CN112574104A - 一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物 - Google Patents
一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物 Download PDFInfo
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Abstract
本发明公开了一种用于SARS‑CoV‑2靶点Mpro抑制剂的乙酰胺类化合物包括以下化学结构：
本发明用于SARS‑CoV‑2靶点Mpro抑制剂的乙酰胺类化合物具有良好生物活性，也是SARS‑CoV‑2Mpro的新化学骨架，本发明的化合物具有多个可修饰的化学位点，具有良好改进潜力，本发明的乙酰胺类化合物对新型冠状病毒的Mpro抑制效果明显，普遍的IC50都低于100uM，具有用于新型冠状病毒的治疗的巨大潜力。
Description
技术领域
本发明医药领域，具体涉及一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物。
背景技术
新型冠状病毒肺炎(Corona Virus Disease 2019，COVID-19)，简称“新冠肺炎”，是一类急性传染性疾病，由2019新型冠状病毒(2019-nCoV)感染引起。人感染了新型冠状病毒以后，其主要症状包括呼吸道症状、发热、咳嗽、气促和呼吸困难等，在较严重病例中，感染可导致肺炎、严重急性呼吸综合征、肾衰竭，甚至死亡。新的冠状病毒流行，β冠状病毒似乎表现出大约十年的周期性爆发趋势，尚无可控制这种疾病症状或传播的特定药物或疫苗，因此仍在研发针对冠状病毒的治疗药物一项非常紧迫的任务。与大多数冠状病毒科基因组一样，SARS-CoV-2的基因组编码两个大的多聚蛋白pp1a和pp1ab。这些多蛋白被ORF1a/b编码的两种蛋白酶Mpro(3C-like protease或3CLpro)和PLpro(papain-likeprotease)裂解并转化为成熟的nsps。主要蛋白酶对于病毒复制和控制宿主细胞反应至关重要，这使其对病毒的传播非常重要。它被认为是抗病毒药物研发的主要目标。Mpro形成二聚体，每个单体包含两个区域，即N末端催化区域和C末端区域。SARS-CoV和SARS-CoV-2中的Mpro序列具有96％的同一性，并且两种酶之间的最小差异在蛋白质表面。
发明内容
本发明的目的，就是为了解决上述问题而提供了一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，具有良好生物活性，也是SARS-CoV-2Mpro的新化学骨架，本发明的化合物具有多个可修饰的化学位点，具有良好改进潜力。
本发明的目的是这样实现的：
本发明的一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物包括以下化学结构：
其中，R11选自H-，Me-，MeO-，t-Bu-；
R12选自H-，MeO-；
R21选自H-，Me-；
R22选自H-，Me-，MeO-，Cl-；
R23选自H-，Me-，
R24选自H-，Me-，MeO-，CF3-，Ph-,
R3选自H-，Me-，MeO-。
上述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物中R11和R12为MeO-；R21和R23选自H-；R22、R24和R3为Me-。
上述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物中R11为Me-；R12、R21、R22、R23和R3选自H-；R24为MeO-。
上述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物中R11为t-Bu-；R22为Cl-；R12、R21、R23、R24和R3为H-。
上述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物中R11和R3为MeO-；R24、R23为
R12、R21、R22为H-。
上述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物中R11为Me-；R12、R21、R22、R23和R3选自H-；R24为MeO-。
上述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物中R11和R3为MeO-；R12、R22、R24为H-；R21和R23为Me-。
上述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物中R11、R12和R22为MeO-；R21、R23、R24和R3为H-。
上述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物中R11和R12为MeO-；R21和R24为Me-；R22、R23和R3为H-。
上述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物中R11和R12为MeO-；R21、R22、R23和R3选自H-；R24为CF3-。
本发明用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物具有良好生物活性，也是SARS-CoV-2Mpro的新化学骨架，本发明的化合物具有多个可修饰的化学位点，具有良好改进潜力，本发明的乙酰胺类化合物对新型冠状病毒的Mpro抑制效果明显，普遍的IC50都低于100uM，具有用于新型冠状病毒的治疗的巨大潜力。
具体实施方式
下面将结合实施例，对本发明作进一步说明。
本发明公开了一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物包括以下化学结构：
其中，R11选自H-，Me，MeO-，t-Bu-；
R12选自H-，MeO-；
R21选自Me-，H-；
R22为H-，Me-，MeO-，Cl-；
R23选自H-，Me-，
R24选自H-，Me，MeO-，CF3-，Ph-,
R3选自H-，Me-，MeO-。
以下实施例使用的材料和仪器来源如下：
Mpro蛋白(恺佧生物科技(上海)有限公司，Kactus Biosystems Co.Ltd)
底物：Dabcyl-KTSAVLQ/SGFRKME(Edans)(杭州固拓生物科技有限公司Go TOPPepdite Biotech Co.Ltd，Cat No:：730985-86-1)
PBS-EDTA缓冲溶液(LEAGENE Biotechnology，产品货号：CZ0025)
DTT(TCI，CAS RN 3483-12-3)
DMSO(TCI，Cat No:D5293)
阳性对照物Ebselen(TCI，CAS RN:60940-34-3|产品编码:E0946)
384-well Solid Black Flat Bottom(PerkinElmer,ProxiPlate-384F Plus)
酶标仪(公司：BioTek，型号SYNERGY4)
离心机(公司：Beckman，型号：Allegra-15R)
震荡仪(公司：Scilogex，型号：XW-80A)
实施例1-11的反应体系如表1所示(其中mM为10-3mol/L,μM为10-6mol/L)：
表1实施例1-11反应体系(20μL)
| 加样种类 | 加样用量 | 加样浓度 | 实际浓度 | 溶解溶剂 |
| M<sup>pro</sup>蛋白 | 10μL | 0.2μM | 0.1μM | PBS-EDTA(pH7.4)缓冲溶液+4mM DTT |
| 底物 | 5μL | 20μM | 5μM | DMSO |
| Drug | 2μL | ～ | 1/10 | 75％DMSO+25％DMF |
| 缓冲溶液 | 3μL | ～ | ～ | PBS-EDTA(pH7.4) |
实施例1-11的反应步骤如下(其中mM为10-3mol/L,μM为10-6mol/L)：
(1)化合物梯度稀释：将化合物母液(25mM/L)，用DMSO(25％DMF)按照5倍稀释方式，将化合物稀释为25000uM/L、5000uM/L、1000uM/L、200uM/L、40uM/L、8uM/L、1.6uM/L和0.32uM/L；
(2)制备以下实验组和对照组样品
实验组：Mpro蛋白(10μL)+Drug(2μL)+缓冲溶液(3μL)，30℃反应60min；
对照组(0％)：缓冲溶液(15μL)，30℃反应30min；
对照组(100％)：Mpro蛋白(10μL)+DMSO(2μL)+缓冲溶液(3μL)，30℃反应60min；
(3)每孔加入5μL底物,30℃反应45min；
(4)在384孔板放入酶标仪，激发光波长为340nm，检测535nm处荧光光强；
(5)运行酶标仪，连续读数60min,每10min采集一次数据；
(6)读数结束后，选择酶活性达到最高值时的数据作为最终的处理数据；
数据处理方法如下：
Reaction Activity(％)＝(RLUcompound-RLU0％control)/(RLUDMSO-control-RLU0％control)×100％
RLUcompound代表蛋白酶,药品,缓冲液和底物；
RLU0％control表示缓冲液和底物；
RLUDMSO-control蛋白酶，DMSO(25％DMF)、缓冲液和底物。
处理结果如表2所示：
表2实施例1-11的结构及测试结果
其中，生物活性：IC50>100uM为差；50-100uM为中；20-50uM为良；1-20uM为优；<1uM为最优。
上述试验结果表明，本发明的乙酰胺类化合物对新型冠状病毒的Mpro抑制效果明显，普遍的IC50都低于100uM，具有用于新型冠状病毒的治疗的巨大潜力。
以上实施例仅供说明本发明之用，而非对本发明的限制，有关技术领域的技术人员，在不脱离本发明的精神和范围的情况下，还可以作出各种变换或变型，因此所有等同的技术方案也应该属于本发明的范畴，应由各权利要求所限定。
Claims (10)
1.一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，包括以下化学结构：
其中，所述R11选自H-，Me-，MeO-，t-Bu-；
所述R12选自H-，MeO-；
R21选自H-，Me-；
R22选自H-，Me-，MeO-，Cl-；
所述R23选自H-，Me-，
所述R24选自H-，Me，MeO-，CF3-，Ph-,
所述R3选自H-，Me-，MeO-。
2.如权利要求1所述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，所述R11和所述R12为MeO-；所述R21和R23为H-；所述R22、R24和R3为Me-。
3.如权利要求1所述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，所述R11为Me-；所述R12、R21、R22、R23和R3为H-；所述R24为MeO-。
4.如权利要求1所述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，所述R11为t-Bu-；所述R22为Cl-；所述R12、R21、R23、R24和R3为H-。
5.如权利要求1所述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，所述R11和R3为MeO-；所述R24、R23为
所述R12、R21、R22为H-。
6.如权利要求1所述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，所述R11为Me-；所述R12、R21、R22、R23和R3选自H-；所述R24为MeO-。
7.如权利要求1所述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，所述R11和R3为MeO-；所述R12、R22、R24为H-；所述R21和R23为Me-。
8.如权利要求1所述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，所述R11、R12和R22为MeO-；所述R21、R23、R24和R3为H-。
9.如权利要求1所述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，所述R11和R12为MeO-；所述R21和R24为Me-；所述R22、R23和R3为H-。
10.如权利要求1所述的用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物，其特征在于，所述R11和R12为MeO-；所述R21、R22、R23和R3选自H-；所述R24为CF3-。
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| CN111896504A (zh) * | 2020-06-17 | 2020-11-06 | 山东省医学科学院基础医学研究所 | 一种新型冠状病毒Mpro蛋白酶靶点药物筛选试剂盒及其应用 |
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