CN109651189A - 一种苯甲酰腙类神经氨酸酶抑制剂及其制备方法和用途 - Google Patents
一种苯甲酰腙类神经氨酸酶抑制剂及其制备方法和用途 Download PDFInfo
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Abstract
本发明提供了一种苯甲酰腙类神经氨酸酶抑制剂,其特征在于,具有通式I所示的结构:
Description
技术领域
本发明涉及一种苯甲酰腙类神经氨酸酶抑制剂,以神经氨酸酶为作用靶标。
背景技术
H1N1流感病毒是甲型流感病毒中的一种,属于正粘病毒科家族的RNA病毒。目前而言,H1N1是更容易引起大流行的严重威胁人类健康的流感病毒之一。神经氨酸酶也称为唾液酸酶,是流感病毒被摸上的一种糖蛋白,最早是在1933年英国人威尔逊.史密斯发现的,其酶学代码为EC3.3.1.18。它具有水解唾液酸的活性,从而能够切断病毒与宿主细胞的联系,形成新的感染,在病毒生理周期中的作用已被系统研究及广泛的关注。神经氨酸酶抑制剂是目前应用最广泛的抗流感药物之一,已上市的该类药物主要有扎那米韦(Zanamivir)和奥司他韦(Oseltamivir)。奥司他韦,俗称“达菲”,是磷酸奥司他韦在人体内的代谢产物,生物利用率较高,对甲型及乙型流感病毒均有效。但是,达菲价格相对昂贵,在普通人群中很难普及,且对都中流感病毒已产生耐药性,有诸多的局限性,扎那米韦因其口服利用率低、肾消除迅速,只能吸入或者注射给药,给药途径单一,患者顺应性差,因此,迫切需要开发更有效,更持久的抗流感病毒药物。
因此,为了寻找新的神经氨酸酶抑制剂,我们要从新的结构开始探索。最近,很多的文献利用计算机虚拟筛选的方法来寻找具有预期的生物活性的全新结构的抑制剂(Jour.Med.Chem.2012.55,9973-9987.)。本发明同样是运用了虚拟筛选的方法来寻找新的神经氨酸酶的抑制剂。
发明内容
本发明的目的是提供一种以神经氨酸酶中的奥司他韦结合位点为靶标的苯甲酰腙类神经氨酸酶抑制剂及其制备方法和应用。
本发明主要针对苯甲酰腙类神经氨酸酶抑制剂进行设计与合成。首先利用计算机辅助药物设计,通过模型建立、分子对接、分子动力学模拟手段得到新化合物的模拟结果,其中最具参考价值的是运用分子动力学方法得到的化合物与神经氨酸酶复合物的吉布斯结合自由能。就奥司他韦而言,其结合自由能的预测值为-10.62kcal·mol-1(文献:Bio&Medic Chem.Lett,2017,27,5429-5435),以之为参考,本发明设计出结合自由能更小的新化合物,新化合物的结构以及结合自由能数值展示在表1中。结合自由能的结果越小,则说明化合物的活性可能更高。
本发明提供了一种苯甲酰腙类神经氨酸酶抑制剂,其特征在于,其结构为:
其中,R1为H或OH,R为F、Cl、NO2、OCH3、OH以及NHCOCH3中的至少一种。
优选地,所述的苯甲酰腙类神经氨酸酶抑制剂的结构为:
表1本发明中设计的化合物以及其结合能数值
本发明还提供了上述的苯甲酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,包括:将式(II)所示化合物和水合肼加入到反应容器中,加入无水乙醇溶解混合,室温下反应,得到式(III)所示化合物,将式(IV)所示化合物用乙醇溶解得到乙醇溶液,将所得的式(III)所示化合物加入乙醇溶液中,滴加乙酸溶液,室温下反应,得到苯甲酰腙类神经氨酸酶抑制剂。
本发明提供的苯甲酰腙类神经氨酸酶抑制剂的制备方法,其合成路线如下:
优选地,所述的式(II)所示化合物和水合肼的摩尔比为1:5。
优选地,所述的式(III)所示化合物和式(IV)所示化合物的摩尔比为1:1。
优选地,所述的乙酸溶液的浓度为99%,乙酸溶液和式(III)所示化合物的用量比为1:25。
本发明还提供了上述的苯甲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。
与现有技术相比,本发明的合成的化合物具有优良的神经氨酸酶抑制活性。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解,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R-1为例,其结构式如下:
(1)准确称取3,5-二羟基苯甲酸甲酯(式(II)所示化合物)178.2mg(1.060mmol)、水合肼0.5mg(15.625mmol)置于圆底烧瓶中,然后加入5.0mL无水乙醇溶解混合,搅拌均匀,室温下反应16小时,浓缩,过滤,干燥,得到中间体3,5-二羟基苯甲酸酰肼。
(2)准确称取5-氯-2-硝基苯甲醛(式(IV)所示化合物)180.0mg(0.978mmol),用5ml乙醇溶解,准确称取中间体3,5-二羟基苯甲酸酰肼164.0mg(0.978mmol)加入乙醇溶液中,然后滴加1-2滴(共0.05-0.1mL)的浓度为99%的乙酸溶液,搅拌均匀,室温下反应6小时,TLC(乙酸乙酯:石油醚=4:1)监测反应完全。
(3)反应结束后,浓缩,过滤,干燥,得到化合物R-1,产率为87.5%
所得目标化合物:R-1,黄色粉末:1H NMR(500MHz,DMSO-d6):δ12.17(s,1H),δ9.60(s,2H),8.87(s,1H),δ8.13(d,J=13.5Hz,1H),δ8.08(s,1H),δ7.73(d,J=9.0Hz,1H),δ6.78(s,2H),δ6.45(s,1H).13C NMR(125MHz,DMSO-d6):δ158.98,147.02,141.92,138.86,135.25,131.53,130.58,127.47,106.35.HRMS(ESI)calcd for C14H10ClN3O5[M+H]+:336.038175;Found:336.038979.
实施例2-10
采用类似于实施例1的方法分别合成化合物R2-10,其中,式(II)所示化合物和式(IV)所示化合物分别如下表所示,各原料的摩尔数与实施例1相同。
R-2,黄色粉末:1H NMR(500MHz,DMSO-d6):δ11.95(s,1H),δ9.62(s,2H),8.49(s,1H),δ8.45(d,J=6.5Hz,1H),δ8.13(s,1H),δ7.70-7.65(m,1H);δ6.77(s,2H),δ6.45(s,1H),.13C NMR(125MHz,DMSO-d6):δ164.02,158.91,156.61,154.51,144.62,137.76,135.59,134.71,132.38,124.43,119.56,106.31.HRMS(ESI)calcd forC14H10FN3O5[M+H]+:320.067725;Found:320.067734.
R-3,黄色粉末:1H NMR(500MHz,DMSO-d6):δ12.04(s,1H),δ9.53(s,2H),8.57(s,2H),δ8.32-8.33(m,1H),δ7.61(t,J=7.5Hz,1H);δ6.76(s,2H),δ6.45(s,1H),.13C NMR(125MHz,DMSO-d6):δ165.06,163.71,162.73,158.77,144.54,138.28,135.01,127.11,123.76,121.53,117.87,106.30.HRMS(ESI)calcd forC14H10FN3O5[M+H]+:320.067725;Found:320.067727.
R-4,黄色粉末:1H NMR(500MHz,DMSO-d6):δ11.56(s,1H),δ9.58(s,2H),8.90(s,1H),δ8.30(s,1H),δ6.96(s,2H),δ6.73(s,2H),δ6.41(s,1H);δ3.82(s,6H).13C NMR(125MHz,DMSO-d6):δ163.78,158.85,148.59,138.33,136.12,125.14,106.22,105.06,56.475.HRMS(ESI)calcd for C16H16N2O6[M+H]+:333.108113;Found:333.108474.
R-5,白色粉末:1H NMR(500MHz,DMSO-d6):δ11.51(s,1H),δ9.57(s,2H),9.54(s,1H),δ8.31(s,1H),δ7.30(s,1H),δ7.05(d,J=8.0Hz,1H),δ6.84(d,J=8.0Hz,1H);δ6.73(s,2H),6.41(s,1H),δ3.83(s,3H).13C NMR(125MHz,DMSO-d6):δ163.72,158.85,149.39,148.51,136.12,126.29,122.65,115.88,109.36,106.20,56.00.HRMS(ESI)calcd forC15H14N2O5[M+H]+:303.097548;Found:303.098583.
R-6,白色粉末:1H NMR(500MHz,DMSO-d6):δ11.59(s,1H),δ10.13(s,1H),9.57(s,2H),δ8.36(s,1H),δ7.67(dd,J=8.5Hz,2H),δ7.63(dd,J=8.5Hz,2H);δ6.74(s,2H),6.42(s,1H),δ2.07(s,3H).13C NMR(125MHz,DMSO-d6):δ169.08,163.78,158.86,147.83,141.38,136.02,129.48,128.23,119.41,106.23,24.53.HRMS(ESI)calcd for C16H15N3O4[M+H]+:314.113532;Found:314.114390.
R-7,黄色粉末:1H NMR(500MHz,DMSO-d6):1H NMR(500MHz,DMSO-d6):δ11.74(s,1H),δ11.61(s,1H),9.18(s,2H),δ8.85(s,1H),δ8.36(s,1H),δ7.79(d,J=10.0Hz,1H),δ7.20(d,J=10.0Hz,1H),δ6.93(s,2H).13C NMR(125MHz,DMSO-d6):δ163.79,153.65,146.04,145.12,137.51,133.37,126.60,124.18,123.66,120.14,107.67.HRMS(ESI)calcdfor HRMS(ESI)calcd for C14H11N3O7[M+H]+:334.068615;Found:334.066976.
R-8,黄色粉末:1H NMR(500MHz,DMSO-d6):δ12.03(s,1H),δ9.21(s,2H),8.93(s,1H),δ8.84(s,1H),δ8.13(d,J=10.0Hz,1H),δ8.07(s,1H),δ7.73(d,J=10.0Hz,1H),δ6.96(s,2H).13C NMR(125MHz,DMSO-d6):δ163.69,146.84,146.09,140.91,138.85,137.91,131.64,130.64,127.41,127.31 123.07,107.86.HRMS(ESI)calcd for C14H10ClN3O6[M+Na]+:374.015287;Found:374.015034.
R-9,黄色粉末:1H NMR(500MHz,DMSO-d6):δ11.80(s,1H),δ9.20(s,2H),8.90(s,1H),δ8.46(s,1H),δ8.44(d,J=5.0Hz,1H),δ8.12-8.10(m,1H);δ7.67(q,J=10.0Hz,1H),δ6.94(s,2H),.13C NMR(125MHz,DMSO-d6):δ163.91,156.49,154.38,146.05,143.74,137.69,134.66,132.53,124.26,123.40,119.67,107.74.HRMS(ESI)calcd for C14H10FN3O5[M+H]+:336.062882;Found:336.062640.
R-10,黄色粉末:1H NMR(500MHz,DMSO-d6):δ11.80(s,1H),δ9.20(s,2H),8.89(s,1H),δ8.45(s,1H),δ8.44(d,J=5.0Hz,1H),δ8.10(s,1H);δ7.67(t,J=10.0Hz,1H),δ6.94(s,2H),.13C NMR(125MHz,DMSO-d6):δ156.48,154.38,146.05,143.68,137,74,137.68,134.66,132.57,124.24,123.44,119.69,1119.52,107.75.HRMS(ESI)calcd forC14H10FN3O5[M+H]+:336.062882;Found:336.062605.
实施例11,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手动单道可调式移液器,0.5-10μL,10-100μL,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的初始浓度配制成1000μm/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3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.再置于多功能荧光酶标仪中,震荡混匀,1分钟;
e.于37摄氏度中孵育30分钟,激发波长设置为322nm,发射波长设置为450nm,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Milli-Q水。
计算化合物R1-10对神经氨酸酶的IC50值。
2.2实验结果
表2本发明化合物和阳性对照奥司他韦对神经氨酸酶的抑制活性
Claims (7)
1.一种苯甲酰腙类神经氨酸酶抑制剂,其特征在于,其结构为:
其中,R1为H或OH,R为F、Cl、NO2、OCH3、OH以及NHCOCH3中的至少一种。
2.一种苯甲酰腙类神经氨酸酶抑制剂,其特征在于,其结构为:
3.权利要求1或2所述的苯甲酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,包括:将式(II)所示化合物和水合肼加入到反应容器中,加入无水乙醇溶解混合,室温下反应,得到式(III)所示化合物,将式(IV)所示化合物用乙醇溶解得到乙醇溶液,将所得的式(III)所示化合物加入乙醇溶液中,滴加乙酸溶液,室温下反应,得到苯甲酰腙类神经氨酸酶抑制剂。
4.如权利要求3所述的苯甲酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,所述的式(II)所示化合物和水合肼的摩尔比为1:5。
5.如权利要求3所述的苯甲酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,所述的式(III)所示化合物和式(IV)所示化合物的摩尔比为1:1。
6.如权利要求3所述的苯甲酰腙类神经氨酸酶抑制剂的制备方法,其特征在于,所述的乙酸溶液的浓度为99%,乙酸溶液和式(III)所示化合物的用量比为1:25。
7.权利要求1或2所述的苯甲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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CN110183349A (zh) * | 2019-06-11 | 2019-08-30 | 湖南大学 | 乙二酰腙衍生物及其制备方法与应用 |
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CN110183349B (zh) * | 2019-06-11 | 2021-04-30 | 湖南大学 | 乙二酰腙衍生物及其制备方法与应用 |
CN112079744A (zh) * | 2019-06-13 | 2020-12-15 | 湖南大学 | 芳香酰腙衍生物及其作为na抑制剂的应用 |
CN112079744B (zh) * | 2019-06-13 | 2021-07-30 | 湖南大学 | 芳香酰腙衍生物及其作为na抑制剂的应用 |
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