CN111233790A - 一种酰腙类神经氨酸酶抑制剂及其制备方法和应用 - Google Patents
一种酰腙类神经氨酸酶抑制剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种酰腙类神经氨酸酶抑制剂及其制备方法和应用,其具有通式L所示的结构:
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种酰腙类神经氨酸酶抑制剂及其制备方法和应用。
背景技术
神经氨酸酶是分布于流感病毒被膜上的一种糖蛋白,可以协助成熟的流感病毒脱离原来的宿主细胞去感染新的细胞。神经氨酸酶抑制剂可以同时抑制甲、乙型流感病毒,不易引起抗药性且耐受性好,可以有效阻断流感病毒的复制过程,在流感病毒的生命历程中扮演着重要角色。目前已经上市的神经氨酸酶抑制剂包括奥司他韦(Oseltamivir,达菲)、扎那米韦(Zanamivir,易乐韦)、帕拉米韦(Peramivir)和拉尼那米韦(Laninamivir),其中奥司他韦是唯一口服有效的神经氨酸酶抑制剂。随着上述药物的使用,临床上出现了多种病毒变异株,且大多数变异株对上述药物会产生耐药性,因此,迫切需要开发新型耐药的神经氨酸酶抑制剂。
发明内容
本发明的目的就是为了解决上述问题而提供一种新型的酰腙类神经氨酸酶抑制剂及其制备方法和应用。
本发明的目的通过以下技术方案实现:
本发明中,利用计算机虚拟筛选技术以及计算机辅助药物设计中的分子对接、分子动力学模拟等手段针对神经氨酸酶的结构进行设计,并且合成了结构新颖的神经氨酸酶抑制剂,最终对其进行神经氨酸酶抑制活性的测试。
一种酰腙类神经氨酸酶抑制剂,其具有式L所示的结构:
本发明还提供一种上述的神经氨酸酶抑制剂的制备方法,反应方程式如下所示:
本发明提供的酰腙类神经氨酸酶抑制剂的制备方法,具体步骤包括:
(1)将间苯二甲醛在硼氢化钠作用下进行单还原生成式Ⅰ所示3-(羟甲基)苯甲醛;
(2)将式Ⅰ所示3-(羟甲基)苯甲醛与三溴化磷作用生成式Ⅱ所示3-(溴甲基)苯甲醛;
(3)将式Ⅱ所示3-(溴甲基)苯甲醛与取代苯酚在碳酸铯和碘化钾的作用下,在有机溶剂中加热生成式Ⅲ所示结构化合物;
(4)将草酸二乙酯与水合肼反应制备式Ⅳ所示草酸单乙酯酰肼;
(5)将式Ⅲ所示结构化合物与式Ⅳ所示草酸单乙酯酰肼在水中反应得到式Ⅴ所示结构化合物;
(6)将式Ⅴ所示结构化合物与N-(3-氨丙基)吗啉在有机溶剂中回流得到式L所示结构终产物。
上述步骤(1)中,间苯二甲醛与硼氢化钠的摩尔比为2:1~3:1,所用溶剂乙醇:四氢呋喃体积比为2:3,反应温度为冰浴。
上述步骤(2)中,式Ⅰ所示化合物3-(羟甲基)苯甲醛与三溴化磷的摩尔比为1:1.2,所用溶剂为二氯甲烷,反应温度为冰浴。
上述步骤(3)中,式Ⅱ所示3-(溴甲基)苯甲醛、取代苯酚、碳酸铯和碘化钾的摩尔比为1:1.1:1.5:0.6,所用溶剂为N,N-二甲基甲酰胺,反应温度为60℃。
上述步骤(4)中,草酸二乙酯与水合肼的摩尔比为2:1~3:1,所用溶剂为无水乙醇,反应温度为冰浴。
上述步骤(5)中,式Ⅲ所示结构化合物与式Ⅳ所示草酸单乙酯酰肼摩尔比为1:1.1~1:1.5,反应溶剂为水,反应温度为室温。
上述步骤(6)中,式Ⅴ所示结构化合物与N-(3-氨丙基)吗啉摩尔比为1:1.05~1:1.1,有机溶剂为甲醇或乙醇,反应温度为70~80℃。
本发明合成的化合物结构新颖,均为首次报道,实验表明具有良好的神经氨酸酶抑制活性,有望用于制备抑制神经氨酸酶活性的药物。
具体实施方式
下面结合实施实例对本发明的技术方案进行详细阐述,应该说明的是,下述说明仅是为了解释本发明,并不对其内容进行限定。即在阅读了本发明讲授的内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
以合成化合物L-1为例,其结构式如下:
(1)准确称取间苯二甲醛原料5.2g(38.8mmol),加入到盛有24ml乙醇和36ml四氢呋喃的圆底烧瓶中,随后在冰浴条件下,少量多次(分四次)加入0.65g(17.2mmol)硼氢化钠固体,继续反应5h左右,TLC点板监测至间苯二甲醛原料点完全消失,停止反应。旋蒸除溶剂,所得剩余物用水和乙酸乙酯萃取,收集有机相,加入饱和食盐水溶液洗涤,随后将有机相用无水硫酸钠干燥过夜,过滤,旋蒸,拌样,进行硅胶柱层析分离,所用洗脱剂为PE:EA=3:1,收集得到式Ⅰ所示单还原产物3-(羟甲基)苯甲醛,所得产物为无色液体,收率为74%。1H NMR(500MHz,DMSO)δ10.01(s,1H),7.88(s,1H),7.78(d,J=5.0Hz,1H),7.65(d,J=10.0Hz,1H),7.54(t,J=7.5Hz,1H),5.46(s,1H),4.62(s,2H).13C NMR(125MHz,CDCl3)δ192.91,142.19,136.32,132.99,129.13,128.95,127.75,63.96.
(2)准确称取式Ⅰ所示结构3-(羟甲基)苯甲醛1.36g(10mmol)于100ml圆底烧瓶中,加入20ml二氯甲烷溶液,随后在冰浴条件下加入1.12ml(12mmol)三溴化磷,继续反应过夜。停止反应,加入少量去离子水淬灭,水相用二氯甲烷萃取3~4次,合并二氯甲烷层,加入饱和食盐水溶液洗涤,将所得有机相用无水硫酸钠干燥,过滤,旋蒸,拌样,进行硅胶柱层析分离,所用洗脱剂为二氯甲烷,收集得到式Ⅱ所示结构3-(溴甲基)苯甲醛,所得产物为白色固体,产率为56%。1H NMR(500MHz,CDCl3)δ9.98(s,1H),7.88(s,1H),7.78(d,J=10.0Hz,1H),7.64(d,J=10.0Hz,1H),7.49(t,J=7.5Hz,1H),4.52(s,2H).13C NMR(125MHz,CDCl3)δ191.65,138.97,136.86,134.92,129.86,129.73,129.61,32.21.
(3)准确称取式Ⅱ所示结构3-(溴甲基)苯甲醛0.40g(2.0mmol)于50ml圆底烧瓶中,加入10ml N,N-二甲基甲酰胺溶液,随后依次加入0.31g(2.2mmol)对硝基苯酚、0.98g(3mmol)碳酸铯及0.2g(1.2mmol)碘化钾固体,加热至60℃反应30min。停止反应,冷却至室温,向反应液中加入20ml乙酸乙酯,有机相用0.5mol/LNaOH溶液和饱和食盐水溶液洗涤,所得有机相用无水硫酸钠干燥,过滤,旋蒸,拌样,进行硅胶柱层析分离,所用洗脱剂为PE:EA=10:1,收集得到式Ⅲ所示结构化合物,所得产物为白色固体,产率为89%。1H NMR(500MHz,CDCl3)δ10.07(s,1H),8.24(d,J=10.0Hz,2H),7.99(s,1H),7.90(d,J=5.0Hz,1H),7.73(d,J=10.0Hz,1H),7.62(t,J=7.5Hz,1H),7.07(d,J=10.0Hz,2H),5.26(s,2H).13C NMR(125MHz,CDCl3)δ191.90,163.30,141.89,136.82,133.24,130.08,129.60,128.12,126.02,114.86,69.81.
(4)准确称取2.92g(20mmol)草酸二乙酯溶于20ml无水乙醇中,取0.5g(10mmol)水合肼溶于15ml无水乙醇中,随后在冰浴条件下将水合肼的乙醇溶液缓慢滴加到草酸二乙酯的乙醇溶液中,20min内滴加完,室温搅拌过夜,反应结束后,常压过滤收集滤液,旋蒸除乙醇,向所得剩余液中加入20ml乙酸乙酯,用40ml水萃取四次,收集水相,所得式Ⅳ所示结构的草酸单乙酯酰肼即保存在水相中。
(5)准确称取0.4g(1.56mmol)式Ⅲ所示结构化合物,加入式Ⅳ所示结构的草酸单乙酯酰肼水溶液15ml,室温搅拌过夜,反应结束后,抽滤即得式Ⅴ所示结构化合物,所得产物为白色固体,产率为88%,不经纯化,直接投下一步。
(6)准确称取0.37g(1.0mmol)式Ⅴ所示结构化合物溶于20ml溶剂甲醇中,加入N-(3-氨丙基)吗啉0.16g(1.1mmol),随后在70℃下加热回流1h,停止反应,冷却至室温,待大部分固体完全析出,抽滤得式L所示结构终产物,产率为89%。
所得目标化合物:L-1,白色固体,产率89%,熔点193.3~196.7℃.1H NMR(500MHz,DMSO)δ12.18(s,1H),9.16(t,J=5.0Hz,1H),8.60(s,1H),8.23(d,J=5.0Hz,2H),7.83(s,1H),7.67(d,J=5.0Hz,1H),7.57–7.49(m,2H),7.25(d,J=10.0Hz,2H),5.33(s,2H),3.59(t,J=5.0Hz,4H),3.25(q,J=5.0Hz,2H),2.33(m,6H),1.66(p,J=6.5Hz,2H).13CNMR(125MHz,DMSO)δ164.00,159.92,157.05,150.83,141.50,137.28,134.73,130.37,129.67,127.96,126.81,126.37,115.87,70.23,66.61,56.78,53.77,38.44,25.55.HRMS(ESI)calcd for C23H27N5O6[M+H]+:470.203410;Found:470.203112.
实施例2-15
采用类似于实施例1所示的合成方法分别合成化合物L2-L15,各原料的摩尔数与实施例1相同。
L-2,白色固体,产率86%,熔点148.9~149.4℃.1H NMR(500MHz,CDCl3)δ10.86(s,1H),9.36(t,J=5.0Hz,1H),8.38(s,1H),7.87(s,1H),7.72(d,J=5.0Hz,1H),7.50(d,J=5.0Hz,1H),7.41(t,J=7.5Hz,1H),7.19(t,J=10.0Hz,1H),6.58–6.51(m,3H),5.03(s,2H),3.81(m,7H),3.49(q,J=5.0Hz,2H),2.51(m,6H),1.76(p,J=5.0Hz,2H).13C NMR(125MHz,CDCl3)δ160.87,159.83,159.52,155.94,150.92,137.85,133.54,130.01,129.97,129.04,127.74,126.78,106.88,106.76,101.42,69.43,66.77,58.18,55.29,53.86,40.24,24.13.HRMS(ESI)calcd for C24H30N4O5[M+H]+:455.228897;Found:455.228586.
L-3,白色固体,产率89%,熔点205.0~205.3℃.1H NMR(500MHz,DMSO)δ12.16(s,1H),9.79(s,1H),9.16(t,J=5.0Hz,1H),8.60(s,1H),7.78(s,1H),7.63(d,J=5.0Hz,1H),7.50(m,4H),6.96(d,J=5.0Hz,2H),5.12(s,2H),3.60(t,J=5.0Hz,4H),3.26(q,J=5.0Hz,2H),2.33(m,6H),2.01(s,3H),1.66(p,J=5.0Hz,2H).13C NMR(125MHz,DMSO)δ168.21,159.92,157.02,154.42,150.96,138.53,134.56,133.31,130.11,129.48,127.49,126.55,120.96,115.28,69.44,66.61,56.78,53.77,38.44,25.57,24.26.HRMS(ESI)calcdfor C25H31N5O5[M+H]+:482.239796;Found:482.239519.
L-4,白色固体,产率87%,熔点147.7~150.1℃.1H NMR(500MHz,CDCl3)δ10.98(s,1H),9.39(t,J=5.0Hz,1H),8.42(s,1H),7.86(s,1H),7.74(d,J=5.0Hz,1H),7.52(d,J=10.0Hz,1H),7.40(t,J=7.5Hz,1H),7.11–6.90(m,4H),5.11(s,2H),3.82(t,J=5.0Hz,4H),3.50(q,J=5.0Hz,2H),2.50(m,6H),1.76(p,J=5.0Hz,2H).13C NMR(125MHz,CDCl3)δ159.54,156.00,153.86,150.95,146.58,137.41,133.62,129.91,129.08,127.77,126.77,124.37,121.73,116.28,115.73,70.76,66.76,58.16,53.85,40.25,24.11.HRMS(ESI)calcd for C23H27FN4O4[M+H]+:443.208910;Found:443.208705.
L-5,黄色固体,产率90%,熔点190.3~190.7℃.1H NMR(500MHz,CDCl3)δ10.82(s,1H),9.33(t,J=5.0Hz,1H),8.37(s,1H),7.86(t,J=5.0Hz,2H),7.72(d,J=10.0Hz,1H),7.57(d,J=5.0Hz,1H),7.51(t,J=7.5Hz,1H),7.42(t,J=7.5Hz,1H),7.11(d,J=10.0Hz,1H),7.05(t,J=7.5Hz,1H),5.21(s,2H),3.82(t,J=5.0Hz,4H),3.50(q,J=5.0Hz,2H),2.51(m,6H),1.77(p,J=5.0Hz,2H).13C NMR(125MHz,CDCl3)δ159.44,156.00,151.71,150.65,140.18,136.44,134.19,133.60,129.51,129.25,127.99,126.18,125.74,120.88,115.09,70.57,66.77,58.18,53.86,40.23,24.12.HRMS(ESI)calcd for C23H27N5O6[M+H]+:470.203410;Found:470.203028.
L-6,白色固体,产率86%,熔点191.6~192.3℃.1H NMR(500MHz,DMSO)δ12.19(s,1H),9.18(t,J=5.0Hz,1H),8.61(s,1H),8.16(dd,J=20.0,10.0Hz,2H),7.84(s,1H),7.68(d,J=5.0Hz,1H),7.58–7.48(m,3H),5.41(s,2H),3.59(t,J=5.0Hz,4H),3.26(q,J=5.0Hz,2H),2.32(m,6H),1.66(p,J=5.0Hz,2H).13C NMR(125MHz,DMSO)δ159.92,157.05,152.58,150.75,140.85,136.77,134.81,130.42,129.72,128.12,126.95,121.85,115.13,112.65,112.47,71.01,66.62,56.80,53.78,38.46,25.56.HRMS(ESI)calcd forC23H26FN5O6[M+H]+:488.193988;Found:488.194321.
L-7,白色固体,产率92%,熔点172.5~173.1℃.1H NMR(500MHz,CDCl3)δ10.61(s,1H),9.33(t,J=7.5Hz,1H),8.29(s,1H),7.88(s,1H),7.73(d,J=10.0Hz,1H),7.55(d,J=5.0Hz,1H),7.42(t,J=7.5Hz,1H),6.97–6.85(m,4H),5.17(s,2H),3.90(s,3H),3.84(t,J=5.0Hz,4H),3.50(q,J=5.0Hz,2H),2.53(m,6H),1.77(p,J=5.0Hz,2H).13C NMR(125MHz,CDCl3)δ159.56,155.99,151.14,149.70,147.96,138.08,133.51,129.87,129.02,127.56,126.69,121.72,120.81,114.32,111.91,70.53,66.75,58.14,55.88,53.84,40.21,24.10.HRMS(ESI)calcd for C24H30N4O5[M+H]+:455.228897;Found:455.228761.
L-8,白色固体,产率91%,熔点157.9~158.7℃.1H NMR(500MHz,DMSO)δ12.18(s,1H),9.18(t,J=5.0Hz,1H),8.59(s,1H),7.78(s,1H),7.62(d,J=5.0Hz,1H),7.49(m,2H),6.96(d,J=10.0Hz,2H),6.86(d,J=10.0Hz,2H),5.09(s,2H),3.69(s,3H),3.60(t,J=5.0Hz,4H),3.25(q,J=10.0Hz,2H),2.32(m,6H),1.66(p,J=6.6Hz,2H).13C NMR(125MHz,DMSO)δ159.93,157.02,154.00,152.68,150.98,138.68,134.57,130.06,129.47,127.47,126.49,116.19,115.06,69.75,66.61,56.80,55.77,53.77,38.45,25.56.HRMS(ESI)calcdfor C24H30N4O5[M+H]+:455.228897;Found:455.229220.
L-9,黄色固体,产率88%,熔点171.3~171.6℃.1H NMR(500MHz,DMSO)δ12.20(s,1H),9.18(t,J=5.0Hz,1H),8.60(s,1H),7.92(dd,J=10.0,5.0Hz,1H),7.83(s,1H),7.77(d,J=5.0Hz,1H),7.66(d,J=10.0Hz,1H),7.53(m,2H),7.29(d,J=10.0Hz,1H),5.32(s,2H),3.90(s,3H),3.60(t,J=5.0Hz,4H),3.25(q,J=10.0Hz,2H),2.33(m,6H),1.66(p,J=6.6Hz,2H).13C NMR(125MHz,DMSO)δ159.93,157.03,153.97,150.79,149.34,141.39,137.29,134.73,130.38,129.61,127.95,126.87,117.95,112.71,107.04,70.49,66.56,56.76,56.51,53.74,38.43,25.52.HRMS(ESI)calcd for C24H29N5O7[M+H]+:500.213975;Found:500.213981.
L-10,白色固体,产率92%,熔点184.3~185.2℃.1H NMR(500MHz,DMSO)δ12.18(s,1H),9.17(t,J=5.0Hz,1H),8.60(s,1H),7.80(s,1H),7.64(d,J=5.0Hz,1H),7.51(m,2H),7.24(d,J=5.0Hz,1H),7.10(dd,J=10.0,5.0Hz,1H),6.95(d,J=10.0Hz,1H),5.17(s,2H),3.77(s,3H),3.60(t,J=5.0Hz,4H),3.25(q,J=5.0Hz,2H),2.33(m,6H),1.66(p,J=6.7Hz,2H).13C NMR(125MHz,DMSO)δ159.93,157.02,150.86,149.08,137.98,134.62,130.28,129.53,127.70,126.75,124.08,116.96,114.15,112.11,70.24,66.62,56.79,56.19,53.78,38.44,25.57.HRMS(ESI)calcd for C24H29BrN4O5[M+H]+:533.139409;Found:533.139191.
L-11,淡黄色固体,产率88%,熔点200.7~201.3℃.1H NMR(500MHz,DMSO)δ12.20(s,1H),9.18(t,J=5.0Hz,1H),8.61(s,1H),8.07(t,J=7.5Hz,1H),7.81(s,1H),7.68(d,J=10.0Hz,1H),7.54(dt,J=15.0,7.5Hz,2H),7.46(dd,J=10.0,5.0Hz,1H),7.02(t,J=7.5Hz,1H),5.39(s,2H),3.60(t,J=5.0Hz,4H),3.25(q,J=5.0Hz,2H),2.33(m,6H),1.66(p,J=6.5Hz,2H).13C NMR(125MHz,DMSO)δ166.44,164.43,159.91,157.03,150.79,136.79,136.56,134.71,129.68,128.37,128.28,127.73,126.74,108.40,103.84,71.13,66.60,56.79,53.77,38.44,25.54.HRMS(ESI)calcd for C23H26FN5O6[M+H]+:488.193988;Found:488.194683.
L-12,白色固体,产率87%,熔点181.3~181.9℃.1H NMR(500MHz,DMSO)δ12.19(s,1H),9.18(t,J=5.0Hz,1H),8.61(s,1H),7.82(s,1H),7.65(d,J=5.0Hz,1H),7.56(d,J=10.0Hz,1H),7.50(t,J=7.5Hz,1H),7.45(dd,J=7.9,1.3Hz,1H),7.30(t,J=7.5Hz,1H),7.24(d,J=10.0Hz,1H),6.97(t,J=7.5Hz,1H),5.27(s,2H),3.59(t,J=5.0Hz,4H),3.26(q,J=5.0Hz,2H),2.33(m,6H),1.66(p,J=6.6Hz,2H).13C NMR(125MHz,DMSO)δ159.94,157.03,153.99,150.90,137.93,134.66,130.48,129.87,129.58,128.75,127.55,126.55,122.27,122.09,114.86,70.03,66.62,56.80,53.78,38.45,25.57.HRMS(ESI)calcd for C23H27ClN4O4[M+H]+:459.179360;Found:459.179221.
L-13,白色固体,产率90%,熔点154.4~155.1℃.1H NMR(500MHz,CDCl3)δ10.66(s,1H),9.37(t,J=5.0Hz,1H),8.33(s,1H),7.89(s,1H),7.74(d,J=5.0Hz,1H),7.50(d,J=5.0Hz,1H),7.44(t,J=7.5Hz,1H),7.22(t,J=7.5Hz,1H),6.97(d,J=5.0Hz,2H),6.86(d,J=10.0Hz,1H),5.06(s,2H),3.84(t,J=5.0Hz,4H),3.50(q,J=5.0Hz,2H),2.53(m,6H),1.77(p,J=6.0Hz,2H).13C NMR(125MHz,CDCl3)δ159.57,159.25,156.07,150.99,137.27,134.87,133.72,130.33,129.89,129.08,127.92,126.65,121.31,115.31,113.22,69.56,66.75,58.08,53.83,40.17,24.18.HRMS(ESI)calcd for C23H27ClN4O4[M+H]+:459.179360;Found:459.179751.
L-14,白色固体,产率91%,熔点184.3~185.2℃.1H NMR(500MHz,DMSO)δ12.18(s,1H),9.17(t,J=7.5Hz,1H),8.59(s,1H),7.79(s,1H),7.64(d,J=10.0Hz,1H),7.53(d,J=5.0Hz,1H),7.48(t,J=7.5Hz,1H),7.34(d,J=10.0Hz,2H),7.06(d,J=10.0Hz,2H),5.16(s,2H),3.59(t,J=5.0Hz,4H),3.25(q,J=6.5Hz,2H),2.33(m,6H),1.66(p,J=6.7Hz,2H).13C NMR(125MHz,DMSO)δ159.92,157.54,157.03,150.89,138.04,134.63,130.18,129.74,129.56,127.68,126.61,124.99,117.06,69.59,66.61,56.77,53.77,38.43,25.56.HRMS(ESI)calcd for C23H27ClN4O4[M+H]+:459.179360;Found:459.179178.
L-15,白色固体,产率93%,熔点161.5~161.8℃.1H NMR(500MHz,DMSO)δ12.19(s,1H),9.18(t,J=5.0Hz,1H),8.59(s,1H),7.79(s,1H),7.64(d,J=5.0Hz,1H),7.53(d,J=10.0Hz,1H),7.48(t,J=7.5Hz,1H),7.13(t,J=7.5Hz,2H),7.04(dd,J=10.0,5.0Hz,2H),5.14(s,2H),3.60(t,J=5.0Hz,4H),3.25(q,J=6.5Hz,2H),2.32(m,6H),1.66(p,J=6.6Hz,2H).13C NMR(125MHz,DMSO)δ159.92,158.02,157.03,156.15,155.01,150.91,138.25,134.60,130.17,129.53,127.62,126.59,116.56,116.50,116.41,116.23,69.81,66.60,56.79,53.77,38.44,25.55.HRMS(ESI)calcd for C23H27FN4O4[M+H]+:443.208910;Found:443.209178.
实施例16
抑制神经氨酸酶活性实验
1.实验仪器和材料
多功能荧光酶标仪,SP-Max 3500FL型,上海闪谱生物科技有限公司;
超净工作台;
Bond A3Pipette手动单道可调试移液器,0.5-10ul,10-100ul,泰坦科技;
96孔板(黑色),灭菌,康宁;
神经氨酸酶抑制剂筛选试剂盒,P0309,碧云天生物科技,包括:神经氨酸酶检测缓冲液,10ml;神经氨酸酶,1ml;神经氨酸酶荧光底物,1ml;Milli-Q水,1.2ml;
阳性对照药,奥司他韦酸,上海贺康生物技术有限公司。
2.实验方法
将阳性对照药及目标化合物用DMSO溶解,初始浓度配制成1000um/l,将其按照倍比稀释成7个浓度梯度,依次为1000μM/l,200μM/l,40μM/l,8μM/l,1.6μM/l,0.32μM/l,0.064μM/l,配制三组;
2.1样品检测准备
a.神经氨酸酶检测缓冲液每孔加入70微升于96孔酶标板中;
b.神经氨酸酶每孔加入10微升;
c.每孔加入10微升配好浓度的待测神经氨酸酶抑制剂样品。
2.2检测
a.将96孔板置于多功能荧光酶标仪中,震荡混匀1分钟;
b.温度设置为37摄氏度,孵育2分钟,使神经氨酸酶与待测样品充分混匀、相互作用;
c.取出96孔板,每孔再加入神经氨酸酶荧光底物10微升;
d.再次置于多功能荧光酶标仪中,震荡混匀1分钟;
e.于37摄氏度孵育60分钟,激发波长设置为322nm,发射波长设置为440nm,孵育结束后开始测试;
f.重复上述操作步骤,平行检测3次。
注:96孔板中的第一个孔作为空白组,不加待测样品,加入10微升DMSO溶液。
计算化合物L1-L15对神经氨酸酶的IC50值。
2.3实验结果
本发明制备得到的化合物和阳性对照奥司他韦酸(OSC)对神经氨酸酶的抑制活性结果如表1所示,可以看出化合物L8、L10、L14及化合物L15具有最好的抑制神经氨酸酶的活性,IC50值分别为0.60μM、7.31μM、6.20μM和5.29μM,明显高于阳性对照OSC(IC50=17.00μM)。另外,在4位上引入相同取代基的活性普遍高于2位上化合物的活性,如化合物L1和L5,化合物L4和L15,化合物L7和L8以及化合物L12和L14,这可能与抑制剂化合物与底物氨基酸的结合模式及形成的氢键数目有关。
表1本发明化合物和阳性对照奥司他韦酸(OSC)对神经氨酸酶的抑制活性
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
3.根据权利要求2所述的酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,步骤(1)所述间苯二甲醛与硼氢化钠的摩尔比为2:1~3:1,所用溶剂为乙醇与四氢呋喃的混合液,反应温度为冰浴。
4.根据权利要求3所述的酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,乙醇与四氢呋喃的体积比为2:3。
5.根据权利要求2所述的酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,步骤(2)所述3-(羟甲基)苯甲醛与三溴化磷的摩尔比为1:1.2,所用溶剂为二氯甲烷,反应温度为冰浴。
6.根据权利要求2所述的酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,步骤(3)所述3-(溴甲基)苯甲醛、取代苯酚、碳酸铯和碘化钾的摩尔比为1:1.1:1.5:0.6,所用溶剂为N,N-二甲基甲酰胺,反应温度为60℃。
7.根据权利要求2所述的酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,步骤(4)所述草酸二乙酯与水合肼的摩尔比为2:1~3:1,所用溶剂为无水乙醇,反应温度为冰浴。
8.根据权利要求2所述的酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,步骤(5)所述式Ⅲ所示结构化合物与草酸单乙酯酰肼摩尔比为1:1.1~1:1.5,反应溶剂为水,反应温度为室温。
9.根据权利要求2所述的酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,步骤(6)所述式Ⅴ所示结构化合物与N-(3-氨丙基)吗啉摩尔比为1:1.05~1:1.1,有机溶剂为甲醇或乙醇,反应温度为70~80℃。
10.如权利要求1所述的酰腙类神经氨酸酶抑制剂在制备能够抑制神经氨酸酶活性的药物中的应用。
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