CN116421587A - Application of bis (phenylvinyl) compounds in preparation of coronavirus 3CL protease inhibitor - Google Patents
Application of bis (phenylvinyl) compounds in preparation of coronavirus 3CL protease inhibitor Download PDFInfo
- Publication number
- CN116421587A CN116421587A CN202310311466.2A CN202310311466A CN116421587A CN 116421587 A CN116421587 A CN 116421587A CN 202310311466 A CN202310311466 A CN 202310311466A CN 116421587 A CN116421587 A CN 116421587A
- Authority
- CN
- China
- Prior art keywords
- cov
- coronavirus
- sars
- bis
- curcumin
- 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.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 53
- 241000711573 Coronaviridae Species 0.000 title claims abstract description 35
- -1 phenylvinyl Chemical group 0.000 title claims abstract description 18
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title claims abstract description 8
- 238000002360 preparation method Methods 0.000 title claims description 7
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 title description 4
- 108091005804 Peptidases Proteins 0.000 claims abstract description 23
- 239000004365 Protease Substances 0.000 claims abstract description 23
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 claims abstract description 21
- 239000003814 drug Substances 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 claims abstract description 4
- 208000015181 infectious disease Diseases 0.000 claims abstract description 3
- 241001678559 COVID-19 virus Species 0.000 claims description 16
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical class C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 claims description 12
- 241000315672 SARS coronavirus Species 0.000 claims description 10
- 108010055591 SARS coronavirus 3C-like protease Proteins 0.000 claims description 10
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 claims description 5
- BUWQOPHMYRXMLL-NXZHAISVSA-N (1e,4e)-1,5-bis(3,4-dimethoxyphenyl)penta-1,4-dien-3-one Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)\C=C\C1=CC=C(OC)C(OC)=C1 BUWQOPHMYRXMLL-NXZHAISVSA-N 0.000 claims description 2
- ZMGUKFHHNQMKJI-CIOHCNBKSA-N (1e,4z,6e)-1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(\O)=C\C(=O)\C=C\C1=CC=C(OC)C(OC)=C1 ZMGUKFHHNQMKJI-CIOHCNBKSA-N 0.000 claims description 2
- VMMZAMVBGQWOHT-UTLPMFLDSA-N (1e,6e)-1,7-bis(3,4-dimethoxyphenyl)-4,4-dimethylhepta-1,6-diene-3,5-dione Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)C(C)(C)C(=O)\C=C\C1=CC=C(OC)C(OC)=C1 VMMZAMVBGQWOHT-UTLPMFLDSA-N 0.000 claims description 2
- HMJSBVCDPKODEX-NXZHAISVSA-N (1e,6e)-1,7-bis(3,4-dimethoxyphenyl)hepta-1,6-diene-3,5-dione Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)CC(=O)\C=C\C1=CC=C(OC)C(OC)=C1 HMJSBVCDPKODEX-NXZHAISVSA-N 0.000 claims description 2
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- MUYJSOCNDLUHPJ-XVNBXDOJSA-N dihydrocurcumin Chemical compound C1=C(O)C(OC)=CC(CCC(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 MUYJSOCNDLUHPJ-XVNBXDOJSA-N 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000000499 gel Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 229940002612 prodrug Drugs 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- MUYJSOCNDLUHPJ-UHFFFAOYSA-N bishydrocurcumin Natural products C1=C(O)C(OC)=CC(CCC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 MUYJSOCNDLUHPJ-UHFFFAOYSA-N 0.000 claims 1
- BWHPKBOLJFNCPW-UHFFFAOYSA-N dihydrocurcumin Natural products C1=C(O)C(OC)=CC(CCC(=O)C=C(O)C=CC=2C=C(OC)C(O)=CC=2)=C1 BWHPKBOLJFNCPW-UHFFFAOYSA-N 0.000 claims 1
- 230000006806 disease prevention Effects 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 20
- 230000000694 effects Effects 0.000 abstract description 15
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 102000004169 proteins and genes Human genes 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- 101800000535 3C-like proteinase Proteins 0.000 description 6
- 101800002396 3C-like proteinase nsp5 Proteins 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- NMRUIRRIQNAQEB-UHFFFAOYSA-N demethoxycurcumin Natural products OC(=CC(C=CC1=CC(=C(C=C1)O)OC)=O)C=CC1=CC=C(C=C1)O NMRUIRRIQNAQEB-UHFFFAOYSA-N 0.000 description 6
- FFRFJIZJLZXEJX-YPCIICBESA-N 1-(3,4-Dihydroxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(O)C(O)=CC=2)=C1 FFRFJIZJLZXEJX-YPCIICBESA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 101710172711 Structural protein Proteins 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- HJTVQHVGMGKONQ-LUZURFALSA-N demethoxycurcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=CC(O)=CC=2)=C1 HJTVQHVGMGKONQ-LUZURFALSA-N 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- OJFGQVZAISEIPG-IJIVKGSJSA-N tetrahydroxycurcumin Chemical compound C1=C(O)C(O)=CC=C1\C=C\C(=O)CC(=O)\C=C\C1=CC=C(O)C(O)=C1 OJFGQVZAISEIPG-IJIVKGSJSA-N 0.000 description 3
- UEPVWRDHSPMIAZ-IZTHOABVSA-N (1e,4z,6e)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-(4-hydroxyphenyl)hepta-1,4,6-trien-3-one Chemical compound C1=C(O)C(OC)=CC(\C=C\C(\O)=C\C(=O)\C=C\C=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-IZTHOABVSA-N 0.000 description 2
- 244000163122 Curcuma domestica Species 0.000 description 2
- 102100038284 Cytospin-B Human genes 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108020000999 Viral RNA Proteins 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- OJFGQVZAISEIPG-UHFFFAOYSA-N bisdemethylcurcumin Natural products C1=C(O)C(O)=CC=C1C=CC(=O)CC(=O)C=CC1=CC=C(O)C(O)=C1 OJFGQVZAISEIPG-UHFFFAOYSA-N 0.000 description 2
- 235000003373 curcuma longa Nutrition 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 241001493065 dsRNA viruses Species 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- UEPVWRDHSPMIAZ-UHFFFAOYSA-N p-hydroxycinnamoyl feruloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(O)=CC(=O)C=CC=2C=CC(O)=CC=2)=C1 UEPVWRDHSPMIAZ-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 238000000611 regression analysis Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 101800000504 3C-like protease Proteins 0.000 description 1
- 241000008904 Betacoronavirus Species 0.000 description 1
- 208000001528 Coronaviridae Infections Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 1
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 1
- 101710144121 Non-structural protein 5 Proteins 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 101800001016 Picornain 3C-like protease Proteins 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 101800000596 Probable picornain 3C-like protease Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000002279 cholagogic effect Effects 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides application of bis (phenylvinyl) compounds in preparing coronavirus 3CL protease inhibitors and preparing medicines for preventing and/or treating diseases caused by coronaviruses. The invention discovers that the bis (phenylvinyl) compound has the effect of inhibiting the activity of coronavirus 3CL protease, has low half inhibition concentration and good inhibition effect, can play the role of resisting coronavirus, can be used for preventing and/or treating infection caused by coronavirus and can be used for preparing medicines for preventing and/or treating diseases caused by coronavirus 。
Description
Technical Field
The invention belongs to the field of medicine, in particular to a preparation method of a bis (phenylvinyl) compound for preparing coronavirus 3CL pro Use of inhibitors.
Background
Coronaviruses belong to the genus Coronaviridae (Coronavir) in the phylogenetic classification, and viruses of the same genus are RNA viruses with a envelope and a linear single positive strand genome, which are a large virus family widely existing in nature. Besides the new coronaviruses, MERS-CoV and SARS-CoV are coronaviruses which seriously harm human health in recent years. After the human is infected by coronavirus, common signs include respiratory symptoms, cough, fever, dyspnea and the like, and severe symptoms can cause pneumonia, severe acute respiratory syndrome, renal failure and even death.
Coronaviruses are irregularly shaped, contain about 3 ten thousand bases and 14 open reading frames, and encode replicase, 4 structural proteins (S, E, M, N), 16 non-structural proteins, and 9 helper proteins. Wherein NSP is a non-structural protein of SARS-CoV-2 virus (nonstructural protein), which plays an important role in the replication and transcription cycle of the virus. NSP5 is the main protease of SARS-CoV-2, also known as 3C-Like protease, and has high structural similarity and conservation (FIG. 1), thus 3CL pro Can be used as a homologous target for developing transcription drugs for inhibiting various coronavirus infection replication.
Viral RNA replicates after entering human cells, encoding first into multimeric precursor proteins, and then the multimeric precursor proteins are proteolytically produced into functional proteins, the hydrolysis process being mainly completed by 3CL proteases. The protease cleaves 12 smaller proteins from the multimeric precursor protein, which will be involved in viral RNA replication. Because the 3CL protease is a core protease for proteolysis of a single positive strand RNA virus multimeric precursor, plays a vital role in inhibiting the virus replication process, and has no homologous protein in human body, the 3CL protease becomes an ideal target for antiviral drug development, in addition, the 3CL protease is highly conserved in beta coronaviruses, and the screened 3CL protease inhibitor has a certain degree of broad-spectrum coronavirus resistance. At present, small molecule coronavirus main protease 3CL protease inhibitors with good curative effect and high specificity are not found.
Bis (phenylvinyl) compounds have various biological activities, and the compounds have various pharmacological actions such as anti-tumor, cholagogic, anti-infection, antiviral, antibacterial, antioxidant and the like. However, there is no report about the inhibition of 3CL protease by bis (phenylvinyl) compounds.
Disclosure of Invention
The invention aims to provide a bis (phenylvinyl) compound and application thereof in preparing a coronavirus 3CL protease inhibitor and a medicine for preventing and/or treating diseases caused by coronaviruses.
The invention is realized by the following technical scheme:
the invention provides application of bis (phenylvinyl) compounds in preparation of coronavirus 3CL protease inhibitors.
The invention also provides application of the bis (phenylvinyl) compounds in preparing medicines for preventing and/or treating diseases caused by coronaviruses.
In the technical scheme of the invention, the coronavirus is MERS-CoV, SARS-CoV or SARS-CoV-2.
In the technical scheme of the invention, the diseases caused by the coronavirus are infectious diseases or complications thereof caused by MERS-CoV, SARS-CoV or SARS-CoV-2.
In the technical scheme of the invention, the structural formula of the bis (phenylvinyl) compound is shown as formula I:
R 1 、R 2 、R 3 、R 4 、R 5 and R is 6 Each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, and a methoxy group.
In the technical scheme of the invention, the representative compound of the formula I is selected from the following compounds:
the invention provides a medicine for treating and/or preventing diseases caused by coronaviruses, which comprises one or more of bis (phenylvinyl) compounds per se, and pharmaceutically acceptable acids, bases, salts, esters, solvates, stereoisomers, tautomers and prodrugs thereof.
In the technical scheme of the invention, the dosage form of the medicine comprises: any one of capsule, tablet, granule, gel, sustained release agent, oral liquid, dripping pill, emulsion, injection and nanometer preparation.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers that the bis (phenylvinyl) compound has the effect of inhibiting the activity of 3CL protease of coronavirus, has low half inhibition concentration and good inhibition effect, can play the role of resisting coronavirus, and can be used for preventing and/or treating infection caused by coronavirus and preparing medicines for preventing and/or treating diseases caused by coronavirus.
Drawings
FIG. 1 is the inhibitory effect of demethylated curcumin on SARS-CoV 3CL protease of the invention;
FIG. 2 shows the inhibition of SARS-CoV 3CL protease by demethoxycurcuma longa of the present invention;
FIG. 3 is the inhibition of SARS-CoV 3CL protease by bisdemethylated curcumin of the present invention;
FIG. 4 is the inhibition of SARS-CoV-2 3CL protease by demethylated curcumin according to the invention;
FIG. 5 is the inhibition of SARS-CoV-2 3CL protease by demethoxycurcuma longa of the present invention;
FIG. 6 shows the inhibition of SARS-CoV-2 3CL protease by bisdemethylated curcumin according to the invention.
Detailed Description
For a further understanding of the present invention, the present invention is described below in conjunction with the following examples, which are provided to further illustrate the features and advantages of the present invention and are not intended to limit the claims of the present invention.
The following raw material sources are exemplary
Compound 1 (CAS: 149732-51-4), compound 2 (CAS: 22608-11-3), compound 3 (CAS: 160096-59-3), compound 4 (CAS: 60831-46-1), compound 5 (CAS: 52328-97-9), compound 6 (CAS: 52328-98-0), compound 7 (CAS: 76474-56-1), compound 8 (CAS: 38552-39-5), and compound 9 (CAS: 1217503-60-0) were purchased from Shanghai Michelin Biochemical Co., ltd.
Example 1 Compounds 1-9 in vitro enzyme Activity inhibition assay for SARS-CoV 3CL protease
Inhibition of SARS-CoV 3CL protease activity by 9 compounds (each compound was tested in triplicate) was evaluated using fluorescence resonance energy transfer.
Taking DMSO as a solvent, ageing the compound to obtain a proper amount and preparing a solution with a certain concentration gradient, adding 5 mu L of the prepared solution into a black 96-well plate, adding 91 mu L of Assay Reagent (Assay Buffer: SARS-CoV Mpro/3 CLpro=90:1, purchased from Shanghai Biyun Biotechnology Co., ltd.), uniformly mixing, then carrying out light-proof incubation at 37 ℃ for 10min, and quickly adding 4 mu L of Substrate (100 mu M Dabcyl-KTSAVLQSGFRKME-Edans, purchased from Shanghai Biyun Biotechnology Co., ltd.) into each wellShanghai Biyunshan Biotechnology Co., ltd.) is mixed again, incubated at 37℃in the absence of light, and after the signal is stabilized gradually (after about 5min incubation), fluorescence measurement is carried out in 5-30min using a multifunctional enzyme-labeled instrument (Varioskan Flash, sieimer, feishan technology Co., ltd.) and the percent inhibition of the sample is calculated from the result after measurement, wherein the excitation wavelength is 340nm and the emission wavelength is 490nm. A control group was set, wherein 100% enzyme activity control was Assay Reagent without compound, blank control was Assay Buffer without SARS-CoV Mpro/3CL protease, and the rest of the treatment methods were unchanged. IC's for samples (inventive compounds 1-9) were calculated using nonlinear regression analysis using GraphPad Prism software 50 Values. The experimental results are shown in tables 1-2 and FIGS. 1-3.
TABLE 1 inhibitory Activity of Compounds 1-9 against SARS-CoV 3CL protease
Compounds of formula (I) | IC 50 /μM | Compounds of formula (I) | IC 50 /μM | Compounds of formula (I) | IC 50 / |
1 | 16.84±1.87 | 4 | 10.22+1.12 | 7 | 59.69±2.01 |
2 | 3.80±1.18 | 5 | 53.46±1.91 | 8 | 70.47±0.63 |
3 | 62.81±0.78 | 6 | 44.36±1.24 | 9 | 48.84±1.79 |
TABLE 2 inhibition of SARS-CoV 3CL protease by Compounds 1, 2 and 4 (%)
Experimental results show that compounds 1-9 have inhibitory activity on SARS-CoV 3CL protease, wherein compound 1 (demethylcurcumin), compound 2 (demethoxycurcumin) and compound 4 (bisdemethylcurcumin) have strong inhibitory effects on SARS-CoV 3CL protease (shown in Table 1), and IC 50 The values are below 20 μm (shown in Table 2 and FIGS. 1-3), wherein demethoxycurcumin has the strongest inhibitory activity, and IC 50 The value reaches 3.80+/-1.18 mu M, and can be used for preparing anti-coronavirus medicines.
Example 2 in vitro enzyme Activity inhibition assay for SARS-CoV-2 3CL protease by Compounds 1-9
Inhibition of SARS-CoV-2 3CL protease activity by 9 compounds (each compound was tested in triplicate) was evaluated using fluorescence resonance energy transfer.
Taking DMSO as a solvent, ageing the compound into a proper amount and preparing a solution with a certain concentration gradient, adding 5 mu L of the prepared solution into a black 96-well plate, adding 91 mu L of Assay Reagent (Assay Buffer: SARS-CoV Mpro/3 CLpro=90:1, purchased from Shanghai Biyun Biotechnology Co., ltd.), uniformly mixing, then incubating at 37 ℃ in the absence of light for 10min, quickly adding 4 mu L of Substrate (100 mu M Dabcyl-KTSAVLQSGFRKME-Edans, purchased from Shanghai Biyun Biotechnology Co., ltd.) into each well, uniformly mixing again, continuing to incubate at 37 ℃ until the signal is gradually stabilized (after about 5 min), performing fluorescence measurement by using a multifunctional enzyme-labeling instrument (Simer Feichi technologies Co., varioskan) within 5-30min, and calculating the inhibition percentage of the sample according to the result, wherein the excitation wavelength is 340 nm. A control group was set, wherein 100% enzyme activity control was Assay Reagent without compound, blank control was Assay Buffer without SARS-CoV Mpro/3CL protease, and the rest of the treatment methods were unchanged. IC of samples (Compounds 1-9 of the invention) were calculated by nonlinear regression analysis using GraphPad Prism software 50 Values. The experimental results are shown in tables 3-4 and FIGS. 4-6.
TABLE 3 inhibitory Activity of Compounds 1-9 against SARS-CoV-2 3CL protease
Compounds of formula (I) | IC 50 /μM | Compounds of formula (I) | IC 50 /μM | Compounds of formula (I) | IC 50 / |
1 | 22.88±1.36 | 4 | 13.06±1.09 | 7 | 65.64±2.16 |
2 | 8.19±0.91 | 5 | 57.03±1.47 | 8 | 76.44±0.48 |
3 | 69.67±0.86 | 6 | 50.22±2.81 | 9 | 61.35±0.83 |
TABLE 4 inhibition of SARS-CoV-2 3CL protease by Compounds 1, 2 and 4 (%)
Experimental results show that the compounds 1-9 have inhibition activity on SARS-CoV-2 3CL protease, wherein the compound 1 (demethyl curcumin), the compound 2 (demethyl curcumin) and the compound 4 (bisdemethyl curcumin) have strong inhibition effect on SARS-CoV-2 3CL protease (shown in table 3), the IC50 values are below 30 mu M (shown in table 4 and figures 4-6), the IC50 value of demethyl curcumin reaches 6.75+/-1.99 mu M, and the compounds can be used as anti-coronavirus medicaments for development and research.
In conclusion, the demethylated curcumin, demethylated curcuma longa and bisdemethylated curcuma longa have excellent inhibitory activity on 3CL proteases of two coronaviruses of SARS-CoV and SARS-CoV-2, and can be used as anti-coronavirus drugs for development and research.
The above is only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited by this, and any modification made on the basis of the technical scheme according to the technical idea of the present invention falls within the protection scope of the claims of the present invention.
Claims (10)
1. Use of bis (phenylvinyl) compounds in the preparation of coronavirus 3CL protease inhibitors.
2. The application of bis (phenylvinyl) compounds in preparing medicines for preventing and/or treating diseases caused by coronaviruses.
3. The use according to claim 1 or 2, wherein the bis (phenylvinyl) compound has the structural formula shown in formula i:
R 1 、R 2 、R 3 、R 4 、R 5 and R is 6 Each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, and a methoxy group.
4. Use according to claim 1 or 2, wherein the bis (phenylvinyl) compound is demethylated curcumin, dimethoxy curcumin, bisdemethylated curcumin, tetramethyl curcumin, dimethyl curcumin, dihydro curcumin, 1, 5-bis (3, 4-dimethoxy phenyl) -1, 4-pentadien-3-one or (1 e,4 e) -1- (4-hydroxy-3, 5-dimethoxy phenyl) -5- (3, 4, 5-trimethoxyphenyl) -1, 4-pentadien-3-one.
5. Use according to claim 1 or 2, characterized in that demethylated curcumin, demethylated curcuma or bisdemethylated curcumin.
6. The use according to claim 1 or 2, wherein the coronavirus is MERS-CoV, SARS-CoV or SARS-CoV-2.
7. The use according to claim 1, wherein the coronavirus 3CL protease is SARS-CoV 3CL protease or SARS-CoV-2 3CL protease.
8. The use according to claim 2, wherein the coronavirus-caused disease is MERS-CoV, SARS-CoV or SARS-CoV-2-caused infectious disease or complications thereof.
9. A medicament for treating and/or preventing diseases caused by coronaviruses, which is characterized by comprising one or more of bis (phenylvinyl) compounds, pharmaceutically acceptable acids, bases, salts, esters, solvates, stereoisomers, tautomers and prodrugs thereof.
10. The medicament for the treatment and/or prevention of diseases caused by coronaviruses according to claim 9, wherein the dosage form of the medicament comprises: any one of capsule, tablet, granule, gel, sustained release agent, oral liquid, dripping pill, emulsion, injection and nanometer preparation.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310311466.2A CN116421587A (en) | 2023-03-27 | 2023-03-27 | Application of bis (phenylvinyl) compounds in preparation of coronavirus 3CL protease inhibitor |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310311466.2A CN116421587A (en) | 2023-03-27 | 2023-03-27 | Application of bis (phenylvinyl) compounds in preparation of coronavirus 3CL protease inhibitor |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116421587A true CN116421587A (en) | 2023-07-14 |
Family
ID=87090050
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310311466.2A Pending CN116421587A (en) | 2023-03-27 | 2023-03-27 | Application of bis (phenylvinyl) compounds in preparation of coronavirus 3CL protease inhibitor |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116421587A (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1568945A (en) * | 2004-05-13 | 2005-01-26 | 陈建操 | Application of curcumin to preparation of pharmaceutical for SARS |
CN115770236A (en) * | 2021-09-08 | 2023-03-10 | 四川省中医药转化医学中心 | Application of turmeric in preparing anti-respiratory virus medicine |
-
2023
- 2023-03-27 CN CN202310311466.2A patent/CN116421587A/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1568945A (en) * | 2004-05-13 | 2005-01-26 | 陈建操 | Application of curcumin to preparation of pharmaceutical for SARS |
CN115770236A (en) * | 2021-09-08 | 2023-03-10 | 四川省中医药转化医学中心 | Application of turmeric in preparing anti-respiratory virus medicine |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Yuan et al. | Clofazimine broadly inhibits coronaviruses including SARS-CoV-2 | |
Nguyen et al. | Cannabidiol inhibits SARS-CoV-2 replication and promotes the host innate immune response | |
CN113289018B (en) | Application of old medicines such as auranofin and the like and compositions thereof in resisting single positive strand RNA viruses | |
WO2021170093A1 (en) | Application of disulfiram in coronavirus resistance | |
Cao et al. | Luteoloside acts as 3C protease inhibitor of enterovirus 71 in vitro | |
WO2021169957A1 (en) | Application of n-substituted pyridyl benzisoselenazolone compound | |
CN113679726A (en) | Application of salvia miltiorrhiza extract and quinone compounds in resisting coronavirus | |
Arita et al. | Kakkonto, shosaikoto, Platycodon grandiflorum root, and gypsum (a Japanese original combination drug known as saikatsugekito): Pharmacological review of its activity against viral infections and respiratory inflammatory conditions and a discussion of its applications to COVID‐19 | |
Ren et al. | Natural flavonoid pectolinarigenin alleviated hyperuricemic nephropathy via suppressing tgfβ/SMAD3 and JAK2/STAT3 signaling pathways | |
CN113262224A (en) | Application of nelfinavir in preparing medicine for preventing and treating new coronary pneumonia | |
Salgado-Benvindo et al. | Honokiol Inhibits SARS-CoV-2 Replication in Cell Culture at a Post-Entry Step | |
CN116421587A (en) | Application of bis (phenylvinyl) compounds in preparation of coronavirus 3CL protease inhibitor | |
Zhang et al. | Punicalagin suppresses inflammation in ventilator‐induced lung injury through protease‐activated receptor‐2 inhibition‐induced inhibition of NLR family pyrin domain containing‐3 inflammasome activation | |
CN118403036A (en) | Application of honokiol and analogues thereof in preparation of anti-coronavirus 3CL protease medicines | |
Chen et al. | Honokiol inhibits endoplasmic reticulum stress‑associated lipopolysaccharide-induced inflammation and apoptosis in bovine endometrial epithelial cells | |
WO2021227887A1 (en) | Compound for treating and/or preventing diseases caused by coronavirus and use thereof | |
Tang et al. | BPR3P0128, a non-nucleoside RNA-dependent RNA polymerase inhibitor, inhibits SARS-CoV-2 variants of concern and exerts synergistic antiviral activity in combination with remdesivir | |
CN115707464A (en) | Inhibition of schaftoside on novel coronavirus main protease and medicinal application thereof | |
CN118403049A (en) | Application of notopterol and analogues thereof in preparation of coronavirus 3CL protease inhibitor | |
CN114246847A (en) | Application of chalcone compound in treatment of coronavirus infection | |
CN118634234A (en) | Application of oleuropein and analog thereof in preparation of anti-coronavirus drugs | |
Sugasti et al. | Inhibition of p38 Mitogen-Activated Protein Kinase Impairs Mayaro Virus Replication in Human Dermal Fibroblasts and HeLa Cells | |
CN115813893A (en) | Application of naphthyl skeleton compound in preparing coronavirus 3CL protease inhibitor | |
CN117618402A (en) | Application of gossypol and optical isomer thereof in preparation of medicines for preventing and/or treating diseases caused by coronaviruses | |
CN117618418A (en) | Application of 2-phenyl-4H-chromen-4-one compound in preparation of coronavirus 3CL protease inhibitor |
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 |