Design,Synthesis And Biological Evaluation Of Novel Heterocyclic Oxadiazole Derivatives

As one member of the most vital nitrogen-containing five-membered heterocyclic compounds,1,3,4-oxadiazole and its derivatives demonstrating broad spectrum of bioactivities,such as antibacterial,antifungal,pesticide,herbicidal,anticancer and anti-inflammatory activities,have been as one of the research and development hotspots in the field of medicine and agriculture.In this thesis,a range of novel 1,3,4-oxadiazole thioether derivatives were designed and synthesized through introducing heterocyclic moiety containing oxygen and nitrogen into 1,3,4-oxadiazole thioether,also,their bioactivities were evaluated.The crucial intermediates 1,3,4-oxadiazole-2-thiol substituted at 5-position can be obtained by esterification,hydrazinolysis and ring-closed reaction from heterocyclic acid.Finally,33 1,3,4-oxadiazole derivatives were synthesized and their structure were confirmed by ¹H NMR?¹³C NMR and HRMS.1.The antibacterial activities of all the title compounds against Xanthomonas oryzae pv.oryzae,Ralstonia solanacearum and Xanthomonas axonopodis pv.citri were examined using the turbidimeter test in vitro.The results showed that part of the compounds showed excellent antibacterial activities,especially for Xanthomonas oryzae pv.Oryzae.Further studied suggested that the EC₅₀ values of target compound A₄ reached up to 7.56?g/mL and A₁₀ reached up to 13.4?g/mL which was much better than the control agent Bismerthiazol(EC₅₀0 value was 92.6?g/mL),When 1,3,4-oxadiazole thioether were substituted by 3,5,6-trichloro-3-methoxypyridine moiety,compound A10 exhibited significant antibacterial inhibition effects with EC₅₀0 value 33.5?g/mL toward Ralstonia solanacearum(thiediazole copper,EC₅₀ 217?g/mL)and EC₅₀value 24.7?g/mL toward Xanthomonas axonopodis pv.citri?thiediazole copper,EC5077.0?g/mL?.Furthermore,the antifungal activity of target compounds was tested via the poison plate technique against three phytopathogenic fungal strains including Botrytis cinerea,Fusarium oxysporum,and Sclerotinia Slerotiorum,target compounds demonstrated poor to good antifungal activity.2.The Nematocidal bioassays of compounds A1-A33 were evaluated by Contact killing method toward Meloidogyne incongnita,the result suggest that some of them exhibited moderate insecticidal activity in vivo and in vitro.3.In vivo antibacterial activities tests under greenhouse conditions revealed that the curative activity and protect activities of compound A10 against rice bacterial leaf blight can reach up to 56.3%and 56.0%at concentration of 200?g/mL which were better than those of bismerthiazol?43.5%and 40.9%?and Thiodiazole Copper?42.6%and 39.2%?.in addition,a responsively label-free quantitative proteomic analysis was conducted to explore the possible action mechanism of compound A10 toward Xoo.Experimental results shows that 253 proteins were differentially expressed,among which 152 proteins were up-regulated and 101 proteins were down-regulated,mainly in the process of the process of histidine metabolism,glycometabolism and glyconeogenesis after treated by compound A10 at concentration of 7 times of EC₅₀.Besides,the results of signal path analysis demonstrated that A10 can affect hisitidine synthesis and break glyconeogenesis in Xoo.SEM images were used in a concentration-dependent manner to further explore the antibacterial mechanism.In this study,this phenomenon further indicated that the designed compounds had versatile capabilities to influence and disturb the normal life of bacteria and consequently led to their death.The outcome was in accordance to the quantitative proteomic analysis.