.65 ?).The result of molecular docking suggests that introduction of a fluorine atom facilitates the adoption of a complementary shape of the designed ligands with TMV PC,and this possibly improves the anti-TMV inhibitory potency.