CN112675172B - Application of diketopiperazine compound in preparation of anti-coronavirus drugs - Google Patents
Application of diketopiperazine compound in preparation of anti-coronavirus drugs Download PDFInfo
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Abstract
The invention discloses an application of diketopiperazine compounds in preparing anti-coronavirus medicines. Specifically, the invention relates to a compound shown as a formula I, or a pharmaceutically acceptable salt thereof. The invention discovers that the compound can effectively inhibit the replication of alpha coronavirus HCoV-229E and IC of the compound on HCoV-229E in vitro501.23 μ g/ml, shows that the compound has anti-coronavirus activity, and can be used for treating infection caused by coronavirus.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a diketopiperazine compound, a pharmaceutically acceptable salt thereof and application of a composition containing the compound or the pharmaceutically acceptable salt thereof in preparation of an anti-coronavirus medicine.
Background
Coronaviruses (CoV), which are widely present in nature, are RNA viruses with enveloped, genomically linear single-stranded positive strands, which only infect vertebrates, are associated with a variety of diseases in humans and animals and can cause diseases in the respiratory, digestive and nervous systems of humans and animals.
The previously known human-infecting coronavirus are 6 kinds, namely human coronavirus HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1, and severe acute respiratory syndrome coronavirus SARS-CoV and middle east respiratory syndrome coronavirus MERS-CoV, and SARS-CoV-2 is the currently known 7 th coronavirus which can infect human. Of the above coronaviruses, the first 4 coronaviruses cause mild common cold, while the last 3 coronaviruses cause severe symptoms and are highly contagious, even causing fatal viral pneumonia. The search for drugs that are effective against coronaviruses is at hand.
Polythiodiketopiperazines (ETPs) are a class of secondary metabolites produced primarily by fungi and are structurally characterized by a sulfur-bridge containing diketopiperazine core in the molecule. The compound has wide biological activity, such as cell proliferation inhibition, antiviral activity, immunosuppressive activity and the like, and a sulfur bridge structure can be a key group for the compound to exert the biological activity. Epicocin C is a new-structure polythiodiketopiperazine compound firstly found in a fermentation product of Cordyceps sinensis colonization fungus Epicoccum nigrum in the subject group [ see Journal of Natural Products 2007,70,1522-1525], and the structural formula is shown in formula I. Subsequently, Yu et al also reported the isolation of epicoccin C from Epicoccum nigrum [ see, Journal of Natural Products 2010,73,1240-1249], Zhu et al reported the isolation of epicoccin C from Phoma sp. OUCMDZ-1847 [ see, Journal of Natural Products 2014,77,132-137], Wang et al reported the isolation of epicoccin C from Epicoccum nigrum SD-388 [ see, chemistry & Biodiversity 2020,17, e2000320 ]. At present, the report of the compound as a medicine for preparing anti-coronavirus is not available.
Disclosure of Invention
The invention aims to provide a new application of diketopiperazine compounds in preparing anti-coronavirus medicines. Pharmacodynamic tests prove that the compound can effectively inhibit the replication of the alpha group coronavirus HCoV-229E in an in vitro cell model and has the potential for preparing anti-coronavirus medicaments.
The structural formula of the diketopiperazine compound is shown as a formula I.
The compound shown in the formula I or the pharmaceutically acceptable salt thereof provided by the invention has the following application (a) and/or (b) and/or (c):
(a) the application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preparing products for treating diseases caused by coronavirus or coronavirus infection;
(b) the application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preparing products for preventing diseases caused by coronavirus or coronavirus infection;
(c) the application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preparing a coronavirus inhibitor.
The product may be a medicament or a pharmaceutical formulation.
The coronavirus inhibitor can inhibit replication of coronavirus.
The coronavirus can be alpha coronavirus and/or beta coronavirus, and is at least one of human coronavirus 2019-nCoV, HCoV-229E, HCoV-OC43, SARS-CoV and MERS-CoV.
In the above applications, the phrase "a pharmaceutically acceptable salt of a compound of formula I" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of the compounds of formula I are well known in the art and include, but are not limited to, sodium, potassium, calcium, hydrochloride, nitrate, sulfate, bisulfate, phosphate, hydrogenphosphate, acetate, oxalate, lactate, citrate, tartrate, maleate, and the like.
In the above applications, the compound represented by formula I or a pharmaceutically acceptable salt thereof may be used as one of the active ingredients or as the only active ingredient in the preparation of a medicament or pharmaceutical preparation.
In the above applications, the compound represented by formula I or a pharmaceutically acceptable salt thereof may be used as one of the active ingredients or as the only active ingredient in the preparation of a medicament or pharmaceutical preparation.
In the above application, carrier material can also be added during preparation of the medicine.
Carrier materials include, but are not limited to, water-soluble carrier materials (e.g., polyethylene glycol, polyvinylpyrrolidone, organic acids, etc.), sparingly soluble carrier materials (e.g., ethyl cellulose, cholesterol stearate, etc.), enteric carrier materials (e.g., cellulose acetate phthalate, and carboxymethylcellulose, etc.). The materials can be prepared into various dosage forms, including but not limited to tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, liposomes, transdermal agents, buccal tablets, suppositories, freeze-dried powder injections and the like. Can be common preparation, sustained release preparation, controlled release preparation and various particle drug delivery systems. In order to form the unit dosage form into a tablet, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate and the like; wetting agents and binders such as water, glycerin, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrating agents such as dried starch, alginate, agar powder, brown algae starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitol fatty acid ester, sodium dodecylsulfate, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, glyceryl tristearate, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate and the like; lubricants, for example talc, silica, corn starch, stearates, boric acid, liquid paraffin, polyethylene glycol and the like. The tablets may further be formulated as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. In order to prepare a unit administration form into a pill, various carriers well known in the art can be widely used. Examples of the carrier are, for example, diluents and absorbents such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaolin, talc powder and the like; binders such as acacia, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste or batter, etc.; disintegrating agents, such as agar powder, dried starch, alginate, sodium dodecylsulfate, methylcellulose, ethylcellulose, etc. In order to prepare the unit dosage form into suppositories, various carriers known in the art can be widely used. As examples of the carrier, there may be mentioned, for example, polyethylene glycol, lecithin, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glyceride esters and the like. In order to prepare the unit dosage form into preparations for injection such as solution, emulsion, lyophilized powder for injection and suspension, all diluents commonly used in the art, for example, water, ethanol, polyethylene glycol, 1, 3-propanediol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol fatty acid ester, etc. can be used. In addition, for the preparation of isotonic injection, sodium chloride, glucose or glycerol may be added in an appropriate amount to the preparation for injection, and conventional cosolvents, buffers, pH adjusters and the like may also be added. In addition, colorants, preservatives, flavors, flavorings, sweeteners or other materials may also be added to the pharmaceutical preparation, if desired. The preparation can be used for injection administration, including subcutaneous injection, intravenous injection, intramuscular injection, intracavity injection and the like; luminal, e.g., rectal and vaginal; administration to the respiratory tract, e.g., nasally; administration to the mucosa.
The invention also provides a medicine or a medicine composition, and the active ingredient of the medicine or the medicine composition is the compound shown in the formula I or the pharmaceutically acceptable salt thereof.
The medicament or the medicament composition has at least one of the following effects:
1) treating a disease caused by a coronavirus or a coronavirus infection;
2) preventing disease caused by coronavirus or coronavirus infection;
3) inhibiting coronavirus.
The above-mentioned drugs or pharmaceutical compositions can be prepared into dosage forms such as solutions, tablets, capsules or injections according to conventional methods known to those skilled in the art.
When the compound shown in the formula I or the pharmaceutically acceptable salt thereof provided by the invention is used for preventing and/or treating infection caused by coronary virus, an effective amount of the compound shown in the formula I or the pharmaceutically acceptable salt thereof is administered to a subject organism.
The dosage and method of administration of the compounds of the present invention will depend upon a variety of factors including the age, weight, sex, physical condition, nutritional status, the strength of the activity of the compound, time of administration, metabolic rate, the severity of the condition, and the subjective judgment of the treating physician. The preferable dosage is 0.01-100 mg/kg body weight/day, and the optimal dosage is 0.1-10 mg/kg body weight/day.
In the present invention, the term "effective amount" refers to a dose that achieves treatment, prevention, alleviation and/or alleviation of the disease or disorder described herein in a subject.
In the present invention, the term "subject" may refer to a patient or other animal, particularly a mammal, such as a human, dog, monkey, cow, horse, etc., that receives a composition of the invention to treat, prevent, alleviate and/or alleviate a disease or disorder described herein.
In the present invention, the disease caused by coronavirus may be respiratory infection and/or digestive infection.
The respiratory system infection is respiratory tract infection and/or lung infection; the respiratory tract infection can be nasopharyngitis, rhinitis, pharyngolaryngitis, tracheitis and/or bronchitis; the pulmonary infection may be pneumonia; the digestive system infection may be diarrhea.
In the present invention, the diseases caused by coronavirus generally include viral pneumonia, severe acute respiratory syndrome, and the like.
In the present invention, the coronavirus infection usually causes viral pneumonia, severe acute respiratory syndrome and other diseases.
The invention selects the alpha group coronavirus HCoV-229E, discusses the application possibility of the diketopiperazine compound shown in the formula I in the preparation of anti-coronavirus medicines, and finds that the compound can remarkably inhibit the replication of the alpha group coronavirus HCoV-229E in vitro through experimental research and has the potential for preparing the anti-coronavirus medicines.
Drawings
FIG. 1 shows NMR of a compound of formula I1H-NMR spectrum.
FIG. 2 shows NMR of a compound of formula I13C-NMR spectrum.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are commercially available, and are not known to manufacturers.
The coronavirus HCoV-229E used in the examples was Human coronavirus 229E strain (Human coronavirus 229E (Human coronavirus 229E: (Able-Able)
VR-740TM) ); the literature: hamre D, Procknow JJ.A new virus isolated from the human respiratory track, Proc.Soc.Exp.biol.Med.121:190-193,1966.PubMed: 4285768.
Example 1 test of Effect of Compounds of formula I on anti-HCoV-229E Activity in vitro
1. Purpose of experiment
To investigate the efficacy of the compounds of formula I against coronavirus in vitro, the median Inhibitory Concentration (IC) of the compounds against coronavirus (HCoV-229E) in Huh7 cells was determined using a cytopathic effect (CPE) experiment50) And SI. Ribavirin (RBV) was used as a positive control drug.
The experiment was conducted in the national academy of medical sciences pharmaceutical and Biotechnology research institute, BSL-2 biosafety laboratory (laboratory building 329 room).
2. Material
And (3) testing the sample:
the compound of formula I, which is prepared and isolated for the laboratory (see literature: Journal of Natural Products 2007,70,1522-1525) is an amorphous powder with a purity of more than 98%; the structure identification map is shown in figures 1 and 2;
a positive control medicament ribavirin injection (RBV) is purchased from limited department of pharmaceutical industry of Hubei Tian of Tianjin Jinyao group, has the specification of 100mg/ml, is diluted to the required concentration when in use, and is stored in a refrigerator at 4 ℃.
Cells
The passage human hepatoma cell Huh7 cell is subcultured and stored in the institute of pharmaceutical and biotechnology of Chinese academy of medical sciences, and contains 10% fetal bovine serum (inactivated total bovine serum) and 1% double-antibodyAnti- (penicillin and streptomycin) DMEM or 1640 medium, 5% CO at 37 ℃2Culturing in an incubator, and carrying out subculture once every 2-3 days.
Strain
HCoV-229E was passaged in Huh7 cells and stored at-80 ℃ in a freezer.
3. Experimental methods
Cell culture
Take Huh7 cells as an example: adding 3ml of 0.25% Trypsin-EDTA (pancreatin cell digestive juice) into a culture bottle full of Huh7 cells, digesting for 1-2 minutes at 37 ℃, removing the digestive juice, adding the culture solution, blowing, passaging at a ratio of 1:4, passaging once every 2-3 days, preparing 20 ten thousand cells per ml during plating, inoculating a 96-well cell culture plate, wherein each well is 0.1ml, the temperature is 37 ℃, and the CO content is 5%2The cells were cultured overnight and the experiment was performed after the cells had grown into a monolayer.
Activity assay against HCoV-229E (CPE method)
The experiment was carried out in passaged Huh7 cells, 1X 10 Huh7 cells4One well was inoculated into a 96-well plate, and 100. mu.l of HCoV-229E virus solution (100 TCID) was incubated overnight50) Infecting Huh7 cells in a 96-well plate, diluting a drug to be detected by using a maintenance solution, respectively carrying out determination on two administration schemes of simultaneous administration and 2h administration after infection, carrying out an experiment on the drug to be detected by using samples of which the doses are 8 times diluted by three times, setting 2 parallel holes for each dose, and simultaneously setting a virus control group without the drug. The cell lesion is observed under a microscope by using an index for observing cell lesion, and the cell death ratios are respectively marked as 4+ (cell death ratio is 75-100%), 3+ (cell death ratio is 50-75%), 2+ (cell death ratio is 25-50%), 1+ (cell death ratio is 0-25%) and 0+ (cell survival). Observing the result when the lesion number of the virus control group reaches 4+, recording and calculating the half inhibition concentration (formula as below) and selection index (SI ═ TC) of the drug to the virus by using a Reed-Muench method50/IC50)。
Wherein: a is the concentration of the drug with the cumulative inhibition rate of less than 50 percent, B is the inhibition rate with the cumulative inhibition rate of more than 50 percent, C is the inhibition rate with the cumulative inhibition rate of less than 50 percent, and D is the log dilution multiple
Cytotoxicity assay method (CPE method)
The cells were arranged at 1.5X 104And inoculating the cells/well in a 96-well plate, adding a maintenance solution containing the drug to be detected after overnight culture, diluting the drug to be detected by three times to obtain samples with 8 doses, performing experiments, and continuing culture. After 2 days of administration, the toxicity of the drug to cells under an inverted microscope was observed, and the median toxic concentration TC was calculated by the Reed-Muench method50The calculation formula is as follows:
wherein: a is the concentration of the drug with the cumulative inhibition rate of less than 50 percent, B is the inhibition rate with the cumulative inhibition rate of more than 50 percent, C is the inhibition rate with the cumulative inhibition rate of less than 50 percent, and D is the log dilution multiple
4. Results of the experiment
Inhibition of HCoV-229E by drugs in Huh7 cells
As shown in Table 1, the IC of the compound of formula I against HCoV-229E strain was determined by CPE method501.23 mug/ml, selection index SI of 12.98; IC of RBV versus HCoV-229E504.81. mu.g/ml, with a selection index SI of 19.23.
TABLE 1 inhibition of HCoV-229E by compounds in Huh7 cells (IC)50) (CPE method)
5. Conclusion
Under the experimental condition, the compound of the formula I has an inhibition effect on HCoV-229E strain; RBV has inhibitory effect on HCoV-229E strain, and the anti-coronavirus HCoV-229E activity of RBV is equivalent to that of the literature and the results before the experiment, which indicates that the experimental system is established.
While specific embodiments of the invention have been described in detail, those skilled in the art will understand that: various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof. The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
Claims (1)
1. The use of a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the use is as follows (a) and/or (b) and/or (c):
(a) the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a coronavirus infection;
(b) the application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preparing the medicament for preventing coronavirus infection;
(c) the application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preparing a coronavirus inhibitor;
the coronavirus is HCoV-229E;
formula I.
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