CN104066738A - 新型抗菌化合物 - Google Patents
新型抗菌化合物 Download PDFInfo
- Publication number
- CN104066738A CN104066738A CN201280054909.4A CN201280054909A CN104066738A CN 104066738 A CN104066738 A CN 104066738A CN 201280054909 A CN201280054909 A CN 201280054909A CN 104066738 A CN104066738 A CN 104066738A
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- Prior art keywords
- triazole
- group
- composition
- vitamin
- sabpl
- Prior art date
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- 230000000845 anti-microbial effect Effects 0.000 title description 2
- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 19
- 150000003852 triazoles Chemical class 0.000 claims description 67
- -1 uridylic Chemical compound 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 36
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- 241000894006 Bacteria Species 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 208000015181 infectious disease Diseases 0.000 claims description 13
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 10
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
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Abstract
公开了一类新型生物素蛋白连接酶(BPL)抑制剂,其具有针对多种金黄色葡萄球菌分离株的抗菌活性,且其为无毒的,所述金黄色葡萄球菌分离株包括临床上重要的抗甲氧西林金黄色葡萄球菌(MRSA)。
Description
优先权声明
本国际专利申请要求2011年9月23日递交的澳大利亚临时专利申请2011903946和2011年9月26日递交的澳大利亚临时专利申请2011903957的优先权,它们的全部内容通过引用纳入本文。
技术领域
本发明涉及具有有效的生物素蛋白连接酶(BPL)抑制活性的新型生物素衍生物。
背景技术
菌血症是对现代社会的长期威胁并对医疗系统产生了重大负担。仅在澳大利亚,据估计每年有200,000例医院获得性感染,在住院中占2百万张病床。感染的患者住院时间是其他患者的3倍,导致额外的花费并导致用于其他患者的可用病床的短缺。大量的这类患者(估计每年治疗12,000人)将产生血流感染。17%至29%的这类患者将在医院中死亡,主要是由于无效的治疗选择。金黄色葡萄球菌(Staphylococcusaureus)是最重要的病原体,其具有每30天20%的致死率。进入血流变成致病菌将导致威胁生命的骨感染和关节感染、心内膜炎、肺炎和败血症。尽管严重的葡萄球菌感染的公众印象是其为医院获得性的,但重要的是认识到60%的严重金黄色葡萄球菌感染现在被认为是在社区中开始的。
用于金黄色葡萄球菌感染的常规抗菌治疗是使用抗青霉素酶的青霉素。然而,现在在澳大利亚,医院相关的菌株和社区相关的菌株中对这种药物的抗性是普遍的。多重耐药菌株,例如抗甲氧西林的金黄色葡萄球菌(MRSA)的医院菌株现在在大多数澳大利亚医院存在,而且万古霉素介导的金黄色葡萄球菌(VISA)菌株也开始出现。2005至2006年澳大利亚医院的调查显示,分离的全部金黄色葡萄球菌的24%的菌株是MRSA。对万古霉素(被认为是最后的防线)不敏感的菌株造成了特殊的临床问题,因为只有非常少的药物能够治疗它们,且这种确实存在的药物(例如利奈唑胺)具有显著的毒性。此外,万古霉素对抗MRSA的万古霉素敏感菌株的疗效被认为是次优的。所有这些等同于患有MRSA感染的患者比患有青霉素敏感的金黄色葡萄球菌感染的患者多花费5倍的医疗费用。
有必要补充新型抗生素的药物研发渠道以对抗药物耐受细菌,包括金黄色葡萄球菌,其是巨大且不断增加的医疗问题的原因。
生物素蛋白连接酶(BPL)是在所有生物体中发现的至关重要的酶。BPL将辅基生物素(维生素H)连接至一系列酶上,该酶被称为生物素依赖性羧化酶。这些酶在代谢反应、例如膜的生物合成中起重要作用;其是所有生物体中的关键过程。由于生物素辅基的连接是正常酶功能绝对必需的,所以BPL活性的抑制可用于抑制细胞生长。
考虑到BPL在所有生物体中的重要作用,来自病原体的BPL酶的抑制剂将对一系列非病毒感染的疾病提供选择性治疗或广谱治疗的机会。
专利申请WO2009/062241描述金黄色葡萄球菌生物素蛋白连接酶的晶体结构及其用于识别与酶的生物素结合域相互作用的分子的用途。WO2006/056007描述了识别BPL抑制剂的方法。
然而,这些文件都未公开BPL抑制剂。
现已意外发现,某一类化合物抑制重要的代谢酶BPL,且在本专利申请中描述了其结构。
本发明的目的在于提供一类新型抗生素。
本发明的另一目的在于提供一类新型抗生素,其选择性地用于特定细菌靶标。
本发明的还一目的在于提供一类新型抗生素,其选择性地进入菌细胞但不进入哺乳动物细胞。
本发明的目的是克服,或至少基本上改进现有技术的缺点和不足。
本发明的其他目的和优点将结合附图、通过以下描述变得清楚,其中,通过说明和实施例的方式,公开本发明的实施方案。
发明概述
本发明涉及式(I)的化合物
其中
n是选自1至10的整数;
R1选自下列组成的组中:
咪唑,
吡唑,
吡咯,
噻吩,
四唑,
恶唑,
三唑
其中X选自H或OH,
磷酸二酯,
其中L选自Na+、K+;
X选自CH2、CF2、NH,
R3选自下列组成的组中:
H、C1-C10烷基、C1-C10烯基、C1-C10炔基;
核苷,例如,但不限于腺苷、胞苷、尿苷、鸟苷、胸苷或肌苷;
腺嘌呤、鸟嘌呤、胸腺嘧啶、尿嘧啶、胞嘧啶;
苯并恶唑酮、苯并恶唑、苯并呋喃、苯并咪唑;
其中:
R5,R6,R7,R8选自由H、C1-C5烷基、卤素、NH2、OH2、NR12R13、SH、SR13组成的组:
其中R12和R13选自由H、C1-C5烷基组成的组;
R9选自由N、NH组成的组;
R10选自由CH2、C=O、C=N-R组成的组;
R11选自由N、NH、O、S组成的组;
萘基、其中:
X选自由O、NR12R13、SR13组成的组;
R14、R15、R16、R17、R18、R19、R20选自由H、C1-C5烷基、卤
素、NH2、OH2、NR12R13、SH、SR13组成的组:
其中R12和R13选自由H、C1-C5烷基组成的组。
优选地,药物组合物包括作为活性成分的至少一种式(I)的化合物和任选地一种或多种药学上可接受的赋形剂。
优选地,药物组合物用于治疗选由自细菌感染、真菌感染或原生动物感染组成的组中的感染。
至少一种根据式(I)的化合物作为活性成分在制备用于治疗和/或预防细菌感染、真菌感染、原生动物感染的药物中的用途。
这种方法的挑战在于研发靶标为病原体且对宿主无损伤的抑制剂。这些化合物被称为“特异性抑制剂”。研究表明在不同生物体中的BPL存在明显差异,包括分子量、氨基酸序列及动力学性质。在特异性抑制剂的发现和研究中将利用这些差异。
附图说明
图1通过用箭头表示的空间相互作用表明在ROESY2D1H NMR实验中观察到的相互作用。
图2示出了本发明的三唑类似物6.02-6.10及磷酸二酯6.34。
图3a–3c示出了生物素三唑BPL抑制剂的生物数据。
图4a示出了结合在SaBPL活性部位的生物素酚-5′AMP2.02的x-射线晶体结构。
图4b示出了结合在SaBPL活性部位的三唑4.01的晶体结构。
图4c示出了(4a)和(4b)中SaBPL的骨架原子的叠加作用。
图4d示出了结合在SaBPL活性部位的三唑6.09的晶体结构。
发明详述
本发明的药物组合物可以通过不同途径施用。例如,其可通过例如片剂、胶囊、糖浆剂和悬浮液的药剂形式口服施用;也可通过溶液或乳剂等形式肠胃外施用。
所述组合物还可以霜剂、香膏剂、香脂剂等形式局部施用,并例如通过施用贴剂或绷带经皮肤施用。其还可作为栓剂在直肠中直接施用。所述制剂包括生理学上可接受的载体、赋形剂、活化剂、螯合剂、稳定剂等。在注射施用的情况下,可加入生理学上可接受的缓冲剂、增溶剂或等渗剂。
本说明书中包括的工作实施例详细地描述了获得几种根据通式(I)的化合物的合适的方法。根据这些实施例,获得没有明确举例的工作实施例的适当修改的化合物在本领域技术人员的公知常识范围内。对于本领域技术人员同样显而易见的是,这些实施例只是说明性的,并不应该作为对本发明范围的限制。
具体实施方式
三唑4.01–4.13的合成利用结构单元炔烃4.16,4.17和3.12及叠氮化物4.18–4.21(如方案1A所示)并包括最优化的CuAAC和RuAAC偶联的条件(如方案1B所示)。
方案1A:用于合成三唑4.01–4.15的前体
方案1B:a)20mol%Cu纳米粉末,2:1偶氮二环己腈(AcCN)/H2O;b)Cp*RuCl(PPh3)2,1:1四氢呋喃(THF)/二甲基甲酰胺(DMF),80℃.
叠氮化物4.18–4.21的合成由腺嘌呤4.22完成,如方案2所示。用K2CO3处理腺嘌呤4.22,然后用合适的二卤代烷烃4.23–4.26的DMF溶液处理。然后所得到的卤化物4.27–4.31用NaN3的DMF溶液处理,转化为叠氮化物4.19–4.22,其产率如方案2所示。
方案2:a)烷基二卤化物4.23–4.26,K2CO3,DMF;b)NaN3,DMF获得正链生物素(norbiotin)炔烃4.16需要4.34的胺官能团转化为4.35的醇。
方案3:a)DPPA,三乙胺,叔丁醇;b)6N HCl,H2O;c)NaNO2,乙酸,1:1THF/H2O或Na2[Fe(CN)5NO]·2H2O,NaOH,H2O;d)i)对甲苯磺酰氯,吡啶;ii)LiBr,2-丁酮,iii)锂-乙炔化物EDA,二甲基亚砜(DMSO)
用叠氮磷酸二苯酯(DPPA)和三乙胺的叔丁醇溶液回流处理生物素1.01以获得酰基叠氮化物4.31,其经过库尔提斯(Curitius)重排获得Boc保护的生物素胺4.32,在急骤层析纯化后的产率为51%。4.32的Boc基的脱保护通过6N HCl处理完成以得到产率为87%的4.33且不需要层析。
正链生物素炔烃4.16的合成路径需要自由基介导的生物素巴顿脱羧至正链生物素溴化物4.38及随后的溴化物转化为正链生物素炔烃4.16,如方案3所示。
生物素1.01在用亚硫酰氯和DMF的二氯甲烷(DCM)溶液处理后转化为酸性氯化物4.35,并在巴顿脱羧反应中直接使用、而不需要进一步纯化,如方案4所示。已研究用于1.01至4.38的巴顿脱羧作用的多种条件,例如激活源(光、加热和AIBN)及溶剂体系(参见表1)。
方案4:a)亚硫酰氯,DMF,DCM;b)条件参见表1
表1:用于研究生物素4.35脱羧作用的条件,如方案4所示
a急骤层析后的分离产率.
如表1中所述,用含有1:1THF/BrCCl3(0%,条目6)、1:1DMF/BrCCl3(7%,条目7)、2:1DMF/BrCCl3(15%,条目8)和8:1DMF/BrCCl3(21%,条目9)的溶剂混合物进行1.01的巴顿脱羧作用。结果发现8:1DMF/BrCCl3获得生物素4.38产率的最大提高(条目11)。
具有足够的正链生物素溴化物4.38时,进行正链生物素炔烃4.16的合成(参见方案5)。用锂乙炔化物EDA复合物的DMSO溶液处理正链生物素溴化物4.38以获得正链生物素炔烃4.16,其在急骤层析后产率为41%。正链生物素炔烃4.16用于如下所述的三唑4.09和4.11的合成。
方案5:a)锂-乙炔化物EDA复合物,DMSO;
高生物素炔烃4.17
高生物素炔烃4.17的合成如方案6所示。该合成途径包括获得已报道的高生物素4.40的合成,然后通过官能团转化获得高生物素炔烃4.17。
方案6:a)KCN,DMF;6N b)NaOH,H2O,回流;c)亚硫酰氯,甲醇;d)LiAlH4,THF;e)对甲苯磺酰氯,吡啶;f)LiBr,丁酮;g)锂-乙炔化物EDA,DMSO
在环境温度下用氰化钠的DMF溶液处理生物素甲苯磺酸盐3.22以获得产率为72%的腈4.39。腈4.39用4N氢氧化钠在回流下水解,然后用6N HCl酸化,在真空过滤后获得产率为96%的高生物素4.40,且不需要进一步纯化。用亚硫酰氯的酸酯化得到定量产率的甲酯4.41,其用LiAlH4还原以得到产率为91%的高生物素酚4.42。通过在吡啶中与甲苯磺酰氯反应完成高生物素酚4.42至甲苯磺酸盐4.43的转化。粗制甲苯磺酸盐4.43用锂溴化物的2-丁酮溶液回流处理以获得高生物素溴化物4.44,经过高生物素酚4.42和急骤层析两个步骤后产率为51%。最后,在15℃向高生物素溴化物4.44的DMSO溶液中加入锂乙炔化物EDA复合物获得产率为36%的高生物素乙炔4.17。
通过CuAAC(铜催化的叠氮化物-炔烃环加成反应)和RuAAC(钌催化的叠氮化物-炔烃环加成反应)合成三唑4.01–4.13
三唑4.01–4.04,4.12和4.13的合成如方案7所示,产率如本文中所示。将适量的炔烃和叠氮化物溶解于用20mol%铜纳米粉末处理的2:1的乙腈和水的混合物中,超声处理15分钟并在35℃下搅拌4小时。由于叠氮化物4.19的溶解度低,4.02的CuAAC形成在乙腈:水:DMSO(5:4:1)的溶剂混合物中完成。通过1H NMR ROESY和COSY实验确定4.01–4.04,4.12和4.13的1,4-三唑结构异构体结构。
通过CuAAC和RuAAC合成三唑4.01–4.13
三唑4.01–4.04,4.12和4.13的合成如方案7所示,产率如本文中所示。将适量的炔烃和叠氮化物溶解于用20mol%铜纳米粉末处理的2:1的乙腈和水的混合物中,超声处理15分钟并在35℃下搅拌4小时。由于叠氮化物4.19的溶解度低,4.02的CuAAC形成在乙腈:水:DMSO(5:4:1)的溶剂混合物中完成。通过1H NMR ROESY和COSY实验确定4.01–4.04,4.12和4.13的1,4-三唑结构异构体结构。
方案7:a)铜纳米粉末,2:1乙腈/水,超声处理,40℃.
三唑4.09和4.10的合成,如方案8所示,保留了戊糖环因为三唑4.09和4.10最初都作为三唑3.25的类似物研发。因此炔烃4.16和4.17分别用叠氮化物3.16的2:1的乙腈和水的混合物溶液处理,所示混合物溶液含有20mol%铜纳米粉末。三唑4.09和4.10通过急骤层析纯化,分离产率分别为68%和61%。
方案8:a)铜纳米粉末,2:1乙腈/水,超声处理,35℃.
三唑4.05–4.08的合成如方案9所示。将叠氮化物4.18–4.21在80℃用炔烃3.12与Cp*Ru(PPh3)2Cl的1:1的DMF和THF的溶剂混合物处理。所得到的三唑4.05–4.08通过急骤层析分离和纯化,产率如方案9中所述。通过1H NMR ROESY和COSY实验确定4.05–4.08的1,5-三唑结构。
方案9:a)Cp*Ru(PPh3)2Cl,2:1THF\DMF,80℃
确定三唑4.01–4.13的1,4和1,5结构异构体
三唑4.01–4.13的1D1H NMR和2D COSY确定了单独结构异构体的存在。三唑H5共振的化学位移列于表4中。2D ROESY1H NMR实验表明1,4-三唑和1,5-三唑4.01–4.12通过与相邻的亚甲基质子(HA和HC)及5位上的三唑环(HB)的空间相互作用具有差异(参见表4)。已发现1,4-三唑(4.01–4.04,4.09–4.12)通过三唑质子HB与相邻的亚甲基质子HA和HC之间的空间相互作用提供特征(参见表4)。相反地,1,5-三唑(4.05–4.08)只通过亚甲基HB与三唑HA之间的空间相互作用存在差异。
然而,作为式(I)中R1基团存在的其他环状结构也是有用的,其结构例如,仅通过示例的方式,其中R1选自下列组成的组中:
吡唑,
相比于非选择性生物素蛋白连接酶抑制剂生物素酚-5’-AMP,这些抑制剂是有吸引力的。
生物素酚-5’-AMP2.02
叠氮化物结构单元6.16,6.17,6.22–6.25及6.31–6.33的合成
这些三唑结构(6.02–6.10)的逆合成分析。图2示出了所述叠氮化物结构单元6.16,6.17,6.22–6.25及6.31–6.33,其与炔烃3.12偶联。所述叠氮化物如方案10和11所示制备。
用碳酸钾处理苯酚且所得到的酚盐分别用烷基二卤化物6.12和6.13烷基化以分别获得6.14和6.15,参见方案10。然后将所述卤化物6.14和6.15与叠氮化钠的DMF溶液反应以获得叠氮化物6.15和6.16。类似地,1-萘基6.22和6.23及2-萘基6.24和6.25的合成分别由1-萘酚和2-萘酚制备,且采用与苯基6.15和6.16相同的条件。通过傅里叶变换红外光谱(FT-IR spectroscopy)在2093–2098cm-1之间的吸收确定叠氮化物的形成。
方案10:a)Br(CH2)nBr,K2CO3,DMF;b)NaN3,DMF
通过环化2-氨基-甲酚与羰基二咪唑(CDI)获得2-苯并恶唑酮6.27,如方案11所示。该物质用碳酸钾处理后,分别与烷基二卤化物6.26、6.12和6.13的DMF溶液反应,以分别获得卤化物6.28–6.30。所述卤化物6.28–6.30与叠氮化钠的DMF溶液反应转化为叠氮化物6.31–6.33,如方案11所示。
方案11:a)CDI,DCM;b)Br(CH2)nBr,K2CO3,DMF;c)NaN3,DMF通过CuAAC合成1,4-三唑6.02–6.10
通过用生物素3.12和铜纳米粉末(20mol%)的2:1的乙腈/水溶液分别处理叠氮化物6.16、6.17、6.22–6.25和6.31–6.33完成三唑6.02–6.10的合成(参见表1)。三唑6.04(34%)和6.05(41%)获得的产率明显低于三唑6.02、6.03和6.06–6.10(51%–74%)的产率。此外,已发现1-萘基类似物6.02和6.03长时间在DMSO溶液中都分解(超过一天)。
表2:
a急骤层析后分离的产率
结构6.03、6.07和6.09的2D ROESY NMR表明通过质子HA和HB与HA和HC之间的空间偶联,说明获得的1,4-双取代模式多于1,5-双取代模式,参见图1。结合SaBPL的三唑6.09的X-射线晶体结构确定了1,4-双取代模式的结合机制。
设计并合成磷酸二酯6.34
已发现生物素三唑抑制剂有效并选择性地对抗SaBPL,以三唑4.01(Ki=0.66±0.15μM)和三唑6.09(Ki=0.09±0.02μM)作为主要实施例。然而,发现三唑4.01和6.09与含有抑制剂的磷酸二酯生物素酚-5’-AMP2.02(Ki0.03±0.001μM)相比,其对抗SaBPL的有效性低22倍到3倍。
合成磷酸二酯6.34
苯并恶唑酮6.34的合成途径如方案13所示。
方案13:a)NaOH,H2O,Δ;b)K2CO3,四丁基碘化铵(TBAI),DMF;c)LiOH,1:1THF/H2O d)三乙胺,DCM;e)i)5-乙基硫代四唑,偶氮二环己腈(AcCN);ii)叔丁基过氧化氢(TBHP);iii)5%三氟乙酸(TFA),DCM;f)NaI,丙酮,Δ
磷酸二酯6.34的合成需要获得亚磷酸酯前体6.37。这通过苯并恶唑酮与4-溴-丁氧乙酸酯的烷基化以获得产率为78%的6.36,然后通过乙酸酯基团的脱保护获得产率为78%的6.35。在文献的步骤之后,通过用4-溴丁醇和4-氯丁醇分别处理6.27实现乙醇6.35的最初合成,但分别获得低产率,为5%和11%。低产率的原因可能是碱介导的卤化醇的分子内环化作用的结果,如方案13所示。6.35与N,N-二异丙基-甲氧基磷酰胺氯化物的亚磷酸化获得粗产率为67%的亚磷酸盐6.37。随后粗制亚磷酸胺6.37用5-乙基硫代-四唑和DMTr-生物素酚2.19的乙腈溶液处理以获得6.38,其亚磷酸盐用叔-丁氧基过氧化氢氧化并用5%三氟乙酸(TFA)酸化,由6.35获得磷酸三酯6.39,产率为39%。最后,通过在回流下与NaI的丙酮溶液反应完成6.39的脱甲基化以在反相HPLC纯化后获得产率为67%的6.34。
表4:三唑4.01–4.12的1H NMR ROESY实验简述
a方法A:铜纳米粉末,2:1乙腈/水,超声处理,35℃,方法B:Cp*Ru(PPh3)2Cl,2:1THF\DMF,80℃。b由DMSO-d6获得的1H NMR,c由CDCl3和5%CD3OD获得的1HNMR,d由CDCl3获得的1H NMR.e通过与HB的空间相互作用观察到的
生物数据
酶抑制试验
如前Polyak等,J.Biol.Chem(1999)274(46)32847-54所述进行并入生物素结构域基质的BPL催化的3H-生物素的定量。简言之,反应混合物含有:50mM Tris HCl pH8.0、3mM ATP、4.5μM生物素、0.5μM3H-生物素、5.5mM MgCl2、100mM KCl、0.1mg/mL BSA和10μM金黄色葡萄球菌丙酮酸羧化酶的生物素结构域。该反应通过将BPL加至终浓度为4nM起始。在37℃20分钟后,将反应的4μL等份试样点样至用生物素和三氯乙酸预处理的沃特曼(Whatman)纸上。在空气干燥前用10%v/v冰冷的三氯乙酸洗涤滤液两次并用乙醇洗涤一次。通过液体闪烁进行蛋白质结合的放射性标记的生物素的定量。将酶活性的一个单位定义为每分钟并入1nmol生物素所需的BPL的量。由剂量-反应曲线通过在相同酶浓度下改变抑制剂的浓度测定每种化合物的IC50值。用GraphPadPrism使用log10(抑制剂)与标准化响应的非线性拟合分析数据。使用公式1计算Ki(化合物的绝对抑制常数):
公式1.
其中Km是基质对酶的亲和力([生物素]=1μM)且[S]是基质浓度([生物素]=5μM)。
通过随着改变3H-生物素浓度而改变抑制剂的浓度研究抑制模式。将数据绘图为双倒数曲线并使用双倒数曲线(Lineweaver-Burk)分析评估。
三唑6.02–6.10用于测定对金黄色葡萄球菌的生物素蛋白连接酶(SaBPL)、大肠杆菌的生物素蛋白连接酶(EcBPL)和人类的生物素蛋白连接酶(HsBPL)的抑制活性(表3)。通过测量不同抑制剂浓度的BPL活性确定化合物的抑制活性。由剂量-反应曲线测定IC50值并计算Ki值。结果如表3所示。
表3:选择的三唑类似物及其抗SaBPL、EcBPL和HsBPL的抑制试验结果
*化合物的溶解度有限并阻止进一步定量。
SAR系列中的三唑化合物示出了对SaBPL的良好选择性,超过了大肠杆菌和人类的同工酶。针对SaBPL,生物素三唑抑制SaBPL的效力为1μM或更好。对于人类和大肠杆菌生物素蛋白连接酶,试验中的生物素三唑达到维持可溶的最高浓度(200μM),未测量到抑制活性。
化合物3.25是BPL反应中间体生物素-5-AMP和抑制剂生物素酚-5-AMP2.02的结构同系物,其中磷酸酯键被1,4三唑取代。生物素三唑3.25的效力比2.02低60倍,但比泛抑制剂(pan inhibitor)显示出更高的选择性(2.02=7.5倍Hs相对SaBPL;3.25=>>16倍Hs相对SaBPL)。去除3.25的核糖部分使其在主要结构4.01中的效力提高3倍。
已发现2-萘基6.07有效并选择性地对抗SaBPL且Ki为1.17±0.17μM。尽管相比于腺嘌呤4.01的亲本主要结构,2-萘基6.07的有效性更低(下降7倍),但是保留的对SaBPL的选择性突出了1,2,3-三唑环作为选择性所需的组分。
苯并恶唑酮6.09是针对SaBPL最有效和选择性的实例,且Ki=0.09±0.02μM。该抑制剂相比于主要腺嘌呤结构4.01,效力明显提高了7倍,且相比于非选择性生物素酚-5’-AMP2.02效力仅降低3倍。重要地,生物素三唑示出了对SaBPL的选择性比对人类和大肠杆菌的BPL高1000倍(图3a)。
抗菌试验
使用如CLSI(临床和实验室标准协会,文件M07-A8,2009,Wayne,Pa.)推荐的微量液体培养基稀释试验评估生物素-三唑的抗菌活性,所述微量液体培养基为阳离子调节的Mueller-Hinton液体培养基(TrekDiagnostics Systems,英国)。使用DMSO溶解化合物。使用DMSO作为稀释剂对每个化合物进行系列的两倍稀释。盘上接种100μL的5×104CFU的各菌株(DMSO的最终浓度为5%(V/V)),并在35℃下培养16-20小时,在波长620nm处通过光谱学测量生长培养物的光密度。
使用了革兰氏阴性和革兰氏阳性细菌。抗菌试验结果表明苯并恶唑酮6.09在浓度为8微克/毫升时阻止了80%金黄色葡萄球菌ATCC49775的细胞生长(图3b)。然而,没有观察到其他革兰氏阴性细菌例如粪肠球菌(Enterococcus faecalis)或屎肠球菌(Enterococcus faecium)的生长抑制。
细胞培养毒性
将HepG2细胞悬浮在含有10%胎牛血清的Dulbecco改良的Eagle培养基中,然后以5000、10000或20000细胞/孔接种于96孔组织培养板中。24小时后,使用不同浓度的化合物处理细胞,从而使所有孔的DMSO浓度是一致的4%(V/V)。处理24或48小时后,将WST-1细胞增殖试剂(Roche)加入到每个孔中并在37℃下培养0.5小时。将WST-1试验通过测量WST-1试剂的水解定量监测细胞的代谢活性,在450nm的吸光度下检测其产物。
当使用人类HepG2细胞培养模型时,生物素三唑也没有示出具有毒性(图3c)。这与生物素三唑对于HsBPL有限的活性一致(IC50>200μM)。
在图3a中,分化性抑制。在体外用不同浓度的生物素三唑6.09测定BPL活性。使用来自金黄色葡萄球菌(·),大肠杆菌(□)和人(×)的重组BPL进行该试验。
图3b示出了抗葡萄球菌活性。采用微量液体培养稀释试验,用不同浓度的BPL抑制剂测定金黄色葡萄球菌ATCC49775的生长的抑制。曲线图示出了包括在生长基中的下列物质的效果:生物素酚-5-AMP2.02(ο)、生物素三唑4.01(◆)和6.09(·),以及没有抑制剂(■)。也包括了抗生素红霉素(×)。
在图3c中,使用细胞增殖试验在HepG2中评估生物素三唑系列的细胞毒性。以20000,1000或5000细胞/孔接种细胞,并用含有64μg/ml化合物和2%DMSO的培养基处理48小时。在该系列中的处理是(从左到右)DMSO赋形剂(小方框)、BPL043(大方框)、3.25(横条纹)、4.01(竖条纹)、6.09(向上斜条纹)和6.07(向下斜条纹)。
X-射线晶体学
通过X射线结晶学证实了生物素三唑结合到SaBPL的机制。Apo-SaBPL被缓冲交换在50mM Tris HCl pH7.5,50mM NaCl,1mMDTT和5%(v/v)甘油中,并且浓度为5mg/mL。然后,向每种化合物以10:1的摩尔比添加BPL。使用悬滴法,在4℃,以8–12%Peg8000的0.1M Tris pH7.5或8.0和10%(v/v)甘油作为储层结晶复合物。使用汉普顿(Hampton)硅环挑取单独的结晶,并通过在储层缓冲液中的含有25%(v/v)甘油的冷冻保护剂划线,之后收集数据。用澳大利亚同步加速器使用ADSC量子210r探测器将X射线衍射数据收集在大分子晶体束线。以1°为每个帧的摆动角度,每秒收集90个图像。使用HKL整合数据,并且使用CCP4程序组件精选。使用PRODRG Web界面获得每个化合物的PDB和CIF文件。使用COOT手动建模循环建立该模型,并用REFMAC完善。使用MOLPROBITY对最终模型的质量进行评价。
结合SaBPL的4.01和6.09的X射线结构,揭示了当与生物素酚-5’-AMP2.02的磷酸二酯连接子比较时,1,4-三唑连接子提供了与酶的有限的结合。生物素酚-5’-AMP2.02的磷酸二酯连接子形成与SaBPL相互作用的氢键网络(参见图4)。X射线数据表明三唑6.09,可以与磷酸二酯连接子互换以获得磷酸二酯6.34。
图4:结合在酶活性部位的SaBPL的有效抑制剂。(4a)结合在SaBPL的活性部位的生物素酚-5′AMP2.02的晶体结构。示出了与SaBPL的氨基酸相互连接的氢键。(4b)结合在SaBPL的活性部位的三唑4.01的晶体结构。示出了与SaBPL的氨基酸相互连接的氢键。(4c)叠加了来自(4a)和4b)的SaBPL的骨架原子以揭示在2.02和4.01的构象中显著的重叠(显示为立体图)。(4d)结合在SaBPL的活性部位的三唑6.09的晶体结构。示出了与SaBPL的氨基酸相互连接的氢键。
通过原位点击化学合成并筛选三唑类似物4.01–4.08
然后进行经由靶标引导的原位点击化学合成,制备SaBPL的基于三唑的抑制剂。SaBPL活性部位和设计的三唑3.25抑制剂的结构特征提供了研究这种方法的机会。SaBPL的活性部位的特点在于有两个独特的凹部(ATP和生物素结合凹部),如在X射线结晶结构图中所看到的,它们彼此临近。更重要地,如在结合SaBPL的三唑3.25中发现,三唑连接子位于SaBPL活性部位的两个独特的凹部之间。
在两个三唑3.25(生物素炔烃3.12和腺苷叠氮化物3.16)片段上进行起始的原位点击实验,如方案10所示。极其重要的是这些片段的至少一个能够结合在SaBPL的活性部位内。重要地,结构单元生物素炔烃3.12能够结合SaBPL(Ki=0.33±0.05μM),然而,腺苷叠氮化物3.16对于SaBPL具有有限的结合亲和力。使用野生型SaBPL进行腺苷3.16和生物素炔烃3.12的原位点击实验。观察到野生型酶对于以高速率提供原位环化加成反应用于通过HPLC或LC-MS检测是无效的。因此,Arg122,其已知作为结合SaBPL的配体的守卫,选择性的突变成Gly122用于原位点击实验。使用SaBPL-R122G完成3.16和3.12之间的环化加成反应(方案14)。
方案14:使用突变体SaBPL-R122G,用炔烃3.12和叠氮化物3.16进行的原位点击实验,以获得三唑3.25(基于HPLC)。
基于成功使用原位点击化学形成三唑3.25,我们研究了三唑类似物4.01–4.08的筛选(参见方案11)。提出了仅彼此靠近的具有适当链长及其相应的叠氮化物和炔烃官能团的片段将经历1,3-两级环化加成反应。彼此远离的具有其官能团的片段将不会经历1,3-两极环化加成反应。换句话说,SaBPL仅将选择并形成能够结合在活性位点的三唑类似物。
酶抑制和抗菌试验结果
分析三唑4.01–4.15对于SaBPL、EcBPL和HsBPL的抑制,对于SaBPL,三唑4.01、4.09和4.13显示出了微摩尔分子浓度的抑制,如表5所示。通过变化抑制剂的浓度,在相同的酶浓度下,根据剂量响应曲线测定每个化合物的IC50。
表:三唑4.01、4.09、4.13和3.25对于SaBPL、HsBPL和EcBPL的抑制
如表5所示,三种三唑类似物都是有效的并选择性对抗SaBPL(4.01、4.09和4.13)。三唑4.01是这些抑制剂中最有效的(Ki=0.66±0.15uM,IC50=4.0±0.9),并且其效力大于先前的三唑3.25(Ki=1.83±0.33uM)3倍。类似于3.25,发现三唑4.01相比于EcBPL(>200μM)和HsBPL(>200μM)具有至少400倍的选择性抗SaBPL。
三唑和三唑4.09的生物素基团之间的系链是一个短于三唑3.25的碳。发现该类似物抑制SaBPL,其Ki=7.53±1.90,它的效力相比于三唑3.25(Ki=1.83±0.33uM)低4倍。
三唑4.13,其具有与三唑4.01相同的腺嘌呤和生物素环之间的链长,但是发现三唑环“分离”指向生物素环从而抑制SaBPL,具有Ki=2.86±0.75μM。它的效力相比于三唑4.01(Ki=0.66±0.15μM)低4倍。类似于三唑4.01,三唑4.13示出了对于SaBPL(Ki=2.86±0.75μM)的选择性高于HsBPL(Ki>10μM)和EcBPL(Ki>10μM)。
类似物的合成
化合物1-6是先导SaBPL抑制剂BPL068的类似物。化合物1-6和BPL068的主要区别在于在BPL068中发现的、BPL068涉及1,4-取代的1,2,3-三唑,用可选的5元杂化系统例如,1,2,4-三唑(3和4),1,2,4-恶二唑(5和6)和1,3,4-恶二唑(1和2)的置换。化合物1-6中的生物素和苯并恶唑酮组分如在BPL068中所发现的保持不变。同时,化合物2、4和6的链长如在BPL068中所发现的保持不变。化合物1、3和5在生物素和5-元杂环之间具有短的链长。假定,用化合物1-6中发现的那些基团取代BPL068的5-元杂环1,2,3-三唑环,将保留或增强氢键与SaBPL之间的相互作用。SaBPL和BPL068的1,2,3-三唑之间的相互作用是Asp180、Arg122和Arg125。
方案15示出了用于制备上述化合物的合成途径。
方案15:a)i)亚硫酰氯,甲醇;ii)NH2NH2.H2O,甲醇;b)KCN,DMF,50℃c)NH2OH,乙醇,Δ;d)碳二亚胺(EDCI),二异丙基乙胺(DIPEA),DMF;e)MS,1:1DMF/甲苯,Δ;f)乙酰氯,乙醇;g)2:1DMF/甲苯,MW,150℃
如上所述合成化合物1-6。1和2的合成首先通过使用氰化钾将文献报道的溴化物111转化成腈12开始,其然后用羟胺在碱性条件下处理以获得肟13。EDCI-介导的肟13和生物素7之间的偶联导致N-氧化物酯14形成。14的环脱水得到目标1,2,4-恶二唑1。类似地,EDCI-介导的肟13和高生物素8之间的偶联得到N-氧化物酯15,其一经在无水条件下加热,即获得1,2,4-恶二唑2。
三唑3和4和恶二唑5和6的合成需要获得生物素酰肼92,高生物素酰肼10和酰亚胺酯16。生物素7和高生物素8分别在酸性条件下酯化,以获得相应的甲酯,其一经用水合肼处理,即获得生成的酰肼(9和10)。用盐酸盐气体(乙酰氯/乙醇)原位处理腈12以获得酰亚胺酯16。在酰亚胺酯16和生物素酰肼9之间的单微波反应中获得1,2,4-恶二唑3和1,2,4-三唑5的混合物。类似地,高生物素酰肼10和酰亚胺酯16在碱性条件下的微波反应获得1,2,4-恶二唑5和1,2,4-三唑6以大约2:1的比例存在的混合物。通过硅胶色谱分离化合物3–6。
3-[4-[5-[4-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]丁基]-1,2,4-恶二唑-3-基]丁基]-5-甲基-1,3-苯并恶唑-2-酮(1)
含有分子筛的化合物14(10mg,0.020mmol)的无水甲苯(0.5ml)和无水DMF(0.5ml)溶液在氮气氛围下回流,搅拌4小时。冷却反应混合物,并真空浓缩,用96:4二氯甲烷/甲醇纯化,以获得白色固体(5mg,51%)。
1H NMR(600MHz,CDCl3):δ7.07(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),6.80(s,1H),5.35(bs,1H),4.67(bs,1H),4.51–4.54(m,1H),4.32–4.34(m,1H),3.82–3.85(m,2H),3.15–3.18(m,1H),2.94(dd,J=5.4,13.2Hz,1H),2.89(t,J=7.8Hz,2H),2.79–2.81(m,2H),2.74(d,J=13.2Hz,1H),2.40(s,3H),1.46–1.87(m,10H);13C NMR(150MHz,CDCl3):δ179.3,169.8,162.7,154.9,140.7,133.8,131.0,122.7,109.6,108.9,61.7,60.0,55.0,41.7,40.6,27.9,27.6,27.1,26.01,25.7,25.3,24.0,21.5;HPLC Rt=17.12分钟。
3-[4-[5-[5-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]戊基]-1,2,4-恶二唑-3-基]丁基]-5-甲基-1,3-苯并恶唑-2-酮(2)
含有分子筛的化合物15(8mg,0.015mmol)的无水甲苯(0.5ml)和无水DMF(0.5ml)溶液在氮气氛围下回流,搅拌4小时。冷却反应混合物,并真空浓缩,用96:4二氯甲烷/甲醇纯化,以获得白色胶状物(2mg,26%)。
1H NMR(600MHz,CDCl3):δ7.07(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,1H),6.78(s,1H),4.88(bs,1H),4.70(bs,1H),4.52–4.54(m,1H),4.32–4.34(m,1H),3.82–3.85(m,2H),3.14–3.18(m,1H),2.93(dd,J=5.4,12.6Hz,1H),2.85(t,J=7.2Hz,2H),2.78–2.80(m,2H),2.74(d,J=12.6Hz,1H),2.40(s,3H),1.39–1.87(m,14H);13C NMR(150MHz,CDCl3):δ179.6,169.8,162.7,154.9,140.7,133.8,131.0,122.8,109.6,108.8,62.0,60.1,55.3,41.7,40.5,28.8,28.5,27.1,26.3,26.2,25.3,24.0,21.5;LRMS:(M+Na+)508.1,预期的508.2;HPLC Rt:17.76分钟。
3-[4-[5-[4-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]丁基]-1H-1,2,4-三唑-3-基]丁基]-5-甲基-1,3-苯并恶唑-2-酮(3)
和
3-[4-[5-[4-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]丁基]-1,3,4-恶二唑-2-基]丁基]-5-甲基-1,3-苯并恶唑-2-酮(5)
向生物素酰肼92(28mg,0.108mmol)的无水DMF(0.5ml)悬浮液中加入酰亚胺酯16(32mg,0.102mmol)、DIPEA(52mg,0.410mmol)和无水甲苯(0.5ml)。搅拌混合物并在150℃下微波2小时(具有可变压力和功率),真空浓缩,并通过硅胶色谱纯化,以含有5%甲醇的二氯甲烷洗脱,从而获得1,2,4-恶二唑5(16mg,33%),以含有12%甲醇的二氯甲烷洗脱获得1,2,4-三唑3(7mg,15%)。
1,2,4-恶二唑(5):1H NMR(600MHz,CDCl3):δ7.08(d,J=7.8Hz,1H),6.91(d,J=7.8Hz,1H),6.79(s,1H),5.42(bs,1H),4.84(bs,1H),4.51–4.54(m,1H),4.32–4.34(m,1H),3.85(t,J=6.6Hz,2H),3.15–3.18(m,1H),2.93(dd,J=5.4,12.6Hz,1H),2.90(t,J=7.2Hz,2H),2.84(t,J=7.8Hz,2H),2.74(d,J=12.6Hz,1H),2.72(s,3H),1.50–1.90(m,10H);13C NMR(150MHz,CDCl3):δ166.8,166.2,163.0,154.9,140.7,133.9,130.9,122.9,109.7,108.8,61.8,60.1,55.2,41.5,40.5,28.1,28.0,27.0,26.2,24.8,25.7,23.4,21.5;LRMS(M+Na+):494.2预期的494.2HPLC Rt:16.07分钟
1,2,4-三唑(3):1H NMR(600MHz,CDCl3):δ13.26(bs,1H),7.53(bs,1H),7.06(d,J=7.8Hz,1H),6.89(d,J=7.8Hz,1H),6.78(s,1H),6.54(bs,1H),4.56–4.58(m,1H),4.41–4.43(m,1H),3.83(t,J=6.6Hz,2H),3.00–3.17(m,1H),2.96(dd,J=6.6,12.0Hz,1H),2.71–2.86(m,5H),1.60–1.88(m,6H),1.27–1.45(m,4H);13C NMR(150MHz,CDCl3):δ165.1,155.0,140.7,133.8,131.0,122.7,109.6,108.9,61.7,60.2,59.9,41.9,41.0,29.7,28.2,27.9,27.7,27.2,27.0,25.2,21.5;LRMS:(M+H+):471.1预期的471.2;HPLC Rt:13.77分钟。
3-[4-[5-[5-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]戊基]-1H-1,2,4-三唑-3-基]丁基]-5-甲基-1,3-苯并恶唑-2-酮(4)
和
3-[4-[5-[5-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]戊基]-1,3,4-恶二唑-2-基]丁基]-5-甲基-1,3-苯并恶唑-2-酮(6)
向高生物素酰肼10(30mg,0.110mmol)的DMF(0.5ml)悬浮液中加入酰亚胺酯16(36mg,0.115mmol)、DIPEA(58mg,0.464mmol)和甲苯(0.25ml)。搅拌混合物并在150℃下微波2小时(具有可变压力和功率),真空浓缩,并通过硅胶色谱纯化,以含有5%甲醇的二氯甲烷洗脱,从而获得1,2,4-恶二唑6(17mg,32%),以含有10%甲醇的二氯甲烷洗脱获得1,2,4-三唑4(10mg,18%)。
1,2,4-恶二唑(6):1H NMR(600MHz,CDCl3):δ7.08(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),5.79(bs,1H),5.24(bs,1H),4.50–4.53(m,1H),4.30–4.33(m,1H),3.84–3.86(m,2H),3.14–3.17(m,1H),2.85–2.93(m,3H),2.73–2.83(m,3H),1.44–1.89(m,14H);13C NMR(150MHz,CDCl3):δ167.0,166.1,163.4,154.9,140.7,133.9,130.9,122.8,109.7,108.8,62.0,60.1,55.7,41.5,40.5,28.9,28.5,28.4,27.0,25.9,25.2,24.7,23.4,21.5;LRMS:(M+Na+):508.1预期的508.2;HPLC Rt:16.67分钟。
1,2,4-三唑(4):1H NMR(600MHz,CDCl3):δ13.75(bs,1H),7.86(bs,1H),7.05(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),6.78(s,1H),6.37(bs,1H),4.60–4.61(m,1H),4.35(dd,J=3.6,7.2Hz,1H),3.78–3.86(m,2H),3.15–3.18(m,1H),2.93–2.97(m,2H),2.74–2.79(m,4H),2.39(s,3H),1.35–1.84(m,14H);13C NMR(150MHz,CDCl3):δ165.2,162.8,154.9,140.6,133.8,131.0,122.7,109.5,108.9,61.2,60.6,55.2,41.9,40.8,28.2,28.1,27.8,27.3,27.1,26.3,25.2,21.5LRMS:(M+Na+):507.2预期的507.2;HPLC Rt=14.21分钟。
6-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]己烷酰肼(10)
向高生物素8(150mg,0.58mmol)的无水甲醇(1.5ml)悬浮液中逐滴加入亚硫酰氯(276mg,169μL,2.32mmol),并在氮气氛围下搅拌2小时。真空浓缩混合物,悬浮于甲醇(2ml)中,并加入水合肼(0.5ml),搅拌16小时。真空浓缩反应混合物,溶于水(5ml)中,并用氯仿(2x5ml)洗涤。在真空下浓缩水层,以获得白色粉末(121mg,77%)。
1H NMR(300MHz,D2O):δ4.59(dd,J=7.8,4.5Hz,1H),4.41(dd,J=7.8,4.5Hz,1H),δ2.98(dd,J=13.2,4.9Hz,1H),2.76(d,J=13.2Hz,1H),2.19–2.24(m,2H),1.24–1.77(m,8H);13C NMR(75MHz,D2O):δ176.4,166.0,62.8,60.9,56.1,40.3,34.1,28.7,28.6,28.4,25.4.
5-(5-甲基-2-氧代-1,3-苯并恶唑-3-基)戊腈(12)
溴化物111(500mg,1.77mmol),氰化钾(126mg,1.94mmol)的无水DMF(5ml)溶液在50℃下,在氮气氛围下搅拌8小时。将反应混合物冷却至室温,并用二氯甲烷(50ml)稀释,并用水(50ml)和盐水(50ml)洗涤。有机层在硫酸钠中干燥,过滤并真空浓缩。通过硅胶色谱纯化残留物,以3:2乙酸乙酯/己烷混合物洗脱,从而获得白色固体(289mg,71%)。
1H NMR(300MHz,CDCl3):δ7.05(d,J=7.8Hz,1H),6.90(d,J=7.8Hz,1H),6.78(s,1H),3.84(t,J=6.9Hz,2H),2.44(t,J=6.9Hz,2H),2.38(s,3H),1.89–1.99(m,2H),1.69–1.78(m,2H);13C NMR(75MHz,CDCl3):δ154.9,140.6,134.0,130.7,123.0,119.2,109.7,108.8,41.0,26.8,22.4,21.6,16.7。
N'-羟基-5-(5-甲基-2-氧代-1,3-苯并恶唑-3-基)戊烷脒(13)
羟胺盐酸盐(345mg,5.00mmol)和酚酞(1晶体)的无水甲醇(5ml)溶液在氮气氛围下回流,搅拌。逐滴加入甲醇钠,直到粉色溶液保持不变(大约使用350mg)。将热溶液直接过滤到化合物2(115mg,0.50mmol)的无水乙醇(5ml)溶液中。反应混合物在氮气氛围下回流搅拌6小时。将反应混合物冷却,真空浓缩并通过硅胶色谱纯化,以19:1二氯甲烷/甲醇洗脱,从而获得棕色固体(68mg,52%)。
1H NMR(300MHz,CDCl3):δ7.00(d,J=8.1Hz,1H),6.82–6.88(m,1H),6.76–6.76(m,1H),4.85(bs,1H),3.76(t,J=6.9Hz,2H),3.61(bs,2H),2.32(s,3H),2.11(t,J=7.5Hz,2H),1.69–1.79(m,2H),1.51–1.61(m,2H);13C NMR(75MHz,CDCl3)δ177.7,140.9,134.4,131.0,123.3,109.9,109.3,100.3,41.7,30.5,27.1,24.0,21.7;LRMS(M+H+):264.1预期的264.1。
[(Z)-[1-氨基-5-(5-甲基-2-氧代-1,3-苯并恶唑-3-基)戊叉]氨基]5-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]戊酸酯(14)
向生物素7(23mg,0.092mmol)和化合物13(22mg,0.083mmol)的无水DMF(0.5ml)悬浮液中加入EDCI(16mg,0.10mmol)和DIPEA(13mg,0.10mmol),并且室温下,在氮气氛围下搅拌12小时。反应混合物用二氯甲烷(25ml)稀释,并用水(25ml)和盐水(25ml)洗涤。有机层通过硫酸钠干燥,过滤并真空浓缩。通过硅胶色谱纯化残留物,以19:1二氯甲烷/甲醇洗脱,从而获得黄色油状物(21mg,51%)。
1H NMR(600MHz,CDCl3):δ7.08(d,J=8.4Hz,1H),6.91(d,J=8.4Hz,1H),6.80(s,1H),5.60(bs,1H),5.04(m,3H),4.50–4.51(m,1H),4.30–4.32(m,1H),3.85(t,J=6.6Hz,2H),3.14–3.17(m,1H),2.91(dd,J=5.4,13.2Hz,1H),2.73(d,J=13.3Hz,1H),2.42(t,J=7.8Hz,2H),2.40(s,3H),2.34(t,J=7.8Hz,2H),1.47–1.86(m,10H);13C NMR(150MHz,CDCl3):δ171.0,163.3,158.0,155.4,140.7,134.1,130.7,123.0,109.7,109.0,61.8,60.1,55.3,41.0,40.5,32.7,30.1,28.2,28.1,26.8,24.9,23.7,21.5
[(Z)-[1-氨基-5-(5-甲基-2-氧代-1,3-苯并恶唑-3-基)戊叉]氨基]6-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]己酸酯(15)
向高生物素83(10mg,0.039mmol)和化合物13(11mg,0.043mmol)的无水DMF(0.5ml)悬浮液中加入EDCI(7mg,0.047mmol)和DIPEA(6mg,0.045mmol),并且室温下,在氮气氛围下搅拌12小时。反应混合物用二氯甲烷(25ml)稀释,并用水(25ml)和盐水(25ml)洗涤。有机层通过硫酸钠干燥,过滤并真空浓缩。通过硅胶色谱纯化残留物,以19:1二氯甲烷/甲醇洗脱,从而获得黄色油状物(18mg,46%)。
1H NMR(600MHz,CDCl3):δ7.08(d,J=7.2Hz,1H),6.91(d,J=7.2Hz,1H),6.80(s,1H),5.38(bs,1H),4.99(bs,2H),4.60(bs,1H),4.49–4.52(m,1H),4.29–4.32(m,1H),3.82–3.87(m,2H),3.13–3.17(m,1H),2.91(dd,J=4.8,12.6Hz,1H),2.73(d,J=12.6Hz,1H),2.40(s,3H),2.32–2.38(m,2H),2.12(t,J=7.2Hz,2H),1.40–1.86(m,12H);LRMS(M+Na+):526.2预期的526.2。
5-(5-甲基-2-氧代-1,3-苯并恶唑-3-基)戊酰亚胺盐酸盐(16)
向腈11(100mg,0.43mmol)的无水乙醇(0.5ml)溶液中加入乙酸(0.5ml),并且使溶液在密封的圆底烧瓶中搅拌6小时。真空浓缩反应混合物以获得白色固体(135mg,100%)。
1H NMR:7.02(d,J=8.1Hz,1H),6.86(d,J=8.1Hz,1H),6.80(s,1H),4.42(q,J=6.3Hz,2H),3.78–3.81(m,2H),2.63(t,J=6.9,2H),2.34(s,3H),1.68–1.86(m,4H),1.39(t,J=6.6Hz,3H);LRMS(M+H+):277.1预期的277.2
上述化合物,3-[4-[5-[5-[(3aS,4S,6aR)-2-氧代-1,3,3a,4,6,6a-六氢噻吩并[3,4-d]咪唑-4-基]戊基]-1,2,4-恶二唑-3-基]丁基]-5-甲基-1,3-苯并恶唑-2-酮(2),已经示出了具有抗生物素蛋白连接酶的抑制活性,所述生物素蛋白连接酶来自金黄色葡萄球菌和结核分枝杆菌(Mycobacteriatuberculosis),Ki金黄色葡萄球菌生物素蛋白连接酶=2.2±0.8μM,Ki结核分枝杆菌生物素蛋白连接酶=290±16μM。
虽然本发明已在本文中示出并在被设想为是最实际和优选的实施例中描述,但是应当理解的是在本发明的范围内可以进行改变,其不限于本文描述的细节,而是应与所附权利要求的全部范围一致,从而涵盖任何和所有的等价结构和申请。
Claims (6)
1.一种式(I)的化合物
其中
n是选自1至10的整数;
R1选自下列组成的组中:
咪唑,
吡唑,
吡咯,
噻吩,
四唑,
恶唑,
三唑
,其中X选自H或OH,
磷酸二酯,
其中L选自Na+、K+;
X选自CH2、CF2、NH,
R3选自下列组成的组中:
H、C1-C10烷基、C1-C10烯基、C1-C10炔基;
核苷,例如,但不限于腺苷、胞苷、尿苷、鸟苷、胸苷或肌苷;
腺嘌呤、鸟嘌呤、胸腺嘧啶、尿嘧啶、胞嘧啶;
苯并恶唑酮、苯并恶唑、苯并呋喃、苯并咪唑,
其中:
R5、R6、R7、R8选自由H、C1-C5烷基、卤素、NH2、OH2、NR12R13、SH、SR13组成的组:
其中R12和R13选自由H、C1-C5烷基组成的组;
R9选自由N、NH组成的组;
R10选自由CH2、C=O、C=N-R组成的组;
R11选自由N、NH、O、S组成的组;
萘基、其中:
X选自由O、NR12R13、SR13组成的组;
R14、R15、R16、R17、R18、R19、R20选自由H、C1-C5烷基、卤素、NH2、OH2、NR12R13、SH、SR13组成的组:
其中R12和R13选自由H、C1-C5烷基组成的组。
2.一种药物组合物,包括作为活性成分的至少一种根据权利要求1所述的式(I)的化合物和任选地一种或多种药学上可接受的赋形剂。
3.根据权利要求2所述的药物组合物,用于治疗选自由细菌感染、真菌感染、原生动物感染组成的组中的感染。
4.根据权利要求3所述的药物组合物,其中所述细菌感染是金黄色葡萄球菌感染。
5.根据权利要求3所述的药物组合物,其中所述细菌感染是结核分枝杆菌感染。
6.至少一种根据权利要求1至6任一项所述的化合物作为活性成分在制备用于治疗和/或预防细菌感染、真菌感染、原生动物感染的药物中的用途。
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AU2011903957A AU2011903957A0 (en) | 2011-09-26 | Novel antimicrobial compounds | |
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PCT/AU2012/001138 WO2013040647A1 (en) | 2011-09-23 | 2012-09-21 | Novel antimicrobial compounds |
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Cited By (3)
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CN104530008A (zh) * | 2014-12-18 | 2015-04-22 | 浙江工业大学 | 一种含1,2,3-三唑的苯并咪唑类化合物及其应用 |
CN106046087A (zh) * | 2016-06-13 | 2016-10-26 | 武汉工程大学 | 1,5‑二取代1,2,3‑三唑糖缀合物及其衍生物 |
CN106083959A (zh) * | 2016-06-13 | 2016-11-09 | 武汉工程大学 | 1,4(‑no2),5‑三取代1,2,3‑三唑糖缀合物及其衍生物 |
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GB201205360D0 (en) * | 2012-03-27 | 2012-05-09 | Univ Edinburgh | Biotinidase resistant biotinyl compounds |
WO2020087122A1 (en) * | 2018-10-30 | 2020-05-07 | University Of Adelaide | Novel antibiotic compounds |
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US8134010B2 (en) * | 2004-05-05 | 2012-03-13 | Renopharm Ltd. | Thiazole-based nitric oxide donors having aryl substituent(s) and uses thereof |
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EP0529590A1 (en) * | 1991-08-27 | 1993-03-03 | Takeda Chemical Industries, Ltd. | Intermediates for D-biotin synthesis and their production |
WO2006056007A1 (en) * | 2004-11-23 | 2006-06-01 | Adelaide Research & Innovation Pty Ltd | Inhibitors of biotin protein ligase |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104530008A (zh) * | 2014-12-18 | 2015-04-22 | 浙江工业大学 | 一种含1,2,3-三唑的苯并咪唑类化合物及其应用 |
CN106046087A (zh) * | 2016-06-13 | 2016-10-26 | 武汉工程大学 | 1,5‑二取代1,2,3‑三唑糖缀合物及其衍生物 |
CN106083959A (zh) * | 2016-06-13 | 2016-11-09 | 武汉工程大学 | 1,4(‑no2),5‑三取代1,2,3‑三唑糖缀合物及其衍生物 |
CN106046087B (zh) * | 2016-06-13 | 2019-05-03 | 武汉工程大学 | 1,5-二取代1,2,3-三唑糖缀合物及其衍生物 |
CN106083959B (zh) * | 2016-06-13 | 2019-05-28 | 武汉工程大学 | 1,4(-no2),5-三取代1,2,3-三唑糖缀合物及其衍生物 |
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US20140296177A1 (en) | 2014-10-02 |
EP2758405A4 (en) | 2015-04-29 |
EP2758405A1 (en) | 2014-07-30 |
WO2013040647A1 (en) | 2013-03-28 |
CN104066738B (zh) | 2017-03-15 |
US9108978B2 (en) | 2015-08-18 |
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