含双酰胺结构的1,2,4-噁二唑类衍生物的设计、合成及抗菌活性

Design, Synthesis and Anti-fungal Activity of 1,2,4-OxadiazoleDerivatives Containing Diamide Moiety

为了寻找新型抗菌先导化合物,采用活性亚结构拼接的方法引入新的活性片段及取代基,设计合成了27个新型含双酰胺结构的1,2,4-噁二唑类衍生物4a~4c和6a~6x,经核磁共振氢谱(^(1)H NMR)和高分辨质谱(HRMS)确证其化学结构.抗菌活性测试结果表明,当浓度为3.13 mg/L时,化合物6f, 6i, 6m, 6n和6q对大豆锈病(Phakopsorapachyrhiz)的防效分别为80%, 90%, 80%, 90%和70%,优于杀菌剂Flufenoxadiazam(30%)和对照药剂苯醚甲环唑(50%);化合物6i和6n的抗菌活性优异,当浓度为1.56 mg/L时,对大豆锈病仍有50%和70%的抗菌活性.化合物6n在浓度为1.56mg/L时,对玉米锈病(Pucciniasorghi)具有100%防效的优异抗菌活性.分子对接模拟结果表明,化合物6n与组蛋白去乙酰化酶4(HDAC 4)具有多种相互作用,与PRO-298, LEU-299及HIS-158号残基形成的氢键作用可能是其抗菌活性优异的重要原因.

To search the novel and efficient antifungal lead compounds,twenty-seven 1,2,4-oxadiazole derivatives(compounds 4a─4c and 6a─6x)containing diamide moiety with novel chemical structures were designed and synthesized,which was based on the method of the splicing of bioactive substructures.The structures of target compounds were characterized by means of ^(1)H NMR and HRMS spectra.The bioassay results showed that,at the concentration of 3.13 mg/L,the control effect of compounds 6f,6i,6m,6n and 6q against Soybean rust(Phakopsora-pachyrhiz)were 80%,90%,80%,90%and 70%,respectively.The above activities were all better than Flufenoxa-diazam(30%)and the control agent Difenoconazole(50%).Compound 6n also showed prominent antifungal activity against Corn rust(Pucciniasorghi),which control effect was 100%at the concentration of 1.56 mg/L.The molecular docking simulation revealed that compound 6n has various interactions with histone deacetylase 4(HDACs 4),which compound 6n interacts with PRO-298,LEU-299 and HIS-158 through hydrogen bond may be the important source why it showed prominent antifungal activity.