CN111732565A - 一种蛇床子素酯类化合物及其应用 - Google Patents
一种蛇床子素酯类化合物及其应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
Description
技术领域
本发明属于有机化学领域,具体为一种蛇床子素酯类化合物及其应用。
背景技术
蛇床子素的化学名称为7-甲氧基-8-异戊烯基香豆素,它又被人们称之为甲氧基欧芹酚、欧芹酚甲醚,其结构式如式1。
自从1909年,蛇床子素这种天然化合物被Herzog和Krohn两人从欧前胡的根中提取分离出来以后,蛇床子素被广泛应用于医药领域和农药领域。在农业方面,蛇床子素具有杀虫、调节植物生长、增强植物抗病性等多种生物活性;在医学方面,蛇床子素生理活性广泛,具有抗肿瘤、抗肝炎、抗骨质疏松、抗心律失常、抗衰老及改善学习记忆、镇静等作用。
为此,国内外的学者开始对天然产物蛇床子素进行结构修饰与改造,目的是为得到生物活性好、有研究价值的蛇床子素衍生物。通过分析已有研究文献,发现蛇床子素在抗菌方面的应用研究报道较少,仅有研究报道蛇床子及提取物有抗菌活性([1]李宁,杨小红.蛇床子有效成分对金黄色葡萄球菌凝固酶活性的影响[J].广东医学,2007,28(6):876-877;[2]李晶红,谷继伟,王曦.蛇床子提取物的抗菌作用研究[J].黑龙江医药科学,2013,36(4):87-87, 89.)。因此,为了寻找结构新颖的抗菌候选化合物,本发明以中药蛇床子中提取分离的单体化合物蛇床子素为先导化合物,运用药物化学、有机合成等理论知识,对蛇床子素8位异戊烯基进行结构改造和修饰,设计合成一种蛇床子素酯类化合物,进行抗菌活性研究。
发明内容
本发明以蛇床子素为先导化合物,运用现代药物设计理念与有机合成技术等知识,对蛇床子素8位异戊烯基进行结构改造和修饰,设计合成了一类蛇床子素酯类化合物,进行抗菌活性研究。
本发明的主要目的在于提供蛇床子素酯类化合物,如通式Ⅲ所示:
其中,R为1~5个C原子的饱和烷烃基;或R为2-5个C原子的烯烃基;或R为五元环的芳香烃基;或R为六元环的芳香烃基;或R为(CH2)n-R1,其中, n=1-3,R1为芳香烃基;或R为CH=CH-R1,其中R1为芳香烃基。
本发明通式Ⅲ所述活性蛇床子素酯类化合物可与临床抗菌药物或与抗菌活性成分组合使用。
本发明通式Ⅲ所述蛇床子素酯类化合物可用于制备抗金黄色葡萄球菌(S.aureus)的药物或药物组合物。
本发明通式Ⅲ所述蛇床子素酯类化合物可用于制备耐甲氧西林金黄色葡萄球菌(MRSA)的药物或药物组合物。
下面的合成路线描述了本发明通式Ⅲ化合物的制备方法,为有机化学领域的常规和熟知方法。
其中,SeO2为二氧化硒,NaBH4为硼氢化钠,DCC为二环己基碳二亚胺,DMAP为4- 二甲氨基吡啶。
部分通式Ⅲ中蛇床子素酯类化合物的化学结构表示如下:
对本发明所提供的蛇床子素酯类化合物进行抗菌活性研究,结果表明:部分目标化合物的具有显著的抗菌活性,尤其是对金黄色葡萄球菌和耐甲氧西林金黄色葡萄球菌的抗菌活性远远优于蛇床子素及对照药磺胺嘧啶。该发明表明对蛇床子素8位进行结构改造和修饰,能有效改善其抗菌活性。
具体实施方式
下面结合实施例进一步介绍本发明,但本发明不仅限于下述实施例,可以预见本领域技术人员在结合现有技术的情况下,实施情况可能产生种种变化。
本发明通式Ⅲ化合物的制备:
其中,SeO2为二氧化硒,NaBH4为硼氢化钠,DCC为二环己基碳二亚胺,DMAP为4- 二甲氨基吡啶。
实施例1:化合物Ⅲ-1的制备
首先,称取3.0mmol(0.330g)二氧化硒于干燥三口瓶中,加入10mL二甲亚砜,搅拌使其溶解,再称取蛇床子素1.0mmol(0.244g),溶解于10mL二甲亚砜,缓慢滴入三口瓶中,薄层色谱点样跟踪反应体系,100℃搅拌回流,反应10min,停止反应,抽滤,用30mL 乙酸乙酯萃取3次,上层用饱和食盐水和蒸馏水洗涤至pH=5-6,洗涤液用无水硫酸钠干燥 4h之后,过滤,于旋转蒸发仪中浓缩,得粗产品,柱层析纯化,得黄色固体,即中间体I。
然后,另取50mL圆底烧瓶,加1.0mmol(0.258g)中间体I,再加入15mL无水乙醇使其溶解,称取2.0mmol(0.076g)硼氢化钠,用30mL无水乙醇溶解,滴入圆底烧瓶中,薄层色谱点样跟踪反应体系,常温下搅拌反应3h,停止反应,抽滤,用30mL乙酸乙酯萃取3次,上层用饱和食盐水和蒸馏水洗涤至弱酸性,洗涤液用无水硫酸钠干燥4h之后,过滤,用旋转蒸发仪浓缩,得粗产品,柱层析纯化,得白色固体,即中间体Ⅱ。
最后,再取一干燥三口瓶,加入1.0mmol(0.260g)中间体Ⅱ和15mL无水二氯甲烷,在2-5℃冰浴条件下搅拌使其溶解,再称取2.0mmol(0.272g)苯乙酸、2.0mmol(0.412g) DCC(二环己基碳二亚胺)、0.5mmol(0.061g)DMAP(4-二甲氨基吡啶)于滴液漏斗中,加入15mL二氯甲烷溶解后,缓慢滴入三口瓶中。薄层色谱点样跟踪反应体系,反应50min,停止反应,抽滤,用10%NaOH溶液与饱和食盐水洗涤滤液至pH=7,洗涤液用无水硫酸镁干燥4h之后,过滤,旋转蒸发仪浓缩,得粗产品,柱层析分离纯化,得白色固体,即化合物Ⅲ-1。
实施例2:化合物Ⅲ-8的制备
首先,称取3.0mmol(0.330g)二氧化硒于干燥三口瓶中,加入10mL二甲亚砜,搅拌使其溶解,再称取蛇床子素1.0mmol(0.244g),溶解于10mL二甲亚砜,缓慢滴入三口瓶中,薄层色谱点样跟踪反应体系,100℃搅拌回流,反应10min,停止反应,抽滤,用30mL乙酸乙酯萃取3次,上层用饱和食盐水和蒸馏水洗涤至pH=5-6,洗涤液用无水硫酸钠干燥4h之后,过滤,于旋转蒸发仪中浓缩,得粗产品,柱层析纯化,得黄色固体,即中间体I。
然后,另取50mL圆底烧瓶,加1.0mmol(0.258g)中间体I,再加入15mL无水乙醇使其溶解,称取2.0mmol(0.076g)硼氢化钠,用30mL无水乙醇溶解,滴入圆底烧瓶中,薄层色谱点样跟踪反应体系,常温下搅拌反应3h,停止反应,抽滤,用30mL乙酸乙酯萃取3次,上层用饱和食盐水和蒸馏水洗涤至弱酸性,洗涤液用无水硫酸钠干燥4h之后,过滤,用旋转蒸发仪浓缩,得粗产品,柱层析纯化,得白色固体,即中间体Ⅱ。
最后,再取一干燥三口瓶,加入1.0mmol(0.260g)中间体Ⅱ和15mL无水二氯甲烷,在2-5℃冰浴条件下搅拌使其溶解,再称取2.0mmol(0.276g)对羟基苯甲酸、2.0mmol(0.412g)DCC(二环己基碳二亚胺)、0.5mmol(0.061g)DMAP(4-二甲氨基吡啶)于滴液漏斗中,加入15mL二氯甲烷溶解后,缓慢滴入三口瓶中。薄层色谱点样跟踪反应体系,反应50min,停止反应,抽滤,用10%NaOH溶液与饱和食盐水洗涤滤液至pH=7,洗涤液用无水硫酸镁干燥4h之后,过滤,旋转蒸发仪浓缩,得粗产品,柱层析分离纯化,得白色固体,即化合物Ⅲ-8。
实施例3:化合物Ⅲ-9的制备
首先,称取3.0mmol(0.330g)二氧化硒于干燥三口瓶中,加入10mL二甲亚砜,搅拌使其溶解,再称取蛇床子素1.0mmol(0.244g),溶解于10mL二甲亚砜,缓慢滴入三口瓶中,薄层色谱点样跟踪反应体系,100℃搅拌回流,反应10min,停止反应,抽滤,用 30mL乙酸乙酯萃取3次,上层用饱和食盐水和蒸馏水洗涤至pH=5-6,洗涤液用无水硫酸钠干燥4h之后,过滤,于旋转蒸发仪中浓缩,得粗产品,柱层析纯化,得黄色固体,即中间体I。
然后,另取50mL圆底烧瓶,加1.0mmol(0.258g)中间体I,再加入15mL无水乙醇使其溶解,称取2.0mmol(0.076g)硼氢化钠,用30mL无水乙醇溶解,滴入圆底烧瓶中,薄层色谱点样跟踪反应体系,常温下搅拌反应3h,停止反应,抽滤,用30mL乙酸乙酯萃取3次,上层用饱和食盐水和蒸馏水洗涤至弱酸性,洗涤液用无水硫酸钠干燥4h之后,过滤,用旋转蒸发仪浓缩,得粗产品,柱层析纯化,得白色固体,即中间体Ⅱ。
最后,再取一干燥三口瓶,加入1.0mmol(0.260g)中间体Ⅱ和15mL无水二氯甲烷,在2-5℃冰浴条件下搅拌使其溶解,再称取2.0mmol(0.296g)肉桂酸、2.0mmol(0.412g) DCC(二环己基碳二亚胺)、0.5mmol(0.061g)DMAP(4-二甲氨基吡啶)于滴液漏斗中,加入15mL二氯甲烷溶解后,缓慢滴入三口瓶中。薄层色谱点样跟踪反应体系,反应50min,停止反应,抽滤,用10%NaOH溶液与饱和食盐水洗涤滤液至pH=7,洗涤液用无水硫酸镁干燥4h之后,过滤,旋转蒸发仪浓缩,得粗产品,柱层析分离纯化,得白色固体,即化合物Ⅲ-9。
实施例4:化合物Ⅲ-11的制备
首先,称取3.0mmol(0.330g)二氧化硒于干燥三口瓶中,加入10mL二甲亚砜,搅拌使其溶解,再称取蛇床子素1.0mmol(0.244g),溶解于10mL二甲亚砜,缓慢滴入三口瓶中,薄层色谱点样跟踪反应体系,100℃搅拌回流,反应10min,停止反应,抽滤,用 30mL乙酸乙酯萃取3次,上层用饱和食盐水和蒸馏水洗涤至pH=5-6,洗涤液用无水硫酸钠干燥4h之后,过滤,于旋转蒸发仪中浓缩,得粗产品,柱层析纯化,得黄色固体,即中间体I。
然后,另取50mL圆底烧瓶,加1.0mmol(0.258g)中间体I,再加入15mL无水乙醇使其溶解,称取2.0mmol(0.076g)硼氢化钠,用30mL无水乙醇溶解,滴入圆底烧瓶中,薄层色谱点样跟踪反应体系,常温下搅拌反应3h,停止反应,抽滤,用30mL乙酸乙酯萃取3次,上层用饱和食盐水和蒸馏水洗涤至弱酸性,洗涤液用无水硫酸钠干燥4h之后,过滤,用旋转蒸发仪浓缩,得粗产品,柱层析纯化,得白色固体,即中间体Ⅱ。
最后,再取一干燥三口瓶,加入1.0mmol(0.260g)中间体Ⅱ和15mL无水二氯甲烷,在2-5℃冰浴条件下搅拌使其溶解,再称取2.0mmol(0.148g)丙酸、2.0mmol(0.412g) DCC(二环己基碳二亚胺)、0.5mmol(0.061g)DMAP(4-二甲氨基吡啶)于滴液漏斗中,加入15mL二氯甲烷溶解后,缓慢滴入三口瓶中。薄层色谱点样跟踪反应体系,反应50min,停止反应,抽滤,用10%NaoH溶液与饱和食盐水洗涤滤液至pH=7,洗涤液用无水硫酸镁干燥4h之后,过滤,旋转蒸发仪浓缩,得粗产品,柱层析分离纯化,得白色固体,即化合物Ⅲ-11。
目标化合物Ⅲ的相关数据如表1所示:
表1
本发明的抗菌活性测试:以蛇床子素、磺胺嘧啶为对照药物,采用微量稀释法测定通式Ⅲ蛇床子素酯类化合物对金黄色葡萄球菌(S.aureus)、耐甲氧西林金黄色葡萄球菌(MRSA) 及大肠杆菌(E.coli)的最小抑菌浓度(MIC),部分化合物抗菌活性数据如表2所示。
表2
从上述实验结果可以清楚的看出,本发明所要保护的通式Ⅲ的化合物具有潜在抗菌活性。大多数化合物对金黄色葡萄球菌(S.aureus)、大肠杆菌(E.coli)和耐甲氧西林金黄色葡萄球菌(MRSA)的抗菌活性优于对照品蛇床子素和对照药磺胺嘧啶,尤其对金黄色葡萄球菌(S.aureus)和耐甲氧西林金黄色葡萄球菌(MRSA)的抗菌活性更显著。其中,化合物Ⅲ-2、Ⅲ-3、Ⅲ-4、Ⅲ-7、Ⅲ-8、Ⅲ-9对金黄色葡萄球菌(S.aureus)的MIC值远远小于对照品蛇床子素和对照药磺胺嘧啶;化合物Ⅲ-2、Ⅲ-3、Ⅲ-4、Ⅲ-6、Ⅲ-7、Ⅲ-9对耐甲氧西林金黄色葡萄球菌(MRSA)的MIC值远远也小于对照品蛇床子素和对照药磺胺嘧啶,均表现出显著的抗菌活性;另外化合物Ⅲ-2对大肠杆菌(E.coli)的抗菌活性也优于对照品蛇床子素和对照药磺胺嘧啶。其潜在的抗菌活性可用于抗金黄色葡萄球菌(S.aureus)和抗耐甲氧西林金黄色葡萄球菌(MRSA)的应用。同时,也可与其他抗菌活性物质组合使用。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2008209672A1 (en) * | 2007-02-02 | 2008-08-07 | Novartis Ag | Chromene S1P1 receptor antagonist |
CN103554075A (zh) * | 2013-10-30 | 2014-02-05 | 南京农业大学 | 一种制备蛇床子素类似物的新方法 |
CN109053798A (zh) * | 2018-07-23 | 2018-12-21 | 遵义医学院 | 一种大黄酸酯衍生物及其制备方法与应用 |
CN110396078A (zh) * | 2018-04-25 | 2019-11-01 | 西华大学 | 蛇床子素衍生物及其制备方法和应用 |
-
2020
- 2020-07-28 CN CN202010738242.6A patent/CN111732565B/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2008209672A1 (en) * | 2007-02-02 | 2008-08-07 | Novartis Ag | Chromene S1P1 receptor antagonist |
CN103554075A (zh) * | 2013-10-30 | 2014-02-05 | 南京农业大学 | 一种制备蛇床子素类似物的新方法 |
CN110396078A (zh) * | 2018-04-25 | 2019-11-01 | 西华大学 | 蛇床子素衍生物及其制备方法和应用 |
CN109053798A (zh) * | 2018-07-23 | 2018-12-21 | 遵义医学院 | 一种大黄酸酯衍生物及其制备方法与应用 |
Non-Patent Citations (4)
Title |
---|
ACS: "RN:73292-94-1", 《STN REGISTRY数据库》 * |
AMILA A. DISSANAYAKE,等: "Lipid Peroxidation and Cyclooxygenase Enzyme Inhibitory Compounds from Prangos haussknechtii", 《J. NAT. PROD.》 * |
张新勇等: "蛇床子化学成分的研究", 《中草药》 * |
杨家强,等: "蛇床子素酯类衍生物的合成及抗菌活性", 《应用化学》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114805111A (zh) * | 2022-05-23 | 2022-07-29 | 遵义医科大学 | 一种苯丙烯酰胺类化合物及其制备方法与应用 |
CN114805111B (zh) * | 2022-05-23 | 2024-02-06 | 遵义医科大学 | 一种苯丙烯酰胺类化合物及其制备方法与应用 |
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