Synthesis,3D-QSAR and Molecular Docking of Hydroxamate Inhibitors  

异羟肟酯类抑制剂的合成、3D-QSAR和分子对接

作　　者：WU Kaiyue DUAN Wengui MA Xianli LIN Guishan CUI Yucheng QIN Liqing 吴凯越;段文贵;马献力;林桂汕;崔玉成;秦丽清(广西大学化学化工学院,广西高校应用化学技术与资源开发重点实验室,广西南宁530004)

机构地区：[1]School of Chemistry and Chemical Engineering,Guangxi University,Guangxi Colleges and Universities Key Laboratory of Applied Chemistry Technology and Resource Development,Nanning 530004,China

出　　处：《林产化学与工业》2024年第6期83-95,共13页Chemistry and Industry of Forest Products

基　　金：国家自然科学基金资助项目(32260366)。

摘　　要：In search of natural renewable resource-based bioactive molecules,20 hydroxamate inhibitors were designed and synthesized using cinamaldehyde as the starting material.Their structures were characterized by FT-IR,^(1)HNMR,^(13)C NMR,and HRMS.And in vitro antifungal activity of the target compounds against 8 tested fungi was preliminarily evaluated by the agar dilution method.The bioassay results revealed that at the concentration of 50 mg/L,the target compounds exhibited certain inhibitory activity against 8 tested fungi,in which compounds 5r(R=o,o-Cl),5c(R=m-F),5b(R=o-F)and 5p(R=o,p-Cl)displayed better inhibitory activity of 93.3%,76.8%,75.3%and 72.3%,respectively,against P.piricola than that of the positive control chlorothalonil.At the same time,3D-quantitative structure-activity relationship(3D-QSAR)study was carried out to explore the relationship of the molecular structures with their antifungal activity against P.piricola.And a reasonable and effective 3D-QSAR model(r^(2)=0.980,q^(2)=0.501)has been established.Besides,molecular docking was also performed to reveal the binding mode of the target compound 5r(R=o,o-Cl)with succinate dehydrogenase(SDH).It was found that compound 5r could be well embedded in the active pocket of the receptor protein.This showed a similar mode with SDH inhibitors(SDHI)carboxin.为了探寻天然可再生资源基生物活性分子,以肉桂醛为原料设计并合成了20个新型异羟肟酯类抑制剂,采用FT-IR、^(1)H NMR、^(13)C NMR和HRMS对所有目标化合物的结构作了表征,并通过琼脂稀释法初步评估了目标化合物对8种植物病原菌的体外抑菌活性。研究结果表明:在质量浓度50 mg/L下,目标化合物对8种植物病原菌均表现出一定的抑制活性,其中化合物5r(R=o,o-Cl)、5c(R=m-F)、5b(R=o-F)和5p(R=o,p-Cl)对苹果轮纹病菌的抑制活性分别为93.3%、76.8%、75.3%和72.3%,优于阳性对照百菌清。同时,对目标化合物进行了三维定量构效关系(3D-QSAR)研究,探究了分子结构与其抑制苹果轮纹病菌(P.piricola)活性的关系,建立了一个合理有效的3D-QSAR模型(r^(2)=0.980,q^(2)=0.501)。此外,通过分子对接揭示了目标化合物5r(R=o,o-Cl)与琥珀酸脱氢酶(SDH)的结合模式,发现化合物5r可以很好地嵌入受体蛋白的活性口袋,与商用SDH抑制剂(SDHI)萎锈灵具有相似的作用模式。

关 键 词：HYDROXAMATE antifungal activity 3D-QSAR molecular docking 

分 类 号：TQ35[化学工程]