Design, Synthesis And Biological Activity Of 1,3,4-oxadiazole Hydrazide Derivatives Containing N-heterocyclic Group

According to market research in the past 5 years,the annual sales of succinate dehydrogenase inhibitors(SDHIs)fungicides were increasing at a growth rate of 30%,boscalid currently has the largest sales and market share.To date,succinate dehydrogenase inhibitors have been quickly adopted by the market.Currentl,novel SDHI fungicides have broken the limitation of only for basidiomycetes,and increased the antimicrobial activity against different plant pathogenic fungi,such as ascomycetes and deuteromycetes.Among them,succinate dehydrogenase inhibitor class were mainly nitrogen-containing heterocyclic amides,such as:pyrazole amide,thiophene amide,pyridine amide and pyrazinamide etc..Based on the literature research and the preliminary work,the 1,3,4-oxadiazole skeleton has excellent biological activity.Therefore,a series of 1,3,4-oxadiazole hydrazide derivatives were designed and synthesized through introducing the N-heterocyclic hydrazide group into the scaffold of 1,3,4-oxadiazole.Finally,the target compounds were confirmed by ¹H NMR,¹³C NMR,¹⁹F NMR and HRMS.The in vitro antimicrobial activity of all target compounds against the Gibberella zeae(G.z.),Fusarium oxysporum(F.o.),Sclerotinia sclerotiorum(S.s.),Colletotrichun higginsianum(C.h),Phytophora infestins(P.i.),Botryosphaeria dothidea(B.d.)and Rhizoctonia solani Kühn(R.s.)were evaluated by mycelia growth inhibition tests,while the hymexazol(HM),carbendazim(CB),prochloraz(PC),azoxystrobin(AZX),fluopyram(FB)and boscalid(BS)was served as a reference drug.Notably,compound a2 exerted the best antifungal activity against G.z.(EC50=0.470?g/m L),which was significantly better than the control drugs hymexazol(EC₅₀=59.0?g/m L)and fluopyram(EC₅₀=3.76?g/m L),and was equipotent to the carbendazim(EC₅₀=0.947?g/m L)and prochloraz(EC₅₀=0.570?g/m L).The in vitro antibacterial activity of target compounds against Xanthomonas oryzae pv.oryzae(Xoo),Xanthomonas axonopodis pv.Citri(Xac)and Pseudomonas syringae pv.actinidiae(Psa)were assessed by turbidimetric method,while bismerthiazol(BT)and thiediazole copper(TC)as control drugs.Interestingly,compound a4 has the best activity against Xoo and compound a5 against Xac in vitro,with EC₅₀ values of 8.43 and 3.98?g/m L,respectively,which were better than the control drugs bismerthiazol(EC50=31.9?g/m L and 50.5?g/m L)and thiediazole copper(EC50=76.8?g/m L and 70.0?g/m L).In addition,compound a4 exhibited good biological activity against bacterial leaf blight in vivo.Moreover,the preliminary action mechanism of compound a2 against G.z.was investigated.Primarily,most of mycelium of G.z.were wrinkled and distorted after incubated with compound a2 through imaging using scanning electron microscopy(SEM).Addtionally,SDH enzyme inhibitory activity experiments,SDH enzyme fluorescence quenching experiments and SDH enzyme molecular docking experiments were further employed to reveal the potential action mechanism.The outcoming suggested that compound a2 could cause microorganism to lethal through targeting SDH.