喹唑啉酮肟醚衍生物的设计、合成、杀菌活性及其与琥珀酸脱氢酶受体的结合模式

王金玲; 李忠

doi:10.16801/j.issn.1008-7303.2022.0067

喹唑啉酮肟醚衍生物的设计、合成、杀菌活性及其与琥珀酸脱氢酶受体的结合模式

doi: 10.16801/j.issn.1008-7303.2022.0067

王金玲,
李忠^,

1.
华东理工大学药学院，上海市化学生物学 (芳香杂环) 重点实验室，上海 200237

基金项目: 国家重点研发计划 (2017YFD0200505)

详细信息

作者简介:
王金玲，13598081737@163.com

通讯作者:
李忠，lizhong@ecust.edu.cn

中图分类号: O624.6；O623.626；TQ450.11
计量
- 文章访问数: 221
- HTML全文浏览量: 72
- PDF下载量: 50
- 被引次数: 0
出版历程
- 收稿日期: 2022-05-10
- 录用日期: 2022-06-27
- 网络出版日期: 2022-07-19
- 刊出日期: 2022-10-10

Design, synthesis, antifungal activities and binding mode with succinate dehydrogenase receptor of quinazolinone oxime ether derivatives

WANG Jinling,
LI Zhong^,

1.
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

Funds: the National Key Research and Development Program of China (2017YFD0200505).

摘要

摘要: 为寻找高活性杀菌化合物，以氟吡菌酰胺为对照，在前期发现的新型硝基甲基喹唑啉酮骨架的基础上，通过中间体衍生化法和活性亚结构拼接等手段，设计、合成了25个未见文献报道的喹唑啉酮肟醚衍生物，所有化合物的结构均通过核磁共振氢谱 (¹H NMR)、碳谱 (¹³C NMR) 及高分辨质谱 (HR-EI-MS) 确证。活体杀菌活性测试表明，目标化合物 A19 和 A25 在500 mg/L下对小麦赤霉病菌Fusarium graminearum的防效分别为43.74%和42.46%，活性远低于氟吡菌酰胺。初步分析，其理化性质以及其与琥珀酸脱氢酶 (SDH) 受体结合模式方面的差异可能是导致这些化合物活性比氟吡菌酰胺低的主要原因。
- 喹唑啉酮 /
- 肟醚 /
- 中间体衍生化法 /
- 杀菌活性 /
- 琥珀酸脱氢酶受体 /
- 结合模式
Abstract: In order to discover novel compounds with high fungicidal activities, fluopyram was used as a control, based on the previous discovery of a novel nitromethylquinazolinone skeleton, 25 novel quinazolinone oxime ether derivatives were designed and synthesized by intermediate derivatization and sub-structural combination methods. Their structures were characterized by ¹H NMR, ¹³C NMR and HR-EI-MS spectral data. The preliminary in vivo antifungal evaluation results showed that compounds A19 and A25 were 43.74% and 42.46% control Fusarium graminearum at a concentration of 500 mg/L, respectively. However, the antifungal activities were much lower than that of fluopyram. The differences in physicochemical properties and binding mode with succinate dehydrogenase (SDH) receptor between these compounds and fluopyram may be the major factor which reduced the antifungal activities.
- quinazolinone /
- oxime ether /
- intermediate derivatization method /
- antifungal activities /
- succinate dehydrogenase receptor /
- binding mode

HTML全文

1 含有肟醚结构的代表性农药^[9]

1. Representative pesticides containing oxime ether structures^[9]

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2 目标化合物的分子设计示意图

2. Design strategy of the target compounds

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3 目标化合物的合成路线

3. Synthetic route of target compounds

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图 1 氟吡菌酰胺(淡红色)及A19 (绿色)与SDH受体的结合模式

Figure 1. Binding mode of fluopyram (light red) and A19 (green) with SDH receptor

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表 1 关键中间体7的合成条件筛选

Table 1. Screening of synthetic conditions for key intermediate 7


编号 Number	反应试剂 Reagents	温度 Temperature/℃	溶剂 Solvent	收率 Yield/%
1	Mg(ClO₄)₂/i-Pr₂NEt	r.t.	CH₃CN	80
2	Mg(ClO₄)₂/Et₃N	r.t.~80	CH₃CN	-
3	LiBF₄/i-Pr₂NEt	r.t.	CH₃CN	75
4	CS₂/TBD	0~r.t.	DCM	75
5	NaNO₂	r.t.	DMSO/H₂O	68
6	n-BuLi/Me₃SiSiMe₃	0~ r.t.	THF	71
7	SnCl₂	r.t.	THF	85
8	SnCl₂	r.t.	EtOH	80
9	SnCl₂	r.t.	DCM	54
10	AlCl₃	r.t.	THF	50

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表 2 目标化合物的理化性质以及活体杀菌活性

Table 2. The physiochemical properties and in vivo antifungal activities of target compounds

化合物 Compd.	理化性质 Physiochemical properties				防治效果 Control efficacy/% (500 mg/L)
化合物 Compd.	logP	logS	pK_a	TPSA/Å²	小麦赤霉病菌 Fusarium graminearum
A1	1.65	−2.87	1.22	63.05	14.46
A2	1.14	−2.59	1.22	63.05	11.11
A3	2.48	−3.65	1.22	63.05	17.97
A4	1.65	−3.21	1.22	63.05	16.67
A5	1.00	−3.58	1.22	63.05	23.70
A6	0.95	−3.72	1.22	63.05	31.85
A7	1.93	−3.71	1.22	63.05	8.89
A8	2.53	−4.25	1.22	63.05	24.65
A9	2.18	−4.01	1.22	72.28	32.59
A10	2.52	−4.24	1.22	63.05	22.22
A11	2.53	−4.25	1.22	63.05	32.56
A12	2.23	−4.35	1.22	63.05	−5.37
A13	2.35	−4.32	1.22	63.05	8.15
A14	2.36	−4.39	1.22	63.05	32.59
A15	2.78	−4.79	1.22	63.05	34.07
A16	2.90	−4.41	1.22	63.05	12.59
A17	2.89	−4.42	1.22	63.05	−6.67
A18	3.06	−4.66	1.22	63.05	15.56
A19	3.51	−4.94	1.22	63.05	43.74
A20	4.00	−5.23	1.22	63.05	12.59
A21	2.87	−4.50	1.22	63.05	−2.96
A22	3.30	−4.93	1.22	63.05	37.78
A23	2.29	−4.21	1.22	63.05	12.59
A24	3.27	−5.11	1.22	63.05	12.59
A25	2.20	−3.87	1.33	75.94	42.46
氟吡菌酰胺 fluopyram	3.87	−5.13	1.72	41.99	100.00
CK	—	—	—	—	0.00

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