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 PDF

Info

Publication number
CN112574104A
CN112574104A CN202011465724.5A CN202011465724A CN112574104A CN 112574104 A CN112574104 A CN 112574104A CN 202011465724 A CN202011465724 A CN 202011465724A CN 112574104 A CN112574104 A CN 112574104A
Authority
CN
China
Prior art keywords
cov
sars
pro
meo
target
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202011465724.5A
Other languages
English (en)
Other versions
CN112574104B (zh
Inventor
张增辉
戚逸飞
郑磊
董素珍
何丽萍
鲍劲霄
陈艳梅
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
East China Normal University
Original Assignee
East China Normal University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by East China Normal University filed Critical East China Normal University
Priority to CN202011465724.5A priority Critical patent/CN112574104B/zh
Publication of CN112574104A publication Critical patent/CN112574104A/zh
Application granted granted Critical
Publication of CN112574104B publication Critical patent/CN112574104B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/86Hydrazides; Thio or imino analogues thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses

Landscapes

  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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:
Figure DDA0002834101710000011
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

一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物
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:
Figure BDA0002834101700000021
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-,
Figure BDA0002834101700000022
R24选自H-,Me-,MeO-,CF3-,Ph-,
Figure BDA0002834101700000023
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
Figure BDA0002834101700000024
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:
Figure BDA0002834101700000031
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-,
Figure BDA0002834101700000041
R24选自H-,Me,MeO-,CF3-,Ph-,
Figure BDA0002834101700000042
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
Figure BDA0002834101700000061
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:
Figure FDA0002834101690000011
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-,
Figure FDA0002834101690000012
所述R24选自H-,Me,MeO-,CF3-,Ph-,
Figure FDA0002834101690000013
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
Figure FDA0002834101690000021
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-。
CN202011465724.5A 2020-12-14 2020-12-14 一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物 Active CN112574104B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202011465724.5A CN112574104B (zh) 2020-12-14 2020-12-14 一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202011465724.5A CN112574104B (zh) 2020-12-14 2020-12-14 一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物

Publications (2)

Publication Number Publication Date
CN112574104A true CN112574104A (zh) 2021-03-30
CN112574104B CN112574104B (zh) 2023-11-03

Family

ID=75132197

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202011465724.5A Active CN112574104B (zh) 2020-12-14 2020-12-14 一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物

Country Status (1)

Country Link
CN (1) CN112574104B (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104592349A (zh) * 2015-02-15 2015-05-06 天津国际生物医药联合研究院 冠状病毒主蛋白酶的小分子抑制剂、制备方法及其应用
CN105837487A (zh) * 2016-03-17 2016-08-10 天津国际生物医药联合研究院 MERS-CoV主蛋白酶小分子抑制剂及其制备方法和用途
CN106187933A (zh) * 2016-06-27 2016-12-07 南开大学 不对称芳香二硫醚类化合物及其在制备抗sars冠状病毒感染药物中的应用
US20190216753A1 (en) * 2016-09-26 2019-07-18 Qingdao Primedicine Pharmaceutical Company, Ltd. N-methyl-d-aspartate receptor allosteric modulators and methods for their use
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
CN112043706A (zh) * 2020-09-27 2020-12-08 山东大学 Trazodone在制备冠状病毒木瓜样蛋白酶PLPro抑制剂药物中的应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104592349A (zh) * 2015-02-15 2015-05-06 天津国际生物医药联合研究院 冠状病毒主蛋白酶的小分子抑制剂、制备方法及其应用
CN105837487A (zh) * 2016-03-17 2016-08-10 天津国际生物医药联合研究院 MERS-CoV主蛋白酶小分子抑制剂及其制备方法和用途
CN106187933A (zh) * 2016-06-27 2016-12-07 南开大学 不对称芳香二硫醚类化合物及其在制备抗sars冠状病毒感染药物中的应用
US20190216753A1 (en) * 2016-09-26 2019-07-18 Qingdao Primedicine Pharmaceutical Company, Ltd. N-methyl-d-aspartate receptor allosteric modulators and methods for their use
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
CN112043706A (zh) * 2020-09-27 2020-12-08 山东大学 Trazodone在制备冠状病毒木瓜样蛋白酶PLPro抑制剂药物中的应用

Also Published As

Publication number Publication date
CN112574104B (zh) 2023-11-03

Similar Documents

Publication Publication Date Title
Ghosh et al. Drug development and medicinal chemistry efforts toward SARS‐coronavirus and Covid‐19 therapeutics
Lee et al. Inhibitor recognition specificity of MERS-CoV papain-like protease may differ from that of SARS-CoV
Thiel et al. Mechanisms and enzymes involved in SARS coronavirus genome expression
Afonso et al. African swine fever virus multigene family 360 and 530 genes affect host interferon response
Fadaka et al. Understanding the epidemiology, pathophysiology, diagnosis and management of SARS-CoV-2
Ortiz-Alcantara et al. Small molecule inhibitors of the SARS-CoV Nsp15 endoribonuclease
Domingo et al. Use of a short fragment of the C-terminal E gene for detection and characterization of two new lineages of dengue virus 1 in India
US20100143888A1 (en) Enzymatic diagnostic test for sars and other viral diseases
US20230293457A1 (en) Application of disulfiram in coronavirus resistance
Amin et al. Protease targeted COVID-19 drug discovery: What we have learned from the past SARS-CoV inhibitors?
Al-Molawi et al. Caspase-mediated cleavage of the feline calicivirus capsid protein
CN112574104A (zh) 一种用于SARS-CoV-2靶点Mpro抑制剂的乙酰胺类化合物
Wang et al. Inhibition of Enterovirus 71 replication by 7-hydroxyflavone and diisopropyl-flavon7-yl Phosphate
Duan et al. Novel genotyping and quantitative analysis of neuraminidase inhibitor resistance-associated mutations in influenza a viruses by single-nucleotide polymorphism analysis
US11464765B2 (en) Use of an N-substituted pyridyl benzisoselazolone compound
Saharan et al. Rapid detection of viruses using loop-mediated isothermal amplification (LAMP): A review
Ghosh et al. SARS-CoV-2 papain-like protease (PLpro) inhibitory and antiviral activity of small molecule derivatives for drug leads
CN114617880B (zh) Iowh-032在制备抗冠状病毒药物中的应用及药物
Webster et al. The active adenovirus protease is the intact L3 23K protein
US20210301319A1 (en) Protease assays and their applications
Grierson et al. The protease of adenovirus serotype 2 requires cysteine residues for both activation and catalysis
Shah et al. Computational approaches for the discovery of cysteine protease inhibitors against malaria and SARS
US20190024195A1 (en) Methods and reagents for detection of chikungunya virus and zika virus
CN114469937B (zh) Pf-05231023在制备抗冠状病毒感染药物中的应用
CN114617861B (zh) Tpi-1及其衍生物在制备抗冠状病毒药物中的应用及药物

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant