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
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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:
wherein X is
One of the following;
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:
wherein X is
One of the following;
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.
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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 |
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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 |
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