CN114507230A - 一种双环吡啶酮类衍生物、其合成方法及其用途 - Google Patents
一种双环吡啶酮类衍生物、其合成方法及其用途 Download PDFInfo
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- CN114507230A CN114507230A CN202011287793.1A CN202011287793A CN114507230A CN 114507230 A CN114507230 A CN 114507230A CN 202011287793 A CN202011287793 A CN 202011287793A CN 114507230 A CN114507230 A CN 114507230A
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- compound
- alkyl
- membered heteroaryl
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
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- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1029—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom
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- C09K2211/10—Non-macromolecular compounds
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- C09K2211/1025—Heterocyclic compounds characterised by ligands
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- C09K2211/1037—Heterocyclic compounds characterised by ligands containing one nitrogen atom as the heteroatom with sulfur
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1044—Heterocyclic compounds characterised by ligands containing two nitrogen atoms as heteroatoms
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Abstract
本发明属于有机化合物(药物)合成领域,具体涉及一种双环吡啶酮类衍生物、其合成方法及其用途。针对现有技术中双环吡啶酮类化合物的合成过程中用到的原料、催化剂和反应条件具有毒性、危险性比较高等特点。本发明提供了一系列双环吡啶酮类化合物及其衍生物。该类双环吡啶酮类化合物及其衍生物可以通过廉价、低毒性的柠檬酸进行合成,生产成本低,且合成的过程简单。该类衍生物能够作为中间体进一步合成各种结构的双环吡啶酮类化合物,非常适宜于工业化的生产。该化合物具有良好的抗菌活性和荧光特性。
Description
技术领域
本发明属于有机化合物(药物)合成领域,具体涉及一种双环吡啶酮类衍生物、其合成方法及其用途。
背景技术
双环吡啶酮类化合物是一种以氮原子为连接点的稠杂环化合物,因其具有广泛的应用价值而成为合成化学家研究的热点。众多研究显示双环吡啶酮类化合物可作为ACE抑制剂、人体鼻病毒3C-蛋白酶抑制剂、钙通道阻滞剂、周期素激酶抑制剂等。其显现出抗肿瘤、抗病毒、抗菌、抗疟疾、抗糖尿病等广泛的生物活性。临床上常用于癌症(胃癌、肝癌、皮肤癌、白血病等)治疗的喜树碱、用于老年痴呆治疗的石杉碱甲等,这些药物分子中均含有双环吡啶酮结构母环,其结构如下。
双环吡啶酮结构的构建方法从最初环上的重排,到分子内关环、分子间
反应,发展到金属试剂促进的环合反应。但已报道的合成方法大多以过渡金属、酸、碱等作为催化剂,使用有毒溶剂且反应条件苛刻。虽然这类原料、催化剂和反应条件具有毒性、危险性比较高等特点,但在双环吡啶酮类化合物的合成过程中由于缺少替代的合成方法,它们仍在广泛使用。
由于双环吡啶酮结构合成中存在上述的问题,导致双环吡啶酮结构的化合物在应用方面受到较多的限制。
柠檬酸是重要的有机小分子,在化学工业,食品业,化妆业等具有极多的用途。但是作为廉价原料用于有机合成领域相对较少。
发明内容
针对现有技术中双环吡啶酮类化合物的合成过程中用到的原料、催化剂和反应条件具有毒性、危险性比较高等特点。本发明提供一种双环吡啶酮类衍生物、其合成方法及其用途。其目的在于:提供一种新的构建双环吡啶酮结构的方法,该合成方法采用廉价、毒性低的柠檬酸作为原料,无需使用任何有毒溶剂,反应条件温和,适宜于工业化生产。
式I所示的化合物、或其立体异构体、或其药学上可接受的盐:
其中,其中,R1、R2选自H、取代或未取代的C1~C10烷基、取代或未取代的C1~C10烯基、取代或未取代的C6~C20芳基、取代或未取代的3-10元杂环烷基、取代或未取代的3-20元杂芳基、羧基;其中,所述取代基是C1~C10烷基、C6~C20芳基、C1~C10烷氧基、C1~C10酯基、氰基、羟基、羧基、卤素或硝基;
X1选自S、O、NH。
优选的,所述R1、R2选自H、苯基、4-取代苯基、5元杂芳基、5-取代5元杂芳基、苯乙烯基或羧基;
进一步优选的,所述R1、R2选自H、苯基或羧基。
优选的,所述R3选自H或甲基。
优选的,所述X1选自S、NH、NRX;
RX选自取代或未取代的C1~C10烷基、取代或未取代的C1~C10酰基;其中,所述取代基是3-20元杂芳基、烷基取代的3-20元杂芳基;
优选的,所述X1选自S、NH、NRX;
优选的,式I所示化合物具体为:
本发明还提供上述化合物的制备方法,通过如下反应步骤进行:
其中,X1、R1和R2如权利要求1-6任一项所述。
优选的,具体过程为将柠檬酸与原料A混合后于60~180℃下水热反应得到式I的化合物;
优选的,所述反应温度为140℃;和/或,反应时间为0.5~12h,进一步优选为4h;和/或,所述柠檬酸与原料A的摩尔比为1:(0.5~2),进一步优选为1:1。
本发明还提供一种双环吡啶酮类衍生物的合成方法,它是将式I所述的化合物、或其立体异构体、或其药学上可接受的盐作为中间体合成双环吡啶酮类化合物。
本发明还提供式II所示的化合物、或其立体异构体、或其药学上可接受的盐:
其中,R1、R2选自H、取代或未取代的C1~C10烷基、取代或未取代的C1~C10烯基、取代或未取代的C6~C20芳基、取代或未取代的3-10元杂环烷基、取代或未取代的3-20元杂芳基、羧基;其中,所述取代基是C1~C10烷基、C6~C20芳基、C1~C10烷氧基、C1~C10酯基、氰基、羟基、羧基、卤素或硝基;
R3选自H、取代或未取代的C1~C10烷基;其中,所述取代基是C1~C10烷氧基、C1~C10酯基、氰基、羟基、羧基、卤素或硝基;
X1选自S、O、NH、NRX;
RX选自取代或未取代的C1~C10烷基、取代或未取代的C1~C10酰基;其中,所述取代基是C1~C10烷氧基、C1~C10酯基、3-20元杂芳基、烷基取代的3-20元杂芳基、氰基、羟基、羧基、卤素或硝基;
X2、X3选自H或卤素;其中,所述卤素为F、Cl或Br;
优选的,所述式II化合物选自:
本发明还提供式I或式II所示的化合物、或其立体异构体、或其药学上可接受的盐在制备抗菌药物中的用途;和/或,作为荧光分子的用途;
优选的,所述抗菌药物是用于抑制金色葡萄球菌、耐甲氧西林金黄色葡萄球菌和大肠杆菌的药物。
本发明提供了一系列双环吡啶酮类化合物及其衍生物。该类双环吡啶酮类化合物及其衍生物可以通过廉价、低毒性的柠檬酸进行合成,生产成本低,且合成的过程简单。
本发明合成的式I化合物能够作为合成的中间体,进一步合成各种具有双环吡啶酮结构的化合物化合物,例如式II所示的化合物、ACE-inhibitour、FN750、Camptothecin和Huperzine A。适宜于双环吡啶酮类化合物的工业化的生产。
另一方面,本发明提供了双环吡啶酮类化合物中双环吡啶酮结构的构建方法。该合成方法具有如下优点:
(1)原料采用柠檬酸,具有廉价和低毒性的优点,减少生产过程对环境保护的压力;
(2)反应过程中不使用任何有毒溶剂和催化剂,进一步减轻环保压力;
(3)反应温度较为温和,使得生成过程的危险性和能耗较低;
(4)该合成方法化学选择性高;
(5)本发明的制备方法对底物具有一定的普适性等特点,为后续双环吡啶酮相关衍生物的合成提供了一条切实可行的合成路径。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1为本发明实施例中得到的化合物a-i对大肠杆菌ATCC25922的抗菌作用;
图2为本发明实施例中得到的化合物a-i对金黄色葡萄球菌ATCC25923的抗菌作用;
图3为本发明实施例中得到的化合物a-i对金黄色葡萄球菌标准耐药株ATCC33591的抗菌作用;
图4为本发明实施例中得到的化合物a-i对金黄色葡萄球菌标准耐药株ATCC43300的抗菌作用。
图5化合物a的紫外可见吸收光谱图(上)及荧光发射光谱图(下);
图6化合物b的紫外可见吸收光谱图(上)及荧光发射光谱图(下);
图7化合物c的紫外可见吸收光谱图(上)及荧光发射光谱图(下);
图8化合物d的紫外可见吸收光谱图(上)及荧光发射光谱图(下);
图9化合物e的紫外可见吸收光谱图(上)及荧光发射光谱图(下);
图10化合物f的紫外可见吸收光谱图(上)及荧光发射光谱图(下);
图11化合物g的紫外可见吸收光谱图(上)及荧光发射光谱图(下);
图12化合物h的紫外可见吸收光谱图(上)及荧光发射光谱图(下);
图13化合物i的紫外可见吸收光谱图(上)及荧光发射光谱图(下)。
具体实施方式
下面提供过具体的实施例对本发明的技术方案做进一步的说明。
实施例1(化合物a)
依次向反应水热合成釜中加入10mmol(1eq)柠檬酸,再加入10mmol(1eq)的(S,S)-1,2-二苯基乙二胺,于140℃下无溶剂反应12h后监测反应情况。
待反应完全后,将得到的产品经过重结晶得到红褐色固体即为化合物a。
(2S,3S)-5-氧代-2,3-二苯基-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-羧酸(化合物a)核磁数据表征为:
1H NMR(400MHz,DMSO–d6)δ13.29(s,1H),8.42(s,1H),7.46–7.31(m,8H),7.26–7.21(m,2H),6.01(d,J=1.5Hz,1H),5.91(d,J=1.5Hz,1H),5.32(d,J=2.7Hz,1H),4.85(d,J=2.7Hz,1H).13C NMR(101MHz,DMSO–d6)δ175.02,171.76,167.17,160.07,154.26,145.22,142.12,139.87,129.52,129.29,128.78,128.49,126.22 126.09,105.79,80.83,72.92,68.07,66.60,43.17.[C21H18N2O3+H]+332.1161;Found:333.1234.
(2S,3S)-5-氧代-2,3-二苯基-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-羧酸的熔点为:M.p 149.5-150.1。
实施例2(化合物b)
与实施例1的制备过程相同,采用的胺为乙二胺,得到的产物化合物b为5-氧代-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-羧酸,为棕色固体。
5-氧代-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-羧酸的核磁数据表征为:
1H NMR(400MHz,DMSO–d6)δ7.49(s,1H),5.94(d,J=1.6Hz,1H),5.67(d,J=1.5Hz,1H),4.02(t,J=8.9Hz,2H),3.64(t,J=8.8Hz,2H).
5-氧代-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-羧酸的熔点为:M.p 139.8~139.9℃。
实施例3(化合物i)
与实施例1的制备过程相同,采用的胺为半胱氨酸,得到的产物化合物i为(S)-5-氧代-2,3-二氢-5H-四氢噻唑[3,2-a]吡啶-3,7-二羧酸,为黄色固体。
(S)-5-氧代-2,3-二氢-5H-四氢噻唑[3,2-a]吡啶-3,7-二羧酸核磁数据表征为:
1H NMR(400MHz,DMSO–d6)δ6.60(d,J=1.4Hz,1H),6.56(d,J=1.5Hz,1H),5.47(dd,J=8.9,1.3Hz,1H),3.91(dd,J=11.9,9.0Hz,1H),3.61(dd,J=11.9,1.4Hz,1H)。
(S)-5-氧代-2,3-二氢-5H-四氢噻唑[3,2-a]吡啶-3,7-二羧酸的熔点为:M.p181.1~182.3℃。
实施例4(化合物e)
将化合物i和K2CO3(3mmol,414mg)溶解在DMF(10mL)中并在40℃搅拌30分钟,然后向其中加入MeI(300mg,1.1mmol)将混合物在40℃下搅拌3小时,直到通过TLC检测到反应完全。将反应混合物放入水中,用乙酸乙酯(EA)萃取,在减压下浓缩。粗产物通过硅胶色谱法用乙酸乙酯/石油醚纯化,得到纯产物。
甲基(2S,3S)-5-氧代-2,3-二苯基-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-羧酸酯核磁数据表征为:1H NMR(400MHz,DMSO–d6)δ8.52(s,1H),7.46–7.35(m,6H),7.35–7.32(m,2H),7.26–7.21(m,2H),6.03(d,J=1.6Hz,1H),5.93(d,J=1.6Hz,1H),5.34(d,J=2.7Hz,1H),4.88(d,J=2.7Hz,1H),3.84(s,3H).HRMS(ESI)Calcd for[C21H18N2O3+H]+346.1317;Found:347.1321.
甲基(2S,3S)-5-氧代-2,3-二苯基-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-羧酸酯熔点为:108.7-109.8℃。
实施例5(化合物d)
将化合物a和K2CO3(3mmol,414mg)溶解在DMF(10mL)中并在40℃搅拌30分钟,然后向其中加入MeI(300mg,1.1mmol)将混合物在40℃下搅拌3小时,直到通过TLC检测到反应完全。将反应混合物放入水中,用乙酸乙酯(EA)萃取,在减压下浓缩。粗产物通过硅胶色谱法用乙酸乙酯/石油醚纯化,得到纯产物。
甲基-5-氧代-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-羧酸酯的核磁表征:1H NMR(400MHz,DMSO–d6)δ7.59(s,1H),5.94(d,J=1.6Hz,1H),5.67(d,J=1.6Hz,1H),4.03(t,J=9.0Hz,2H),3.79(s,3H),3.65(t,J=9.0Hz,2H).13C NMR(101MHz,DMSO–d6)δ166.24,160.61,155.04,142.92,104.23,81.07,53.00,44.61,42.43.HRMS(ESI)Calcd for[C9H10N2O3+H]+195.0764;Found:194.0691.M.p:120.5-122.0℃。
实施例6(化合物g)
将化合物e和K2CO3(3mmol,414mg)溶解在DMF(10mL)中并在40℃搅拌30分钟,然后向其中加入MeI(300mg,1.1mmol)将混合物在40℃下搅拌3小时,直到通过TLC检测到反应完全。将反应混合物放入水中,用乙酸乙酯(EA)萃取,在减压下浓缩。粗产物通过硅胶色谱法用乙酸乙酯/石油醚纯化,得到纯产物。
甲基(2S,3S)-1-甲基-5-氧代-2,3-二苯基-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-甲酸酯的核磁氢谱为:1H NMR(400MHz,DMSO–d6)δ7.46–7.33(m,6H),7.25–7.17(m,4H),6.09(d,J=1.5Hz,1H),5.87(d,J=1.5Hz,1H),5.31(d,J=3.7Hz,1H),4.79(d,J=3.7Hz,1H),3.86(s,3H),2.79(s,3H).13C NMR(101MHz,DMSO–d6)δ166.20,160.27,153.84,144.14,139.21,138.52,129.82,129.36,128.71,126.74,126.24,106.20,79.81,72.84,67.08,53.25,31.08.HRMS(ESI)Calcd for[C22H20N2O3+H]+361.1547;Found:360.1474.M.p:117.1-118.9℃.
实施例7(化合物c)
将化合物e和Cs2CO3(3mmol,975mg)溶解在DMF(10mL)中并在40℃搅拌30分钟,然后向其中加入MeI(300mg,1.1mmol)将混合物在40℃下搅拌3小时,直到通过TLC检测到反应完全。将反应混合物放入水中,用乙酸乙酯(EA)萃取,在减压下浓缩。粗产物通过硅胶色谱法用乙酸乙酯/石油醚纯化,得到纯产物。
甲基(2S,3S)-1-乙酰基-5-氧代-2,3-二苯基-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-甲酸酯(7):1H NMR(400MHz,DMSO–d6)δ7.51–7.37(m,7H),7.32(d,J=7.0Hz,2H),7.28–7.23(m,2H),6.62(d,J=1.5Hz,1H),5.77(d,J=3.7Hz,1H),5.44(s,1H),3.89(s,3H),2.03(s,3H).13C NMR(101MHz,DMSO–d6)δ165.31,158.98,145.70,143.62,139.74,138.40,130.06,129.58,129.32,129.07,126.32,125.59,115.45,89.79,67.81,53.51,24.16.HRMS(ESI)Calcd for[C23H20N2O4+H]+389.1496;Found:388.1423.M.p:181.0-183.7℃.
实施例8(化合物f)
将化合物e(692mg,2mmol),NBS(10mmol,1.78g)和BPO(0.2mmol,46.4mg)溶于DCM(20mL)中并在室温下搅拌12h,直到通过TLC检测到完全转化。将反应混合物倒入水中,并用DCM(3×30mL)萃取。然后将合并的有机层用无水Na2SO4干燥。减压除去溶剂。将残余物溶解在THF-NH 4Cl(水溶液)(v/v=1∶1)中,然后将钐粉末加入到混合物中,并在室温在氩气下搅拌12h,通过TLC检测。然后将固体滤出,并将混合物用EtOAc(3×30mL)萃取,并将合并的有机层用无水Na2SO4干燥。减压除去溶剂,残余物通过硅胶色谱法用乙酸乙酯/石油醚纯化,得到纯产物。
甲基6,8-二溴-5-氧代-2,3-二苯基-1,2,3,5-四氢咪唑[1,2-a]吡啶-7-碳酸酯:1H NMR(400MHz,DMSO–d6)δ9.03(s,1H),7.47–7.38(m,6H),7.36–7.32(m,2H),7.28–7.24(m,2H),5.46(d,J=4.0Hz,1H),4.93(d,J=3.8Hz,1H),3.92(s,3H).13C NMR(101MHz,DMSO–d6)δ165.47,154.82,151.29,148.55,140.96,139.13,129.56,129.50,129.05,128,87,126.47,126.39,93.98,70.75,67.89,66.96,53.71.HRMS(ESI)Calcd for[C21H16Br2N2O3+H]+501.9528;Found:502.9600.M.p:70.3-71.8℃
实施例9(化合物h)
将化合物e(692mg,2mmol)和Cs2CO3(977mg,414mg)溶解在THF(10mL)中并在60℃搅拌30分钟,然后用1,4-二溴丁烷(648mg,3mmol)将其加入到混合物中,并在40℃下搅拌3h,通过TLC监测。将反应混合物放入水中,用乙酸乙酯(EA)萃取,在减压下浓缩。粗产物通过硅胶色谱法用乙酸乙酯/MeOH纯化,得到纯产物。将产物溶解于MeCN中,加入等当量的4-甲基吡啶并在室温在氩气下搅拌12h,通过TLC监测。减压除去溶剂,残余物通过硅胶色谱法用DCM/MeOH纯化,得到纯产物。
1-(4-((2S,3S)-7-(甲氧羰基)-5-氧代-2,3-二苯基2,3-四氢咪唑[1,2-a]吡啶-1(5H)-基)丁基)-4-吡啶-1-盐(9):1H NMR(400MHz,DMSO–d6)δ8.81(d,J=6.6Hz,2H),7.97(d,J=6.3Hz,2H),7.41(m,6H),7.23(m,2H),7.19–7.15(m,2H),6.09(d,J=1.4Hz,1H),5.93(d,J=1.4Hz,1H),5.31(d,J=3.0Hz,1H),4.79(d,J=3.0Hz,1H),4.47(t,J=6.7Hz,2H),3.87(s,3H),3.51(m,1H),2.93(m,1H),2.61(s,3H),1.84–1.74(m,2H),1.43(m,2H).13CNMR(101MHz,DMSO–d6)δ166.19,159.85,159.26,153.19,144.06,143.96,139.63,139.35,129.77,129.39,129.28,128.82,128.63,126.75,126.08,106.44,79.12,70.56,66.91,59.71,53.25,49.05,43.26,28.36,23.61,21.84.389.1496[C31H32N3O3+]+494.2438;Found:494.2433.
试验例1:化合物a-i体外抗菌活性研究
一、实验方法
最低抑菌浓度(MIC)测试方法
1、实验菌株:选取耐甲氧西林金黄色葡萄球菌(ATCC33591)和耐甲氧西林金黄色葡萄球菌(ATCC43300)以及普通菌株大肠杆菌(ATCC25922)和金黄色葡萄球菌(ATCC25923)为MIC值测定菌株。
2、药物稀释:以乙醇和无菌水为溶剂,将合成化合物和泰妙菌素分别溶解和稀释,配制成浓度为1280μg·mL-1的母液,置于冰箱避光密封保存备用。
3、菌液制备:取各受试菌进行活化,挑取单克隆菌落于0.9%生理盐水中,将菌液配置成0.5麦氏浓度(1.5×108CFU·mL-1),后用Mueller-Hinton无菌肉汤培养基(MHB)稀释10倍备用。
4、MIC测定:在96孔板中除边缘孔和第二列孔外其余孔分别加入100μL MHB,向第二孔加入160μL MHB和40μL母液。采用二倍稀释法分别对化合物和阳性对照进行稀释,共稀释成128–0.25μg·mL-110个不同浓度梯度的稀释液,再向除边缘孔外每孔加入100μL菌浮液,充分混匀,最后向边缘孔每孔加入无菌水200μL。37℃恒温培养18–24h,观察受试菌的生长情况,以无生长的药物最低浓度为该药对该受试菌的MIC值;以配制化合物浓度等同的乙醇溶液为阴性对照,,每株受试菌进行3个平行实验,实验重复3次。实验结果见图1,实验图选取药物浓度为0.125μg·mL-1处的OD值作图。
二、实验结果
化合物a-i的MIC测试结果如图1-4所示。
化合物a-i对大肠杆菌ATCC25922和金黄色葡萄球菌ATCC25923表现出良好的抑制活性(除了化合物c对大肠杆菌ATCC25922抑制活性比较差外),同时,对金黄色葡萄球菌标准耐药株ATCC33591和ATCC43300都表现出一定的抗菌效果。其中化合物(b、d、i)在0.125μg·mL-1处对ATCC33591没有抑制活性,但是化合物b、d、i对金黄色葡萄球菌耐药菌株ATCC43300的抑制活性较好。综合以上结果,本发明中的双环吡啶酮类化合物均表现出了优良的抑菌效果。
试验例2:化合物a-i光谱研究
一、实验方法
1、不同溶剂对荧光(紫外)性质的影响的测试方法
1)实验溶剂:分别选取N’N-二甲基甲酰胺、二甲亚砜、乙酸乙酯、水,甲醇、丙酮、四氢呋喃、乙腈、二氯甲烷等作溶剂,其中这几种样品纯度均符合分析测试要求。
2)实验条件:实验温度为室温(25℃),狭缝宽度=2.5nm,样品浓度C=10-5M。
3)实验步骤:分别称取1-2mg样品溶解于不同溶剂中,得到浓度为10-3M的母液,置于冰箱中避光保存备用。测试时将对应的母液取出30μL稀释到3mL,得到10-5M的待测液。将待测液在紫外分光光度计上测得吸收光谱及最大吸收值,然后再在荧光光仪器上用该吸收值激发得到荧光发射光谱。实验重复3次。
二、实验结果
化合物a-i的紫外可见吸收光谱及荧光发射光谱如图5-13所示。
实验表明,在多种溶剂中,化合物a-i具有在325-425nm具有紫外吸收特性,且能够发射425-550nm的荧光。因而,化合物a-i具有作为荧光分子的应用潜力。
通过上述实施例1-9可见,本发明能够通过一种简单、低毒性和高选择性高的合成方法合成一类双环吡啶酮类衍生物。通过试验例1-2的测试结果,可直本发明方法制备得到的双环吡啶酮类衍生物普遍具有抗菌活性和荧光发射特性,具有广泛的应用潜力。
Claims (10)
3.按照权利要求1所述的化合物、或其立体异构体、或其药学上可接受的盐,其特征在于:所述R3选自H或甲基。
7.按照权利要求6所述的制备方法,其特征在于:具体过程为将柠檬酸与原料A混合后于60~180℃下水热反应得到式I的化合物;
优选的,所述反应温度为140℃;和/或,反应时间为0.5~12h,进一步优选为4h;和/或,所述柠檬酸与原料A的摩尔比为1:(0.5~2),进一步优选为1:1。
8.一种双环吡啶酮类衍生物的合成方法,其特征在于:它是将权利要求1-6任一项所述的化合物、或其立体异构体、或其药学上可接受的盐作为中间体合成双环吡啶酮类化合物。
9.式II所示的化合物、或其立体异构体、或其药学上可接受的盐:
其中,R1、R2选自H、取代或未取代的C1~C10烷基、取代或未取代的C1~C10烯基、取代或未取代的C6~C20芳基、取代或未取代的3-10元杂环烷基、取代或未取代的3-20元杂芳基、羧基;其中,所述取代基是C1~C10烷基、C6~C20芳基、C1~C10烷氧基、C1~C10酯基、氰基、羟基、羧基、卤素或硝基;
R3选自H、取代或未取代的C1~C10烷基;其中,所述取代基是C1~C10烷氧基、C1~C10酯基、氰基、羟基、羧基、卤素或硝基;
X1选自S、O、NH、NRX;
RX选自取代或未取代的C1~C10烷基、取代或未取代的C1~C10酰基;其中,所述取代基是C1~C10烷氧基、C1~C10酯基、3-20元杂芳基、烷基取代的3-20元杂芳基、氰基、羟基、羧基、卤素或硝基;
X2、X3选自H或卤素;其中,所述卤素为F、Cl或Br;
优选的,所述式II化合物选自:
10.按照权利要求1-6或9任一项所述的式I或式II所示的化合物、或其立体异构体、或其药学上可接受的盐在制备抗菌药物中的用途;和/或,作为荧光分子的用途;
优选的,所述抗菌药物是用于抑制金色葡萄球菌、耐甲氧西林金黄色葡萄球菌和大肠杆菌的药物。
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