CN114377015B - Application of naftopidil in preparation of anti-influenza virus drugs - Google Patents
Application of naftopidil in preparation of anti-influenza virus drugs Download PDFInfo
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- CN114377015B CN114377015B CN202011130906.7A CN202011130906A CN114377015B CN 114377015 B CN114377015 B CN 114377015B CN 202011130906 A CN202011130906 A CN 202011130906A CN 114377015 B CN114377015 B CN 114377015B
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- CN
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- Prior art keywords
- influenza
- naftopidil
- subtype
- virus
- pharmaceutically acceptable
- Prior art date
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- HRRBJVNMSRJFHQ-UHFFFAOYSA-N Naftopidil Chemical compound COC1=CC=CC=C1N1CCN(CC(O)COC=2C3=CC=CC=C3C=CC=2)CC1 HRRBJVNMSRJFHQ-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229950005705 naftopidil Drugs 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title description 10
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- 150000003839 salts Chemical class 0.000 claims abstract description 13
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- -1 amino acid salt Chemical class 0.000 claims description 14
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- 229940024606 amino acid Drugs 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- 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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicines, discloses application of naftopidil in preparing an anti-influenza virus medicine, and particularly discloses application of naftopidil shown in a structural formula (I) and pharmaceutically acceptable salts thereof in preparing medicines for preventing or treating influenza virus infection. Including the combined use of naftopidil and other antiviral agents.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of Naftopidil (CAS: 57149-07-2) in preparation of medicines for preventing or treating influenza virus infection. The invention comprises the use of naftopidil, alone or in combination, in the prevention or treatment of influenza virus infection.
Background
Influenza virus (Influenza virus) is an important threat to global public health safety, and about 5-10% of adults and 20-30% of children are infected with Influenza virus every year according to World Health Organization (WHO) statistics, wherein 300-500 thousands of severe patients and about 25-50 thousands of deaths are observed [ Ziegler T, mamahit A, cox NJ:65years of Influenza surveillance by a world health organization-coordinat ed global network.Influza and other respiratory viruses (2018) 12 (5): 558-565 ]. Influenza viruses belong to the Orthomyxoviridae (Orthomyxoviridae) and are classified into four types a, b, c and t, wherein influenza a, b and c viruses can infect humans and cause respiratory diseases. Influenza a virus has the greatest epidemic range and the greatest hazard. Wherein 5000 tens of thousands of people die in the spanish influenza epidemic situation in 1918; in 2009 swine influenza epidemic, about 57 thousands of deaths were also caused worldwide [ First global estimates of 2009h1n1pandemic mortality released by cdc-led collaboration (2012):// www.cdc.go v/flu/spotlights/handmic-global-estimates. Htm ].
Influenza is spherical, has a diameter of about 80-120nm, is an enveloped virus, and its genome is single-stranded segmented RN A. A total of 8 RNAs encoding at least 10 viral proteins [ David M Knope P, peter M Howley, MD: fields virology,6th edition.2.Lippincott Williams&Wilkins (LWW), (2013) ]. Influenza virus envelopes are derived from the host cell membrane, on which three viral proteins are embedded: hemagglutinin protein (HA), neuraminidase (NA), and M2 ion channels. Influenza a viruses are serologically classified according to HA and NA, 18 HA and 10 NA have been found, so there are 180 subtypes theoretically, epidemiological data show that H1N1 subtype (spanish influenza 1918 and swine influenza 2009), H2N2 subtype (asian influenza 1950), H3N2 subtype (hong kon influenza 1960) caused a massive lethal influenza epidemic.
In addition to influenza pandemics, seasonal influenza occurs annually, mainly in winter, most often caused by influenza a or b viruses, with H1N1 and H3N2 being more common. Symptoms after seasonal influenza include sudden fever, cough (usually dry), headache, muscle and joint pain, sore throat, and runny nose. Cough can be severe and can last for 2 weeks or more. Most people recover from fever and other symptoms within a week, and do not need to be treated. However, influenza can lead to serious illness or death in high-risk populations [ How can I avoid getting the fluWorld Health Organization website:https:// www.w ho.int/news-room/q-a-detail/how-can-i-avoid-getting-the-flu ].
The existing Anti-influenza virus drugs include three classes of 7 [ Amarelle L, leculona E, sznajder JI: anti-influenza treatment: drugs currently used and under development.archiv os de bronconeumologia (2017) 53 (1): 19-26.]: the M2 ion channel inhibitors amantadine and rimantadine; the neuraminidase inhibitors oseltamivir, zanamivir, peramivir and lanamivir; CAP dependent endonuclease inhibitor Ballo Sha Weima Boc ester (baloxavir marboxil). The 7 anti-influenza virus drugs have a commonality: all are medicines taking influenza virus proteins as targets, so that when the targets of the medicines are mutated, the affinity of the medicines is reduced, and the influenza viruses escape to become drug-resistant viruses. For example, the influenza M2 ion channel inhibitors amantadine and rimantadine have been used for a long period of time, and the viruses have generated stable drug resistant mutations, and the WHO has not recommended amantadine and rimantadine for the treatment of influenza A virus [ Summary of influ enza antiviral susceptibility surveillance findings, september 2010-march 2011 (2011): https:// www.who.int/influhenza/gisrs_laboratory/updates/anti-viral_persistence/en/].
Although there are 7 anti-influenza drugs that have been or are in use, there are still 5-15 hundred million human influenza virus infections and diseases per year. The U.S. center of disease control statistics, 2010-2018, the number of patients infected with influenza A virus in the United states annually is 930-4900 ten thousand, and the death is 1.2-7.9 ten thousand [ Influenza (flu) (2020): https:// ww w.cdc, gov/flu/abaut/burden/index. That is, after the supply of anti-influenza drugs and the injection of influenza vaccines, 5% -20% of the entire population is still infected and diseased, which is due mainly to the nature of influenza virus itself, influenza virus variation and recombination (Reassortment) of viral RNA genome. For example, neuraminidase inhibitors are the most commonly used anti-influenza A virus drugs in clinic, wherein oseltamivir (darfein) is most widely used, and clinical data show that patients can obtain better curative effects only when the patients take the drug 48 hours after infection of viruses [ Summary of influenza antiviral susceptibility surveillance findings, september 2010-March 2011 (2011): https:// www.who.int/influenza/gisrs_lab laboratory/updates/anti-susceptability/en/].
Naftopidil was first synthesized by german Boehringer Mannheim company, an oral α1 adrenergic receptor antagonist (α1 receptor blocker) developed by japan Asahi Kasei Corporation for the treatment of lower urinary tract symptoms (lower urinary tract symptoms, LUTS) [ Homma Y, araki I, igawa Y, et al japanese Society of Neurogenic blade.clinical guideline for male lower urinary tract symptons.int J urol.2009;16 775-790 ], marketed in Japan in 1999, currently used in Japan and Korea [ Takei R-I, ikegaki I, shibata K, tsujimoto G, asano T.Naftopidil, a novel α1-adrenoceptor antagonist, displays selective inhibition of canine prostatic pressure and high affinity binding to cloned human α1-adrenoceptors.Jpn J Pharmacol.1999;79 (4):447-454.]. BPH is an adenoma, formed by a mixture of increased numbers of epithelial and/or stromal cells, a common histological condition in older men. Benign enlargement of the prostate caused by BPH (benign prostate enlargement, BPE) can cause bladder outlet obstruction (bladder outlet obstruction, bo) and lead to lower urinary tract symptoms [ McConnell J, abrams P, denis L, khoury S, roehrborn C, editors. Main Lower Urinary Tract Dysfunction Evaluation and management. Ed 21.Paris:Health Publications;2006.pp.69-142 ]. There are two classes of drugs used to treat lower urinary tract symptoms due to BPH: 5 alpha-reductase inhibitors (5 alpha-reductase inhibitors,5 ARI) and alpha 1 adrenergic receptor antagonists, naftopidil belonging to the latter. Naftopidil reduces prostate smooth muscle tone by blocking the α1 receptor, improving bladder outlet obstruction, and thus reducing lower urinary tract symptoms [ McConnell J, abrams P, denis L, khoury S, roehrborn C, editors, malle Lower Urinary Tract Dysfunction Evaluation and management. Ed 21.Paris:Health Publications;2006.pp.143-194 ]. Studies have shown that α1a and α1d subtype adrenergic receptor expression levels in BPH tissue are increased by 9-fold and 3-fold, respectively, whereas naftopidil binds to both subtypes of the α1d subtype adrenergic receptor, wherein the affinity for the α1d subtype adrenergic receptor (Ki: 1.2 nM) is 3-fold compared to the α1a subtype receptor (Ki: 3.7 nM) [ Shibata K, foglar, horie K, et al kmd-3213,a novel,potent,alpha 1a-adrenoceptor-selective antagonist: characterization using recombinant human alpha 1-adrenoceptors and native tisses. Mol pharmacol.1995;48 (2):250-258.]. Naftopidil has good safety, and researches show that 100 BPH patients orally take 75mg daily for 6 weeks continuously, 50mg daily after stopping taking medicine for 1 week continuously for 6 weeks, and no obvious adverse reaction is seen [ Oh-oka H.Usefile of naftopidil for dysuria in benign prostatic hyperplasia and its optimal dose: comparison between 75and 50mg.Urol Int.2009;82 (2):136-142.]. No report on anti-influenza virus activity or any antiviral activity of naftopidil was found by literature search.
The invention applies an influenza virus infection model to evaluate the antiviral activity of known compounds/medicines on the market, and discovers that naftopidil has broad-spectrum anti-influenza virus activity and has stronger inhibitory activity on influenza A and B virus infection. The data show that the anti-influenza virus activity of naftopidil is equivalent to that of ribavirin which is a first-line antiviral drug, wherein the anti-influenza virus activity of naftopidil is stronger than that of ribavirin, and the naftopidil has good safety. The naftopidil anti-influenza virus has high value of new application and application prospect. The invention relates to an invention patent related to new application of a known compound.
Disclosure of Invention
The invention solves the technical problem of providing application of naftopidil and pharmaceutically acceptable salts thereof in preparing medicines for preventing or treating influenza virus infection.
Specifically, in order to solve the technical problems of the invention, the following technical scheme is adopted:
the first aspect of the technical scheme of the invention provides application of naftopidil and pharmaceutically acceptable salts thereof shown in structural formula (I) in preparation of medicines for preventing or treating influenza viruses
The pharmaceutically acceptable salts of naftopidil comprise pharmaceutically acceptable organic salts or inorganic salts, wherein the organic salts comprise sulfonate, carboxylate, amino acid salt and fatty acid salt, and the inorganic salts comprise hydrochloride, bromate, iodate, sulfate, bisulfate, phosphate, hydrogen phosphate, dihydrogen phosphate and nitrate. Preferably bisulphates, sulphates, hydrochlorides and iodates.
The sulfonate comprises alkyl sulfonate containing 1-15 carbon atoms, benzene sulfonate, p-toluene sulfonate, o-toluene sulfonate and m-toluene sulfonate; the carboxylate comprises tartrate, maleate, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, adipate, pamoate and lactate; amino acid salts include glutamate, aspartate; fatty acid salts include long chain fatty acid salts containing 2 to 18 carbon atoms.
Wherein the influenza virus comprises influenza A virus, influenza B virus, influenza C virus and influenza D virus.
The influenza A virus comprises an H1N1 subtype, an H1N2 subtype, an H2N3 subtype, an H3N1 subtype, an H3N2 subtype, an H3N8 subtype, an H5N1 subtype, an H5N2 subtype, an H5N3 subtype, an H5N6 subtype, an H5N8 subtype, an H5N9 subtype, an H6N1 subtype, an H6N2 subtype, an H7N1 subtype, an H7N2 subtype, an H7N3 subtype, an H7N4 subtype, an H7N7 subtype, an H7N9 subtype, an H9N2 subtype, an H10N7 subtype, an H10N8 subtype, an H11N2 subtype, an H11N9 subtype, an H17N10 subtype and an H18N11 subtype. Wherein the influenza A H1N1 virus comprises A/PurtoRico/8/1934, A/WSN/33, A/Hubei Hongshan/52/2005, A/Beijing Fangzheng/262/1995, A/Guangdong Lou/219/2006 and A/FM/1/47 strains; influenza A H3N2 viruses include strains A/Jiangxi Dong lake/312/2006, A/Ji Fang/15/90, A/Yue Fang/243/1972, A/Han Fang/359/1995, A/New York/238/2015, A/Brisbane/10/07, A/Perth/16/09 and A/Udorn/307/72. Influenza B viruses include the B/Jiangxi New/BV/39/2008, B/Ji Fang/13/1997, B/Shenzhen/155/2005, B/Sichuan/63/2001, B/Zhejiang/2/2001, B/Shandong/7/97, B/Durban/39/98, B/Shandong Taian Taishan/1219/2009, B/Sichuan/34/2001B/Yamagata/16/88, B/Victoria/2/87, B/Johannesburg/1/99 and B/Maputo/1/99 strains.
The second aspect of the technical scheme of the invention provides application of a pharmaceutical composition in preparing anti-influenza virus drugs, which is characterized in that the pharmaceutical composition comprises naftopidil shown in a structural formula (I) and pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or excipients; the pharmaceutical composition may also contain other antiviral agents
Wherein the influenza virus comprises influenza A virus, influenza B virus, influenza C virus and influenza D virus.
The influenza A virus comprises an H1N1 subtype, an H1N2 subtype, an H2N3 subtype, an H3N1 subtype, an H3N2 subtype, an H3N8 subtype, an H5N1 subtype, an H5N2 subtype, an H5N3 subtype, an H5N6 subtype, an H5N8 subtype, an H5N9 subtype, an H6N1 subtype, an H6N2 subtype, an H7N1 subtype, an H7N2 subtype, an H7N3 subtype, an H7N4 subtype, an H7N7 subtype, an H7N9 subtype, an H9N2 subtype, an H10N7 subtype, an H10N8 subtype, an H11N2 subtype, an H11N9 subtype, an H17N10 subtype and an H18N11 subtype. Wherein the influenza A H1N1 virus comprises A/PurtoRico/8/1934, A/WSN/33, A/Hubei Hongshan/52/2005, A/Beijing Fangzheng/262/1995, A/Guangdong Lou/219/2006 and A/FM/1/47 strains; influenza A H3N2 viruses include strains A/Jiangxi Dong lake/312/2006, A/Ji Fang/15/90, A/Yue Fang/243/1972, A/Han Fang/359/1995, A/New York/238/2015, A/Brisbane/10/07, A/Perth/16/09 and A/Udorn/307/72. Influenza B viruses include the B/Jiangxi New/BV/39/2008, B/Ji Fang/13/1997, B/Shenzhen/155/2005, B/Sichuan/63/2001, B/Zhejiang/2/2001, B/Shandong/7/97, B/Durban/39/98, B/Shandong Taian Taishan/1219/2009, B/Sichuan/34/2001B/Yamagata/16/88, B/Victoria/2/87, B/Johannesburg/1/99 and B/Maputo/1/99 strains.
The pharmaceutical compositions may be prepared according to methods well known in the art. Any dosage form suitable for human or animal use may be made by combining the compounds of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by the enteral or parenteral route, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosal, ocular, pulmonary and respiratory, cutaneous, vaginal, rectal, etc.
The dosage form may be a liquid, solid or semi-solid dosage form. The liquid preparation can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including injection solution, powder injection and transfusion), eye drop, nasal drop, lotion, liniment, etc.; the solid dosage forms can be tablets (including common tablets, enteric coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules and enteric coated capsules), granules, powder, micropills, dripping pills, suppositories, films, patches, aerosol (powder) and sprays; the semisolid dosage form may be an ointment, gel, paste, or the like.
The compound of the invention can be prepared into common preparations, slow release preparations, controlled release preparations, targeted preparations and various microparticle administration systems.
For the preparation of the compounds of the present invention into tablets, various excipients known in the art may be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent can be water, ethanol, isopropanol, etc.; the binder may be starch slurry, dextrin, syrup, mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrating agent can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer and multilayer tablets.
In order to make the administration unit into a capsule, the compound of the present invention as an active ingredient may be mixed with a diluent, a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient of the compound can be prepared into particles or pellets by mixing with a diluent, an adhesive and a disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants and glidants used to prepare the tablets of the compounds of the invention may also be used to prepare capsules of the compounds of the invention.
For the preparation of the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixture may be used as solvent, and appropriate amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator may be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol, glucose, etc. can be added as propping agent for preparing lyophilized powder for injection.
In addition, colorants, preservatives, fragrances, flavoring agents, or other additives may also be added to the pharmaceutical formulation, if desired.
The inventors of the present invention have found that naftopidil can block infection of host cells by influenza virus. Can also be combined with other antiviral drugs.
For the purpose of administration, the drug or the pharmaceutical composition of the present invention can be administered by any known administration method to enhance the therapeutic effect.
The dosage of the pharmaceutical composition of the present invention may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route of administration and the dosage form, etc.
The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention has a synergistic effect with other therapeutic agents, its dosage should be adjusted according to the actual circumstances.
Beneficial technical effects
The inventor of the invention carries out anti-influenza virus infection activity evaluation on 300 known compounds/medicines on the market, discovers that naftopidil has stronger inhibitory activity on influenza A virus and influenza B virus infection, and the data show that the anti-influenza virus activity of naftopidil is equivalent to that of a first-line antiviral medicine ribavirin, wherein the anti-influenza A virus activity is stronger than that of ribavirin. The result of clinical study on middle-aged and elderly LUTS/BPH male patients shows that the patients have good resistance to naftopidil, and the patients do not have obvious adverse reaction or side effect after continuously taking 75 mg/day for 12 weeks. Because the infection course of the influenza virus is about 1 week, and the side effect of the naftopidil is very slight, the new application value of the naftopidil for resisting the influenza virus is considered to be higher, and the naftopidil has application prospect.
Drawings
FIG. 1 shows the results of evaluation of the activity of naftopidil blocking A/Puerto Rico/8/1934 (H1N 1) infected A549 cells.
FIG. 2 shows the results of evaluation of the activity of naftopidil blocking A/Jiangxi Dong lake/312/2006 (H3N 2) infected A549 cells.
FIG. 3 shows the results of evaluation of the activity of naftopidil blocking B/Jiangxi New construction/BV/39/2008 infected MDCK cells.
FIG. 4 influence of naftopidil on A549 cell viability
FIG. 5 influence of naftopidil on MDCK cell viability
Detailed Description
Example 1 principle of detecting influenza Virus infection model
A/Puerto Rico/8/1934 (H1N 1), A/Jiangxi east lake/312/2006 (H3N 2) and B/Jiangxi newly-built/BV/39/2008 are classical seasonal influenza strains. Lung tissue is the major organ infected with influenza virus. The detection model mainly detects the inhibition effect of the compound on influenza A virus (A/Puerto Rico/8/1934 and A/Jiangxi Dong lake/312/2006) infected lung cancer A549 cells and the inhibition effect of the compound on B/Jiangxi newly-built/BV/39/2008 infected MDCK cells.
The detection model preincubates the compound and the cells for 20 hours before infection, then infects the cells with virus, detects the activity of A549 cells at 48 hours after infection, and calculates the inhibition rate of the compound on virus infection by comparing the activity of the compound with the activity of the cells of a solvent control group and normal cells which are not infected with virus.
Example 2 principle of cell viability assay model
ATP plays an important role in various physiological processes of cells, provides energy for organisms directly, and is an important index reflecting cell viability and is positively related to the number of living cells. Thus, the number of viable cells in the test sample can be reflected by quantitative detection of ATP levels in the cell lysate.
The model adoptsLuminescent Cell Viability Assay luminescence cell viability assay kit (Promega Corp.) quantitatively detects ATP levels and quantitatively evaluates the effect of compounds on viability of A549 cells and MDCK cells.
Example 3 Experimental methods and results of A549 cell model infected with A/Puerto Rico/8/1934 (H1N 1)
A549 cells were plated at 4×10 per well 4 The individual cells were seeded in 96-well plates and after 4 hours naftopidil was added at final concentrations of 30 μm, 10 μm, 3 μm and 1 μm, respectively, the normal cell control group was not added with any compound, the solvent control group was added with an equal volume of DMSO, and the culture was continued for 20 hours. The medium in the plates was aspirated, the cells were rinsed once with PBS, and A/Puerto Rico/8/1934 virus infection (MOI=0.01) was added and incubated at 37℃for 1 hour. The medium was aspirated, rinsed once with PBS, medium containing test compound was added, normal cell control was added to medium, and solvent control was added to medium containing equivalent amount of DMSO. After 48 hours useCell viability was detected by luminescence (Promega Corp.) using the cell viability detection kit, i.e.the relative luciferase activity in the cell lysates (relative luminescence units, RLUs). Cytopathic and viral inhibition rates were calculated for each experimental group according to formulas (1) and (2). Analyzing experimental data by using Graph Pad Prism software, taking a concentration-inhibition ratio as a scatter diagram, obtaining a dose-response curve by nonlinear fitting, and calculating half-effective concentration EC of a compound to be tested 50 。
(1) Cytopathic rate%＝(100-RLUs Administration group (or RLUs) Solvent control group )/RLUs Normal cell control group )×100％
(2) Percent viral inhibition = (solvent control group cytopathic rate-dosing group cytopathic rate)/solvent control group cytopathic rate x 100%
The results show that naftopidil can block A/Puerto Rico/8/1934 (H1N 1) from infecting A549 cells, and the antiviral activity is superior to that of ribavirin which is a first-line antiviral drug (the results are shown in Table 1, and the dose-response curves are shown in figure 1).
Evaluation results of Activity of Compounds of Table 1 on influenza A Virus A/Puerto Rico/8/1934 (H1N 1) infected A549 cells
Example 4 Experimental methods and results of A549 cell model infected with A/Jiangxi Dong lake/312/2006 (H3N 2)
A549 cells were plated at 4×10 per well 4 The individual cells were seeded in 96-well plates and after 4 hours naftopidil was added at final concentrations of 30 μm, 10 μm, 3 μm and 1 μm, respectively, the normal cell control group was not added with any compound, the solvent control group was added with an equal volume of DMSO, and the culture was continued for 20 hours. The medium in the plates was aspirated, the cells were rinsed once with PBS, and infection with A/Jiangxi Dongfu/312/2006 virus (MOI=0.02) was added and incubated at 37℃for 1 hour. The medium was aspirated, rinsed once with PBS, medium containing test compound was added, normal cell control was added to medium, and solvent control was added to medium containing equivalent amount of DMSO. After 48 hours useCell viability was detected by luminescence (Promega Corp.) using the cell viability detection kit, i.e.the relative luciferase activity in the cell lysates (relative luminescence units, RLUs). Cytopathic and viral inhibition rates were calculated for each experimental group according to formulas (1) and (2). Analyzing experimental data by using Graph Pad Prism software, taking a concentration-inhibition ratio as a scatter diagram, and obtaining a dose-response curve by nonlinear fittingCalculation of the median effective concentration EC of the test Compound 50 。
(1) Cytopathic rate% = (100-RLUs) Administration group (or RLUs) Solvent control group )/RLUs Normal cell control group )×100％
(2) Percent viral inhibition = (solvent control group cytopathic rate-dosing group cytopathic rate)/solvent control group cytopathic rate x 100%
The results show that naftopidil can block A549 cells from being infected by A/Jiangxi Dong lake/312/2006 (H3N 2), and the antiviral activity is superior to that of ribavirin which is a first-line antiviral drug (the results are shown in Table 2, and the dose-response curves are shown in figure 2).
Evaluation results of Activity of the Compound of Table 2 on influenza A Virus A/Jiangxi Dong lake/312/2006 (H3N 2) infected A549 cells
Example 5 Experimental methods and results of B/Jiangxi New/BV/39/2008 infected MDCK cell model
MDCK cells were used at 4X 10 per well 4 The individual cells were seeded in 96-well plates and after 4 hours naftopidil was added at final concentrations of 30 μm, 10 μm, 3 μm and 1 μm, respectively, the normal cell control group was not added with any compound, the solvent control group was added with an equal volume of DMSO, and the culture was continued for 20 hours. Media in the plates were aspirated and the cells were rinsed once with PBS and infected with B/jiang new/BV/39/2008 virus (100 x tcid) 50 ) Incubation was carried out at 37℃for 1 hour. The medium was aspirated, rinsed once with PBS, medium containing test compound was added, normal cell control was added to medium, and solvent control was added to medium containing equivalent amount of DMSO. After 48 hours useCell viability was detected by luminescence (Promega Corp.) using the cell viability detection kit, i.e.the relative luciferase activity in the cell lysates (relative luminescence units, RLUs). Calculating cytopathic rate and viral inhibition of each experimental group according to formulas (1) and (2)The production rate is high. Analyzing experimental data by Grap hPad Prism software, taking a concentration-inhibition ratio as a scatter diagram, obtaining a dose-response curve by nonlinear fitting, and calculating half-effective concentration EC of a compound to be detected 50 。
(1) Cytopathic rate% = (100-RLUs) Administration group (or RLUs) Solvent control group )/RLUs Normal cell control group )×100％
(2) Percent viral inhibition = (solvent control group cytopathic rate-dosing group cytopathic rate)/solvent control group cytopathic rate x 100%
The results show that naftopidil can block B/Jiangxi new construction/BV/39/2008 from infecting MDCK cells, and the inhibition activity is equivalent to that of a first-line antiviral drug ribavirin (the results are shown in table 3, and the dose response curves are shown in figure 3).
Table 3 evaluation results of Compound on MDCK Activity against influenza B Virus B/Jiangxi New construction/BV/39/2008 infection
Example 6 detection of the Effect of Compounds on cell viability
A549 cells or MDCK cells were seeded at 8000 cells/well into 96-well plates with 100 μl of cell fluid per well, 37 ℃,5% co 2 Culturing for 24h. The next day test compounds were added to the cells at different concentrations with equivalent amounts of DMSO (0.1% v/v) as solvent control. After further culturing for 48h, 100. Mu.L of CellTiter-Glo reagent was added to each well, mixed with shaking for 2min, incubated at room temperature for 10min, and RLUs [ Tang K, he S, zhang X, et al, tangeretin, an extract from Citrus peels, blocks cellular entry of arenaviruses that cause viral hemorrhagic fever. Anti-viral Res.2018,160:87-93 were assayed in each well.]. Cell viability of the dosing wells was calculated using DMSO solvent well RLUs values of 100%.
Cell viability% = fluorescence intensity Administration group Fluorescence intensity Solvent control group ×100％。
The experimental results show that naftopidil has no effect on the viability of a549 cells and MDCK cells at half the effective concentration (the results are shown in tables 4 and 5, and the dose-response curves are shown in fig. 4 and 5).
TABLE 4 influence of naftopidil on A549 cell viability
TABLE 5 influence of naftopidil on MDCK cell viability
Claims (6)
1. The application of naftopidil or pharmaceutically acceptable salt thereof shown in the structural formula (I) in preparing medicines for preventing or treating influenza A virus infection or influenza B virus infection;
2. the use according to claim 1, characterized in that the pharmaceutically acceptable salt is a pharmaceutically acceptable organic or inorganic salt.
3. Use according to claim 2, characterized in that the organic salt is a sulfonate, carboxylate, amino acid salt or fatty acid salt, and the inorganic salt is a hydrochloride, bromate, iodate, sulfate, bisulfate, phosphate, hydrogen phosphate, dihydrogen phosphate or nitrate.
4. Use according to claim 3, characterized in that said sulfonate is an alkyl sulfonate containing 1-15 carbon atoms, a benzene sulfonate, a p-toluene sulfonate, an o-toluene sulfonate, an m-toluene sulfonate; the carboxylate is tartrate, maleate, fumarate, citrate, malate, cinnamate, benzoate, malonate, succinate, glutarate, adipate, pamoate and lactate; the amino acid salt is glutamate and aspartate; the fatty acid salt is long-chain fatty acid salt containing 2-18 carbon atoms.
5. The application of a pharmaceutical composition in preparing a medicament for preventing or treating influenza A virus infection or influenza B virus infection is characterized in that the pharmaceutical composition comprises naftopidil shown in a structural formula (I) and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier or excipient,
6. the use according to claim 5, wherein said pharmaceutical composition further comprises an additional antiviral agent.
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