JP7746776B2 - Antibacterial, antifungal and antiviral agents - Google Patents

Description

The present invention relates to an antibacterial, antifungal, and antiviral agent and an antibacterial, antifungal, and antiviral treatment method.

There are a wide variety of bacteria, molds, and viruses that have adverse effects on humans, animals, and plants, and numerous antibacterial, antifungal, and antiviral agents have been developed to combat them. In particular, with the recent global spread of the novel coronavirus (SARS-CoV-2), demand for antibacterial, antifungal, and antiviral agents has been increasing.

Antibacterial, antifungal, and antiviral agents are broadly divided into inorganic and organic types. Organic antibacterial, antifungal, and antiviral agents are characterized by low cost and rapid action, and for example, benzalkonium chloride, a quaternary ammonium salt, is widely used (see, for example, Patent Document 1). However, such quaternary ammonium salts have issues such as discoloration, coloring, and emulsion aggregation.

JP 2008-189645 A

There is a strong need to discover and develop new types of antibacterial, antifungal, and antiviral agents to reduce the damage to human health and the economy caused by a wide variety of pathogenic bacteria, fungi, and viruses.

The present invention was made in consideration of the above-mentioned background art, and its object is to provide an antibacterial, antifungal, and antiviral agent containing a carboxyl group-containing O-substituted monohydroxylamine or a carboxyl group-containing oxime.

As a result of extensive research to solve the above problems, the inventors discovered that specific carboxyl group-containing O-substituted monohydroxylamines or carboxyl group-containing oximes have antibacterial, antifungal, and antiviral activity against bacteria, mold, and viruses, leading to the completion of the present invention. Specifically, the present invention has the following gist:

[1] An antibacterial, antifungal, and antiviral agent containing one or more of a carboxyl group-containing O-substituted monohydroxylamine derivative represented by the following general formula (1), a carboxyl group-containing oxime derivative represented by the following general formula (2), and chemically acceptable salts thereof.

(In formulas (1) and (2), R represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an arylalkyl group having 7 to 15 carbon atoms. n represents an integer of 1 to 6. Multiple Rs may be the same or different.)
[2] The antibacterial, antifungal and antiviral agent according to [1], characterized in that in general formulas (1) and (2), R is any one of a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a benzyl group and a phenyl group.

[3] The antibacterial, antifungal and antiviral agent according to [1], wherein the carboxyl group-containing O-substituted monohydroxylamine or a chemically acceptable salt thereof is aminooxyacetic acid or a chemically acceptable salt thereof.

[4] The antibacterial, antifungal and antiviral agent according to [1], wherein the carboxyl group-containing oxime derivative or a chemically acceptable salt thereof is 2-methylideneaminooxyacetic acid, 2-ethylideneaminooxyacetic acid, or a chemically acceptable salt thereof.

[5] A method for treating bacteria, fungi, or viruses using the antibacterial, antifungal, and antiviral agent described in any one of [1] to [4].

The antibacterial, antifungal, and antiviral agent of the present invention inhibits the activity of a wide variety of bacteria, fungi, and viruses. As a result, the damage caused by bacteria, fungi, and viruses to human health and the economy can be reduced.

The antibacterial, antifungal, and antiviral agent of the present invention is characterized by containing one or more of a carboxyl group-containing O-substituted monohydroxylamine derivative, a carboxyl group-containing oxime derivative, and a chemically acceptable salt thereof.

In the carboxyl group-containing O-substituted monohydroxylamine derivatives represented by the above general formula (1), the carboxyl group-containing oxime derivatives represented by the above general formula (2), and their chemically acceptable salts, R represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an aryl group having 6 to 14 carbon atoms, or an arylalkyl group having 7 to 15 carbon atoms. Furthermore, n represents an integer from 1 to 6, and multiple Rs may be the same or different.

The alkyl group having 1 to 18 carbon atoms may be linear, branched, or cyclic, and is not particularly limited. Examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl (cetyl), heptadecyl, octadecyl (stearyl), oleyl, elaidyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 3-methylbutyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, 2-ethylhexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Aryl groups having 6 to 14 carbon atoms are not particularly limited, but examples include phenyl, naphthyl, anthryl, tolyl, xylyl, cumenyl, vinylphenyl, biphenylyl, and phenanthryl groups.

Arylalkyl groups having 7 to 15 carbon atoms are not particularly limited, but examples include benzyl, phenylethyl, phenylpropyl, naphthylmethyl, anthrylmethyl, tolylmethyl, xylylmethyl, cumenylmethyl, vinylphenylmethyl, biphenylylmethyl, and phenanthrylmethyl groups.

Of these, particularly preferred are carboxyl group-containing O-substituted monohydroxylamines and carboxyl group-containing oximes in which, in general formulas (1) and (2), R is any of a hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, benzyl group, and phenyl group.

The hydroxylamino groups of the carboxyl group-containing O-substituted monohydroxylamine derivative represented by the above general formula (1) may partially or entirely form a chemically acceptable salt with an inorganic or organic acid. The type of salt is not particularly limited, but examples include inorganic acid salts such as hydrochloride, hydrobromide, perchlorate, silicate, tetrafluoroborate, hexafluorophosphate, sulfate, nitrate, and phosphate, and organic acid salts such as acetate, citrate, fumarate, maleate, trifluoromethanesulfonate, trifluoroacetate, benzoate, and tosylate.

The carboxyl groups of the carboxyl group-containing O-substituted monohydroxylamine derivative represented by the general formula (1) and the carboxyl group-containing oxime derivative represented by the general formula (2) may partially or entirely form chemically acceptable salts with inorganic or organic bases. The type of salt is not particularly limited, but examples include metal salts such as sodium salts, potassium salts, rubidium salts, cesium salts, magnesium salts, calcium salts, strontium salts, barium salts, zinc salts, iron salts, copper salts, and silver salts, as well as ammonium salts with ammonium, methylamine, dimethylamine, trimethylamine, pyridine, ethanolamine, diethanolamine, trishydroxymethylaminomethane, polyethyleneimine, and the like.

Furthermore, the carboxy group of the carboxy group-containing O-substituted monohydroxylamine derivative represented by the above general formula (1) may form an intramolecular salt with the hydroxylamino group within the molecule, or may form an intermolecular salt.

The carboxyl group-containing oxime derivative represented by the above general formula (2) can take stereoisomers (syn or anti) due to the carbon-nitrogen double bond, and either stereoisomer can be used as the antibacterial, antifungal, and antiviral agent of the present invention.

In antibacterial, antifungal, and antiviral agents containing a carboxyl group-containing O-substituted monohydroxylamine derivative represented by the above general formula (1) or a carboxyl group-containing oxime derivative represented by the above general formula (2), or a chemically acceptable salt thereof, the carboxyl group-containing O-substituted monohydroxylamine derivative or the carboxyl group-containing oxime derivative (or a chemically acceptable salt thereof) may be in the form of a solution dissolved in a solvent. The solvent is not particularly limited, but examples include water, methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, dimethylformamide, isopropyl ether, dioxane, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol monobutyl ether, toluene, and xylene.

The carboxyl group-containing O-substituted monohydroxylamine derivative represented by the above general formula (1) and the carboxyl group-containing oxime derivative represented by the above general formula (2) can be produced by known methods, or commercially available products can be used as is or after derivatization.

The carboxyl group-containing O-substituted monohydroxylamine derivative represented by the above general formula (1) is preferably aminooxyacetic acid, and the carboxyl group-containing oxime derivative represented by the above general formula (2) is preferably 2-methylideneaminooxyacetic acid or 2-ethylideneaminooxyacetic acid.

In other words, in the present invention, the antibacterial, antifungal, and antiviral agent preferably contains aminooxyacetic acid, 2-methylideneaminooxyacetic acid, or 2-ethylideneaminooxyacetic acid.

The carboxyl group-containing O-substituted monohydroxylamine derivatives represented by the above general formula (1) and the carboxyl group-containing oxime derivatives represented by the above general formula (2) can be suitably used as active ingredients in antibacterial, antifungal, and antiviral agents. In this specification, "antibacterial, antifungal, and antiviral" includes inhibiting the growth of bacteria, fungi, and viruses, killing bacteria, fungi, and viruses, and reducing the infectivity of bacteria, fungi, and viruses.

Bacteria that can be targeted by the antibacterial, antifungal, and antiviral agents of the present invention are not particularly limited, but include, for example, Staphylococcus aureus, Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Bordetella gastrogrenella, Moraxella, Clostridium perfringens, Streptococcus, Hemolyticus, Salmonella typhimurium, Bacillus cereus, Trichophyton, Vibrio cholerae, Vibrio parahaemolyticus, Salmonella, Shigella, Bordetella pertussis, Haemophilus influenzae, Yersinia pestis, Bacillus anthrax, and Clostridium tetani.

Fungi that can be targeted include, but are not limited to, Aspergillus niger, Aspergillus terreus, Eurotium tonohilum, Penicillinium citrinum, Penicillinium funiculosum, Rhizopus oryzae, Cladosporium cladosporioides, Aureobasidium pullulans, Gliocladium virens, Chaetomium globosum, Fusarium moniliforme, and Myrothecium verrucaria.

Target viruses include, but are not limited to, Lassa fever virus, AIDS virus, West Nile virus, dengue fever virus, Japanese encephalitis virus, influenza virus, avian influenza virus, swine influenza virus, smallpox virus, herpes virus, papillomavirus, Sindbis virus, coronavirus, SARS virus, feline calicivirus, norovirus, adenovirus, Marburg virus, measles virus, rabies virus, poliovirus, rhinovirus, rotavirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, tobacco ringspot virus, tobacco rattle virus, tobacco mosaic virus, potato virus, cucumber mosaic virus, beet necrotic yellow vein virus, pepper mild mottle virus, common bean mosaic virus, common bean yellow mosaic virus, peanut stunt virus, bacteriophage, and the novel coronavirus (SARS-CoV-2).

The antibacterial, antifungal, and antiviral agent of the present invention can be used in a variety of dosage forms depending on its intended use. These dosage forms are not particularly limited, but include, for example, solutions, emulsions, suspensions, dispersions, aerosols, wettable powders, dusts, granules, microgranules, and flowable formulations.

The antibacterial, antifungal, and antiviral agent of the present invention may consist solely of the aforementioned carboxy group-containing O-substituted monohydroxylamine derivative, carboxy group-containing oxime derivative, or chemically acceptable salt thereof (hereinafter referred to as "carboxy group-containing O-substituted monohydroxylamines or carboxy group-containing oximes"). However, depending on the purpose, application, etc., it may also contain known additives, such as microbial control agents (antibacterial agents, bactericides, preservatives, antialgic agents, antifungal agents, etc.), other antiviral agents, solvents, binders, carriers, dispersants, emulsifiers, buffers, stabilizers, excipients, binding agents, disintegrants, lubricants, thickeners, humectants, colorants, fragrances, chelating agents, pH adjusters, antioxidants, light stabilizers, antifoaming agents, etc., to the extent that they do not affect the antibacterial, antifungal, and antiviral activity and stability.

The antibacterial, antifungal, and antiviral agent of the present invention can be applied in a variety of fields.

By spraying the antibacterial, antifungal, and antiviral agent of the present invention onto a target object, it is possible to exert antibacterial, antifungal, and antiviral effects on bacteria, mold, and viruses that are attached to the target object, as well as bacteria, mold, and viruses that adhere to the target object after spraying. Examples of target objects include, but are not limited to, interior and exterior materials for automobiles, ships, airplanes, and homes, as well as switches and touch panels for home appliances and elevators, stair railings, doorknobs, etc.

When a solution of carboxyl group-containing O-substituted monohydroxylamines or carboxyl group-containing oximes is sprayed onto an object, the concentration of the carboxyl group-containing O-substituted monohydroxylamines or carboxyl group-containing oximes in the solution is not particularly limited, but can be, for example, in the range of 0.01 to 50% by weight. From the standpoints of workability and antibacterial, antifungal, and antiviral properties, a range of 0.05 to 20% by weight is preferred, and a range of 0.1 to 10% by weight is even more preferred.

The solvent used to prepare the solution is the same as the solvent described above, but from the perspective of exposure safety, water, ethanol, isopropanol, glycerol, polypropylene glycol, or a mixture of these solvents is preferred.

By blending the antibacterial, antifungal, and antiviral agent of the present invention into an article or coating the surface of the article, the article can be treated with an antibacterial, antifungal, and antiviral agent, imparting to the article the ability to reduce or inhibit bacteria, fungi, and viruses. Examples of articles that can be treated with the agent include, but are not limited to, paints, adhesives, synthetic rubber latex, inks, polyvinyl alcohol films, polyvinyl chloride films, resin products, gypsum boards, roofing materials, wall materials, flooring materials, building materials, coated paper, wallpaper, exterior floor coverings, office automation equipment, home appliances, air conditioning equipment, vacuum cleaners, desks, chairs, sofas, benches, windows, handrails, handles, seats, automatic ticket gates, automatic ticket machines, vending machines, doors, fences, handrails, tableware, cooking utensils, packaging film, packaging bags, bottles, bottles, packaging packs, sinks, toilets, stationery, books, shelves, teeth, etc. These include brushes, mirrors, filters, masks, coats, jackets, trousers, skirts, dress shirts, knit shirts, blouses, sweaters, cardigans, nightwear, undergarments, diapers, supports, socks, tights, stockings, hats, scarves, mufflers, collars, stoles, gloves, clothing linings, clothing interlinings, clothing padding, work clothes, uniforms, school uniforms, and other clothing, curtains, screen doors, bedding, bedding batting, bedding covers, pillowcases, sheets, mats, carpets, towels, handkerchiefs, wall coverings, adhesive plasters, bandages, etc.

When carboxyl group-containing O-substituted monohydroxylamines or carboxyl group-containing oximes are blended into an article, there are no particular limitations on the blending amount (content concentration), but examples of the blending amount (content concentration) of carboxyl group-containing O-substituted monohydroxylamines or carboxyl group-containing oximes relative to the article are in the range of 0.001 to 20% by weight, with the range of 0.01 to 10% by weight being preferred from the standpoints of workability and antibacterial, antifungal, and antiviral properties.

The present invention will be described in detail below, but the present invention should not be construed as being limited to these examples.

[Virus inactivation test]
"Test conditions"
1. Test microorganisms Influenza virus: Swine influenza virus H1N1 IOWA strain Cultured cells: MDCK cells (canine kidney-derived cell line)
2. Test method: The test was carried out with reference to "Virus Experiments, General Theory, Revised Second Edition, Maruzen Co., Ltd., Virus Neutralization Test Method."

"District Settings"
Control group (Comparative Example 1)
Comparative Example 1
・0.1 mL of influenza virus solution was added to 1 mL of phosphate buffer solution. ・Sensitization time was 0 minutes and 5 minutes after the start of the test. Test group (Examples 1 and 2)
Example 1
Test material: 3 wt% aqueous aminooxyacetic acid solution. 0.1 mL of influenza virus solution was added to 1 mL of the test material. Sensitization time was 5 minutes after the start of the test. Example 2
Test material: Aqueous solution containing 3% by weight of aminooxyacetic acid and polyethyleneimine (Epomin P-1000, manufactured by Nippon Shokubai) Add 0.1 mL of influenza virus solution to 1 mL of test material Sensitization time: 5 minutes after the start of the test "Test procedure"
Prior to the main test, the effects (cytotoxicity) of the test materials of Examples 1 and 2 on cultured cells were investigated. Each test material was diluted with phosphate buffer and then inoculated into the cultured cells. The highest concentration that showed a normal state of the cells after culture was confirmed, and the influenza virus concentration to be used in the test was determined.

As a result, poor cell growth was confirmed even when the test material in Example 1 was diluted up to 100 times, and the test material in Example 2 was diluted up to 1000 times. For this reason, in this test, the cells were inoculated with diluted materials at a dilution greater than the dilution at which an effect on the cells was observed. The lower limit of measurement for each test material was set to 10 ^3.5 TCID ₅₀ /mL for Example 1 and 10 ^4.5 TCID ₅₀ /mL for Example 2.

2. Main test: Mixing test solutions According to the test category, 1 mL each of the test material and phosphate buffer solution was taken, and the influenza virus solution was added to the concentration determined in the preliminary test.

After adding the influenza virus solution, the mixture was left to stand at room temperature (25°C) for the specified period of time.

3. Main test: Cell inoculation and bacterial count After sensitization for each test section, the mixture was serially diluted 10-fold and inoculated in 100 μL portions onto cells cultured in a 96-well plate. After culturing at 37°C in 5% carbon dioxide for 5 days, the culture supernatant from each well was collected, and the presence or absence of influenza virus growth was confirmed by hemagglutination, and the concentration was calculated.

The results of the virus inactivation test are shown in Table 1. In the control group (Comparative Example 1), no change in the amount of influenza virus was observed from the start of the test until 5 minutes after the start of the test (10 ^6.7 TCID ₅₀ /mL).

On the other hand, 5 minutes after the start of the test, the test group (Example 1) had <10 ^3.5 TCID ₅₀ (>99.93% reduction), and Example 2 had <10 ^4.5 TCID ₅₀ (>99.36% reduction).

This time, we conducted an inactivation test of the test materials against influenza viruses, and found that by reacting with the influenza virus for more than 5 minutes,
Example 1: >99.93%
Example 2: >99.36%
It was found to have a virus inactivation effect.

[Antiviral activity test]
Example 3
A commercially available cotton cloth was impregnated with a 3 wt% aqueous solution of aminooxyacetic acid at a rate of 20 g/ ^m² and then dried at 60°C for 1 hour to prepare a sample for antiviral activity testing. This sample was subjected to a quantitative test of antiviral activity value as specified in JIS L1922. Using influenza virus (H3N2 strain) as the test virus, the antiviral activity value was calculated to be 4.3.

As is clear from Examples 1 to 3, the antibacterial, antifungal, and antiviral agent of the present invention exhibited a high inactivation effect against viruses.

[Antibacterial activity test]
Synthesis Example 1
9.11 g (100 mmol) of aminooxyacetic acid, 4.85 g (110 mmol) of acetaldehyde, and 30 g of water were placed in a 100 mL recovery flask and stirred at room temperature for 1 hour. Water and excess acetaldehyde were removed by distillation under reduced pressure to obtain 11.7 g (100 mmol) of 2-ethylideneaminooxyacetic acid (100% yield).

Examples 4 to 15, Comparative Examples 2 to 3
A commercially available cotton cloth was impregnated with the agent shown in Table 2 and then dried at 60° C. for 1 hour to prepare a sample for antibacterial activity testing. This sample was subjected to a quantitative test of antibacterial activity value by the bacterial liquid absorption method (pour plate culture method) specified in JIS L1902 "Antibacterial activity test method and antibacterial effect of textile products."

The results of the above antibacterial activity tests are shown in Table 2. As is clear from Table 2, the antibacterial, antifungal, and antiviral agent of the present invention exhibited higher antibacterial activity than existing antibacterial agents.

[Antifungal activity test]
Examples 16-17
A commercially available cotton cloth was impregnated with the chemicals shown in Table 3 at a rate of 20 g/ ^m² and then dried at 60°C for 1 hour to prepare a sample for antifungal activity testing. This sample was subjected to a quantitative test of antifungal activity value using the absorption method specified in JIS L1921 "Testing methods for antifungal activity and antifungal effect of textile products." The test fungus used was Cladosporium cladosporioides.

The results of the above antifungal activity tests are shown in Table 3. As is clear from Table 3, the antibacterial, antifungal, and antiviral agent of the present invention demonstrated a high inactivation effect against mold.

Claims (1)

An antibacterial, antifungal and antiviral agent comprising at least one of 2-methylideneaminooxyacetic acid, 2-ethylideneaminooxyacetic acid and chemically acceptable salts thereof .