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
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:
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-;
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。
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-;
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)
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-。
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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