CN113372296A - 用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物及用途 - Google Patents
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- C07D293/00—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms
- C07D293/02—Heterocyclic compounds containing rings having nitrogen and selenium or nitrogen and tellurium, with or without oxygen or sulfur atoms, as the ring hetero atoms not condensed with other rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
- C07D421/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings
- C07D421/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Abstract
本发明属于硒啉类化合物的生物医药领域，本发明提供了一种用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物及用途。本发明的优点在于，解决了现有的硒啉类化合物对具有多重耐药性的病菌活性不足的问题，提供了具有较高多重耐药性病菌活性的新型硒啉类药物的多种化合物，具有较高的应用价值。
Description
本申请要求申请号为202010163408.6的中国专利的优先权，原申请的申请日为2020年03月10日。
技术领域
本发明涉及硒啉类化合物的生物医药技术领域，尤其涉及一种用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物及用途。
背景技术
在现代的医药临床应用过程中，抗生素一直是一种重要的临床试剂。但是抗生素的大量、广泛使用也带来了一定的副作用，其中以抗生素的耐药性较为常见。在目前的医药研发、生产领域，有大量病菌已经对一些抗生素产生了耐药性，例如，金黄色葡萄球菌(S.aureus)是革兰氏阳性病原体，最常从社区和医院获得性感染中分离得到，MRSA指那些表达了mecA或其他对甲氧西林耐药机制的金黄色葡萄球菌，MRSA感染有轻度的皮肤感染至严重导致死亡的感染。为了能够解决这个问题，临床上通常使用另一种抗生素，例如万古霉素是MRSA的一线抗生素，大多数MRSA都对万古霉素有敏感性，但应对具有万古霉素中等抗性的金黄色葡萄球菌的负担相对较高，并且耐万古霉素的金黄色葡萄球菌(VRSA)也越来越常见。对此，需要从另一个角度去解决抗生素耐药性的问题。
发明内容
本发明针对现有技术针对若干种具有多重耐药性的金黄色葡萄球菌缺乏有针对性的抑制剂的缺点，提供了一种用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物及用途。
为了能够解决现有针对一些具有高耐药性的病菌缺少相对应的对抗、抑制手段的问题，除了更换其它的抗生素以外，也有一些理论和应用指出可以通过找寻具有特定靶向的高活性，能够抑制某些多重耐药菌的化合物。在研发过程中，利用对现有的多种抗生素均具有高耐药性的病菌来筛选新合成化合物的生物活性，可以针对这些高耐药性的病菌来选择、设计需要的化合物基团和分子结构。
为了实现上述发明目的，本发明提供以下技术方案：
本发明提供了一种用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，包括以下通式：
其中，所述X为S或者O；
所述R1选自H、醚或者卤素；
所述R2、R3、R4、R5分别独立地选自芳香类杂环、取代烷基、酰胺、醚、脂类、卤素、硅烷类、硫醚、胺类、磷酸基团、亚砜类或者磺酰基。
作为优选，所述R1选自H、F、Br或者-OCH3；所述R2选自H或者甲基。
作为优选，所述R3选自
Br-Cn2-、
或者
其中，Cn2表示长度为自然数的碳链。
作为优选，所述R4选自
或者
作为优选，所述R5选自
或者
本发明还提供了一种用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，具有以下结构：
本发明还提供了用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物的用途，用于抑制多重耐药的金黄色葡萄球菌。
本发明还提供了用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物的混合物或者偶联物。
本发明提供了一种用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，本发明提供的硒啉类化合物活性较高，相比现有的类似硒琳类化合物更高，其化合物活性相比依布硒啉高约5-10倍，相比其它的硒琳类化合物也具有更高的活性，例如己烷硒啉；本发明提供的硒啉类化合物对于金黄色葡萄球菌具有较好的抑制作用，对于特定的金黄色葡萄球菌具有较强的活性。对于耐万古霉素等金黄色葡萄球菌(VRSA)具有较高的活性。
附图说明
图1为实施例1中本申请化合物抑制多重耐药金葡菌的生长图；
图2为实施例1中CPD14的对菌敏感性测试图；
图3为实施例1中CPD35的对菌敏感性测试图；
图4为实施例1中纸片法验证结果图。
具体实施方式
实施例1
(1)通过EZMTT法检测MRSA金黄色葡萄球菌的多重耐药性：
取200μL McF0.5混悬液于96孔板中测定其OD600值范围，取35～37℃ 200rpm恒温摇床震荡培养一定时间后生长状态良好的菌株取200μL于96孔板中测定其OD600值后稀释至McF0.5范围内。
浊度法生长曲线按McF0.5稀释一定倍数(2×、40×、400×、4000×)后取200μL于96孔板中每隔0.5～1h读数OD600或OD750；浊度法药敏生长曲线按McF0.5稀释一定倍数(40×、1000×)后取200μL于含有系列浓度不同化合物或抗生素药液的96孔板中每隔1h读数OD600或OD750；浊度法药敏测试抑制曲线和MIC值根据20～24h的数据计算得到，McF0.5稀释1000×得到的结果为微量肉汤稀释法结果。
EZMTT法生长曲线按McF0.5稀释一定倍数(2×、40×、400×、4000×)并加入EZMTT(200×)试剂后取200μL于96孔板中每隔0.5～1h读数OD450；EZMTT法药敏生长曲线按McF0.5稀释一定倍数(40×、1000×)并加入EZMTT(200×)试剂后取200μL于含有系列浓度不同化合物或抗生素药液的96孔板中每隔1h读数OD450；EZMTT跟踪法药敏测试抑制曲线和MIC值根据药敏生长曲线20～24h的数据计算得到。EZMTT终点法药敏测试抑制曲线和MIC值通过在对应的浊度法药敏测试实验的20～24h加入EZMTT(200×)试剂后0.5-2h读数OD450并处理得到，McF0.5稀释1000×得到的结果为EZMTT微量肉汤稀释法结果。
从医院购买得到21种金黄色葡萄球菌：MRSA-WJC、MRSA-HYL、MRSA-YXY、MRSA-WBY、MRSA-CYZ、MRSA-YJS、MRSA-WJQ、MRSA-CDZ、MRSA-CDR、MRSA-WHR、MRSA-XHX、MRSA-WQL、MRSA-LCL、MRSA-WQLT、MRSA-ZXH、MRSA-ZHF、MRSA-WXM、MRSA-LJS、MRSA-CYZH、MRSA-CBH、MRSA-CBH9和ATCC25923、ATCC29213一起进行筛选，利用EZMTT法筛选了12个MRSA金黄色葡萄球菌(菌1～菌12顺次为MRSA-WJC、MRSA-HYL、MRSA-YXY、MRSA-WBY、MRSA-CYZ、MRSA-YJS、MRSA-ZHF、MRSA-WHR、MRSA-XHX、MRSA-WQLT、MRSA-CBH、MRSA-CYZH)对现有抗菌素的耐药性检测，发现是多重耐药，如表1中的菌7对9种抗菌素耐药，仅有3种抗菌素敏感。上述的12个MRSA金黄色葡萄球菌样本系由市场上购买得到。具体见表1；
表1：EZMTT筛选多重耐药的金黄色葡萄球菌(R耐药；S敏感；I中间；菌1-12均是多重耐药的金黄色葡萄球菌)
(2)化合物的筛选
将本实施例记载的化合物用于以上的12个金黄色葡萄球菌并观察其活性，结果如图1所示，在合成的接近于400个硒啉类化合物中，我们发现部分的硒啉类化合物对于以上的所有耐药菌株均具有活性。
(3)合成方法：
本实施例所记载的化合物均可以使用以下的合成方法进行合成得到。
以下为部分化合物的合成路线：
(a)CPD1-9
其中，ROH选自以下的基团或者取代基：
得到的化合物CPD1-9的结构式为：
本实施例的结构式的合成方法：将6-氨基己酸(25mmol，3.279g)悬浮于50mL甲醇中，在0℃的条件下，缓慢滴加SOCl2(30mmol，3.57g，2.18mL)。然后将该混合物回流3h，冷却至室温后搅拌过夜。旋蒸除溶剂得到物色透明的粘稠液体，置于冰箱，得到白色固体。
在50mL的烧瓶中加入0.465g的苯胺溶于17.5mL的二氯甲烷中，并加入1.5mL的TEA，搅拌。随后将1.30g的2-(chlorocarbonyl)phenylhypochloroselenoite溶于二氯甲烷中，在冰浴下滴加到烧瓶中。滴加完毕后撤去冰浴，搅拌过夜。
后处理，过柱纯化得到纯品。产率89％。
CPD1：MS(ESI)：327，100％：M+H+；m.p.：173.2～174.0℃；1H NMR(500MHz，CDCl3)δ8.14(d，J＝7.7Hz，1H)，7.69(d，J＝7.5Hz，1H)，7.66(dd，J＝8.5，1.3Hz，2H)，7.64(d，J＝0.7Hz，1H)，7.50-7.42(m，3H)，7.29(dd，J＝12.2，4.7Hz，1H).
溶解化合物甲酯(10mmol)在30mL甲醇和水的混合液(MeOH∶H2O＝4∶1)，之后在冰浴下加缓慢加入LiOH·H2O(1.20g，30mmol)。反应完毕后，后处理获化合物甲酸。
取化合物甲酸(10mmol)溶于15ml的无水DMF中，之后加入EDCI(15mmol)，DMAP(10mmol)，室温下搅拌1h，之后再加入R2OH(15mmol)反应过夜。获化合物CPD2-9。
以上合成方法通用于本实施例的所有化合物，其余部分化合物的合成方法如下所示：
(b)CPD10-11
(c)CPD13-14
(c)CPD15-16
CPD55-57
(d)CPD17-33的合成路线
(e)CPD34-49的合成路线
(f)CPD50-54的合成路线
(4)验证例：对实施例1记载的化合物，其它硒啉类化合物对于其它多重耐药的革兰氏阴性菌的抗菌活性检验比对
化合物(0-50μM)与多重耐药金葡菌(105)在0.5X EZMTT指示剂条件下共浴，通过吸光度(450nm)的变化检测化合物对细胞生长的抑制作用。获得的检验结果如表2所示：
表2
①CPD1：MS(ESI)：327，100％：M+H+；m.p.：173.2～174.0℃；1H NMR(500MHz，CDCl3)δ8.14(d，J＝7.7Hz，1H)，7.69(d，J＝7.5Hz，1H)，7.66(dd，J＝8.5，1.3Hz，2H)，7.64(d，J＝0.7Hz，1H)，7.50-7.42(m，3H)，7.29(dd，J＝12.2，4.7Hz，1H).
(5)敏感性测试
选取CPD14和CPD35，采用EMZTT终点法和跟踪法对ATCC25923(标准菌)、ATCC29213(标准菌)、MRSA-CYZH、MRSA-XHX和MRSA-ZHF进行测试，CPD14的测试结果如图2所示，CPD35的测试结果如图3所示。可以看出，40倍稀释的菌MIC值略有增加，但是敏感性不变。
纸片法验证
用枪头挑取划线培养的菌株CYZH，ATCC 25923(标准菌)，ATCC 29213(标准菌)3个MRSA菌株，用生理盐水稀释至麦氏0.5，取40μL均匀涂布于固体肉汤培养基。待培养基表面干燥后，用镊子夹取含有30μg CPD14的药敏纸片及含有DMS0的药敏纸片贴于固体培养基的正中心。倒置后于培养箱37度培养过夜。测试结果如图4所示，从图中可以看出，CPD14具有显著抑制耐药菌生长活性。
由以上实施例可知，本发明提供了一种抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，相比现有的硒琳类化合物Ebselen、己烷硒啉、丙烷硒啉，实施例1记载的化合物具有更高的抗菌活性，对现有的具有多重耐药性的病菌具有较好的抗菌活性。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (8)
1.一种用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，其特征在于，包括以下通式：
其中，所述X为S或者O；
所述R1选自H、醚或者卤素；
所述R2、R3、R4、R5分别独立地选自芳香类杂环、取代烷基、酰胺、醚、脂类、卤素、硅烷类、硫醚、胺类、磷酸基团、亚砜类或者磺酰基。
2.根据权利要求1所述的用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，其特征在于，所述R1选自H、F、Br或者-OCH3；所述R2选自H或者甲基。
3.根据权利要求1所述的用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，其特征在于，所述R3选自
Br-Cn2-、
或者
其中，Cn2表示长度为自然数的碳链。
4.根据权利要求1所述的用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，其特征在于，所述R4选自
或者
5.根据权利要求1所述的用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，其特征在于，所述R5选自
或者
6.一种用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物，其特征在于，具有以下结构：
7.一种根据权利要求1-4任一所述的用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物的用途，其特征在于，用于抑制多重耐药的金黄色葡萄球菌。
8.一种根据权利要求1-4任一所述的用于抑制多重耐药的金黄色葡萄球菌的硒啉类化合物的混合物或者偶联物。
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