含哌啶的新型1,2,4-噁二唑类衍生物的设计合成及抗真菌活性研究
收稿日期: 2022-12-12
修回日期: 2023-02-15
网络出版日期: 2023-04-23
基金资助
南宁市科学研究与技术开发计划项目重大科技专项(20201043); 南宁市创新创业领军人才“邕江计划”创业(2020002-1)
Design, Synthesis and Antifungal Activities of Novel 1,2,4-Oxadiazole Derivatives Containing Piperidine
Received date: 2022-12-12
Revised date: 2023-02-15
Online published: 2023-04-23
Supported by
The Nanning Scientific Research and Technology Development Program(20201043); The Nanning Innovation and Entrepreneurship Leading Talents “YongJiang Plan” Entrepreneurship Project(2020002-1)
为了寻找新型高效的抗菌先导化合物, 采用活性亚结构拼接法, 设计合成了17个含哌啶的新型1,2,4-噁二唑类衍生物4a~4b和6a~6o, 其结构经1H NMR、13C NMR和高分辨质谱(HRMS)表征. N-(1-苯甲酰基哌啶-4-基)-4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯甲酰胺(6e)结构由X射线单晶衍射法加以确证. 抗菌活性测试结果表明: 在浓度为3.13 mg/L时, N-(1-乙酰基哌啶-4-基)-4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯甲酰胺(6a)、N-(1-(环丙甲酰基)哌啶-4-基)-4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯甲酰胺(6c)、6e、4-((4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯甲酰胺基)甲基)哌啶-1-甲酸叔丁酯(4b)和N-((1-(苯甲酰基)哌啶-4-基)甲基-4-(5-(三氟甲基)-1,2,4-噁二唑-3-基)苯甲酰胺(6o)对大豆锈病(Phakopsora pachyrhiz)的抑制率分别为70%、82%、95%、78%和98%, 优于Flufenoxadiazam (30%)和对照药剂苯醚甲环唑(50%); 在浓度为1.56 mg/L时, 化合物6e、6o对大豆锈病仍有80%和75%的抑制率. 化合物6e、6o在浓度为0.10 mg/L时对玉米锈病(Puccinia sorghi)也有着92%和90%抑制率的优异抗菌活性. 分子对接模拟表明, 化合物6e与组蛋白去乙酰化酶4 (HDACs 4)有着多种相互作用, 它与PHE 227及PHE 226形成的氢键作用可能是化合物6e抗菌活性优异的重要原因.
王锋 , 陈钰 , 裴鸿艳 , 张静 , 张立新 . 含哌啶的新型1,2,4-噁二唑类衍生物的设计合成及抗真菌活性研究[J]. 有机化学, 2023 , 43(8) : 2826 -2836 . DOI: 10.6023/cjoc202212015
To search the novel and efficient antifungal lead compounds, seventeen 1,2,4-oxadiazole derivatives 4a~4b and 6a~6o containing piperidine with novel chemical structures were designed and synthesized, which were based on the method of the splicing of bioactive substructures. The structures of target compounds were characterized by 1H NMR, 13C NMR and high-resolution mass spectra (HRMS), and the structure of N-(1-benzoylpiperidin-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadia- zol-3-yl)benzamide (6e) was further confirmed by X-ray single crystal diffraction. The bioassay results showed that, at the concentration of 3.13 mg/L, the inhibition rates of N-(1-acetylpiperidin-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)- benzamide (6a)、N-(1-(cyclopropanecarbonyl)piperidin-4-yl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (6c)、6e、tert-butyl 4-((4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamido)methyl)piperidine-1-carboxylate (4b) and N-((1-benzoyl- piperidin-4-yl)methyl)-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzamide (6o) against Soybean rust (Phakopsora pachyrhiz) were 70%, 82%, 95%, 78% and 98%, respectively. The above activities were all better than flufenoxadiazam (30%) and control agent difenoconazole (50%). Among them, compounds 6e and 6o could still reach 80% and 75% inhibition rates, respectively at the concentration of 1.56 mg/L. Compounds 6e and 6o also showed prominent antifungal activity against corn rust (Puccinia sorghi), which inhibition rates were 92% and 90%, respectively at the concentration of 0.10 mg/L. The molecular docking simulation revealed that compound 6e has various interactions with histone deacetylase 4 (HDACs 4), and the hydrogen bonding formed with PHE 227 and PHE 226 may be an important reason for the prominent antifungal activity of compound 6e.
Key words： piperidine; 1,2,4-oxadiazole; synthesis; antifungal activity; molecular docking
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