CN106083726B - 含有环己基的不对称二硫醚类化合物及其在制备抗菌药物中的用途 - Google Patents
含有环己基的不对称二硫醚类化合物及其在制备抗菌药物中的用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一类含有环己基的不对称二硫醚类化合物及其在制备抗菌药物中的用途。本发明的含有环己基的不对称二硫醚类化合物对耐甲氧西林金黄色葡萄球菌(MRSA)、金黄色葡萄球菌和白色念珠菌具有很强的抑制作用，可用于制备新型的抗菌药物。这些药物可以制成注射剂、片剂、丸剂、胶囊、悬浮剂或乳剂的形式使用。其给药途径可为口服、经皮，静脉或肌肉注射。
Description
技术领域
本发明涉及一类含有环己基的不对称二硫醚类化合物及其在制备抗菌药物中的用途，特别是对耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcusaureus，MRSA)、金黄色葡萄球菌等革兰氏阳性菌有很强的抑制作用，对白色念珠菌(Candida albicans)等真菌有很强的抑制作用。
技术背景
耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus，MRSA)是一种超级耐药菌细菌，其对多种抗生素的抗药性在不断增强。目前对MRSA真正起效的抗生素已为数不多，临床常用的仅万古霉素(vancomycin)、达托霉素(daptomycin)、利奈唑胺(linezolid)、替加环素(tigecycline)和头孢吡普(ceftobiprole)等药物。研究开发化学结构新颖，毒性较低的新型抗耐药菌药物成为刻不容缓。
当今时代，由白色念珠菌、隐球菌和曲霉菌等入侵型真菌引起的感染是影响人类健康的重大问题。目前，医治真菌感染的药剂依赖于类型为数不多的化学药物，如酮康唑为代表的唑类，多烯类抗生素和两性霉素B等等。由于这些抗真菌药物长期使用产生的抗性问题日益明显，设计合成新的有效药物迫在眉睫。
不对称二硫醚类化合物及其生物活性研究较少，2012年王建国等人在CN102775360A和CN102702130B公开了不对称芳香二硫醚类化合物可以抑制植物中的乙酰乳酸合成酶，从而提出了不对称芳香二硫醚类化合物在制备除草剂中的应用。2016年张立新和王建国等人发现不对称芳香二硫醚类化合物通过抑制病毒3C蛋白酶而具有抗病毒活性(专利申请号，201610104430.7)。
发明内容
本发明的目的在于提供一类含有环己基的不对称二硫醚类化合物及其在制备制备抗革兰氏阳性菌药物中和抗真菌药物中的用途，特别是抗耐甲氧西林金黄色葡萄球菌(MRSA)药物和抗白色念珠菌的应用。
本发明的不对称二硫醚类化合物如所示：
通过体外抑制细菌实验表明，本发明的含有环己基的不对称二硫醚类化合物对耐甲氧西林金黄色葡萄球菌(MRSA)和金黄色葡萄球菌具有很强的抑制作用，因此本发明的含有环己基的不对称二硫醚类化合物可用于制备治疗抗革兰氏阳性菌感染的活性化合物。
通过体外抑制真菌实验表明，本发明的含有环己基的不对称二硫醚类化合物对白色念珠菌(Candida albicans)具有很强的抑制作用。因此本发明的含有环己基的不对称二硫醚类化合物可用于制备治疗抗真菌感染的活性化合物。
本发明还提供一种抗菌药物，特别是治疗抗耐甲氧西林金黄色葡萄球菌(MRSA)感染和治疗抗白色念珠菌感染的药物；该药物含有上述的含有环己基的不对称二硫醚类化合物以及一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、增效剂。该药物可以制成注射剂、片剂、丸剂、胶囊、悬浮剂或乳剂的形式使用。其给药途径可为口服、经皮，静脉或肌肉注射。
本发明实质性特点可以从下述实施例中得以体现，但这些实施例仅作为说明，而不是对本发明进行限制。
具体实施方式
下面将详细描述本发明的具体实施方式，这仅用于解释本发明，而不能解释为对本发明的限制。
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从普通商业途径得到。
下述实施例用于合成不对称二硫醚类化合物所使用的化学原料及试剂2-巯基-4-甲氧羰基咪唑、2-巯基-5-乙酰氨基噻唑、2-巯基-4-乙氧羰基咪唑、3-巯基-[1，2，4]-三唑、3-巯基-5-(3，-吡啶)-基-[1，2，4]-三唑、3-巯基-5-(4’-吡啶)-基-[1，2，4]-三唑、环己硫醇、硫脲购自Alfa Aesar(天津)化学品公司、上海晶纯试剂有限公司或美国Aurora化学品公司，其余常规化学原料均为天津本地市售。
实施例1：化合物1的合成
100mL的三口瓶中加入4.0g(34mmol)环己硫醇I和1.9g(25mmol)硫脲II，加入10mL水和30mL醇溶解，冰盐浴搅拌下慢慢同时滴加3mL浓盐酸和3.5mL 30％的H2O2，继续搅拌3h，减压脱溶，残余物用10mL乙醇溶解，并用乙醚稀释，冷却过夜，次日过滤，固体用乙醇-水重结晶，得5.2g白色中间体III(产率90％)。
50mL的单口瓶中加入0.56g(2.5mmol)中间体III和0.34g(2mmol)2-巯基-4-甲酸乙酯基咪唑，加6mL甲醇溶解，冰水浴搅拌，慢慢滴加含0.25g碳酸氢钠的10mL碳酸氢钠的水溶液，反应3h，冷冻过夜，过滤得白色固体，柱分离，最终得0.48g化合物1，产率85％。
用同样方法可以合成化合物2-6。
化合物1-6的结构式和物化参数见表1，1H NMR、13C NMR及高分辨质谱见表2。
实施例2：不对称二硫醚类化合物抗菌活性测定。
1.试验材料
Mueller-Hinton Broth(北京奥博星生物技术有限责任公司)，胰蛋白胨(英国OXOID公司)，酵母浸出粉(英国OXOID公司)，氯化钠(国药集团化学试剂有限公司)，96孔细胞培养板(flat bottom)(美国康宁公司)，阳性对照药物万古霉素和酮康唑，二甲基亚砜DMSO(国药集团化学试剂有限公司)，YPD Agar(美国BD Difco公司)，RPMI Media 1640(美国Gibco公司)，MHB培养基(使用电子天平称取24克Mueller-Hinton Broth干粉，溶解于1000毫升蒸馏水，调节pH至7.2，使用高压蒸汽灭菌锅在121℃下灭菌20分钟制备所得)。耐甲氧西林金黄色葡萄球菌MRSA(代号USA300)菌株，金黄色葡萄球菌菌株(代号ATCC6538)，白色念珠菌(Candida albicans)标准菌株(代号SC5314)，所有菌株以冻存甘油管方式保存于-80℃冰箱，化合物1-6，LB琼脂平板(使用电子天平称取10克Tryptone、5克Yeastextract、5克氯化钠，溶解于1000毫升蒸馏水，调节pH至7.0，加入20克琼脂粉，使用高压蒸汽灭菌锅在121℃下灭菌20分钟，分装至无菌培养皿(30mL/培养皿)待冷却凝固后备用)。
2.菌液准备
测定时取出保藏MRSA菌株的甘油冻存管，在室温下解冻，划线法接种于LB琼脂平板上进行活化，于37℃培养箱培养20小时；用无菌接种环挑取3个MRSA单菌落于3mL MHB培养基中，使用涡旋振荡器充分混匀成为菌液母液，使用血球计数板检测菌浓；使用MHB培养基将菌液母液稀释至2×104细胞/mL，成为待用菌液。
3.药液准备
用电子分析天平称取待测化合物，以无菌DMSO为溶剂配制为1mg/mL的化合物溶液；阳性对照药物万古霉素使用无菌DMSO配制为320μg/mL的溶液，并用DMSO依次稀释为160μg/mL、80μg/mL、40μg/mL、20μg/mL、10μg/mL、5μg/mL、2.5μg/mL等8个浓度梯度。
4.测定药物抑制MRSA的最小抑菌浓度
取无菌96孔细胞培养板，使用8道微量移液器移取40μL MHB培养基至96孔细胞培养板各孔；使用微量移液器吸取2μL步骤3中所述的8个浓度梯度的万古霉素溶液，加入96孔细胞培养板第一列的8个孔中，为阳性对照组；使用微量移液器吸取2μL无菌DMSO，加入96孔细胞培养板第十二列的8个孔中，为阴性对照组；使用微量移液器吸取2μL待检测化合物溶液，依次加入96孔细胞培养板第二列至第十一列各孔中；使用8道微量移液器移取40μL步骤2中所述的待用菌液，加入96孔细胞培养板各孔中；将上述96孔细胞培养板置于37℃培养箱，培养16小时后，观察96孔板各孔中的MRSA生长状况，呈混浊状态的孔中所加的化合物无抗MRSA活性，呈澄清状态的孔中所加的化合物初步判断具有抗MRSA活性。将所检测到的各个具有抗MRSA活性的化合物从1mg/mL的初始浓度依次进行2倍梯度稀释为1mg/mL，500μg/mL，250μg/mL，125μg/mL，62.5μg/mL，31.25μg/mL，15.625μg/mL，7.8125μg/mL 8个不同浓度的化合物溶液；用同样的方法测定，使用酶标仪读取各孔的吸光值OD600。对于每个化合物，MRSA生长被完全抑制的孔所对应的化合物终浓度(化合物溶液浓度/40)即为该化合物对MRSA的最低抑菌浓度MIC。
同样，可以测定化合物1-6抑制金黄色葡萄球菌和白色念珠菌的生物活性。
目标化合物抗菌活性的测试结果见表3。
表1.化合物1-6的物化参数
表2、化合物1-6的1H NMR、13C NMR及高分辨质谱数据
表3.化合物1-6抗MRSA、金黄色葡萄球菌和白色念珠菌的生物活性结果
Claims (4)
1.一种含有环己基的不对称二硫醚类化合物，其特征在于该类化合物为：
2.权利要求1所述含有环己基的不对称二硫醚类化合物作为制备抗耐甲氧西林金黄色葡萄球菌药物和抗白色念珠菌药物中的用途。
3.一种抗菌药物，其特征在于它含有权利要求1所述的含有环己基的不对称二硫醚类化合物以及一种或多种药学上可接受的载体；所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、增效剂。
4.根据权利要求3所述的抗菌药物，其特征在于它是含有所述抗菌药物的注射剂、片剂、丸剂、胶囊、悬浮剂或乳剂。
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