CN107382893B - 具有抗菌活性的利奈唑胺碱阳离子两亲性化合物及其制备方法 - Google Patents
具有抗菌活性的利奈唑胺碱阳离子两亲性化合物及其制备方法 Download PDFInfo
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- CN107382893B CN107382893B CN201710585875.6A CN201710585875A CN107382893B CN 107382893 B CN107382893 B CN 107382893B CN 201710585875 A CN201710585875 A CN 201710585875A CN 107382893 B CN107382893 B CN 107382893B
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- antibacterial activity
- linezolid
- dmso
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- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学领域，公开了具有抗菌活性的利奈唑胺碱阳离子两亲性化合物及其合成方法。本发明通过两步或三步反应，简单、快速得到三种类型的目标产物，主要结构如下所示。体外抗菌活性实验证明，该系列部分化合物对敏感菌株如金黄色葡萄球菌、粪肠球菌、大肠埃希菌和肠道沙门氏菌均表现出良好的抑菌效果，部分化合物对包括甲氧西林耐药的金黄色葡萄球菌（MRSA）、万古霉素耐药的肠球菌（VRE）和产碳青霉烯酶肠杆菌科细菌（CRE）在内的“超级细菌”也表现出优异的抗菌活性。体外红细胞毒性实验也显示该系列化合物具有较小的红细胞毒性，因此，该系列化合物有望作为新的抗菌候选药物。
Description
技术领域
本发明属于药物化学技术领域，公开了具有抗菌活性的利奈唑胺碱阳离子两亲性化合物及其制备方法。
背景技术
自2000年上市以来，利奈唑胺已在美国用于治疗革兰阳性球菌感染(AntimicrobAgents Chemother,2010,54,742)，其中包括耐甲氧西林金黄色葡萄球菌(MRSA)和耐万古霉素肠球菌(VRE)。但是已经有VRE和MRSA等耐药菌对利奈唑胺产生耐药性的报道(TheLancet,2001,358,207)，且MRSA是全世界最常见的耐药细菌(The Lancet,2006,368,874)。
因此，设计和合成新型抗菌药物是今后药物研究工作者的主要目标之一。目前已经有大量研究工作致力于合成噁唑烷酮类似物(Antimicrobial agents andchemotherapy,2001.45(4):p.1151-1161)、保留活性基团吗啉和酰胺而改造其它基团(Biomacromolecules,2016.17(9):p.3094-102)或者用新的双杂环骨架替代利奈唑胺的吗啉部分，但结果表明这些改造后的化合物抗菌活性都没有显著提高(Current Science2005.89(3):p.531-534)。
根据以上菌株对利奈唑胺产生耐药性的实例和现有技术对利奈唑胺的结构改造，本发明人在了解其作用机理的基础上，确定规范了噁唑烷酮(利奈唑胺)的晶体结构与核糖体50S亚基的结合(J Med Chem,2008(51):p.3353–3356)。主要关注抗菌药物开发的替代新策略(Antimicrob Agents Chemother,2009.53(1):p.333-4；Adv Med,2016.2016:p.8762691)，即在氨基上引入活性基团合成更有价值的抗菌药物。通过合成三个系列利奈唑胺碱阳离子衍生物，并评价其抗菌活性，希望得到具有较好抗菌活性的化合物。
发明内容
本发明的目的在于提供一系列抗菌谱广、毒性小的新型利奈唑胺碱阳离子两亲性化合物，有利于新抗菌药物研发。另一目的在于提供其制备方法。
为实现本发明目的，技术方案如下：
所述具有抗菌活性的利奈唑胺碱阳离子两亲性化合物，结构式如下：
优选化合物:2a-2f；6a-6e；6f-6j。
合成本发明利奈唑胺碱阳离子两亲性抗菌化合物(2a-2f，6a-6j)路线如下：
具体通过如下步骤实现：
(1)合成利奈唑胺碱氨基氯乙酰化的中间物(1a)
化合物(1a)的合成：向含利奈唑胺碱和无水碳酸钾混合物的烧瓶中加入丙酮，用注射器加入氯乙酰氯，然后在室温下搅拌反应；反应结束后冰水淬灭反应，析出沉淀，抽滤，冰水洗涤，滤饼放入真空干燥箱干燥即得目标产物；
(2)合成利奈唑胺碱季铵阳离子化合物(2a-2f)
化合物(2a-2f)的合成：向含化合物1a的水热合成反应釜中加入乙腈，然后加入N,N-二甲基正烷基胺，然后在80-85℃油浴下搅拌反应。反应结束后将反应液转入烧瓶内旋蒸，加入乙醚静置，析出固体或油状物，将乙醚除去后蒸干(油状物)或抽滤(固体)，干燥，即得目标产物；
(3)合成利奈唑胺碱氨基还原氨化的中间物(3a-3e)
化合物(3a-3e)的合成：向含利奈唑胺碱和三乙酰氧基硼氢化钠混合物的烧瓶中加入1,2-二氯乙烷，然后加入正烷基醛，氮气保护，然后在室温下搅拌反应；反应过夜，饱和碳酸氢钠溶液淬灭反应并调pH至碱性，经萃取，洗涤、干燥，硅胶柱层析分离即得目标产物；
(4)合成Boc保护的氨基酸(4a-4b)
化合物(4a)的合成：将L-赖氨酸用水溶解，在冰浴下加入氢氧化钠并搅拌，然后加入二叔丁基二碳酸酯的四氢呋喃溶液，加完后将反应移至室温进行反应；反应结束后减压条件下蒸除四氢呋喃，洗去有机层杂质，然后调pH至4-5；经萃取，洗涤，干燥，过滤，滤液蒸干得产物；
化合物(4b)的合成：将L-精氨酸加入到烧瓶内，加入水和叔丁醇，混合物置于冰浴中搅拌，加入氢氧化钠在冰浴下搅拌反应，然后分批加入二叔丁基二碳酸酯，室温下反应；反应结束后，蒸干有机溶剂，萃取水溶液，收集中间层，调PH至3-4；经萃取，洗涤，干燥，过滤，蒸干溶剂得到目标产物；
(5)合成利奈唑胺碱氨基和氨基酸羧基缩合的化合物(5a-5j)
化合物(5a-5j)的合成：在混合溶剂中，化合物3a-3e与Boc保护的氨基酸4a或4b在催化剂条件下发生反应生成化合物5a-5j；所用催化剂为O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)和碱催化剂N,N-二异丙基乙胺(DIPEA)；所用混合溶剂是N,N-二甲基甲酰胺和氯仿；(6)合成利奈唑胺碱阳离子两亲性化合物(6a-6j)
化合物(6a-6j)的合成：溶剂中，化合物5a-5j在原位制备氯化氢的作用下脱去Boc保护基得到目标化合物，原位制备氯化氢的方法是乙酰氯滴加到甲醇中。
本发明通过两步或三步反应，简单、快速得到目标产物，所得新型阳离子抗菌化合物部分对革兰氏阳性的金黄色葡萄球菌ATCC 29213和粪肠球菌ATCC 29212以及革兰氏阴性的大肠埃希菌ATCC 25922和肠道沙门氏菌ATCC 8387表现出良好的抑菌作用，几个化合物的最低抑菌浓度(minimum inhibitory concentration,MIC)能达到2～16μg/mL，并且部分化合物同时对MRSA、VRE、以及产NDM-1型金属酶和KPC型丝氨酸酶的CRE表现出与敏感菌株同等甚至更好抑菌效果。化合物6e对阳性金黄色葡萄球菌的抑菌效果与阳性对照药物利奈唑胺和万古霉素相当，表现出广谱的抑菌活性并且对临床耐药菌株也有较好的抑菌活性，MIC的范围2-16μg/mL。化合物2c～2f,6c～6e,6i～6j对革兰氏阳性菌(ATCC 29213和ATCC 29212)具有较好的活性，然而对革兰氏阴性菌(ATCC 25922和ATCC 8387)的活性相对来说较差，选择性比较显著。体外红细胞毒性试验HC50结果表明该系列化合物2e和6e呈现对红细胞较小的毒性。因此，本发明提供的一系列抗菌谱广、低毒性的利奈唑胺碱阳离子两亲性抗菌化合物，有望作为新的抗菌候选药物进行深入的研究，并对解决目前全球面临耐药菌日益严重的问题有重要意义。
具体实施方式
下面结合具体实施例，进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明要求保护的范围。
合成化合物表征使用的仪器：NMR谱使用瑞典Bruker DPX-400型超导核磁共振仪测定，TMS为内标；高分辨质谱使用Waters-Micromass公司Q-Tof质谱仪测；IR谱使用Nicolet iS10红外光谱仪进行检测，KBr压片。
实施例1 化合物2a～2f,6a～6j的制备
(1)化合物(1a)的合成：
化合物(1a)的合成：向含利奈唑胺碱(1g,3.39mmol)和无水碳酸钾(562mg,4.06mmol)混合物的烧瓶中加入溶剂丙酮(25mL)，然后盖上橡皮塞，再用注射器加入氯乙酰氯(306μL)，然后在室温下搅拌反应，反应0.5-1h后冰水淬灭反应，析出沉淀，抽滤，冰水洗涤，滤饼放入真空干燥箱干燥即得目标产物。
(2)化合物(2a-2f)的合成：
化合物(2a-2f)的合成：向含化合物1a的水热合成反应釜中加入溶剂乙腈，然后加入N,N-二甲基正烷基胺(1a：N,N-二甲基正烷基胺＝1:3，摩尔比)，然后在85℃油浴下搅拌反应。反应24h后将反应液转入烧瓶内旋蒸，溶剂剩余约1/10时加入乙醚静置，析出固体或油状物，将乙醚除去后蒸干(油状物)或抽滤(固体)，干燥，即得目标产物；
(3)化合物(3a-3e)的合成：
化合物(3a-3e)的合成：向含利奈唑胺碱和三乙酰氧基硼氢化钠混合物的烧瓶中加入溶剂1,2-二氯乙烷，然后加入正烷基醛(利奈唑胺碱：正烷基醛：三乙酰氧基硼氢化钠＝1:1.1:1.3，摩尔比)，氮气保护，然后在室温下搅拌反应；反应过夜，饱和碳酸氢钠溶液淬灭反应并调pH至8，二氯甲烷萃取3次，水洗2次，饱和食盐水洗1次，无水硫酸钠干燥，硅胶柱层析分离即得目标产物。(4)化合物(4a-4b)的合成：
化合物(4a)的合成：将L-赖氨酸(5g)用水(100mL)溶解，在冰浴下加入三当量的氢氧化钠并搅拌，在该溶液中缓慢加入的二叔丁基二碳酸酯的四氢呋喃(50mL)溶液，加完后3min将反应移至室温进行反应24h。反应结束后减压条件下蒸掉四氢呋喃，用乙醚洗去有机层杂质，然后用1M的硫酸溶液调pH至4-5。二氯甲烷萃取3次，水洗有机层2次，饱和食盐水洗1次，无水硫酸镁干燥，过滤，滤液蒸干得产物。
化合物(4b)的合成：将L-精氨酸(8.7g，50mmol)加入到500mL圆底烧瓶内，加入水(150mL)和叔丁醇(150mL)，混合物在置于冰浴中搅拌，加入氢氧化钠(7g，175mmol)。在冰浴下搅拌5min后分批加入二叔丁基二碳酸酯(43.7g，200mmol)，加完后在室温下反应48h。反应结束后，蒸干有机溶剂，乙醚萃取水溶液，萃取液分三层，收集中间的一层。柠檬酸调pH至3-4，然后用乙酸乙酯(3×60mL)萃取，水洗有机层两次，无水硫酸镁干燥，过滤，蒸干溶剂得到目标产物。
(5)化合物(5a-5j)的合成：取化合物3a-3e加入25mL单口瓶，然后加入混合溶剂DMF/CHCl3(5:2)冰水浴下搅拌，继而加入N，N-二异丙基乙胺(DIPEA)和HBTU，该混合体系冰水浴下搅拌5分钟后加入Boc保护的氨基酸4a-4b(3a-3e:DIPEA:HBTU:4a-4b＝1:3:1.25:1.25)，然后继续冰水浴下搅拌半个小时后转入室温下反应24小时。反应时间过后，TLC(PE：PA＝1:1)监测反应，显示原料不存在。然后旋蒸蒸去体系中的氯仿，之后加入乙酸乙酯(15mL)；该体系用0.5M硫酸氢钾溶液洗(10mL×3)，合并有机相，水洗(10mL×3)、饱和氯化钠溶液洗(10mL×1)，最终有机相用无水硫酸钠干燥、过滤、浓缩。柱层析(PE：EA＝5:1)纯化得到中间体油状化合物5a-5j，收率约85％。(6)化合物(6a-6j)的合成：将化合物5a-5j溶于甲醇中，塞上翻口橡胶塞冰水浴下搅拌，然后注射器向上述体系中加入乙酰氯(5a-5j:乙酰氯＝1:6，摩尔比)，加毕后体系转入室温下继续反应24小时。反应时间到后，TLC(PE：EA＝1:1)监测反应，显示化合物5a-5j不存在，停止反应，浓缩蒸干体系中的溶剂。真空隔膜泵将体系抽真空得到黄色泡沫状固体，向装有固体的瓶内加入适量无水乙醚，刮下固体清洗、抽滤、真空干燥得到黄色固体目标化合物6a-6j。
(2a):深黄色粘稠油状物，产率78.6％。
1H NMR(400MHz,DMSO)δ9.56(t,J＝5.6Hz,1H),7.49(dd,J＝15.0,2.5Hz,1H),7.19(dd,J＝8.8,2.1Hz,1H),7.06(t,J＝9.3Hz,1H),4.80(dd,J＝7.6,5.5Hz,1H),4.24(s,1H),4.11(t,J＝9.0Hz,1H),3.86(dd,J＝9.0,6.6Hz,1H),3.77–3.69(m,4H),3.54(dd,J＝10.0,5.3Hz,1H),3.46(dd,J＝11.6,5.4Hz,2H),3.39(s,4H),3.20(s,4H),2.98–2.93(m,4H),1.73–1.62(m,2H),1.26(dd,J＝14.7,7.4Hz,2H),0.90(t,J＝7.3Hz,3H).13C NMR(101MHz,DMSO)δ163.95,155.74,153.92,153.31,135.62,135.53,133.36,133.26,119.21,119.17,114.27,114.24,106.91,106.65,70.96,66.13,64.36,61.80,51.14,50.68,50.66,47.37,41.21,23.82,19.09,13.37.HR-MS(ESI)Calcd for C22H34FN4O4[M+H]+:437.2559,found:437.2563.
(2b):黄色黏稠固体，产率97.0％。
1H NMR(400MHz,DMSO)δ9.24(t,J＝5.7Hz,1H),7.49(dd,J＝15.0,2.4Hz,1H),7.22–7.17(m,1H),7.07(t,J＝9.3Hz,1H),4.85–4.74(m,1H),4.16–4.08(m,2H),3.79(dd,J＝9.1,6.8Hz,1H),3.76–3.71(m,4H),3.59–3.47(m,2H),3.42(dd,J＝9.9,7.0Hz,4H),3.17(s,5H),2.99–2.94(m,4H),1.67(s,2H),1.26(s,10H),0.87(t,J＝6.7Hz,3H).13C NMR(101MHz,DMSO)δ163.94,153.90,135.63,133.36,119.23,114.20,106.85,106.60,71.07,66.13,64.57,61.73,51.20,50.69,47.26,41.23,31.11,28.37,25.65,21.99,21.82,13.89.HR-MS(ESI)Calcd for C26H42FN4O4[M+H]+:493.3185,found:493.3192.
(2c):黄色黏稠固体，产率77.4％。
1H NMR(400MHz,DMSO)δ9.52(s,1H),7.50(dd,J＝15.0,2.5Hz,1H),7.23–7.15(m,1H),7.06(t,J＝9.3Hz,1H),4.20(s,1H),4.10(s,1H),3.87–3.81(m,1H),3.76–3.70(m,4H),3.55–3.51(m,1H),3.49–3.40(m,6H),3.24(dd,J＝10.2,6.7Hz,1H),3.18(s,4H),3.00(s,2H),2.98–2.93(m,4H),1.69–1.60(m,2H),1.25(d,J＝5.9Hz,12H),0.86(dd,J＝6.8,3.8Hz,3H).13C NMR(101MHz,DMSO)δ163.98,153.91,119.20,114.21,106.86,71.01,66.12,64.47,62.80,61.72,51.13,50.68,49.93,47.30,41.16,31.20,28.71,28.55,28.44,25.73,25.67,22.05,21.82,21.63,13.91.HR-MS(ESI)Calcd for C27H44FN4O4[M+H]+:
507.3341,found:507.3345.
(2d):淡黄色黏稠固体,产率69.8％。
1H NMR(400MHz,DMSO)δ7.50(dd,J＝15.0,2.4Hz,1H),7.18(dd,J＝8.8,1.7Hz,1H),7.05(t,J＝9.3Hz,1H),4.83–4.76(m,1H),4.24(s,1H),4.09(t,J＝9.0Hz,1H),3.85(dd,J＝7.6,5.3Hz,1H),3.77–3.71(m,5H),3.69(d,J＝4.8Hz,1H),3.56–3.49(m,2H),3.17(s,5H),2.98–2.92(m,5H),2.82(d,J＝4.2Hz,1H),2.56–2.48(m,1H),1.67(s,2H),1.23(s,18H),0.85(t,J＝6.7Hz,3H).13C NMR(101MHz,DMSO)δ164.07,153.92,135.57,135.48,133.38,133.28,119.15,114.16,106.82,106.56,70.97,66.12,51.06,50.67,47.30,31.27,29.00,28.92,28.76,28.69,28.45,25.69,22.06,21.80,13.91.HR-MS(ESI)Calcdfor C30H50FN4O4[M+H]+:549.3811,found:549.3816.
(2e):暗黄色黏稠状物,产率81.8％。
1H NMR(400MHz,DMSO)δ9.38(s,1H),7.50(dd,J＝14.9,2.4Hz,1H),7.19(dd,J＝8.7,1.9Hz,1H),7.06(t,J＝9.4Hz,1H),4.79(s,1H),4.17(s,1H),4.10(t,J＝9.1Hz,1H),3.82(dd,J＝9.0,6.8Hz,1H),3.76–3.70(m,4H),3.56–3.50(m,1H),3.45–3.39(m,2H),3.34(s,3H),3.18(s,4H),2.99–2.94(m,3H),2.93(d,J＝3.4Hz,1H),2.81(d,J＝8.1Hz,1H),1.67(s,2H),1.24(s,22H),0.85(t,J＝6.6Hz,3H).13C NMR(101MHz,DMSO)δ163.95,153.88,153.33,135.52,119.19,114.17,106.84,106.58,71.04,66.13,64.47,61.71,51.19,50.66,47.28,42.38,41.19,31.26,29.03,28.99,28.92,28.82,28.75,28.67,28.57,28.44,26.10,25.67,22.05,21.83,13.90.HR-MS(ESI)Calcd for C32H54FN4O4[M+H]+:577.4124,found:577.4130.
(2f):黄色泡沫状固体，产率81.6％。
1H NMR(400MHz,DMSO)δ9.28(s,1H),7.50(dd,J＝14.8,2.2Hz,1H),7.17(t,J＝12.1Hz,1H),7.09–7.00(m,1H),4.79(s,1H),4.12(dd,J＝17.6,8.3Hz,2H),3.83–3.77(m,1H),3.75–3.71(m,4H),3.53(dd,J＝10.4,4.8Hz,1H),3.49–3.39(m,4H),3.17(s,4H),2.94(dd,J＝11.0,4.1Hz,5H),1.66(s,2H),1.23(s,30H),0.85(t,J＝6.6Hz,3H),0.63–0.63(m,1H).13C NMR(101MHz,DMSO)δ163.95,153.88,135.52,133.36,119.19,114.14,106.81,106.55,71.06,66.12,64.44,61.67,51.22,50.66,47.24,41.96,41.20,31.25,29.00,28.96,28.92,28.75,28.66,28.43,25.95,25.66,22.05,21.82,13.90.HR-MS(ESI)Calcdfor C36H62FN4O4[M+H]+:633.4750,found:633.4757.
(6a):淡黄色固体，产率84.2％。
1H NMR(400MHz,DMSO)δ8.46(d,J＝28.2Hz,3H),8.23(s,3H),7.52(s,1H),7.20(s,1H),7.12(td,J＝9.3,3.4Hz,1H),4.85(s,3H),4.25(dd,J＝42.2,35.7Hz,1H),4.12(s,1H),3.74(s,6H),3.47(dd,J＝14.3,8.3Hz,1H),3.22(ddd,J＝20.0,18.8,7.8Hz,1H),2.99(s,3H),2.74(d,J＝5.5Hz,2H),1.88–1.69(m,2H),1.53(d,J＝62.4Hz,6H),1.31–1.17(m,8H),0.84(t,J＝6.6Hz,3H).13C NMR(101MHz,DMSO)δ169.75,169.13,168.83,155.75,153.88,153.77,153.32,142.74,133.81,127.94,127.09,124.36,119.51,118.94,114.21,109.84,106.85,106.59,71.73,71.08,65.95,52.73,51.58,50.83,49.14,47.65,38.22,38.08,31.16,30.17,29.96,29.19,28.45,28.36,26.52,26.36,26.19,26.10,25.88,21.99,21.17,20.74,13.90.HR-MS(ESI)Calcd for C27H45FN5O4[M+H]+:522.3450,found:522.3453.
(6b):淡黄色泡沫状固体，产率85.3％。
1H NMR(400MHz,DMSO)δ8.47(d,J＝30.5Hz,3H),8.25(d,J＝4.6Hz,3H),7.53(ddd,J＝14.8,12.2,2.3Hz,1H),7.22(d,J＝8.9Hz,1H),7.13(td,J＝9.3,3.7Hz,1H),4.30(dd,J＝68.8,5.2Hz,1H),4.14(q,J＝8.7Hz,1H),3.82–3.70(m,6H),3.59–3.44(m,1H),3.36–3.19(m,1H),3.00(s,3H),2.75(d,J＝8.1Hz,2H),1.76(dd,J＝33.8,16.0Hz,2H),1.61(d,J＝6.8Hz,3H),1.47(dd,J＝15.2,7.6Hz,3H),1.26(t,J＝12.7Hz,10H),0.86(t,J＝6.6Hz,3H).13C NMR(101MHz,DMSO)δ169.13,168.83,155.76,153.87,153.77,153.33,133.75,133.65,119.47,114.20,106.85,106.59,71.69,71.07,65.98,50.81,49.13,48.59,48.52,47.65,38.06,33.91,31.20,31.18,30.17,29.95,28.77,28.68,28.61,28.49,26.51,26.37,26.25,25.94,22.03,20.73,13.91.HR-MS(ESI)Calcd for C28H47FN5O4[M+H]+:536.3607,found:536.3389.
(6c):淡黄色泡沫状固体，产率88.9％。
1H NMR(400MHz,DMSO)δ8.38(d,J＝27.8Hz,3H),8.11(s,3H),7.52(t,J＝13.0Hz,1H),7.21(d,J＝8.9Hz,1H),7.10(dt,J＝13.3,6.7Hz,1H),4.90(d,J＝34.6Hz,1H),4.30(d,J＝62.8Hz,1H),4.16–4.09(m,1H),3.74(s,6H),3.69(d,J＝13.0Hz,1H),3.60–3.52(m,1H),3.48(dd,J＝14.2,8.3Hz,1H),3.33–3.19(m,1H),2.97(s,3H),2.74(s,2H),1.76(s,2H),1.52(dd,J＝47.1,18.5Hz,6H),1.25(s,12H),0.86(t,J＝6.4Hz,3H).13C NMR(101MHz,DMSO)δ66.08,50.70,40.03,39.82,39.62,39.41,39.20,38.99,38.78,31.23,28.64,22.05,13.93.HR-MS(ESI)Calcd for C29H49FN5O4[M+H]+:550.3763,found:550.3767.(6d):淡黄色泡沫状固体，产率87.3％。1H NMR(400MHz,DMSO)δ8.45(d,J＝26.5Hz,3H),8.23(d,J＝4.9Hz,3H),7.59–7.48(m,1H),7.22(dd,J＝8.8,2.5Hz,1H),7.13(dd,J＝9.4,4.0Hz,1H),5.00–4.84(m,1H),4.43–4.19(m,1H),4.14(d,J＝6.9Hz,1H),3.86(s,1H),3.85–3.65(m,6H),3.58(d,J＝11.0Hz,1H),3.52–3.43(m,1H),3.26(ddd,J＝22.7,11.9,5.1Hz,1H),3.00(d,J＝3.8Hz,3H),2.81–2.70(m,2H),1.77(s,2H),1.60(d,J＝5.6Hz,3H),1.47(dd,J＝15.1,7.5Hz,3H),1.25(s,14H),0.85(t,J＝6.7Hz,3H).13C NMR(101MHz,DMSO)δ169.13,168.84,153.87,119.43,114.19,106.84,106.58,66.00,50.80,50.77,31.24,28.95,28.92,28.66,22.05,13.92.HR-MS(ESI)Calcd for C30H51FN5O4[M+H]+:564.3920,found:564.3926.
(6e):深黄褐色泡沫状固体，产率95.7％。
1H NMR(400MHz,DMSO)δ8.52(d,J＝102.0Hz,3H),8.07(s,3H),7.51(dd,J＝9.9,7.4Hz,1H),7.20(s,1H),7.09(td,J＝9.4,4.8Hz,1H),4.91(dd,J＝35.7,9.1Hz,1H),4.26(dd,J＝39.0,32.7Hz,1H),4.13(dd,J＝16.7,8.6Hz,1H),3.86(dd,J＝18.9,10.0Hz,1H),3.74(dd,J＝13.2,8.5Hz,6H),3.49(d,J＝8.6Hz,2H),3.33–3.20(m,1H),2.97(s,3H),2.76(d,J＝5.9Hz,2H),1.80(dd,J＝19.1,11.7Hz,2H),1.60(s,3H),1.43(s,3H),1.24(s,16H),0.85(t,J＝6.7Hz,3H).13C NMR(101MHz,DMSO)δ169.79,168.84,153.89,153.32,119.29,106.58,66.09,51.61,50.69,47.61,38.16,31.24,29.24,28.96,28.82,28.66,26.43,26.16,25.93,22.04,21.16,13.91.HR-MS(ESI)Calcd for C31H53FN5O4[M+H]+:578.4076,found:578.4082.
(6f):黄褐色泡沫状固体，产率86.7％。
1H NMR(400MHz,DMSO)δ9.08–8.94(m,1H),8.44(d,J＝22.3Hz,3H),8.27–8.00(m,1H),7.52(ddd,J＝12.1,8.6,2.5Hz,1H),7.33(d,J＝50.8Hz,1H),7.21(dd,J＝10.8,4.6Hz,1H),7.11(dt,J＝13.8,7.0Hz,1H),4.91(d,J＝43.9Hz,1H),4.41–4.10(m,19H),3.90(dd,J＝14.4,3.6Hz,1H),3.65–3.43(m,2H),3.35(t,J＝11.5Hz,2H),3.22–3.09(m,1H),2.98(s,4H),1.80(s,2H),1.68–1.55(m,3H),1.49(dd,J＝13.7,5.7Hz,6H),1.35–1.19(m,9H),0.86(t,J＝5.7Hz,3H).13C NMR(101MHz,DMSO)δ157.14,153.44,135.11,124.50,119.39,114.19,106.58,83.51,66.00,50.75,48.52,40.04,39.83,39.62,39.42,39.21,39.00,38.79,38.21,34.09,31.19,28.45,27.51,25.87,22.01,13.92.HR-MS(ESI)Calcdfor C27H45FN7O4[M+H]+:550.3512,found:550.3515.
(6g):黄褐色泡沫状固体，产率95.2％。
1H NMR(400MHz,DMSO)δ9.09–8.91(m,1H),8.44(d,J＝23.3Hz,2H),8.09–8.00(m,1H),7.53(dd,J＝13.7,10.7Hz,1H),7.23(dd,J＝17.3,10.6Hz,1H),7.11(dd,J＝10.6,6.5Hz,1H),4.91(d,J＝44.4Hz,1H),4.44(s,1H),4.18(d,J＝26.4Hz,17H),3.96–3.85(m,1H),3.75(d,J＝4.4Hz,4H),3.66–3.55(m,1H),3.48(dd,J＝14.2,7.9Hz,1H),3.32(d,J＝15.5Hz,1H),3.17(s,1H),2.99(s,3H),2.69(s,2H),2.54–2.44(m,1H),1.80(s,1H),1.70–1.53(m,2H),1.50(d,J＝18.0Hz,4H),1.36–1.17(m,8H),0.92–0.80(m,2H).13C NMR(101MHz,DMSO)δ153.84,119.32,106.57,83.53,66.05,50.71,40.07,39.86,39.65,39.44,39.23,39.02,38.82,38.21,31.22,28.63,27.52,25.93,22.04,21.55,13.93.HR-MS(ESI)Calcd for C28H47FN7O4[M+H]+:564.3668,found:564.3673.
(6h):黄褐色泡沫状固体，产率83.3％。
1H NMR(400MHz,DMSO)δ8.40(d,J＝19.8Hz,3H),8.05–7.96(m,1H),7.56–7.46(m,2H),7.20(d,J＝6.6Hz,1H),7.09(td,J＝9.3,5.2Hz,1H),5.30(s,1H),4.94(s,1H),4.66(d,J＝4.4Hz,1H),4.17(dd,J＝32.7,25.7Hz,2H),3.94–3.68(m,39H),3.60(dd,J＝14.4,7.2Hz,1H),3.47(dd,J＝14.3,8.0Hz,1H),3.37–3.25(m,1H),3.15(dd,J＝14.6,7.6Hz,2H),2.97(s,4H),1.79(d,J＝6.1Hz,2H),1.55(t,J＝19.0Hz,4H),1.25(d,J＝4.9Hz,15H),0.85(t,J＝6.7Hz,3H).13C NMR(101MHz,DMSO)δ157.08,127.19,109.74,66.06,50.70,45.26,40.07,39.86,39.65,39.44,39.24,39.03,38.82,38.21,33.99,31.24,28.65,25.93,22.05,13.93,8.37.HR-MS(ESI)Calcd for C29H49FN7O4[M+H]+:578.3825,found:578.3832.
(6i):黄褐色泡沫状固体，产率85.9％。
1H NMR(400MHz,DMSO)δ8.59(s,1H),8.30(d,J＝21.7Hz,2H),7.73(dd,J＝103.9,8.4Hz,1H),7.45–7.36(m,2H),7.28(dd,J＝15.0,7.1Hz,1H),7.13–7.06(m,1H),6.98(td,J＝9.3,4.8Hz,1H),4.73(s,1H),4.16(d,J＝42.3Hz,14H),4.07–3.87(m,4H),3.78(dd,J＝14.4,3.7Hz,1H),3.68–3.58(m,6H),3.36(dd,J＝14.4,7.6Hz,1H),3.20(s,1H),3.03(dd,J＝11.5,5.4Hz,2H),2.97–2.89(m,2H),2.86(s,3H),2.42–2.35(m,4H),1.77–1.59(m,3H),1.47(d,J＝8.0Hz,4H),1.21–1.04(m,15H),0.73(t,J＝6.6Hz,3H).HR-MS(ESI)Calcd forC30H51FN7O4[M+H]+:592.3981,found:592.3985.
(6j):淡黄色泡沫状固体，产率97.5％。
1H NMR(400MHz,DMSO)δ8.77(s,1H),8.47(d,J＝25.3Hz,3H),8.05(d,J＝5.6Hz,1H),7.57–7.50(m,1H),7.45–7.38(m,1H),7.24–7.19(m,1H),7.13(dd,J＝11.3,6.9Hz,1H),5.46–4.80(m,9H),4.15(s,1H),4.04(s,1H),3.76(s,5H),3.68(d,J＝11.0Hz,2H),3.59(t,J＝8.9Hz,2H),3.48(dd,J＝12.5,7.2Hz,1H),3.35(d,J＝6.5Hz,1H),3.16(d,J＝5.7Hz,3H),3.00(s,3H),1.91–1.79(m,2H),1.70–1.53(m,4H),1.48–1.47(m,2H),1.32–1.16(m,16H),0.85(t,J＝6.6Hz,3H).13C NMR(101MHz,DMSO)δ169.69,157.18,127.08,124.34,118.95,109.83,65.99,54.07,54.01,52.75,51.46,50.81,48.44,40.08,39.87,39.66,39.46,39.25,39.04,38.83,38.22,31.25,28.97,28.82,28.72,28.67,27.52,27.09,25.94,24.22,22.05,13.90.HR-MS(ESI)Calcd for C31H53FN7O4[M+H]+:606.4138,found:606.4145.。
应用例1 体外抗菌活性测试：
1、实验方法
微量肉汤稀释法：
(1)抗菌药物贮存液制备：制备抗菌药物贮备液的浓度为2560μg/mL，溶解度低的抗菌药物可稍低于上述浓度。所需抗菌药物溶液量或粉剂量可公式进行计算。配制好的抗菌药物贮存液应贮存于-20℃以下环境，保存期不超过6个月。
(2)待测菌的制备：用接种环挑取过夜培养的MH(A)培养皿上的单菌落于MH(B)培养基中，校准为0.5麦氏比浊标准，约含菌数1×108CFU/mL，然后稀释100倍，即得到约含菌数1×106CFU/mL的菌液，备用。
(3)分别将上述抗菌药物贮备液母液(2560μg/mL)稀释10倍，得到浓度为256μg/mL的抗菌药物溶液。取无菌的96孔板，第一孔加入200μL的抗菌药物，第二至十孔分别加入100μL的MH肉汤培养基，从第一孔吸取100μL加入第二孔，混匀，再吸取100μL至第三孔，依次类推，第十一孔吸取100μL弃去。此时各孔药物浓度依次为：256、128、64、32、16、8、4、2、1、0.5、0.25μg/mL，第十二孔加入200μL菌液(阳性对照)，第十三孔加入200μL MH(B)培养基(阴性对照)。
(4)然后在2至11孔各加入50μL上述备好的菌液，使每管最终菌液浓度约为5×105CFU/mL，第2孔至第11孔药物浓度分别为128、64、32、16、8、4、2、1、05、0.25μg/mL。将接种好的96孔板放置37℃培养箱进行培养，24h观察菌液生长情况。同时用标准株做质控。
(5)结果判断与解释：在读取和报告所测试菌株的MIC前，应检查生长对照管的细菌生长情况是否良好，同时还应检查接种物的传代培养情况以确定其是否污染，质控菌株的MIC值是否处于质控范围。以肉眼观察，药物最低浓度管无细菌生长者，即为受试菌的MIC。
应用例2 体外红细胞溶血性实验
(1)实验材料：10mL EP管，96孔板，新鲜脱脂羊血。
(2)PBS缓冲液：500mL规格，氯化钠4g，氯化钾100mg，二水合磷酸二氢钠1.49g，无水磷酸二氢钾100mg，去离子水定容至490mL，调节PH 7.2-7.4之间，灭菌，用10mL灭过菌的超纯水溶解900mg葡萄糖后加入PBS溶液中。
(3)质量百分5％红细胞悬浮液的制备：
新鲜的脱纤维羊血冷冻与冰箱里，配置好的PBS缓冲液放置于37℃水浴锅中，即用即取。
取两支10mL EP管置于试管架，用移液枪分别吸取5700微升PBS加入两支EP管中，再分别吸取300微升羊血，缓慢加入到PBS溶液中，盖盖子，上下缓慢颠倒混匀，放入离心机1500转离心10min，取出EP管，小心吸取上清，移除上清。再重新分别加入5～7mL PBS溶液，上下缓慢颠倒混匀，放入离心1500转离心10min。如此反复操作，直至离心后上清液不再浑浊。最后一次离心过后，撇去上清液，红细胞沉积物留置待用。
取几支10mL EP管，放置试管架上，于每支EP管中加入5700μL的PBS(37℃)，然后依次加入300μL的红细胞沉积物。上下缓慢颠倒混匀，如此，便配置好5％的红细胞悬液。
(4)样品溶液的配置：用少量的DMSO溶解本发明化合物(DMSO终浓度不能大于0.5％)，并且用相同体积的DMSO做阴性对照。溶解后的本发明化合物用PBS稀释(例如，第一孔浓度定为1000μg/mL，那么第一孔加入的50μL中药物的含量就是2mg，配置成2mg/50μL的溶液)，此时这支EP管内的药物为初始药物。然后平行取九支1.5mL EP管置于试管架中，分别加入200μL的PBS(编号2号、3号、4号……10号)。所有药物都如此平行操作。最后，由初始药物EP管中吸取200μL的药品溶液加入2号EP管中，反复吹洗后吸取200μL到3号EP管中，反复吹洗……重复操作，直到10号EP管。如此，稀释好药物。
(5)铺板：取96孔板，写好实验编号，药品代码，日期。将移液枪调至150μL，将配置好的5％红细胞悬液上下轻缓颠倒混匀，依次吸取铺入96孔板中(6×10)。然后将配置好的药物对应加入96孔板中，一个药物三个复孔。加完后放置37℃恒温箱内孵育1h。
(6)后处理：将96孔板从恒温箱内取出，置于-4℃离心机内离心(3500rpm，5min)。离心完毕，每块板对应都取一块新的96孔板。标注和离心后的板子对照。然后对应地吸取100μL上清液(孔孔对应)。吸取完毕后，与酶标仪中测取OD值，分析数据，得到HC50。
实验结果：
表一：目标化合物2a～2f,6a～6j对革兰氏阴性及阳性敏感菌株的MIC(μg/mL)结果
a:利奈唑胺碱(去乙酰基利奈唑胺)；b:利奈唑胺；c:万古霉素；d:美罗培南
表二：本发明部分化合物对10株无重复MRSA临床株的MIC(μg/ml)
a:耐甲氧西林的金黄色葡萄球菌；b:利奈唑胺；c:万古霉素；d:美罗培南
表三：本发明部分化合物对10株无重复产NDM-1酶临床株MIC(μg/ml)
a:产NDM-1的CRE；b:利奈唑胺；c:万古霉素；d:美罗培南
表四：本发明部分化合物对10株无重复产KPC-2酶临床株MIC(μg/ml)结果
a:产KPC-2酶CRE；b:利奈唑胺；c:万古霉素；d:美罗培南
表五：本发明部分化合物对9株无重复VRE临床株的MIC(μg/ml)结果
a:耐万古霉素的肠球菌；b:利奈唑胺；c:万古霉素；d:美罗培南
表六：四种临床耐药菌株(MRSA,NDM,KPC,VRE)的菌株信息
由表一可见，所合成的化合物2c～2f,6c～6e,6i～6j中，大部分化合物对革兰氏阳性菌金黄色葡萄球菌ATCC 29213和粪肠球菌ATCC 29212，革兰氏阴性菌大肠埃希菌ATCC25922和肠道沙门氏菌ATCC 8387的MIC(μg/mL)均在32μg/mL以下，对革兰氏阳性菌的活性比阴性菌活性好，显示这类化合物具有较好的选择性抗菌活性；同时，其体外红细胞溶血性数据显示，具有较小的毒性。
更重要的是该类化合物中的化合物2d,2e,6e,6j对于MRSA、VRE、产NDM-1和KPC-2酶的CRE临床株菌显示良好的抗菌活性。从上述表格(表一到表五)数据可以看出，该类化合物具有较好的成药前景。
Claims (1)
1.具有抗菌活性的利奈唑胺碱阳离子两亲性化合物，其特征在于，该化合物结构式如下：
n = 11或13。
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003093247A2 (en) * | 2002-04-30 | 2003-11-13 | Orchid Chemicals & Pharmaceuticals Ltd | Antibacterial agents |
| CN105566149A (zh) * | 2016-03-02 | 2016-05-11 | 郑州大学 | 具有抗菌活性的查尔酮阳离子抗菌肽模拟物及其制备方法 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003093247A2 (en) * | 2002-04-30 | 2003-11-13 | Orchid Chemicals & Pharmaceuticals Ltd | Antibacterial agents |
| CN105566149A (zh) * | 2016-03-02 | 2016-05-11 | 郑州大学 | 具有抗菌活性的查尔酮阳离子抗菌肽模拟物及其制备方法 |
Non-Patent Citations (4)
| Title |
|---|
| Cationic Chalcone Antibiotics. Design, Synthesis, and Mechanism of Action;Simon F. Nielsen等;《J. Med. Chem.》;20050304;第48卷(第7期);第2667-2677页 * |
| Membrane Active Vancomycin Analogues: A Strategy to Combat Bacterial Resistance;Venkateswarlu Yarlagadda等;《J. Med. Chem.》;20140505;第57卷;第4558-4568页 * |
| Synthesis and antibacterial bioactivities of cationic deacetyl linezolid amphiphiles;Peng-Yan Bai等;《European Journal of Medicinal Chemistry》;20180623;第155卷;第925-945页 * |
| Synthesis and characterisation of new N-alkyl-N,N-dimethyl[N-(pyridin-2-yl) carbamoyl]methylammonium chlorides;Liyan Wang等;《JOURNAL OF CHEMICAL RESEARCH》;20131206;第733-735页 * |
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