CN111848516B - 溴酚-吡唑啉类化合物及其合成方法和应用 - Google Patents
溴酚-吡唑啉类化合物及其合成方法和应用 Download PDFInfo
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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
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Organic Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明涉及一种化合物,尤其是一种溴酚-吡唑啉类化合物及其合成方法和应用。
背景技术
新冠病毒是一种单链RNA正链包膜乙型冠状病毒,在冠状病毒的生活周期中,所有的复制与转录都是由多蛋白复制酶ppla和pplab来执行的。在成为成熟的功能蛋白之前,ppla和ppab必须在宿主的细胞酶作用下,经过水解,才可以发挥作用。这种在病毒的生命循环中重要的多蛋白水解过程,是由病毒编码的蛋白水解酶主蛋白酶(Main Protease,Mpro)来完成的,对于加工从病毒RNA翻译的多蛋白是必不可少的。因此,抑制这种酶的活性将有效阻止病毒复制。
全球各国正在加紧研发新冠病毒肺炎疫苗,部分疫苗已进入临床试验阶段。但是,冠状病毒存在多种血清型,能够产生反复感染,要想完全免疫比较困难。目前,尚未有治疗COVID-19的特效药物上市,临床上广泛使用广谱抗病毒药物或中药来治疗各种症状,但治疗效果不理想。
新冠肺炎在全球范围内的大流行给整个人类的生存环境带来了极大的挑战,严重影响了人类的生活和生产活动,给人类社会的发展造成了不可估量的损失。因此,研发能够抑制主蛋白酶Mpro的活性,干扰冠状病毒的复制,治疗冠状病毒肺炎的靶向型药物迫在眉睫。
发明内容
本发明的目的是提供一种溴酚-吡唑啉类化合物,经研究发现,该溴酚-吡唑啉类化合物具有高效抑制溴酚-吡唑啉类化合物的活性、以及在细胞水平抑制病毒复制的能力,可以作为靶标药物用来治疗新冠肺炎。
为了实现本发明的目的,本发明首先提供的一种技术方案是:一种溴酚-吡唑啉类化合物,其结构通式为:
其中:R1、R2、R3分别选自H、Br中的任一种;
利用溴素对香草醛(1)进行溴化,生成溴代香草醛(2),再经AlCl3、吡啶脱甲基,得到溴代3,4-二羟基苯甲醛(3);化合物3与取代苯乙酮(4)在SOCl2的作用下,生成中间产物查尔酮(5);在加热回流的乙醇溶液中,化合物(5)与肼环合反应,获得目标产物溴酚-吡唑啉(6);
其中:R1、R2、R3分别选自H、Br中的任一种;
本发明进一步提供了上述化合物的用途,由于该化合物能够抑制主蛋白酶Mpro的活性,因此可以制备成抗病毒制剂,用于治疗治疗冠状病毒肺炎。
进一步地,本发明还提供一种治疗冠状病毒肺炎的药物,该药物包含有效剂量的上述者溴酚-吡唑啉类化合物中的一种或两种以上的混合物。
将上述溴酚-吡唑啉类化合物中的一种或两种以上的混合物,与药学上可接受的药物载体混合可制成预防和/或治疗冠状病毒肺炎的片剂、胶囊剂、口服液、颗粒剂、丸剂或注射剂等。
本发明的有益效果是:本发明提供了一种溴酚-吡唑啉化合物及其合成方法,该化合物具有高效的主蛋白酶Mpro抑制活性,能够在细胞中干扰冠状病毒的复制,提示该化合物具有治疗冠状病毒肺炎的功效,在制备治疗冠状病毒肺炎的药物中具有广阔的应用前景。
附图说明
图1为本发明实施例提供的化合物6a-6g对COVID-19主蛋白酶Mpro的抑制活性测定结果:测定不同浓度的不同化合物对Mpro活性的影响,通过非线性回归确定半数最大抑制浓度(IC50)值;
图2为本发明实施例提供的化合物6a-6c在细胞中抑制病毒复制的测定结果:通过qRT-PCR分析COVID-19病毒感染72h后的Vero E6细胞上清液,评价不同浓度的化合物对病毒RNA复制的影响;
图3为本发明实施例提供的化合物6a在Vero E6细胞中抑制COVID-19病毒复制IC50的测定结果。
具体实施方式
为了便于理解本发明,下面结合附图和具体实施例,对本发明进行更详细的说明。附图中给出了本发明的较佳的实施例。但是,本发明可以以许多不同的形式来实现,并不限于本说明书所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
实施例1:3,4-二溴-5-(3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-5基)-1,2-二羟基苯(6a)的合成和表征
(1)合成路径及具体步骤
取15.2g香草醛(0.1mol,1)加入100mL二氯甲烷中,搅拌均匀。冰浴搅拌下,滴加5.6mL溴素(16.0g,0.1mol)的10mL甲醇溶液。室温反应2小时,冷却到0℃。滴加50mL冰水,有沉淀析出,过滤,冰水洗涤,干燥,得21g白色固体5-溴-香草醛(2a,产率92%,mp 160-162℃)。
将21g 5-溴-香草醛(2a,0.09mol)加入100mL乙酸中,常温搅拌下,滴加10.26mL(0.2mol)溴素的15mL乙酸溶液。加入0.1g还原铁粉,回流反应2小时。冷却到室温,沉淀过滤,固体用乙酸乙酯重结晶,得25.2g白色针状晶体5,6-二溴香草醛(2b,产率81.8%,mp230-233℃)。
将15.5g的5,6-二溴香草醛(2b,0.05mol)加入100mL二氯甲烷中,搅拌均匀,小心加入10g(0.075mol)固体AlCl3。在冰浴搅拌下,缓慢滴加23g(0.290mol)吡啶的10mLCH2Cl2溶液。滴完后,回流反应24小时。冷却,加1M的盐酸调pH<3,分离水相,用乙酸乙酯萃取,干燥,蒸干,得淡黄色固体2,3-二溴-4,5-二羟基苯甲醛13.5g(3b,91.5%,mp:206-208℃)。
称取19.9g(0.1mol)4-溴苯甲醛、16.56g(0.12mol)4-乙氧基苯酚、16.56g(0.12mol)K2CO3、1.9g(0.01mol)CuI,加入200mL DMF中,加热140℃,搅拌反应8h。冷却后,加入200mL水,乙酸乙酯萃取,干燥,蒸干,用石油醚:乙酸乙酯=30:1作为流动相,硅胶色谱柱分离,得到白色鳞片状固体13.1g(51.1%),为中间产物4-(4-乙氧基苯氧基)苯乙酮(4a)。
称取2.96g(0.01mol)2,3-二溴-4,5-二羟基苯甲醛(3b)、2.56g(0.01mol)4-(4-乙氧基苯氧基)苯乙酮(4a),加入20mL乙醇中,搅拌下滴加0.5mL SOCl2的5mL乙醇溶液。加毕,常温搅拌过夜,加入10mL水,静置1h。过滤,固体水、乙醇洗涤,干燥。得3.1g(58%)黄色固体(E)-3-(2,3-二溴-4,5-二羟基苯基)-1-(4-(4-乙氧基苯氧基)苯基)丙-2-烯-1-酮(5a)。
称取267mg(0.5mmol)化合物(5a),溶于3mL乙醇中,搅拌下加入3滴水合肼(浓度85%),溶液变为深红色。加热回流2h,冷却,静置过夜。有白色固体析出,超声震荡后,过滤,水、乙醇洗涤固体,得终产物3,4-二溴-5-(3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-5基)苯-1,2-二羟基(6a),128mg(产率46.7%)。
(2)化合物表征
1H NMR(500MHz,DMSO-d6)δ10.05(s,1H),9.49(s,1H),7.57(d,J=8.6Hz,2H),7.48(s,1H),7.06(s,1H),7.01–6.96(m,2H),6.94(d,J=9.0Hz,2H),6.88(dd,J=5.6,3.0Hz,2H),4.97(t,J=10.2Hz,1H),3.99(q,J=6.9Hz,2H),3.48(dd,J=16.6,10.9Hz,1H),2.60(dd,J=16.5,9.5Hz,1H),1.31(t,J=6.9Hz,3H).
13C NMR(126MHz,DMSO-d6)δ158.57(s),155.52(s),149.33(s),148.12(s),145.75(s),144.14(s),134.84(s),128.04(s),127.60(s),121.34(s),117.54(s),116.05(s),113.59(s),113.43(s),113.21(s),109.81(s),64.07(s),63.81(s),63.08(s),15.14(s).
实施例2:5-(2,3-二溴-4,5-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-1-甲醛基吡唑(6b)的合成和表征
(1)合成路径及具体步骤
称取267mg(0.5mmol)化合物(5a),溶于3mL乙醇和1mL甲酸的混合溶液中,搅拌下加入5滴水合肼(浓度85%)。加热回流2h,冷却,静置过夜。有白色固体析出,超声震荡后,过滤,水、乙醇洗涤固体,得终产物5-(2,3-二溴-4,5-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-1-甲醛(6b),176mg(产率61.1%)。
(2)化合物表征
1H NMR(500MHz,DMSO-d6)δ8.94(s,1H),7.75(d,J=8.3Hz,2H),7.04(d,J=8.9Hz,2H),6.97(dd,J=13.6,8.8Hz,4H),6.53(s,1H),5.63(dd,J=11.4,3.8Hz,1H),4.03–4.00(m,2H),3.91(dd,J=17.8,11.8Hz,1H),3.04(dd,J=17.9,4.3Hz,1H),1.33(t,J=6.9Hz,3H).
13C NMR(126MHz,DMSO-d6)δ160.69(s),159.89(s),156.30(s),155.92(s),148.69(s),146.19(s),129.20(s),125.24(s),121.83(s),117.39(s),116.19(s),112.34(s),63.87(s),59.73(s),42.15(s),15.16(s).
实施例3:5-(2,3-二溴-4,5-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-1-乙酰基吡唑(6c)的合成和表征
(1)合成路径及具体步骤
称取267mg(0.5mmol)化合物(5a),溶于4mL乙酸溶液中,搅拌下加入5滴水合肼(浓度85%)。加热回流2h,冷却,静置过夜。有白色固体析出,超声震荡后,过滤,水、乙醇洗涤固体,得终产物5-(2,3-二溴-4,5-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-1-乙酰基吡唑(6c),121mg(产率41.1%)。
(2)化合物表征
1H NMR(500MHz,DMSO-d6)δ9.97(s,1H),9.54(s,1H),7.73(d,J=8.8Hz,2H),7.01(d,J=9.0Hz,2H),6.98–6.91(m,4H),6.46(s,1H),5.61(d,J=7.8Hz,1H),4.05–3.98(m,2H),3.89–3.82(m,1H),2.95(dd,J=17.9,4.0Hz,1H),2.31(s,3H),1.31(t,J=7.0Hz,3H).
13C NMR(126MHz,DMSO-d6)δ167.56(s),160.39(s),155.80(s),154.41(s),148.79(s),145.96(s),144.29(s),133.22(s),129.05(s),125.62(s),121.63(s),117.45(s),116.15(s),113.99(s),112.15(s),63.84(s),22.11(s),15.13(s).
实施例4:2-(5-(2,3-二溴-4,5-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-1-取代)噻唑-4(5H)酮(6d)的合成和表征
(1)合成路径及具体步骤
称取267mg(0.5mmol)化合物(5a),溶于4mL乙酸中,依次加入54.6mg(0.6mmol)氨基硫脲、1滴浓盐酸,加毕升温到120℃,保温搅拌反应4小时。冷却,加入2mL水,静置1小时,过滤,固体水洗,乙醇洗涤,干燥,得中间产物5-(2,3-二溴-4,5-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-1-硫代酰胺。
称取231mg上步的中间产物加入2mL乙酸中,加入37.8mg(0.4mmol)氯乙酸,49.2mg(0.6mmol)乙酸钠。加热100℃,反应4小时。冷却,加1mL水,静置1小时。过滤,固体水洗、乙醇洗涤,干燥,得137mg白色固体2-(5-(2,3-二溴-4,5-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-1-取代)噻唑-4(5H)酮(6d),产率42.3%。
(2)化合物表征
1H NMR(500MHz,DMSO-d6)δ9.95(s,1H),9.56(s,1H),7.80(d,J=8.7Hz,2H),7.00(d,J=8.0Hz,2H),6.66(d,J=8.1Hz,2H),6.55(d,J=8.7Hz,2H),6.48(s,1H),5.56(d,J=7.8Hz,1H),4.00(m,3H),3.88(s,2H),3.32–3.26(m,1H),1.31(t,J=6.9Hz,3H).
13C NMR(126MHz,DMSO-d6)δ187.24(s),177.25(s),161.30(s),160.53(s),155.94(s),148.54(s),145.88(s),145.56(s),131.88(s),129.80(s),124.41(s),121.78(s),117.51(s),117.27(s),116.14(s),113.15(s),63.86(s),43.92(s),15.13(s).
实施例5:5-(3-溴-4,5-二羟基苯基)-3-(4-甲氧基苯基)-4,5-二氢-1H-吡唑-1-硫代酰胺(6e)的合成和表征
(1)合成路径及具体步骤
将11.6g的5-溴香草醛(2a,0.05mol)加入100mL二氯甲烷中,搅拌均匀,小心加入10g(0.075mol)固体AlCl3。在冰浴搅拌下,缓慢滴加23g(0.290mol)吡啶的10mLCH2Cl2溶液。滴完后,回流反应24小时。冷却,加1M的盐酸调pH<3,分离水相,用乙酸乙酯萃取,干燥,蒸干,得淡黄色固体3-溴-4,5-二羟基苯甲醛9.8g(3a,90.2%,mp:227-228℃)。
称取2.16g(0.01mol)3-溴-4,5-二羟基苯甲醛(3a)、1.5g(0.01mol)4-甲氧基苯乙酮(4b),加入20mL乙醇中,搅拌下滴加0.5mL SOCl2的5mL乙醇溶液。加毕,常温搅拌过夜,加入10mL水,静置1h。过滤,固体水、乙醇洗涤,干燥,得2.0g黄色固体,为中间产物查尔酮(5b),产率57.5%。
称取175mg(0.5mmol)化合物(5b),溶于4mL乙酸中,依次加入54.6mg(0.6mmol)氨基硫脲、1滴浓盐酸,加毕升温到120℃,保温搅拌反应4小时。冷却,加入2mL水,静置1小时,过滤,固体水洗,乙醇洗涤,干燥,得130mg白色固体5-(3-溴-4,5-二羟基苯基)-3-(4-甲氧基苯基)-4,5-二氢-1H-吡唑-1-硫代酰胺(6e),产率61.6%。
(2)化合物表征
1H NMR(500MHz,DMSO-d6)δ9.95(s,1H),9.41(s,1H),8.01(s,1H),7.85(s,1H),7.75(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),6.35(s,1H),5.94(d,J=11.1Hz,1H),3.85–3.80(m,1H),3.73(s,3H),2.93(dd,J=17.9,3.0Hz,1H).
13C NMR(126MHz,DMSO-d6)δ175.97(s),161.70(s),155.51(s),145.89(s),144.14(s),134.18(s),129.42(s),123.72(s),114.60(s),111.91(s),64.20(s),55.86(s),41.99(s).
实施例6:5-(3,4-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-1-硫代酰胺(6f)的合成和表征
(1)合成路径及具体步骤
称取1.38g(0.01mol)4,5-二羟基苯甲醛、2.56g(0.01mol)4-(4-乙氧基苯氧基)苯乙酮(4a),加入20mL乙醇中,搅拌下滴加5mL浓度为10%SOCl2的乙醇溶液,加毕,常温搅拌过夜,加入10mL水,静置1h。过滤,固体水、乙醇洗涤,干燥,得2.6g黄色固体,为中间产物查尔酮(5c),产率69.1%。
称取168mg(0.5mmol)化合物(5c),溶于4mL乙酸中,依次加入54.6mg(0.6mmol)氨基硫脲、1滴浓盐酸,加毕升温到120℃,保温搅拌反应4小时。冷却,加入2mL水,静置1小时,过滤,固体水洗,乙醇洗涤,干燥,得140mg白色固体5-(3,4-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-1-硫代酰胺(6f),产率31.2%。
(2)化合物表征
1H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.73(s,1H),7.89(s,1H),7.83(d,J=8.8Hz,2H),7.74(s,1H),7.06–6.98(m,2H),6.94(dd,J=11.0,9.0Hz,4H),6.61(d,J=8.1Hz,1H),6.47(d,J=2.0Hz,1H),6.39(dd,J=8.1,2.0Hz,1H),5.70(dd,J=11.1,2.8Hz,1H),4.00(q,J=6.9Hz,2H),3.76(dd,J=17.9,11.2Hz,1H),3.02(dd,J=17.8,2.9Hz,1H),1.31(t,J=7.0Hz,3H).
13C NMR(126MHz,DMSO-d6)δ176.11(s),160.51(s),155.79(s),155.04(s),148.78(s),145.55(s),144.70(s),134.49(s),129.47(s),125.69(s),121.64(s),117.36(s),116.80(s),116.12(s),115.86(s),112.97(s),63.83(s),62.89(s),43.01(s),40.45(s),15.13(s)..
实施例7:5-(4,5-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-1-甲酸甲酯(6g)的合成和表征
(1)合成路径及具体步骤
称取188mg(0.5mmol)化合物(5c),溶于4mL乙醇中,依次加入104mg(1.0mmol)肼甲酸乙酯、1滴浓盐酸,加毕回流反应4小时。冷却,静置过夜,析出白色固体。过滤,固体水洗,乙醇洗涤,干燥,得5-(4,5-二羟基苯基)-3-(4-(4-乙氧基苯氧基)苯基)-4,5-二氢-1H-吡唑-1-甲酸甲酯(6g),162mg,产率62.3%。
(2)化合物表征
1H NMR(500MHz,DMSO-d6)δ8.92(s,1H),8.80(s,1H),7.70(d,J=8.7Hz,2H),7.02(d,J=9.0Hz,2H),6.94(dd,J=11.4,9.0Hz,4H),6.64(d,J=8.1Hz,1H),6.53(d,J=1.6Hz,1H),6.44(dd,J=8.1,1.6Hz,1H),5.22(dd,J=11.6,4.1Hz,1H),4.00(q,J=6.9Hz,2H),3.72(dd,J=17.8,11.7Hz,1H),3.60(s,3H),3.02(dd,J=17.8,4.1Hz,1H),1.31(t,J=6.9Hz,3H).
13C NMR(126MHz,DMSO-d6)δ160.18(s),155.79(s),153.66(s),152.90(s),148.80(s),145.81(s),145.09(s),134.14(s),128.90(s),125.96(s),121.70(s),117.38(s),116.88(s),116.05(s),112.88(s),63.83(s),60.97(s),52.84(s),15.13(s).
实施例8:溴酚-吡唑啉类化合物对新型冠状病毒靶点Mpro蛋白酶抑制活性测定
(1)实验材料:
含有Mpro蛋白酶基因的重组质粒由武汉普健生物公司合成,Ni Beads购自SmartLifescience公司,多功能酶标仪为美国Molecular Device公司的SpectraMax i3,96孔黑板购自美国corning,其他常用试剂购自Sigma。
(2)实验方法:
a.重组Mpro蛋白酶的表达与纯化。
将包含SARS-CoV-2来源的Mpro重组质粒(pET28a(+))转化入大肠杆菌菌株BL21(codonplus),再将菌株在LB或2x YT培养基中生长至OD600为0.6-0.8,然后加入0.1mM异丙基-1-硫代-b-D-半乳糖苷(IPTG)在15℃继续生长24小时进行低温诱导表达,1L培养基可收获约8-15克湿菌。按1:5的比例加入裂解液将菌重悬,经超声、高压破碎等方式破碎菌体后,离心取上清经Ni Beads按生产商的说明进行亲和层析纯化,用SDS-PAGE的方法对蛋白纯度进行验证。
b.溴酚-吡唑啉类化合物的Mpro蛋白酶抑制活性测试。
向含1mg底物的管内加入660μL DMSO使底物终浓度为1mM,室温避光震荡10分钟后,分装20μL/每管备用,剩余冻存于-20℃。取20μL浓度为1mM底物,加入2mL缓冲液(20mMSodium Phosphate Buffer,pH 6.8)稀释,并置于摇床上,室温避光震摇5分钟。从冰箱取出Mpro并置于室温解冻5分钟后,用缓冲液稀释至97nM,向96孔板中每孔加入50μL稀释好的Mpro及1μL稀释好不同浓度的实施例1-6的化合物,使用多孔道移液器吸取50μL稀释好的底物,快速加入96孔板中反应,并立即使用多功能酶标仪测量,激发波长320nm,发射波长405nm,每45秒读数1次,连续记录10分钟,取线性区间内斜率作为V0并计算抑制剂IC50。
(3)实验结果:
a.高纯度Mpro蛋白酶的表达纯化
经Ni Beads亲和层析获得了大量的Mpro蛋白酶,经SDS-PAGE鉴定其纯度达95%以上,可用于后续的酶活性测试实验。
b.溴酚-吡唑啉类化合物的Mpro蛋白酶抑制活性测试结果
如图1所示,溴酚-吡唑啉类化合物(6a-6g)对Mpro蛋白酶表现出显著的抑制作用,具有良好的抗治疗COVID-19等冠状病毒肺炎治疗的应用前景。
实施例9:溴酚-吡唑啉类化合物干扰细胞中的病毒复制
为了进一步证实体外的酶促抑制结果,本发明评估了溴酚-吡唑啉类化合物是否可以在临床分离株COVID-19病毒感染的Vero E6细胞中阻止COVID-19病毒复制。
具体操作:将预先播种的Vero E6细胞(5×104细胞/孔)用不同浓度的待测溴酚-吡唑啉类化合物预处理1h,然后添加COVID-19病毒(MOI为0.05)使其感染2h。然后,除去病毒-化合物的混合物,并用新鲜的含有溴酚-吡唑啉类化合物的培养基进一步培养细胞。24小时后,收集细胞上清液,并对上清液中的vRNA进行qRT-PCR分析。
实验结果:如图2所示,在COVID-19病毒感染的Vero细胞中,30μM和10μM浓度的化合物6a、6b、6c,都显示出较强的抗病毒作用。其中,化合物6a抑制病毒复制的能力最强,EC50=4.45uM,见图3。
实施例10:利用溴酚-吡唑啉类化合物制备抗病毒制剂或治疗冠状病毒肺炎的药物
采用上述实施例1-7制备的溴酚-吡唑啉类化合物,可以制备成抑制病毒复制的抗病毒制剂,或者作为活性成分与药学上可接受的载体组合制备成药物组合物。
上述的抗病毒制剂或药物组合物中,活性成分可以是单一一种化合物,也可以是上述化合物中任意两种以上的混合物。可根据需要制成任意剂型。
Claims (5)
2.一种如权利要求1所述的溴酚-吡唑啉类化合物的合成方法,其特征在于,合成路径为:
利用溴素对香草醛(1)进行溴化,生成溴代香草醛(2),再经AlCl3、吡啶脱甲基,得到溴代3,4-二羟基苯甲醛(3);化合物(3)与取代苯乙酮(4)在SOCl2的作用下,生成中间产物查尔酮(5);在加热回流的乙醇溶液中,化合物(5)与肼环合反应,获得目标产物溴酚-吡唑啉(6);
其中:R1、R2、R3分别选自H、Br中的任一种;
3.一种如权利要求1所述的溴酚-吡唑啉类化合物的用途,其特征在于,所述化合物用于制备抑制冠状病毒复制的产品。
4.根据权利要求3所述的溴酚-吡唑啉类化合物的用途,其特征在于,所述的化合物用于制备治疗冠状病毒肺炎的药物。
5.一种用于治疗冠状病毒肺炎的药物,其特征在于,包含有效剂量的如权利要求1所述的溴酚-吡唑啉类化合物中的一种或两种以上的混合物。
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