CN117567421A - 二氢杨梅素衍生物、制备方法及其在制备抑制新冠病毒的药物中的应用 - Google Patents
二氢杨梅素衍生物、制备方法及其在制备抑制新冠病毒的药物中的应用 Download PDFInfo
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- dihydromyricetin
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- benzopyran
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- KJXSIXMJHKAJOD-LSDHHAIUSA-N (+)-dihydromyricetin Chemical class C1([C@@H]2[C@H](C(C3=C(O)C=C(O)C=C3O2)=O)O)=CC(O)=C(O)C(O)=C1 KJXSIXMJHKAJOD-LSDHHAIUSA-N 0.000 title claims abstract description 77
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
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- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
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- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
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Abstract
本发明公开了一种二氢杨梅素衍生物、制备方法及其在制备抑制新冠病毒的药物中的应用，该二氢杨梅素衍生物具有较高的活性，IC50值为0.72μM～2.36μM，能够显著降低SARS‑CoV‑2 3CLpro的蛋白水解活性，从而灭活该关键蛋白酶，阻断冠状病毒复制，可以用于开发具有高活性的SARS‑CoV‑2冠状病毒的抑制剂，用于预防和治疗新型冠状病毒感染引起的疾病。
Description
技术领域
本发明涉及医药技术领域，尤其涉及一种二氢杨梅素衍生物、制备方法及其在制备抑制新冠病毒的药物中的应用。
背景技术
由严重急性呼吸系统综合征冠状病毒2(SARS-CoV-2)引起的全球2019冠状病毒病(COVID-19)大流行继续在全球传播，给公共卫生、经济发展和社会安全带来了巨大威胁。由于接种疫苗，感染率下降，但出现了新的病毒变异，突出了有效抗病毒药物的必要性。在近几年的研究中，科技工作者努力寻找有效治疗靶点，以期发现治疗COVID-19的有效方法。
SARS-CoV-2是一种单链RNA病毒，属于乙型冠状病毒。感染SARS-CoV-2后可发展为严重的、危及生命的急性呼吸窘迫综合征。进入细胞后，病毒RNA基因组让细胞翻译两个大的多蛋白，pp1a和pp1ab，它们被加工成单个的非结构蛋白。Nsp5，也被称为3C样蛋白酶(3CLpro)或主要蛋白酶，是一种半胱氨酸蛋白酶，负责切割多蛋白的11个不同位点，从而转化为成熟的功能蛋白。所以发现3C-like protease(3CLpro)在病毒复制中发挥着不可或缺的作用。已经证实，强烈抑制3CLpro可以成功阻断SARS-CoV-2的复制，并有利于COVID-19的治疗。
二氢杨梅素(Dihydromyricetin,DHM)是显齿蛇葡萄(Ampelopsis grossedentata(Hand.-Mazz.)W.T.Wang)中最主要的黄酮类成分，约占其嫩芽干重30％，具有改变脂质代谢、抗氧化、保肝护肝等活性，还有抗糖尿病、抗动脉粥样硬化、心脏保护、治疗哮喘、抗疲劳、治疗阿尔茨海默病、抗炎、抗肿瘤和抗新冠病毒等作用。虽然最近已经发现了多种SARS-CoV-2 3CLpro抑制剂，但其中大多数仅限于与靶蛋白酶的可逆相互作用。相比之下，共价抑制剂可以通过形成一个稳定的化学键，显著降低SARS-CoV-2 3CLpro的蛋白水解活性，从而灭活该关键蛋白酶，阻断冠状病毒复制。二氢杨梅素以剂量和时间呈依赖性的方式强烈抑制SARS-CoV-2 3CLpro。B环中的连三酚很容易被氧化为醌，而醌又可以与SARS-CoV-2 3CLpro共价结合，从而发挥抗SARS-CoV-2作用。研究发现二氢杨梅素，对SARS-CoV-2 3CLpro的IC50>1.0μM,并未达到很好的抑制冠状病毒活性，障碍了开发二氢杨梅素作为新的抗新冠药物的进程。
综上所述，迫切需要开发具有高活性的SARS-CoV-2冠状病毒的抑制剂，以用于预防和治疗新型冠状病毒感染引起的疾病。
发明内容
为了克服现有技术的不足，本发明目的之一在于提供一种二氢杨梅素衍生物，其具有较高的活性，IC50值在0.72μM～2.36μM的范围内，能够显著降低SARS-CoV-2 3CLpro的蛋白水解活性，从而灭活该关键蛋白酶，阻断冠状病毒复制。
本发明目的之二在于提供一种上述二氢杨梅素衍生物的制备方法，其制备步骤简单，易于推广。
本发明目的之三在于提供一种将上述二氢杨梅素衍生物在制备抑制新冠病毒的药物中的应用，用于预防和治疗新型冠状病毒感染引起的疾病。
本发明目的之一采用如下技术方案实现：
一种二氢杨梅素衍生物，其具有如式(Ⅰ)所示的结构通式：
式中，R各自独立地表示H、或其中，n＝1～10的自然数(如1、2、3、4、5、6、7、8、9、10)，Y＝C1～C4烷基，/>为双键或单键。
进一步地，二氢杨梅素衍生物为2-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)乙酸甲酯、4-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)丁酸甲酯、6-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)己酸甲酯、2-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)乙酸乙酯、4-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)丁酸乙酯、6-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)己酸乙酯、7-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)庚酸乙酯、8-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)辛酸乙酯中的一种或者两种以上。
进一步地，二氢杨梅素衍生物对SARS-CoV-2 3CLpro的IC50为0.72μM～2.36μM。
本发明目的之二采用如下技术方案实现：
一种二氢杨梅素衍生物的制备方法，包括如下步骤：
将二氢杨梅素溶于DMF，充分溶解，加入碳酸钾和溴代羧酸酯类化合物，在60℃反应，TLC检测反应，反应结束后，萃取，水洗涤，合并有机层，旋干溶剂得粗产物；粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，即得。
进一步地，二氢杨梅素与溴代羧酸酯类化合物的摩尔比为(1-3):1。
进一步优选地，二氢杨梅素与溴代羧酸酯类化合物的摩尔比为2:1。
进一步地，溴代羧酸酯类化合物为2-溴乙酸甲酯、4-溴丁酸甲酯、6-溴己酸甲酯、2-溴乙酸乙酯、4-溴丁酸乙酯、6-溴己酸乙酯、7-溴庚酸乙酯、8-溴辛酸乙酯中的一种。
本发明目的之三采用如下技术方案实现：
一种二氢杨梅素衍生物在制备抑制新冠病毒的药物中的应用。
进一步地，所述药物是以二氢杨梅素衍生物为活性成分，加入药学上可接受的辅料或辅助性成分制备而成的制剂。
进一步地，所述药物为口服制剂。
进一步地，所述口服制剂为颗粒剂、溶液剂、丸剂、膏剂或片剂。
进一步地，所述口服制剂的合适剂量应为有效产生治疗作用最低剂量的化合物的量，如0.00001mg/kg-0.1mg/kg。
相比现有技术，本发明的有益效果在于：
本发明的二氢杨梅素衍生物具有较高的活性，IC50为0.72μM～2.36μM，能够显著降低SARS-CoV-2 3CLpro的蛋白水解活性，从而灭活该关键蛋白酶，阻断冠状病毒复制，可以用于开发具有高活性的SARS-CoV-2冠状病毒的抑制剂，用于预防和治疗新型冠状病毒感染引起的疾病。
附图说明
图1为本发明的实施例1的2-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)乙酸甲酯对SARS-CoV-2 3CLpro的抑制效果图；
图2为本发明的实施例2的4-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)丁酸甲酯对SARS-CoV-2 3CLpro的抑制效果图；
图3为本发明的实施例3的6-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)己酸甲酯对SARS-CoV-2 3CLpro的抑制效果图；
图4为本发明的实施例4的2-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)乙酸乙酯对SARS-CoV-2 3CLpro的抑制效果图；
图5为本发明的实施例5的4-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)丁酸乙酯对SARS-CoV-2 3CLpro的抑制效果图；
图6为本发明的实施例6的6-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)己酸乙酯对SARS-CoV-2 3CLpro的抑制效果图；
图7为本发明的实施例7的7-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)庚酸乙酯对SARS-CoV-2 3CLpro的抑制效果图；
图8为本发明的实施例8的8-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)辛酸乙酯对SARS-CoV-2 3CLpro的抑制效果图。
具体实施方式
下面结合具体实施方式，对本发明做进一步描述，需要说明的是，在不相冲突的前提下，以下描述的各实施例之间或各技术特征之间可以任意组合形成新的实施例。
实施例1
合成二氢杨梅素衍生物1，其中，反应化学式为如下式1：
将1.0mmol二氢杨梅素溶于2mL DMF，充分溶解，加入0.5mmol碳酸钾和0.5mmol 2-溴乙酸甲酯，在60℃反应，TLC检测反应，反应结束后，冷却至室温，乙酸乙酯萃取，水洗，合并有机层，旋干，粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，得到2-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)乙酸甲酯60.5mg，得率31％。
化合物的高分辨质谱(ESI)和波谱数据如下：[M+H]+计算值C18H15O10 +391.0665；实际值391.0641；1H NMR(600MHz,DMSO-d6)δ12.51(s,1H),9.49(s,1H),9.23(s,2H),8.88(s,1H),7.27(s,2H),6.67(d,J＝2.2Hz,1H),6.38(d,J＝2.2Hz,1H),4.96(s,2H),3.72(s,3H)；13C NMR(151MHz,DMSO)δ175.90,168.68,163.09,160.44,155.84,147.60,145.76,136.27,136.13,120.67,107.40,104.41,97.84,92.52,64.93,52.06,39.52。
实施例2
合成二氢杨梅素衍生物2，其中，反应化学式为如下式2：
将1.0mmol二氢杨梅素溶于2mL DMF，充分溶解，加入0.5mmol碳酸钾和0.5mmol 4-溴丁酸甲酯，在60℃反应，TLC检测反应，反应结束后，冷却至室温，乙酸乙酯萃取，水洗，合并有机层，旋干，粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，得到4-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)丁酸甲酯60.6mg，得率29％。
化合物的高分辨质谱(ESI)和波谱数据如下：[M+H]+计算值C20H19O10 +419.0978；实际值419.0957；1H NMR(600MHz,DMSO-d6)δ12.49(s,1H),9.45(s,1H),9.21(s,2H),8.87(s,1H),7.27(s,2H),6.64(d,J＝2.1Hz,1H),6.32(d,J＝2.1Hz,1H),4.11(t,J＝6.4Hz,2H),3.61(s,3H),2.48(d,J＝7.3Hz,2H),2.00(p,J＝6.9Hz,2H).13C NMR(151MHz,DMSO)δ175.85,172.94,164.01,160.37,156.00,147.37,145.73,136.17,136.03,120.70,107.32,103.99,97.75,92.16,67.44,51.41,39.52,29.83,23.97。
实施例3
合成二氢杨梅素衍生物3，其中，反应化学式为如下式3：
将1.0mmol二氢杨梅素溶于2mL DMF，充分溶解，加入0.5mmol碳酸钾和0.5mmol 6-溴己酸甲酯，在60℃反应，TLC检测反应，反应结束后，冷却至室温，乙酸乙酯萃取，水洗，合并有机层，旋干，粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，得到6-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)己酸甲酯67.2mg，得率30％。
化合物的高分辨质谱(ESI)和波谱数据如下：[M+H]+计算值C22H23O10 +447.1291；实际值47.1265；1H NMR(600MHz,DMSO-d6)δ12.42(s,1H),9.38(s,1H),9.16(s,2H),8.82(s,1H),7.22(s,2H),6.58(d,J＝2.1Hz,1H),6.25(d,J＝2.1Hz,1H),4.02(t,J＝6.5Hz,2H),3.53(s,3H),2.27(t,J＝7.4Hz,2H),1.68(p,J＝6.7Hz,2H),1.54(p,J＝7.2Hz,2H),1.36(p,J＝7.2,6.7Hz,2H)；13C NMR(151MHz,DMSO)δ175.87,173.38,164.29,160.38,156.06,147.35,145.77,136.19,136.06,120.77,107.36,103.93,97.78,92.16,68.29,51.26,39.52,33.25,28.12,24.99,24.18。
实施例4
合成二氢杨梅素衍生物4，其中，反应化学式为如下式4：
将1.0mmol二氢杨梅素溶于2mL DMF，充分溶解，加入0.5mmol碳酸钾和0.5mmol 2-溴乙酸乙酯，在60℃反应，TLC检测反应，反应结束后，冷却至室温，乙酸乙酯萃取，水洗，合并有机层，旋干，粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，得到2-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)乙酸乙酯65.5mg，得率32％。
化合物的高分辨质谱(ESI)和波谱数据如下：[M+H]+计算值C19H17O10 +405.0822；实际值405.0794；1H NMR(600MHz,DMSO-d6)δ12.50(s,1H),9.43(s,1H),9.13(s,3H),7.25(s,2H),6.65(d,J＝2.2Hz,1H),6.35(d,J＝2.2Hz,1H),4.92(s,2H),4.17(q,J＝7.1Hz,2H),1.20(t,J＝7.1Hz,3H).13C NMR(151MHz,DMSO)δ175.89,168.15,163.10,160.43,155.81,147.57,145.75,136.26,136.12,120.66,107.38,104.37,97.79,92.54,65.00,60.91,39.52,14.07。
实施例5
合成二氢杨梅素衍生物5，其中，反应化学式为如下式5：
将1.0mmol二氢杨梅素溶于2mL DMF，充分溶解，加入0.5mmol碳酸钾和0.5mmol 4-溴丁酸乙酯，在60℃反应，TLC检测反应，反应结束后，冷却至室温，乙酸乙酯萃取，水洗，合并有机层，旋干，粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，得到4-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)丁酸乙酯60.3mg，得率28％。
化合物的高分辨质谱(ESI)和波谱数据如下：[M-H]–计算值C21H19O10 -431.0978；实际值431.0961；1H NMR(600MHz,DMSO-d6)δ12.48(s,1H),9.44(s,1H),9.20(s,2H),8.88(s,1H),7.28(s,2H),6.63(d,J＝2.1Hz,1H),6.32(d,J＝2.1Hz,1H),4.11(t,J＝6.4Hz,2H),4.07(q,J＝7.1Hz,2H),2.46(t,J＝7.3Hz,2H),1.99(p,J＝6.9Hz,2H),1.18(t,J＝7.1Hz,3H)；13C NMR(151MHz,DMSO)δ175.85,172.45,164.02,160.38,156.00,147.37,145.74,136.18,136.04,120.72,107.33,103.99,97.75,92.14,67.46,59.95,39.52,30.04,23.99,14.13。
实施例6
合成二氢杨梅素衍生物6，其中，反应化学式为如下式6：
将1.0mmol二氢杨梅素溶于2mL DMF，充分溶解，加入0.5mmol碳酸钾和0.5mmol 6-溴己酸乙酯，在60℃反应，TLC检测反应，反应结束后，冷却至室温，乙酸乙酯萃取，水洗，合并有机层，旋干，粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，得到6-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)己酸乙酯76.2mg，得率33％。
化合物的高分辨质谱(ESI)和波谱数据如下：[M-H]–计算值C23H23O10 -459.1291；实际值459.1262；1H NMR(600MHz,DMSO-d6)δ12.48(s,1H),9.44(s,1H),9.20(s,2H),8.87(s,1H),6.64(d,J＝2.1Hz,1H),6.31(d,J＝2.1Hz,1H),4.08(t,J＝6.4Hz,2H),4.05(q,J＝7.1Hz,2H),2.31(t,J＝7.4Hz,2H),1.74(p,J＝6.7Hz,2H),1.59(p,J＝7.5Hz,2H),1.42(p,J＝7.2Hz,2H),1.17(t,J＝7.1Hz,3H)；13C NMR(151MHz,DMSO)δ175.84,172.85,164.25,160.35,156.02,147.33,145.73,136.16,136.02,120.72,107.32,103.90,97.76,92.13,68.26,59.70,39.52,33.45,28.08,24.94,24.17,14.15。
实施例7
合成二氢杨梅素衍生物7，其中，反应化学式为如下式7：
将1.0mmol二氢杨梅素溶于2mL DMF，充分溶解，加入0.5mmol碳酸钾和0.5mmol 7-溴庚酸乙酯，在60℃反应，TLC检测反应，反应结束后，冷却至室温，乙酸乙酯萃取，水洗，合并有机层，旋干，粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，得到7-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)庚酸乙酯60.2mg，得率26％。
化合物的高分辨质谱(ESI)和波谱数据如下：[M+H]+计算值C24H27O10 +475.1604；实际值475.1580；1H NMR(600MHz,DMSO-d6)δ12.48(s,1H),9.44(s,1H),9.21(s,2H),8.86(s,1H),7.27(s,2H),6.63(d,J＝2.2Hz,1H),6.32(d,J＝2.2Hz,1H),4.08(t,J＝6.5Hz,2H),4.04(q,J＝7.1Hz,2H),2.29(t,J＝7.3Hz,2H),1.72(p,J＝6.8Hz,2H),1.54(p,J＝7.2Hz,2H),1.40(q,J＝7.6Hz,2H),1.33(q,J＝7.1Hz,2H)),1.17(t,J＝7.1Hz,3H)；13C NMR(151MHz,DMSO)δ175.84,172.91,164.28,160.35,156.03,147.33,145.73,136.16,136.02,120.73,107.33,103.90,97.76,92.12,68.33,59.68,39.52,33.45,28.24,28.11,25.08,24.40,14.15。
实施例8
合成二氢杨梅素衍生物8，其中，反应化学式为如下式8：
将1.0mmol二氢杨梅素溶于2mL DMF，充分溶解，加入0.5mmol碳酸钾和0.5mmol 8-溴辛酸乙酯，在60℃反应，TLC检测反应，反应结束后，冷却至室温，乙酸乙酯萃取，水洗，合并有机层，旋干，粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，得到8-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)辛酸乙酯59.3mg，得率25％。
化合物的高分辨质谱(ESI)和波谱数据如下：[M-H]–计算值C25H27O10 -487.1604；实际值487.1583；1H NMR(600MHz,DMSO-d6)δ12.48(s,1H),9.43(s,1H),9.19(s,2H),8.90(s,1H),7.28(s,2H),6.64(d,J＝2.1Hz,1H),6.32(d,J＝2.1Hz,1H),4.08(t,J＝6.5Hz,2H),4.04(q,J＝7.1Hz,2H),2.27(t,J＝7.4Hz,2H),1.72(p,J＝6.8Hz,2H),1.53(p,J＝7.2Hz,2H),1.40(p,J＝6.9Hz,2H),1.36–1.31(m,2H),1.31-1.26(m,2H),1.16(t,J＝7.1Hz,3H)；13C NMR(151MHz,DMSO)δ175.84,172.91,164.28,160.34,156.02,147.31,145.73,136.15,136.02,120.72,107.32,103.88,97.75,92.10,68.36,59.65,39.52,33.48,28.37,28.33,28.31,25.22,24.40,14.15。
活性测试
二氢杨梅素衍生物对SARS-CoV-2 3CLpro体外抑制测试
1、测试方法
采用荧光共振能量转移法(FRET)检测二氢杨梅素衍生物对SARS-CoV-23CL蛋白酶的抑制活性，在SARS-CoV-2 3CLpro抑制剂筛选试剂盒(增强型)#P0315M(Beyotime，中国)中进行测试。
2、测试步骤
空白对照由91μl检测缓冲液、5μl DMSO和4μl底物组成；100％酶活性对照由90μl检测缓冲液、1μl SARS-CoV-2 3CLpro、5μl DMSO和4μl底物组成。
每孔的放入液体总体积为100μL，每个样品设置3个平行孔。样品孔分别均匀混合90μL检测缓冲液、1μL 3CL蛋白酶和5μL DMSO溶解的不同浓度的二氢杨梅素衍生物，37℃孵育10min。每孔快速加入4uL荧光底物，然后将黑色微孔板放入多功能酶标仪(Tecan Spark,Switzerland)中震荡15秒,37℃孵育5min后检测荧光强度，检测的最大激发波长325nm，最大发射波长393nm。
抑制率(％)＝(RFU 100％酶活性对照-RFU样品)/(RFU100％酶活性对照-RFU空白对照)×100％。(表1)，每个实验重复三遍，求平均值±SD。
3、测试结果，如下表1及图1-图8所示。
表1：二氢杨梅素衍生物对SARS-CoV-2 3CLpro的抑制效果
从上表中可知，二氢杨梅素衍生物对SARS-CoV-2 3CLpro的IC50为0.72μM～2.36μM，具有较高的活性，能够显著降低SARS-CoV-2 3CLpro的蛋白水解活性，从而灭活该关键蛋白酶，阻断冠状病毒复制。
上述实施方式仅为本发明的优选实施方式，不能以此来限定本发明保护的范围，本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。
Claims (10)
1.一种二氢杨梅素衍生物，其特征在于，其具有如式(Ⅰ)所示的结构通式：
式中，R各自独立地表示H、或其中，n＝1～10的自然数，Y＝C1～C4烷基，为双键或单键。
2.根据权利要求1所述的二氢杨梅素衍生物，其特征在于，所述二氢杨梅素衍生物为2-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)乙酸甲酯、4-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)丁酸甲酯、6-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)己酸甲酯、2-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)乙酸乙酯、4-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)丁酸乙酯、6-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)己酸乙酯、7-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)庚酸乙酯、8-((3,5-二羟基-4-氧代-2-(3,4,5-三羟基苯基)-4H-苯并吡喃-7-基)氧基)辛酸乙酯中的一种或者两种以上。
3.根据权利要求1所述的二氢杨梅素衍生物，其特征在于，所述二氢杨梅素衍生物对SARS-CoV-2 3CLpro的IC50为0.72μM～2.36μM。
4.一种如权利要求1-3任一项所述的二氢杨梅素衍生物的制备方法，其特征在于，包括如下步骤：
将二氢杨梅素溶于DMF，充分溶解，加入碳酸钾和溴代羧酸酯类化合物，在60℃反应，TLC检测反应，反应结束后，萃取，水洗涤，合并有机层，旋干溶剂得粗产物；粗产物经反相硅胶柱层析(ODS)纯化，淋洗剂为30％～80％甲醇水溶液，即得。
5.根据权利要求4所述的二氢杨梅素衍生物的制备方法，其特征在于，所述二氢杨梅素与所述溴代羧酸酯类化合物的摩尔比为(1-3):1。
6.根据权利要求5所述的二氢杨梅素衍生物的制备方法，其特征在于，所述二氢杨梅素与所述溴代羧酸酯类化合物的摩尔比为2:1。
7.根据权利要求4所述的二氢杨梅素衍生物的制备方法，其特征在于，所述溴代羧酸酯类化合物为2-溴乙酸甲酯、4-溴丁酸甲酯、6-溴己酸甲酯、2-溴乙酸乙酯、4-溴丁酸乙酯、6-溴己酸乙酯、7-溴庚酸乙酯、8-溴辛酸乙酯中的一种。
8.一种如权利要求1-3任一项所述的二氢杨梅素衍生物在制备抑制新冠病毒的药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述药物是以二氢杨梅素衍生物为活性成分，加入药学上可接受的辅料或辅助性成分制备而成的制剂。
10.根据权利要求9所述的应用，其特征在于，所述药物为口服制剂，所述口服制剂为颗粒剂、溶液剂、丸剂、膏剂或片剂。
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