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

doi:10.6023/cjoc202212015

摘要/Abstract

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.

关键词: 哌啶, 1,2,4-噁二唑, 合成, 抗菌活性, 分子对接

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

引用此文

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.

Feng Wang, Yu Chen, Hongyan Pei, Jing Zhang, Lixin Zhang. Design, Synthesis and Antifungal Activities of Novel 1,2,4-Oxadiazole Derivatives Containing Piperidine[J]. Chinese Journal of Organic Chemistry, 2023, 43(8): 2826-2836.

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Compd.	n	R	EC₅₀/(mg•L^－1)	毒力回归方程	R²
6a	0	CH₃CO	2.942	y=－0.2162＋1.5281x	0.9168
6c	0	cyclo-C₃H₅CO	2.093	y=0.1802＋0.9966x	0.8480
6e^a	0	PhCO	0.952	y=0.5216＋1.0032x	0.9873
6f	0	Naph-CO	3.877	y=－0.2331＋1.2457x	0.9985
4b	1	Boc-CO	1.730	y=0.3299＋0.7142x	0.8683
6l	1	CH₃CO	3.810	y=0.1623＋0.5813x	0.9423
6m	1	cyclo-C₃H₅CO	4.534	y=－0.2851＋1.1959x	0.9382
6n	1	PhSO₂	3.361	y=－0.3308＋1.5779x	0.9918
6o^a	1	PhCO	1.135	y=0.4407＋1.0796x	0.9929
Flufenoxadiazam	—	—	3.428	y=－0.3886＋1.6610x	0.9494
苯醚甲环唑^b	—	—	3.125	y=1.3288x－0.1242	0.9833

Compd.	n	R	EC₅₀/(mg•L^－1)	毒力回归方程	R²
6a	0	CH₃CO	2.942	y=－0.2162＋1.5281x	0.9168
6c	0	cyclo-C₃H₅CO	2.093	y=0.1802＋0.9966x	0.8480
6e^a	0	PhCO	0.952	y=0.5216＋1.0032x	0.9873
6f	0	Naph-CO	3.877	y=－0.2331＋1.2457x	0.9985
4b	1	Boc-CO	1.730	y=0.3299＋0.7142x	0.8683
6l	1	CH₃CO	3.810	y=0.1623＋0.5813x	0.9423
6m	1	cyclo-C₃H₅CO	4.534	y=－0.2851＋1.1959x	0.9382
6n	1	PhSO₂	3.361	y=－0.3308＋1.5779x	0.9918
6o^a	1	PhCO	1.135	y=0.4407＋1.0796x	0.9929
Flufenoxadiazam	—	—	3.428	y=－0.3886＋1.6610x	0.9494
苯醚甲环唑^b	—	—	3.125	y=1.3288x－0.1242	0.9833

Compd.	Erysiphe cichoracearum			Blumeria graminis			Puccinia sorghi
Compd.	100 mg/L	6.25 mg/L	0.39 mg/L	100 mg/L	6.25mg/L	0.39 mg/L	6.25 mg/L	1.56 mg/L	0.39 mg/L	0.10 mg/L
6e	0	0	0	0	0	0	100	100	100	92
6o	0	0	0	0	0	0	100	100	100	90
Flufenoxadiazam	0	0	0	0	0	0	100	90	50	20
氟唑菌酰胺^a	100	100	98	—^b	—	—	—	—	—	—
烯肟菌胺^a	—	—	—	100	100	100	—	—	—	—
嘧菌酯^a	—	—	—	—	—	—	100	100	100	95

Compd.	Erysiphe cichoracearum			Blumeria graminis			Puccinia sorghi
Compd.	100 mg/L	6.25 mg/L	0.39 mg/L	100 mg/L	6.25mg/L	0.39 mg/L	6.25 mg/L	1.56 mg/L	0.39 mg/L	0.10 mg/L
6e	0	0	0	0	0	0	100	100	100	92
6o	0	0	0	0	0	0	100	100	100	90
Flufenoxadiazam	0	0	0	0	0	0	100	90	50	20
氟唑菌酰胺^a	100	100	98	—^b	—	—	—	—	—	—
烯肟菌胺^a	—	—	—	100	100	100	—	—	—	—
嘧菌酯^a	—	—	—	—	—	—	100	100	100	95