吗啉磺酰胺化合物的设计、合成及其抑制大豆萌芽活性的研究

doi:10.6023/cjoc202307014

摘要/Abstract

为了发现新型脱落酸功能类似物, 采用活性亚结构拼接原理设计了含吗啉磺酰胺片段的目标分子. 以吗啉-4-磺酰胺和氟代硝基苯为起始原料, 经芳基亲核取代反应合成了14个目标化合物, 该合成方法操作简单, 底物适用范围广. 种子萌芽实验结果表明, 浓度为50 µmol/L时4a~4d、4k、4m、4n等7个化合物处理后完全抑制萌芽, 25 µmol/L时4a~4d、4k、4m、4n等7个化合物处理后抑制率仍高于95%. 进一步降低至15 μmol/L时, 发现4m、4n的抑制活性高于ABA和先导化合物PM4. 分子对接结果表明, 引入吗啉促使小分子中磺酰基(SO₂)与Ser98形成氢键, 提高了结合受体的能力, 所以4m和4n的打分函数高于ABA和PM4, 活性也更高. 该结果有利于发现新型脱落酸功能类似物.

关键词: 脱落酸功能类似物, 吗啉磺酰胺化合物, 抑制萌芽, 芳基亲核取代反应

In order to obtain novel abscisic acid analogues, morpholine-sulfonamide compound was designed under the principle of active substructure combination. 14 target compounds were obtained through aromatic nucleophilic substitution (S_NAr) when fluoride nitrobenzene and morpholine-4-sulfonamide were used as starting materials. The approach represents simple operation and broad substrate scope. Additionally, the soybean seed germination was inhibited overwhelmingly when treated with compounds 4a~4d, 4k, 4m and 4n at 50 μmol/L. Furthermore, the inhibition activity of compounds 4a~4d, 4k, 4m and 4n was higher than 95% at 25 μmol/L. Finally, the activity of 4m and 4n was much higher than that of ABA and lead compound (PM4) at 15 μmol/L. Moreover, the molecular docking study revealed that 4m and 4n could bind abscisic acid receptor strongly than ABA and PM4. These results are benefit to discovering novel ABA analogues.

Key words: ABA functional analogue, morpholine sulfonamide, inhibition germination, aromatic nucleophilic substitution

引用此文

黄志友, 杨平, 何波, 欧文霞, 袁思雨. 吗啉磺酰胺化合物的设计、合成及其抑制大豆萌芽活性的研究[J]. 有机化学, 2024, 44(1): 309-315.

Zhiyou Huang, Ping Yang, Bo He, Wenxia Ou, Siyu Yuan. Design and Synthesis of Morpholine Sulfonamide Compound and Its Inhibition on Soybean Seed Germination[J]. Chinese Journal of Organic Chemistry, 2024, 44(1): 309-315.

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Entry	T/℃	n(5)∶n(6a)	t/h	Base	Solvent	Yield/%
1	80	1∶1	4	K₃PO₄	DMF	18
2	80	1∶1	8	K₃PO₄	DMF	33
3	80	1∶1	12	K₃PO₄	DMF	40
4	80	1∶1	14	K₃PO₄	DMF	40
5	85	1∶1	12	K₃PO₄	DMF	47
6	90	1∶1	12	K₃PO₄	DMF	53
7	100	1∶1	12	K₃PO₄	DMF	50
8	90	1.1∶1	12	K₃PO₄	DMF	53
9	90	1∶1.1	12	K₃PO₄	DMF	53
10	90	1∶1	12	Na₂CO₃	DMF	45
11	90	1∶1	12	K₂CO₃	DMF	50
12	90	1∶1	12	Cs₂CO₃	DMF	50
13	90	1∶1	12	K₃PO₄	DMAc	51
14	90	1∶1	12	K₃PO₄	1,4-Dioxane	48
15	90	1∶1	12	K₃PO₄	CH₃CN	43

Entry	T/℃	n(5)∶n(6a)	t/h	Base	Solvent	Yield/%
1	80	1∶1	4	K₃PO₄	DMF	18
2	80	1∶1	8	K₃PO₄	DMF	33
3	80	1∶1	12	K₃PO₄	DMF	40
4	80	1∶1	14	K₃PO₄	DMF	40
5	85	1∶1	12	K₃PO₄	DMF	47
6	90	1∶1	12	K₃PO₄	DMF	53
7	100	1∶1	12	K₃PO₄	DMF	50
8	90	1.1∶1	12	K₃PO₄	DMF	53
9	90	1∶1.1	12	K₃PO₄	DMF	53
10	90	1∶1	12	Na₂CO₃	DMF	45
11	90	1∶1	12	K₂CO₃	DMF	50
12	90	1∶1	12	Cs₂CO₃	DMF	50
13	90	1∶1	12	K₃PO₄	DMAc	51
14	90	1∶1	12	K₃PO₄	1,4-Dioxane	48
15	90	1∶1	12	K₃PO₄	CH₃CN	43

Compd.	50 μmol/L		25 μmol/L		15 μmol/L
Compd.	发芽率/%	抑制率/%	发芽率/%	抑制率/%	发芽率/%	抑制率/%
4a	0.0±0.0	100.0±0.0	1.1±1.9	98.8±2.1	63.3±3.3	32.1±3.6
4b	0.0±0.0	100.0±0.0	0.0±0.0	100.0±0.0	61.1±1.9	34.5±2.1
4c	0.0±0.0	100.0±0.0	1.1±1.9	98.8±2.1	65.6±1.9	29.8±2.1
4d	0.0±0.0	100.0±0.0	0.0±0.0	100.0±0.0	67.8±5.1	27.4±5.5
4e	14.4±1.9	84.5±2.1	28.9±5.1	69.0±5.5	—	—
4f	15.6±1.9	83.3±2.1	23.3±3.3	75.0±3.6	—	—
4g	4.4±1.9	95.2±2.1	5.6±1.9	94.0±2.1	—	—
4h	17.8±1.9	81.0±2.1	36.7±3.3	60.7±3.6	—	—
4i	18.9±1.9	79.8±2.1	44.4±3.8	52.4±4.1	—	—
4j	22.2±1.9	76.2±2.1	45.6±1.9	51.2±2.1	—	—
4k	0.0±0.0	100.0±0.0	4.4±1.9	95.2±2.1	71.1±1.9	23.8±2.1
4l	24.4±1.9	73.8±2.1	35.6±3.8	61.9±4.1	—	—
4m	0.0±0.0	100.0±0.0	0.0±0.0	100.0±0.0	55.6±5.1	40.5±5.5
4n	0.0±0.0	100.0±0.0	0.0±0.0	100.0±0.0	57.8±3.8	38.1±4.1
PM4	0.0±0.0	100.0±0.0	11.1±1.9	88.1±2.1	67.8±1.9	27.4±2.1
ABA	2.2±1.9	97.6±2.1	12.2±1.9	86.9±2.1	65.6±5.1	29.8±5.5

Compd.	50 μmol/L		25 μmol/L		15 μmol/L
Compd.	发芽率/%	抑制率/%	发芽率/%	抑制率/%	发芽率/%	抑制率/%
4a	0.0±0.0	100.0±0.0	1.1±1.9	98.8±2.1	63.3±3.3	32.1±3.6
4b	0.0±0.0	100.0±0.0	0.0±0.0	100.0±0.0	61.1±1.9	34.5±2.1
4c	0.0±0.0	100.0±0.0	1.1±1.9	98.8±2.1	65.6±1.9	29.8±2.1
4d	0.0±0.0	100.0±0.0	0.0±0.0	100.0±0.0	67.8±5.1	27.4±5.5
4e	14.4±1.9	84.5±2.1	28.9±5.1	69.0±5.5	—	—
4f	15.6±1.9	83.3±2.1	23.3±3.3	75.0±3.6	—	—
4g	4.4±1.9	95.2±2.1	5.6±1.9	94.0±2.1	—	—
4h	17.8±1.9	81.0±2.1	36.7±3.3	60.7±3.6	—	—
4i	18.9±1.9	79.8±2.1	44.4±3.8	52.4±4.1	—	—
4j	22.2±1.9	76.2±2.1	45.6±1.9	51.2±2.1	—	—
4k	0.0±0.0	100.0±0.0	4.4±1.9	95.2±2.1	71.1±1.9	23.8±2.1
4l	24.4±1.9	73.8±2.1	35.6±3.8	61.9±4.1	—	—
4m	0.0±0.0	100.0±0.0	0.0±0.0	100.0±0.0	55.6±5.1	40.5±5.5
4n	0.0±0.0	100.0±0.0	0.0±0.0	100.0±0.0	57.8±3.8	38.1±4.1
PM4	0.0±0.0	100.0±0.0	11.1±1.9	88.1±2.1	67.8±1.9	27.4±2.1
ABA	2.2±1.9	97.6±2.1	12.2±1.9	86.9±2.1	65.6±5.1	29.8±5.5

Compd.	Total_score	G_score	D_score	PMF_score	Chem_score
4c	5.51	－166.74	－102.12	－59.40	－23.90
4f	5.11	－171.83	－96.88	－54.43	－20.53
4m	7.24	－199.43	－107.20	~64.71	－24.81
4n	6.70	－186.64	－116.82	~65.42	－22.05
PM4	5.46	－186.69	－110.42	－45.26	－26.53
ABA	6.05	－184.31	－102.74	－48.52	－22.00