CN111808062B - 一种蛇床子素磺酸酯类化合物及其应用 - Google Patents
一种蛇床子素磺酸酯类化合物及其应用 Download PDFInfo
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- 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
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
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Abstract
本方案公开了有机化学技术领域中的具有通式Ⅲ所示的蛇床子素磺酸酯类化合物,
Description
技术领域
本发明涉及有机化学领域,具体为一种蛇床子素磺酸酯类化合物及其应用。
背景技术
蛇床子素又名甲氧基欧芹酚或欧芹酚甲醚,化学式为C15H16O3,如式1所示,其化学名称为7-甲氧基-8-异戊烯基香豆素,是蛇床子中含量最高的一种烃基香豆素类有效化学成分,主要存在于伞形科和芸香科植物中,在菊科和豆科少数种中也有分布。
现代药理实验研究表明:蛇床子及蛇床子素具有广泛的生物活性,在医学上它具有抗心律失常、抗高血压、抗衰老、抗惊厥、抗炎、抗***反应、抗肿瘤、抗肝炎、降血糖、镇静、增强记忆力等功效;同时,在农业上的应用研究也有报道,如,有研究表明蛇床子素具有杀虫、抑制病毒等作用。
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磺酸酯类化合物,进行抗菌活性研究。
发明内容
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磺酸酯类化合物,进行抗菌活性研究。
本发明的主要目的在于提供蛇床子素磺酸酯类化合物,如通式Ⅲ所示:
其中,R为1~6个碳原子的取代基;或R为苯基;或R为含N、O、S原子中的1个或2 个或3个杂原子的五元芳香杂环基;或R为含N、O、S原子中的1个或2个或3个杂原子的六元芳香杂环基。
本发明通式Ⅲ所述活性蛇床子素磺酸酯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所述蛇床子素磺酸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所述蛇床子素磺酸酯类化合物可用于制备耐甲氧西林金黄色葡萄球菌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,为有机合成领域的常规和熟知方法。
其中,SeO2为二氧化硒,NaBH4为硼氢化钠,Et3N为三乙胺。
对本发明所提供的蛇床子素磺酸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,Et3N为三乙胺。
实施例1:化合物Ⅲ-1的制备
首先,取3.0mmol(0.330g)二氧化硒于100ml三颈瓶中,加入25ml二甲亚砜,加热使其溶解,于100℃条件下加入溶于25ml二甲亚砜的蛇床子素1.0mmol(0.244g),TLC跟踪反应,回流反应12min,停止反应,趁热抽滤,滤液用50ml乙酸乙酯萃取,用饱和食盐水和蒸馏水洗涤至Ph=5.5-6,收集洗涤液,用无水硫酸钠干燥,抽滤,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:4),得白色固体。
然后,取1.0mmol(0.258g)中间体I于100ml三颈瓶中,加25ml无水乙醇并搅拌使其溶解,加入2.0mmol(0.076g)硼氢化钠,TLC跟踪反应,于室温条件下反应5h后,加乙酸乙酯40ml萃取,用饱和食盐水和蒸馏水洗涤至pH=5.5-6,收集洗涤液,无水硫酸钠干燥,抽滤,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:3),得白色固体,即中间体Ⅱ。
最后,取1.0mmol(0.260g)的中间体Ⅱ置于50ml反应管中,加入5ml无水二氯甲烷并搅拌使其溶解,然后在室温条件下加入2.0mmol(0.352g)苯磺酰氯,再于搅拌条件下缓慢加入2.0mmol(0.202g)三乙胺,混匀后,TLC跟踪反应,于35℃反应24h,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:4),得白色固体,即化合物Ⅲ-1。
实施例2:化合物Ⅲ-5的制备
首先,取3.0mmol(0.330g)二氧化硒于100ml三颈瓶中,加入25ml二甲亚砜,加热使其溶解,于100℃条件下加入溶于25ml二甲亚砜的蛇床子素1.0mmol(0.2440g),TLC跟踪反应,回流反应12min,停止反应,趁热抽滤,滤液用50ml乙酸乙酯萃取,用饱和食盐水和蒸馏水洗涤至pH=5.5-6,收集洗涤液,用无水硫酸钠干燥,抽滤,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:4),得白色固体。
然后,取1.0mmol(0.258g)中间体I于100ml三颈瓶中,加25ml无水乙醇并搅拌使其溶解,加入2.0mmol(0.076g)硼氢化钠,TLC跟踪反应,于室温条件下反应5h后,加乙酸乙酯40Ml萃取,用饱和食盐水和蒸馏水洗涤至pH=5.5-6,收集洗涤液,无水硫酸钠干燥,抽滤,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:3),得白色固体,即中间体Ⅱ。
最后,取1.0mmol(0.260g)的中间体Ⅱ置于50ml反应管中,加入5ml无水二氯甲烷并搅拌使其溶解,然后在室温条件下加入3.0mmol(0.663g)邻硝基苯磺酰氯,再于搅拌条件下缓慢加入3.0mmol(0.303g)三乙胺,混匀后,TLC跟踪反应,于35℃反应24h,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:3),得白色固体,即化合物Ⅲ-5。
实施例3:化合物Ⅲ-9的制备
首先,取3.0mmol(0.330g)二氧化硒于100ml三颈瓶中,加入25ml二甲亚砜,加热使其溶解,于100℃条件下加入溶于25ml二甲亚砜的蛇床子素1.0mmol(0.244g),TLC跟踪反应,回流反应12min,停止反应,趁热抽滤,滤液用50ml乙酸乙酯萃取,用饱和食盐水和蒸馏水洗涤至pH=5.5-6,收集洗涤液,用无水硫酸钠干燥,抽滤,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:4),得白色固体。
然后,取1.0mmol(0.258g)中间体I于100ml三颈瓶中,加25ml无水乙醇并搅拌使其溶解,加入2.0mmol(0.076g)硼氢化钠,TLC跟踪反应,于室温条件下反应5h后,加乙酸乙酯40ml萃取,用饱和食盐水和蒸馏水洗涤至pH=5.5-6,收集洗涤液,无水硫酸钠干燥,抽滤,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:3),得白色固体,即中间体Ⅱ。
最后,取1.0mmol(0.260g)的中间体Ⅱ置于50ml反应管中,加入5ml无水二氯甲烷并搅拌使其溶解,然后在室温条件下加入1.5mmol(0.291g)间氟苯磺酰氯,再于搅拌条件下缓慢加入1.5mmol(0.152g)三乙胺,混匀后,TLC跟踪反应,于35℃反应24h,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:5),得白色固体,即化合物Ⅲ-9。
实施例4:化合物Ⅲ-16的制备
首先,取3.0mmol(0.330g)二氧化硒于100ml三颈瓶中,加入25ml二甲亚砜,加热使其溶解,于100℃条件下加入溶于25ml二甲亚砜的蛇床子素1.0mmol(0.244g),TLC跟踪反应,回流反应12min,停止反应,趁热抽滤,滤液用50Ml乙酸乙酯萃取,用饱和食盐水和蒸馏水洗涤至pH=5.5-6,收集洗涤液,用无水硫酸钠干燥,抽滤,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:4),得白色固体,即中间体I。
然后,取1.0mmol(0.258g)中间体I于100ml三颈瓶中,加25ml无水乙醇并搅拌使其溶解,加入2.0mmol(0.076g)硼氢化钠,TLC跟踪反应,于室温条件下反应5h后,加乙酸乙酯40ml萃取,用饱和食盐水和蒸馏水洗涤至pH=5.5-6,收集洗涤液,无水硫酸钠干燥,抽滤,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:3),得白色固体,即中间体Ⅱ。
最后,取1.0mmol(0.260g)的中间体Ⅱ置于50ml反应管中,加入5ml无水二氯甲烷并搅拌使其溶解,然后在室温条件下加入2.0mmol(0.488g)对三氟甲基苯磺酰氯,再于搅拌条件下缓慢加入2.0mmol(0.202g)三乙胺,混匀后,TLC跟踪反应,于35℃反应24h,浓缩,得粗产品,柱层析分离纯化(V乙酸乙酯:V石油醚=1:3),得白色固体,即化合物Ⅲ-16。
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蛇床子素磺酸酯类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)的最小抑菌浓度(MIC),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-4、Ⅲ-6、Ⅲ-14、Ⅲ-15、、Ⅲ-16对金黄色葡萄球菌(S.aureus)的MIC远远小于对照品蛇床子素和对照药磺胺嘧啶;化合物Ⅲ-14、Ⅲ-16对耐甲氧西林金黄色葡萄球菌(MRSA) 的MIC也远远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-6、Ⅲ-16对大肠杆菌(E.coli)的抑菌效果优于对照品蛇床子素和对照药磺胺嘧啶,表现出显著的抗菌活性。其潜在的抗菌活性可用于制备抗金黄色葡萄球菌(S.aureus)、大肠杆菌(E.coli)和抗耐甲氧西林金黄色葡萄球菌(MRSA)的药物中。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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