CN111228276B - 一种具有抗菌活性的溴代草酰胺双核铜配合物及其组合物 - Google Patents
一种具有抗菌活性的溴代草酰胺双核铜配合物及其组合物 Download PDFInfo
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Abstract
本发明涉及药物合成技术领域，具体为一种具有抗菌活性的溴代草酰胺双核铜配合物及其组合物。本发明利用草酰胺配体好的配位活性合成双核金属配合物，同时又引入邻菲罗啉芳环体系更有利于嵌入核酸分子，作为抗菌活性的作用靶点；溴代草酰胺双核铜配合物既具有铜离子的抗菌活性，同时又因引入了溴代平面环状结构，既调节了分子的立体结构又增加其抗菌活性。
Description
技术领域
本发明涉及药物合成技术领域，具体为一种具有抗菌活性的溴代草酰胺双核铜配合物及其组合物。
背景技术
金属配合物一般具有较强的抗菌、抗炎活性，例如8-羟基喹啉在合适的金属离子如Fe2+、Fe3+、Cu2+等参与下具有抗菌作用，而Mg2+、Mn2+、Fe2+、Ca2+可增强四环素的抗菌活性，其原因是由于形成配合物的缘故。在配合物结构中，具有较好的平面性的芳环结构引入可以增强配合物的抗菌活性，如Cu(Ⅱ)、Zn(Ⅱ)、Fe(Ⅱ)等的1,10-菲咯啉金属配合物表现出好的抗菌活性。但是，目前对铜配合物抗炎的作用机理还不很清楚。在机理研究中科学家们致力于合成具有抗菌活性的铜配合物，并探索它们与DNA作用的活性。
因为药物的活性主要依赖于药物的化学结构，化学结构的变化会引起药物理化性质的变化，从而影响药物的吸收和分布、对酶和受体的结合以及药物的代谢。本发明通过生物电子等排体的置换、引入溴取代基、芳环改变官能团和立体结构等方法合成溴代草酰胺双核铜配合物，研究发现溴代环状结构的引入可以增强溴代草酰胺双核铜配合物的抗菌活性。
鉴于此，我们提出一种具有抗菌活性的溴代草酰胺双核铜配合物及其组合物。
发明内容
本发明的目的在于提供一种具有抗菌活性的溴代草酰胺双核铜配合物及其组合物，以解决上述背景技术中提出的问题。为了弥补上述抗菌药研究和应用现状中的不足，利用草酰胺配体好的配位活性，通过金属铜离子、溴取代基和芳香结构的引入，提供一种具抗菌活性的溴代草酰胺双核铜配合物及其组合物，具体技术方案如下：一种具有抗菌活性的溴代草酰胺双核铜配合物及其组合物，所述溴代草酰胺双核铜配合物的结构式为：
进一步地，所述溴代草酰胺双核铜配合物的结构式中负离子A-是Cl-或者Br-或者
进一步地，一种具抗菌活性的溴代草酰胺双核铜配合物及其组合物的制备方法包括以下步骤：
(1)N-(5-溴-2-羟基苯胺基)草酰乙酯的合成：将2-氨基-4-溴酚在四氢呋喃中溶解，在并与条件下滴入乙二酸单乙酯单酰氯，有红棕色沉淀析出升温回流3～4h，冷却，过滤，分别用冰乙醇、乙醚洗涤，真空干燥，得红棕色固体产物，产率为50.6％；
(2)N-(5-溴-2-羟苯基)-N′-(3-甲氨丙基)草酰胺的合成：将N-甲基-1,3丙二胺溶于无水乙醇溶液中，在冰浴条件下，缓慢的滴加到溶解有步骤(1)制得的N-(5-溴-2-羟基苯胺基)草酰乙酯的无水四氢呋喃中，回流70min，放冷后，加入冰乙醇，有白色沉淀析出，过滤，分别用冰乙醇、乙醚洗涤，真空干燥，得红棕色固体产物，产率为48.4％-67.3％。
(3)溴代草酰胺双核铜配合物的合成：步骤(2)制得的N-(5-溴-2-羟苯基)-N′-(3-甲氨丙基)草酰胺溶于无水甲醇中，滴入NaOH溶液，60℃反应15min，再滴入Cu(ClO4)2·6H2O溶液，反应20min，再滴入邻菲罗啉溶液反应2h，过滤，滤液静止至有晶体析出，产率为47.1％。
(4)将步骤(3)中制得的目标产物与一种或多种药学上可接受的载体或赋形剂用常规的药剂混合、制备技术做成商品药物组合物。
进一步地，所述步骤(2)中加入的N-(5-溴-2-羟基苯胺基)草酰乙酯与N-甲基-1,3丙二胺的摩尔比为1：1-2。
进一步地，所述步骤(3)中加入的高氯酸铜可以置换为氯化铜等金属盐。
与现有技术相比，本发明提供的具有抗菌活性的溴代草酰胺双核铜配合物及其组合物的有益效果：
1、本发明利用草酰胺配体好的配位活性合成双核金属配合物，同时又引入邻菲罗啉芳环体系更有利于嵌入核酸分子，作为抗菌活性的作用靶点；
2、溴代草酰胺双核铜配合物既具有铜离子的抗菌活性，同时又因引入了溴代平面环状结构，既调节了分子的立体结构又增加其抗菌活性。
附图说明
图1为本发明实施例1中所合成的溴代草酰胺双核铜配合物的x-射线衍射结构图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术工作人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
请参阅图1，本发明提供一种技术方案：一种具有抗菌活性的溴代草酰胺双核铜配合物及其组合物，其制备方法如下：
(1)N-(5-溴-2-羟基苯胺基)草酰乙酯的合成：将19mmol(3.54g)2-氨基-4-溴酚在四氢呋喃中溶解，在并与条件下滴入20mmol(2.15mL)乙二酸单乙酯单酰氯，有红棕色沉淀析出升温回流3～4h，冷却，过滤，分别用冰乙醇、乙醚洗涤，真空干燥，得红棕色固体产物3.81g，产率为70.1％；
(2)N-(5-溴-2-羟苯基)-N′-(3-甲氨丙基)草酰胺的合成：将10mmol(1.25mL)N-甲基-1,3丙二胺溶于无水乙醇溶液中，在冰浴条件下，缓慢的滴加到溶解有步骤(1)制得的10mmol(2.88g)N-(5-溴-2-羟基苯胺基)草酰乙酯的无水四氢呋喃中，回流70min，放冷后，加入冰乙醇，有白色沉淀析出，过滤，分别用冰乙醇、乙醚洗涤，真空干燥，得红棕色固体产物1.70g，产率为51.5％-67.3％。
(3)溴代草酰胺双核铜配合物的合成：步骤(2)制得的N-(5-溴-2-羟苯基)-N′-(3-甲氨丙基)草酰胺1.70g(5mmol)溶于无水甲醇中，滴入2mL NaOH溶液(0.75mol/L)，60℃反应15min，再滴入3.71g(10mmol)Cu(ClO4)2·6H2O溶液，反应20min，再滴入0.99g(5mmol)邻菲罗啉溶液反应2h，过滤，滤液静止至有晶体析出，得目标产物1.79g，产率为47.1％。
实施例2
(1)N-(5-溴-2-羟基苯胺基)草酰乙酯的合成：同实施例1。
(2)N-(5-溴-2-羟苯基)-N′-(3-甲氨丙基)草酰胺的合成：同实施例1，仅将N-(5-溴-2-羟基苯胺基)草酰乙酯与N-甲基-1,3丙二胺的摩尔比为1：1-1.5，得目标产物2.22g，产率为67.3％。
(3)溴代草酰胺双核铜配合物的合成：同实施例1。
实施例3
(1)N-(5-溴-2-羟基苯胺基)草酰乙酯的合成：同实施例1。
(2)N-(5-溴-2-羟苯基)-N′-(3-甲氨丙基)草酰胺的合成：同实施例1，仅将N-(5-溴-2-羟基苯胺基)草酰乙酯与N-甲基-1,3丙二胺的摩尔比为1：1-2，得目标产物1.98g，产率为60.2％。
(3)溴代草酰胺双核铜配合物的合成：同实施例1。
实施例4
(1)N-(5-溴-2-羟基苯胺基)草酰乙酯的合成：同实施例1。
(2)N-(5-溴-2-羟苯基)-N′-(3-甲氨丙基)草酰胺的合成：同实施例1。
(3)溴代草酰胺双核铜配合物的合成：同实施例1，仅不加入NaOH溶液溶液调节pH值，得目标产物1.55g，产率为40.7％。
为了验证溴代草酰胺双核铜配合物的抗菌活性，以空白为对照，进行了公知的抗菌活性试验。
1.梯度稀释计数法测定配合物抗菌活性
分别将上述样品溶液用0.03％硫代硫酸钠溶液，依次稀释8组，制备8个浓度梯度。分别取10-7，10-8两个梯度的菌液20μL，接种于平板计数培养基中。倒置放于37℃的培养箱中，24h后取出观察菌落个数。每个样品做3个平行。空白同样做3个平行。结果见表1。
表1菌落个数
“—”denoted that there are no colony
由表1中菌落个数可以看出，样品对大肠杆菌抗菌活性比较弱，但对金黄色葡萄球菌显示出较高的抑制作用。
2.抑菌圈法
用滤纸片法定性判断配合物对大肠杆菌(Escherichia Coli)、金黄色葡萄球菌(Staphylococcus Aureus)的抑菌作用。样品用DMSO做溶剂配成10-3mol/L的药液灭菌后备用。无菌操作用移液枪取10μL(1),20μL(2)药液与已灭菌的小圆滤纸片(直径10mm)上，再将滤纸片贴在平板相应区域，平板中间贴上浸有DMSO的滤纸片作为对照(0)。然后将贴好滤纸片的含菌平板倒置放于37℃的培养箱中，24h后取出观察抑菌圈的大小。每个样品做3个平行。
由表2中抑菌圈的大小可以看出，配合物对大肠杆菌抗菌活性比较弱，但对金黄色葡萄球菌显示出较高的抑制作用，并且随着剂量的增加抑制活性有所提高。
表2抑菌圈直径
“—”denoted that there are no disinfectivity
实施例5
片剂的制备：称取实施例1合成的目标产物50g，利用常规技术，混合以下组分，用85％乙醇制粒，干燥，压片，制成1000片，每日3次，每次2片。
其配方如下：
实施例6
缓释片剂的制备：称取实施例2合成的目标产物100g，利用常规技术，混合以下组分，用90％乙醇制粒，干燥，压片，制成1000片，每日2次，每次1片。
其配方如下：
实施例7
胶囊剂的制备：称取实施例3合成的式目标产物50g，利用常规技术，混合以下组分，用85％乙醇制粒，干燥，装入硬胶囊，制成1000粒，每日3次，每次2粒。
其配方如下：
通过上述具体实施例可知本发明制得的目标产物可以有效的抑制金黄色葡萄球菌的生长，且与一种或多种药学上可接受的载体或赋形剂用常规的药剂混合、制备技术做成商品药物组合物。
以上显示和描述了本发明的基本原理、主要特征和本发明的优点。本行业的技术工作人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的仅为本发明的优选例，并不用来限制本发明，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (1)
1.一种具有抗菌活性的溴代草酰胺双核铜配合物，其特征在于：所述溴代草酰胺双核铜配合物的结构式为：
所述溴代草酰胺双核铜配合物的结构式中负离子A-是Cl-或者Br-或者
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