CN103664690A - 原儿茶酸的酰腙类衍生物及其制法与其抗菌活性 - Google Patents
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Abstract
Description
技术领域
本发明涉及一类新型原儿茶酸的酰腙类衍生物及其制备方法与作为抗菌药物的用途。
背景技术
酚酸类化合物是中药中一类重要有效活性成分,原儿茶酸类化合物作为一种酚酸类化合物,是中药丹参、芙蓉、益智仁中的有效活性成分,在临床具有抗癌、抑菌、抗氧化、消炎、升高自细胞数量等作用,可以有效抑制血小板凝聚,预防心肌梗塞、中风,外用对微生物有抗菌性。
酰腙类化合物是由酰肼与醛或酮缩合而成的一类Schiff碱类化合物,在亲生物的环境下表现出良好的生物活性、较强的配位能力和多样的配位方式,因此在医药、农药、材料和分析试剂等方面受到了广泛的关注。近年来,研究人员发现,酰腙类化合物具有抗菌、消炎和除草等多种生物活性,某些酰腙还具有抗癌作用。因此,对原儿茶酸的结构进行修饰,形成酰腙结构,能增强其抗菌活性。
发明内容
本发明的目的是提供一类新型的原儿茶酸的酰腙类衍生物及其制备方法和用途。本发明的技术方案如下:
一类新型的原儿茶酸的酰腙类衍生物,它具有如下通式:
式中R为:
一种制备权利要求1所述的含原儿茶酸的酰腙类衍生物的方法,其特征是它由下列步骤组成:
步骤1.于50ml乙醇中加入10g原儿茶酸溶解,缓慢滴入3ml浓硫酸,80℃回流,反应10h。反应结束后,蒸干溶剂,加入20ml乙酸乙酯,饱和氯化钠洗涤3次,无水硫酸钠干燥,快速柱层析,得白色固体原儿茶酸乙酯。
步骤2.用20ml乙醇溶解1,4-苯并二噁烷-5-羧酸乙酯,然后加入水合肼(85%)30ml,80℃回流,反应24h。反应结束后,冷却至室温后大量白色固体析出,饱和氯化钠溶液洗涤3次,乙醇洗涤3次除去水合肼,在乙醇中重结晶得白色针状固体,过滤,干燥,得原儿茶酸酰肼6g。
步骤3.用20ml乙醇溶解步骤2中得到的酰肼,然后加入几滴冰醋酸,再向反应液中加入等摩尔量的酮,80℃回流,反应12h。反应结束后,冷却至室温,有大量白色或黄色固体析出,过滤得到产物粗品,将粗品用乙醇重结晶,得到产物,原儿茶酸的酰腙类衍生物。
实验结果表明,本发明的新型含原儿茶酸的酰腙类衍生物对细菌具有明显的抑制作用。因此本发明的含原儿茶酸的酰腙类衍生物可以应用于制备抗菌药物。
具体实施方式
通过以下实施例进一步详细说明本发明,但本发明的范围并不受这些实施例的任何限制。
实施例1:N′-(1-(4-氟苯基)-亚乙基)-2,3-二羟基苯基酰腙的制备
用20ml乙醇溶解原儿茶酸酰肼,然后加入几滴冰醋酸,再向反应液中加入等摩尔量的对氟苯乙酮,80℃回流,反应12h。反应结束后,冷却至室温,有大量白色或黄色固体析出,过滤得到产物粗品,将粗品用乙醇重结晶,得到目标化合物。得到白色或浅黄色粉末,产率81%,mp:183-185℃;1H NMR(300MHz,DMSO-d6,δppm):2.35(s,3H);5.32-5.35(d,J=8.31Hz,1H);5.36-5.38(d,J=5.58Hz,1H);6.94-6.97(m,1H);7.02-7.04(d,J=4.58Hz,1H);7.28-7.31(m,2H);7.34-7.37(d,J=5.72Hz,1H);7.92-7.93(m,2H);10.78(s,1H).MS(ESI):288.27(C15H13FN2O3,[M+H]+).Anal.Calcd for C15H12FN2O3:C,62.50;H,4.55;N,9.72%.Found:C,62.36;H,4.54;N,9.76%.
实施例2:N′-(1-(4-溴苯基)-亚乙基)-2,3-二羟基苯基酰腙的制备
制备方法同实施例1。以对溴苯乙酮代替对氟苯乙酮,得到目标化合物。白色粉末,产率73%,mp:187-189℃;1H NMR(300MHz,DMSO-d6,δppm):2.19(s,3H);5.37-5.39(d,J=8.12Hz,1H);5.41-5.43(d,J=9.23Hz,1H);6.66-6.68(m,1H);7.12-7.14(d,J=7.45Hz,1H);7.43-7.47(m,2H);7.39-7.41(d,J=5.81Hz,1H);7.88-7.91(m,2H);10.79(s,1H).MS(ESI):349.18(C15H13BrN2O3,[M+H]+).Anal. Calcd for C15H12BrN2O3:C,51.60;H,3.75;N,8.02%.Found:C,51.63;H,3.74;N,8.06%.
实施例3:N′-(1-(4-甲氧基)-亚乙基)-2,3-二羟基苯基酰腙的制备
制备方法同实施例1。以对甲氧基苯乙酮代替对氟苯乙酮,得到目标化合物。白色粉末,产率68%,mp:183-186℃;1H NMR(300MHz,DMSO-d6,δppm):2.24(s,3H);2.47(s,3H);5.56-5.58(d,J=10.74Hz,1H);5.69-5.72(d,J=11.61Hz,1H);6.85-6.91(m,4H);7.32-7.35(d,J=5.37Hz,1H);7.58-7.60(d,J=5.63Hz,2H);10.74(s,1H).MS(ESI):300.31(C16H16N2O4,[M+H]+).Anal.Calcd for C16H15N2O4:C,63.99;H,5.37;N,9.33%.Found:C,63.85;H,5.38;N,9.35%.
实施例4:N′-(1-(3-氟苯基)-亚乙基)-2,3-二羟基苯基酰腙的制备
制备方法同实施例1。以对3-氟苯乙酮代替对氟苯乙酮,得到目标化合物。得到白色或浅黄色粉末,产率73%,mp:188-189℃;1H NMR(300MHz,DMSO-d6,δppm):2.39(s,3H);5.29-5.32(d,J=9.28Hz,1H);5.37-5.39(d,J=5.58Hz,1H);6.97-6.99(m,1H);7.12-7.15(d,J=8.57Hz,1H);7.29-7.33(m,2H);7.41-7.45(d,J=8.83Hz,1H);7.96-7.99(m,2H);10.71(s,1H).MS(ESI):288.27(C15H13FN2O3, [M+H]+).Anal.Calcd for C15H12FN2O3:C,62.50;H,4.55;N,9.72%.Found:C,62.36;H,4.54;N,9.76%.
实施例5:N′-(1-(3-溴苯基)-亚乙基)-2,3-二羟基苯基酰腙的制备
制备方法同实施例1。以3-溴苯乙酮代替对氟苯乙酮,得到目标化合物。白色粉末,产率75%,mp:187-189℃;1H NMR(300MHz,DMSO-d6,δppm):2.47(s,3H);5.47-5.49(d,J=9.36Hz,1H);5.58-5.61(d,J=9.03Hz,1H);6.54-6.57(m,1H);7.08-7.11(d,J=8.95Hz,1H);7.41-7.45(m,2H);7.67-7.69(d,J=4.34Hz,1H);7.79-7.83(m,2H);10.65(s,1H).MS(ESI):349.18(C15H13BrN2O3,[M+H]+).Anal.Calcd for C15H12BrN2O3:C,51.60;H,3.75;N,8.02%.Found:C,51.63;H,3.74;N,8.06%.
实施例6:N′-(1-(3-甲氧基)-亚乙基)-2,3-二羟基苯基酰腙的制备
制备方法同实施例1。以3-甲氧基苯乙酮代替对氟苯乙酮,得到目标化合物。白色粉末,产率64%,mp:185-186℃;1H NMR(300MHz,DMSO-d6,δppm):2.57(s,3H);2.68(s,3H);5.36-5.38(d,J=9.57Hz,1H);5.63-5.65(d,J=8.53Hz,1H);6.81-6.87(m,4H);7.33-7.36(d,J=9.04Hz,1H);7.53-7.57(d,J=6.85Hz,2H);10.86(s,1H).MS(ESI):300.31(C16H16N2O4,[M+H]+).Anal.Calcd for C16H15N2O4:C,63.99;H,5.37;N,9.33%.Found:C,63.64;H,5.36;N,9.29%.
实施例7:原儿茶酸的酰腙类衍生物抗菌活性研究
1.实验材料和方法
1.1药品与试剂
Mueller-Hinton培养基(牛肉浸粉5g,酪蛋白水解物17.5g,淀粉1.5g,琼脂12.5g,加入1000mL蒸馏水中)、卡那霉素、青霉素、DMSO、MTT(3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,商品名为噻唑蓝)、异丙醇、盐酸、均为分析纯试剂、合成的化合物1-6、PBS缓冲液(磷酸盐缓冲液0.01mol/L,pH7.4,Na2HPO4.12H2O 2.9g,KH2PO4 0.2g,NaCl 8.0g,KCl 0.2g,蒸馏水1000mL)。
1.2菌种
大肠杆菌(E.coli)、金黄色葡萄球菌(S.aureus)、枯草芽孢杆菌(B.subtilis)、铜绿假单胞菌(P.aeruginosa)
1.3实验方法
1.3.1培养基的配制
取牛肉浸粉5g,酪蛋白水解物17.5g,淀粉1.5g,琼脂12.5g,加入1000mL蒸馏水中,加热煮沸溶解,分装,121℃高压灭菌15分钟备用。
1.3.2试验菌的培养
在无菌室内,取大肠杆菌,金黄色葡萄球菌,枯草芽孢杆菌和铜绿假单胞菌四种试验菌株,于酒精灯下用接种针分别在四种试验菌株斜面上,刮取少量斜面菌苔,用一定量的无菌水制成菌悬液,然后取一定量加到已融化又冷却至50℃左右的MH培养基中,摇匀,即刻倒入无菌培养皿中,待充分冷凝后用胶塞密封后,于37℃培养18-24小时备用。吸取菌液1mL,用MH培养基按1∶1000稀释,使菌液浓度约为105cfu/mL。
1.3.3抗菌实验:
将待测药品溶于DMSO中配制成2mg/mL的溶液,然后用二倍稀释法将药品稀释成一定浓度梯度(50μg/mL,25μg/mL,12.5μg/mL,3.125μg/mL)与DMSO中。于灭菌微量滴定板第一条中分别加入100μL的培养基,第二条为阳性对照,加入100μL菌悬液。其余的孔中加入90μL的菌悬液和10μL的药物溶液。每个药物溶液浓度平行3次。在微量滴定板底部标明细菌名称。将处理完的培养皿于 37℃培养24h,观察。
1.3.4 MIC的测定
在每个微量滴定板都可以直观的测定其MIC值之后,在板的每个孔中加入50μL PBS缓冲液(磷酸盐缓冲液0.01mol/L,pH7.4,Na2HPO4.2H2O 2.9g,KH2PO4 0.2g,NaCl 8.0g,KCl 0.2g,蒸馏水1000mL),其中包含2mg MTT/mL。在室温下继续孵育4-5h。将孔中的物质移出并加入100μL含有5%1mol/L HCl的异丙醇来萃取染料。继续在室温下孵育12h,用酶标仪测定各孔光吸收(OD值),测定波长550nm。根据各孔OD值计算药物对细菌生长的最小抑制浓度。
最小抑制浓度(minimum inhibitory concentration,MIC):在特定环境下孵育24小时,可抑制某种微生物出现明显增长的最低药物浓度即最小抑制浓度,根据测定的光密度(OD值),制作细菌生长抑制率的标准曲线,在标准曲线上求得其对应的药物浓度。
测得的MIC见表1所示
2.实验结果
表1本发明所列原儿茶酸的酰腙类衍生物对细菌的抑制MIC值(μg/mL)
Kanamycin;Penicillin:阳性对照。
Claims (3)
2.一种制备权利要求1所述的原儿茶酸的酰腙类衍生物的方法,其特征是它由下列步骤组成:
步骤1.于50ml乙醇中加入10g原儿茶酸溶解,缓慢滴入3ml浓硫酸,80℃回流,反应10h。反应结束后,蒸干溶剂,加入20ml乙酸乙酯,饱和氯化钠洗涤3次,无水硫酸钠干燥,快速柱层析,得白色固体原儿茶酸乙酯。
步骤2.用20ml乙醇溶解原儿茶酸乙酯,然后加入水合肼(85%)30ml,80℃回流,反应24h。反应结束后,冷却至室温后大量白色固体析出,饱和氯化钠溶液洗涤3次,乙醇洗涤3次除去水合肼,在乙醇中重结晶得白色针状固体,过滤,干燥,得原儿茶酸酰肼6g。
步骤3.用20ml乙醇溶解步骤2中得到的酰肼,然后加入几滴冰醋酸,再向反应液中加入等摩尔量的酮,80℃回流,反应12h。反应结束后,冷却至室温,有大量白色或黄色固体析出,过滤得到产物粗品,将粗品用乙醇重结晶,得到产物,原儿茶酸的酰腙类衍生物。
3.根据权利要求1所述的原儿茶酸的酰腙类衍生物在制备抗菌药物中的应用。
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