JP2013245167A - Autoinducer-2 inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an autoinducer-2 inhibitor which has activity of inhibiting autoinducer-2 and is effective for prevention, treatment and the like of infectious diseases.SOLUTION: An autoinducer-2 inhibitor includes at least one compound selected from a benzaldehyde derivative, a benzoic acid derivative and an acetophenone analog represented by specified formulae including general formula (1), as an active ingredient. In general formula (1), R, Rand Reach independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

Description

  The present invention relates to an autoinducer-2 inhibitor.

  In nature, microorganisms must survive in various environments. In addition to oligotrophic changes, temperature changes and pH changes, living organisms are forced to survive in an environment where phagocytic cells or antibacterial humoral factors (complements, antibodies, lysozyme, etc.) are present. Under these circumstances, bacteria have acquired a mechanism for sensitively sensing changes in their environment. As one of such mechanisms, it is clear that bacteria sense their own density in the environment through specific signaling substances and skillfully control their various biological activities according to their density. ing. Such an information transmission mechanism between cells is called a quorum sensing system.

  Quorum sensing was first reported in the luminescent marine bacteria Vibrio Fischeri and Vibrio Harvey. Recently, however, it has been recognized as a general gene regulatory mechanism in many bacteria. This phenomenon allows bacteria to perform activities such as bioluminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transfer, virulence factor production and sporulation. Can be done.

  Bacteria with a quorum sensing system synthesize and release a signaling molecule called an autoinducer and respond to the signaling molecule to control gene expression as a function of cell density. Until now, acyl homoserine lactone has been referred to as autoinducer-1 (hereinafter also referred to as “AI-1” in the present specification), and 4,5-dihydroxy-2,3-pentanedione has been referred to as autoinducer-2 (hereinafter, referred to as “AI-1”). In this specification, it is also identified as “AI-2”).

It has been reported that clinically important bacteria such as Vibrio bacteria, Pseudomonas aeruginosa, Serratia and Enterobacter use AI-1 for quorum sensing. In addition, it is known that Vibrio Harvey uses AI-1 having high species specificity for intra-species communication and AI-2 having low species specificity for inter-species communication. More recent studies have also shown that certain pathogenic bacteria regulate the production of virulence factors by interspecies quorum sensing by AI-2. Examples of such pathogenic bacteria include Helicobacter pylori which is said to cause gastric ulcer and gastric cancer, Clostridium perfringens which is a causative bacterium such as food poisoning, gas gangrene, and hemorrhagic enteritis. Can be mentioned. Therefore, a substance having an activity of inhibiting AI-2 has been demanded.

  As a substance that inhibits AI-2, furanone compounds, cyclopentene compounds, and the like have been reported so far (see, for example, Patent Documents 1 and 2).

Special table 2003-532698 JP 2005-506953 A

  An object of the present invention is to provide an AI-2 inhibitor that has an activity to inhibit AI-2 and is effective in the prevention and treatment of infectious diseases.

  The present inventors have conducted intensive studies in view of the above problems. As a result, the inventors have found that the following benzaldehyde derivatives, benzoic acid derivatives, and acetophenone analogs have an activity of inhibiting AI-2. The present invention has been completed based on this finding.

  The present invention relates to an AI-2 inhibitor comprising as an active ingredient at least one compound selected from the group consisting of compounds represented by any one of the general formulas (1) to (4).

In the general formula (1), R ¹¹ , R ¹² and R ¹³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

In the general formula (2), R ²¹ and R ²² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

In the general formula (3), two of R ³¹ , R ³² and R ³³ represent a hydrogen atom, and the remaining one represents a hydroxy group or an alkoxy group having 1 to 6 carbon atoms.

In the general formula (4), R ⁴¹ and R ⁴² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁴³ represents a hydroxy group, an alkyl group having 1 to 6 carbon atoms, or 1 carbon atom. Represents an alkoxy group of 6 or less.

The present invention also relates to a pharmaceutical composition or a cosmetic composition containing the AI-2 inhibitor.
Furthermore, this invention relates to the foodstuff composition containing the said AI-2 inhibitor.

  The AI-2 inhibitor of the present invention has an activity of inhibiting AI-2.

  The benzaldehyde derivative, benzoic acid derivative, and acetophenone analog used in the present invention will be described.

In the general formula (1), R ¹¹ , R ¹² and R ¹³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (preferably 4 or less, more preferably 2 or less). Specific examples of the alkyl group represented by R ¹¹ , R ¹² and R ¹³ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and a hexyl group. R ¹¹ , R ¹² and R ¹³ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom or a linear or branched chain having 1 to 4 carbon atoms. Are more preferable, and a hydrogen atom or an alkyl group having 1 or 2 carbon atoms (methyl group, ethyl group) is more preferable.

  Specific examples of the compound represented by the general formula (1) include a compound (3,4,5-trihydroxybenzaldehyde) represented by the formula (1-1) and a formula (1-2) shown below. A compound represented by (3,4-dihydroxy-5-methoxybenzaldehyde), a compound represented by formula (1-3) (3,5-dihydroxy-4-methoxybenzaldehyde), represented by formula (1-4) Compound (3-hydroxy-4,5-dimethoxybenzaldehyde), compound represented by formula (1-5) (4-hydroxy-3,5-dimethoxybenzaldehyde), compound represented by formula (1-6) (3,4,5-trimethoxybenzaldehyde) and the like. However, the present invention is not limited to these.

  As the compound represented by the general formula (1), the compound represented by the formula (1-2) or the formula (1-5) is particularly preferable.

In the general formula (2), R ²¹ and R ²² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (preferably 4 or less, more preferably 2 or less). Specific examples of the alkyl group represented by R ²¹ and R ²² include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and a hexyl group. R ²¹ and R ²² are each independently preferably a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Are more preferable, and a hydrogen atom or an alkyl group having 1 or 2 carbon atoms (methyl group or ethyl group) is more preferable.

  Specific examples of the compound represented by the general formula (2) include the compound represented by the formula (2-1) (2,3-dihydroxybenzaldehyde) and the formula (2-2) shown below. Compound (3-methoxysalicylaldehyde), compound represented by formula (2-3) (3-ethoxysalicylaldehyde), compound represented by formula (2-4) (2,3-dimethoxybenzaldehyde), formula (2) Examples thereof include a compound represented by 2-5) (2-ethoxy-3-methoxybenzaldehyde) and a compound represented by formula (2-6) (3-ethoxy-2-methoxybenzaldehyde). However, the present invention is not limited to these.

  As the compound represented by the general formula (2), the compound represented by the formula (2-3) is particularly preferable.

In the general formula (3), two of R ³¹ , R ³² and R ³³ represent a hydrogen atom, and the remaining one is a hydroxy group or 1 to 6 carbon atoms (preferably 4 or less, more preferably 2 or less). ) Represents an alkoxy group. Specific examples of the alkoxy group of R ³¹ , R ³² and R ³³ include methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butyloxy group, isobutyloxy group, pentyloxy group, hexyloxy group and the like. It is preferable that two of R ³¹ , R ³² and R ³³ are hydrogen atoms, and the remaining one is a hydroxy group or a linear or branched alkoxy group having 1 to 6 carbon atoms, and R ³¹ , R ³² And R ³³ is preferably a hydrogen atom, and the remaining one is preferably a hydroxy group or a linear or branched alkoxy group having 1 to 4 carbon atoms, and R ³¹ , R ³² and R ³³ More preferably, two of them are hydrogen atoms and the remaining one is a hydroxy group or an alkoxy group having 1 or 2 carbon atoms (methoxy group, ethoxy group).

  Specific examples of the compound represented by the general formula (3) include a compound represented by the formula (3-1) (salicylaldehyde) and a compound represented by the formula (3-2) (m- Hydroxybenzaldehyde), a compound represented by formula (3-3) (p-hydroxybenzaldehyde), a compound represented by formula (3-4) (o-methoxybenzaldehyde), represented by formula (3-5) Compound (m-methoxybenzaldehyde), compound represented by formula (3-6) (p-methoxybenzaldehyde), compound represented by formula (3-7) (o-ethoxybenzaldehyde), formula (3-8) A compound represented by formula (m-ethoxybenzaldehyde), a compound represented by formula (3-9) (p-ethoxybenzaldehyde), a compound represented by formula (3-10) (p-butoxybenzaldehyde), and the like. It is done. However, the present invention is not limited to these.

  As the compound represented by the general formula (3), a compound represented by the formula (3-3), the formula (3-6) or the formula (3-8) is particularly preferable.

In the general formula (4), R ⁴¹ and R ⁴² each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (preferably 4 or less, more preferably 2 or less), and R ⁴³ represents a hydroxy group or a carbon group. It represents an alkyl group having a number of 1 to 6 (preferably 4 or less, more preferably 2 or less) or an alkoxy group having a carbon number of 1 to 6 (preferably 4 or less, more preferably 2 or less). Specific examples of the alkyl group for R ⁴¹ , R ⁴² and R ⁴³ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and a hexyl group. Specific examples of the alkoxy group for R ⁴³ include methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butyloxy group, isobutyloxy group, pentyloxy group, hexyloxy group and the like. R ⁴¹ and R ⁴² are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms, preferably a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. Are more preferable, and a hydrogen atom or an alkyl group having 1 or 2 carbon atoms (methyl group or ethyl group) is more preferable. R ⁴³ is preferably a hydroxy group, a linear or branched alkyl group having 1 to 6 carbon atoms, or a linear or branched alkoxy group having 1 to 6 carbon atoms, hydroxy group, 1 to 4 carbon atoms Are more preferably a linear or branched alkyl group, or a linear or branched alkoxy group having 1 to 4 carbon atoms, a hydroxy group, an alkyl group having 1 or 2 carbon atoms (methyl group, ethyl group), or An alkoxy group having 1 or 2 carbon atoms (methoxy group, ethoxy group) is more preferable.

  Specific examples of the compound represented by the general formula (4) include the compound represented by the formula (4-1) (3,4-dihydroxybenzoic acid) and the formula (4-2) shown below. Compound (4-hydroxy-3-methoxybenzoic acid), compound represented by formula (4-3) (3-ethoxy-4-hydroxybenzoic acid), compound represented by formula (4-4) (3 , 4-dimethoxybenzoic acid), a compound represented by formula (4-5) (3 ′, 4′-dihydroxyacetophenone), a compound represented by formula (4-6) (4′-hydroxy-3′-methoxy) Acetophenone), a compound represented by formula (4-7) (3 ′, 4′-dimethoxyacetophenone), a compound represented by formula (4-8) (methyl 3,4-dihydroxybenzoate), formula (4 -9) (methyl 4-hydroxy-3-methoxybenzoate), a compound represented by formula (4-10) (4-hydroxy- And ethyl 3-methoxybenzoate). However, the present invention is not limited to these.

  Examples of the compound represented by the general formula (4) include compounds represented by the formula (4-2), the formula (4-6), the formula (4-9), or the formula (4-10). Particularly preferred.

  Any of the compounds represented by any one of the general formulas (1) to (4) used in the present invention is widely available in general. For example, it may be chemically synthesized by an ordinary synthesis method, extracted from a natural product, or a commercially available product may be used.

  In the AI-2 inhibitor of the present invention, any one of the above compounds may be used alone as an active ingredient, or two or more of the above compounds may be used.

  In the present invention, the active ingredient may be used as it is as an AI-2 inhibitor, or the active ingredient may be dissolved / dispersed in a solvent and used as an AI-2 inhibitor. Although there is no restriction | limiting in particular as a solvent which can be used by this invention, Water, ethanol, polyols (propylene glycol, butylene glycol, glycerol, polyethyleneglycol, etc.), and these liquid mixture are mentioned.

AI-2 in the present invention is not particularly limited as long as it is produced by bacteria and has AI-2 activity.
Specific examples of AI-2 in the present invention include 4,5-dihydroxy-2,3-pentanedione (also referred to herein as DPD) represented by the following formula, and AI-2 activity possessed by DPD: Compounds having equivalent AI-2 activity are included.

When DPD binds to the bacterial AI-2 receptor, it incorporates boron and is converted to furanosyl borate diester. Another specific example of AI-2 in the present invention is the furanosyl borate diester. It is also known that DPD is phosphorylated to become phosphorylated DPD (Phospho-DPD) and expresses AI-2 activity (for example, Taga M. et al., Mol. Microbiol., 2001, 42, p. 777-793). AI-2 in the present invention includes phosphorylated DPD.
Specific examples of the furanosyl borate diester and Phospho-DPD are shown below. However, the present invention is not limited to these.

  Inhibiting AI-2 in the present invention refers to inhibiting the effect of AI-2 on bacteria via quorum sensing, inhibiting AI-2 activity, and degrading AI-2. , Inhibiting the binding of AI-2 to the AI-2 receptor, and the like.

  In the present invention, AI-2 activity refers to an activity in which AI-2 affects bacteria having a quorum sensing system, that is, an activity that promotes the function of bacteria brought about by quorum sensing via AI-2. Bacteria can luminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transfer, pathogenic factor production and spore formation by quorum sensing via AI-2 Etc. are known to perform. Thus, AI-2 activity is, in other words, bioluminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic production by bacteria that recognize AI-2, ie, bacteria having an AI-2 receptor. It can be referred to as activity of synthesis, development of gene acceptability, plasmid conjugation transfer, pathogenic factor production and / or sporulation. In the present invention, AI-2 activity particularly refers to bacterial pathogen production activity.

  Examples of the pathogenic factor include enterotoxin, adenylate cyclase toxin, adhesin, alkaline protease, hemolytic toxin, anthrax toxin, APX toxin, α toxin, β toxin, δ toxin, C2 toxin, C3 toxin, botulinum toxin, bundled line Hair structure subunit, C5A peptidase, cardiotoxin, chemotaxis, cholera toxin, ciliary toxin, clostridial cytotoxin, clostridial neurotoxin, collagen adhesion gene, cytolysin, vomiting toxin, endotoxin, exfoliating toxin, external Toxin, extracellular elastase, fibrinogen, fibronectin binding protein, fibrillar hemagglutinin, fimbria, gelatinase, hemagglutinin, leukotoxin, lipoprotein signal peptidase, listeriolysin O, M protein, neurotoxin, non-fimbria adhesin Edema factor, Examples include hyperenzyme, pertussis toxin, phospholipase, pili, pore forming toxin, proline permease, serine protease, Shiga toxin, tetanus toxin, thiol activated cytolysin, tracheal cell lysin, urease, etc. It is not limited to these.

  Bacteria that can be affected by the active ingredient of the AI-2 inhibitor of the present invention, in other words, bacteria that can suppress the growth and growth of the active ingredient of the AI-2 inhibitor of the present invention are expressed by AI-2. Bacteria whose functions are promoted such as bioluminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transfer, pathogenic factor production and sporulation . For example, a bacterium having an AI-2 receptor, preferably a bacterium having an AI-2 receptor and producing AI-2 can be used.

AI-2 activity can be measured by a bioassay using a reporter bacterium that emits light by recognizing AI-2, preferably a bacterium having an AI-2 receptor and luciferase (eg, Keersmaecker S.C.J. Et al., J. Biol. Chem., 2005, 280 (20), p. 19563-19568). Specifically, Vibrio harveyi BB170 strain is used as a reporter bacterium, cultured in the presence of a test compound, and the luminescence intensity after culturing is measured with a chemiluminescence meter, etc. Can be measured.

Examples of bacteria that can be affected by inhibiting AI-2 or that can suppress proliferation and growth include bacteria belonging to the genus Vibrio, bacteria belonging to the genus Pseudomonas, bacteria belonging to the genus Porphyromonas. , Yersinia (Yersinia) bacteria, Escherichia (Escherichia) bacteria, Salmonella (Salmonella) bacteria, Haemophilus (Haemophilus) bacteria, Helicobacter (Helicobacter) bacteria, Bacillus (Bacillus) bacteria, Borrelia (Borrelia) bacteria, Neisseria (Neisseria) bacteria belonging to the genus Campylobacter (Campylobacter) bacteria belonging to the genus, Day Roh Cox (Deinococcus) bacteria belonging to the genus Mycobacterium (Mycobacterium) bacteria belonging to the genus Enterococcus (Enterococcus) bacteria belonging to the genus Streptococcus (Streptococcus) bacteria belonging to the genus Shigella (Shigella) genus Bacteria, Aeromonas ( Ae romonas) bacteria belonging to the genus, Eikenera (Eikenella) bacteria belonging to the genus Clostridium (Clostridium) bacteria, Staphylococcus (Staphylococcus) bacteria belonging to the genus Lactobacillus (Lactobacillus) bacteria belonging to the genus Actinobacillus (Actinobacillus) bacteria belonging to the genus Actinomyces (Actinomyces) genus bacterium, Bacteroides (Bacteroides) bacteria belonging to the genus, Cap Roh site file moth (Capnocytophaga) bacteria belonging to the genus Klebsiella (Klebsiella) bacteria belonging to the genus, Harobashirasu (Halobacillus) bacteria, Fusobacterium (Fusobacterium) bacteria belonging to the genus Erwinia (Erwinia) bacteria belonging to the genus, Erubenera ( Elbenella) bacteria belonging to the genus Listeria (Listeria) bacteria belonging to the genus Mannheimia (Mannheimia) bacteria belonging to the genus, Peputokokkasu (Peptococcus) bacteria belonging to the genus Prevotella (Prevotella) bacteria belonging to the genus, Proteus (Proteus) bacteria belonging to the genus Serratia (Serratia) bacteria belonging to the genus, Beironera (Veillon ella ) and bacteria belonging to the genus Aggregatibacter . More specifically, Vibrio harveyi (Vibrio harveyi), Vibrio fischeri (Vibrio fischeri), cholera (Vibrio cholerae), Vibrio parahaemolyticus (Vibrio parahaemolyticus), Vibrio Aruginorichikasu (Vibrio alginolyticus), Pseudomonas Hosuhoreumu (Pseudomonas phosphoreum ), poly Philo Sphingomonas gingivalis (Porphyromonas gingivalis), Yersinia enterocolitica (Yersinia enterocolitica), E. (Escherichia coli), Salmonella typhimurium (Salmonella typhimurium), Haemophilus influenzae (Haemophilus influenzae), Helicobacter pylori (Helicobacter pylori), Bacillus subtilis (Bacillus subtilis), Borrelia burgdorferi (Borrelia burgfdorferi), meningococcal (Neisseria meningitidis), Neisseria gonorrhoeae (Neisseria gonorrhoeae), Yersinia pestis (Yersinia pestis), Campylobacter Jeji Two (Campylobacter jejuni), Day Roh Cox radiodurans (Deinococcus radiodurans), Mycobacterium tuberculosis (Mycobacterium tuberculosis), Enterococcus faecalis (Enterococcus faecalis), Streptococcus pneumoniae (Streptococcus pneumoniae), Streptococcus pyogenes (Streptococcus pyogenes), Streptococcus mu chest (Streptococcus mutans), Staphylococcus aureus (Staphylococcus aureus), Mita Shigella (Shigella flexneri), Shigella Boidi (Shigella boydii), Bacillus cereus (Bacillus cereus), Bacillus Kubuchirisu (Bacillus cubtilis), Aeromonas hydrophila ( Aeromonas hydrophila), Salmonella typhi (Salmonella enterica), Eikenera-Korodensu (Eikenella corrodens), Helicobacter Hepatikasu (Helicobacter hepaticus), Clostridium perfringens (Clostridium perfringens), staphylococcal · Haemoritikasu (Staphylococcus haemolyticus), Lactobacillus gasseri (Lactobacillus gasseri), Lactobacillus acidophilus (Lactobacillus acidophilus), Lactobacillus reuteri (Lactobacillus reuteri), Lactobacillus salivarius (Lactobacillus salivarius), Lactobacillus casei (Lactobacillus casei), Streptococcus Sanginisu (Streptococcus sanguinis), Streptococcus anginosus (Streptococcus anginosus), Streptococcus oralis (Streptococcus oralis), Streptococcus bovis (Streptococcus bovis), Streptococcus Gorudoni (Streptococcus gordonii), Streptococcus mitis (Streptococcus mitis), Actinobacillus-Akuchinomai Setemukomitansu (Actinobacillus actinomycetemcomitans), Biburi Vulnificus (Vivrio vulnificus), Vibrio Mimikusu (Vibrio mimicus), Vibrio Anguirarumu (Vibrio anguillarum), Lactobacillus rhamnosus (Lactobacillus rhamnosus), Erwinia Amirobora (Erwinia amylovora), Erwinia Karotobara (Erwinia carotovara), Harobashirasu-halophilus (Halabacilus halophilus), Serratia Pimuchika (Serratia pymuthica), Serratia marcescens (Serratia marcescens), Bacteroides fragilis (Bacteroides fragilis), Bacteroides vulgatus (Bacteroides vulgatus), Bacteroides Disutasonisu (Bacteroides distasonis), Listeria monocytogenes ( Listeria monocytogenes ), Staphylococcus epidermidis , Clostridium difficile ( C lostridium difficile), Aeromonas hydrophila Philia (Aeromonas hydrophilia), Mannheimia Haemoraitika (Mannhemia haemolytica), Klebsiella pneumoniae (Klebsiella pneumoniae), Bacillus anthracis (Bacillus anthracis), Campylobacter coli (Campylobacter coli), Campylobacter rectus (Campylobacter rectus), Proteus mirabilis (Proteus mirabilis), Actinomyces Naesurandi (Actinomyces naeslundii), Actinomyces viscosus (Actinomyces viscosus), Actinomyces Isuraeri (Actinomyces israelii), Peputokokkasu-Anaerobiusu (Peptococcus anaerobius), Fusobacterium nucleatum (Fusobacterium nucleatum), Beironera-Parla (Veillonella parvula), Cap Roh site file moth-Suputi Na (Capnocytophaga sputigena), Prevotella interface media (Prevotella intermedia) and Aggregatibacter actinomycetemcomitans (Aggregatibacter actinomycetemcomitans) and the like.

  The active ingredient of the AI-2 inhibitor of the present invention includes Streptococcus mutans, Polyphyromonas gingivalis, Streptococcus oralis, Streptococcus gordonii, Streptococcus sanguinis, Streptococcus mitis, Actinomyces naeslandi, Peptococcus anaerobii In particular, it is preferably used for the inhibition of AI-2 against Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, Beironella parla, Capnocytofaga sputigena, Prevotella intermedia and Lactobacillus salivalus.

In vivo, the amount of AI-2 is correlated with the symptoms of certain infectious diseases, and the symptoms of infectious diseases can be reduced by administering the active ingredient of the AI-2 inhibitor of the present invention. Therefore, the AI-2 inhibitor of the present invention can be used as an agent for preventing or treating infectious diseases. Furthermore, the AI-2 inhibitor of the present invention can be contained in an agent for preventing or treating infectious diseases.
The infectious disease preventive or therapeutic agent is a non-antibacterial preventive or therapeutic agent that does not exhibit antibacterial activity against the causative bacteria of the infectious disease. As used herein, “non-antibacterial” means not inhibiting bacterial growth and / or growth. From the viewpoint of the presence or absence of antibacterial activity, the preventive or therapeutic agent for non-antibacterial infectious diseases and the preventive or therapeutic agent for antibacterial infectious diseases are completely different.

  The infectious disease that can be prevented or treated by administering the active ingredient of the AI-2 inhibitor of the present invention is an infectious disease that can be prevented or treated by inhibiting AI-2, in other words. Infectious diseases associated with bacteria having a quorum sensing system that utilizes AI-2, specifically such bacteria that can be affected by inhibiting AI-2.

  Specific examples of infections that can be prevented or treated by administering the active ingredient include infections in the oral cavity, skin, vagina, digestive (GI) tract, esophagus, and respiratory tract. More specifically, opportunistic infections caused by opportunistic organisms; acute otitis media (AOM) and exudative otitis media (OME) caused by Streptococcus pneumoniae and Haemophilus influenzae; influenza caused by Haemophilus influenzae; caused by Helicobacter pylori Duodenal ulcer, gastric cancer and gastric ulcer; cholera caused by Vibrio cholerae; plague caused by Plasmodium pestis; meningitis caused by Neisseria meningitidis; Salmonella poisoning caused by Salmonella bacteria such as Salmonella typhimurium; Food poisoning caused, gas gangrene and hemorrhagic enteritis; and diarrhea caused by Escherichia coli etc. (Yoshida A. et al., Appl. Environ. Microbiol., 2005, 71 (5), p. 2372-2380 Wen Z. T. et al., J. Bacter iol., 2004, 189 (9), p.2682-2691; Osaki T. et al., J. Med. Microbiol., 2006, 55 (Pt11), p.1477-1485; and Ohtani K. et al. , Mol. Microbiol., 2002, 44 (1), p. 171-179 etc.).

  In the present specification, prevention of infectious diseases includes suppressing and delaying the onset of infectious diseases, and includes not only prevention before infectious diseases but also prevention of recurrence of infectious diseases after treatment. In the present specification, treatment of an infectious disease includes curing an infectious disease, ameliorating symptoms, and suppressing progression of symptoms.

  The administration target of the AI-2 inhibitor of the present invention and the preventive or therapeutic agent for infectious diseases is preferably a warm-blooded vertebrate, more preferably a mammal. As used herein, mammals include, for example, humans and non-human mammals such as monkeys, mice, rats, rabbits, dogs, cats, cows, horses, and pigs. The AI-2 inhibitor of the present invention and the preventive or therapeutic agent for infectious diseases are suitable for administration to primates such as humans and monkeys, particularly humans. It is particularly preferred to administer to a human suffering from an infectious disease, a human being diagnosed with an infectious disease, a human being likely to suffer from an infectious disease, or a human in need of preventing the infectious disease.

  The form of the AI-2 inhibitor of the present invention and the preventive or therapeutic agent for the infectious disease is not particularly limited. For example, it may be a pharmaceutical composition, a food composition or a cosmetic composition, or be contained in these. Can do.

  When preparing a pharmaceutical composition, it is usually prepared as a preparation containing the active ingredient and preferably a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier generally refers to an inert, non-toxic, solid or liquid, bulking agent, diluent or encapsulating material that does not react with the active ingredient, eg, water. , Ethanol, polyols (for example, propylene glycol, butylene glycol, glycerin, and polyethylene glycol), suitable mixtures thereof, solvents or dispersion media such as vegetable oils, and the like.

  The pharmaceutical composition is orally, parenterally, e.g., in the oral cavity, in the skin, subcutaneously, in the mucosa, intravenously, in the artery, in the muscle, in the abdominal cavity, in the vagina, in the lungs. Administered intracerebrally, ocularly and intranasally. Examples of the preparation for oral administration include tablets, granules, fine granules, powders, capsules, chewables, pellets, syrups, solutions, suspensions and inhalants. As parenteral preparations, suppositories, retention enemas, drops, eye drops, nasal drops, pessaries, injections, mouth washes, ointments, creams, gels, controlled release patches and patches Skin external preparations, and the like. The pharmaceutical compositions of the invention are administered parenterally in the form of sustained-release subcutaneous implants or in the form of targeted delivery systems (eg, monoclonal antibodies, vector delivery, ion implantation, polymer matrices, liposomes and microspheres). May be.

  The pharmaceutical composition may further contain additives conventionally used in the pharmaceutical field. Such additives include, for example, excipients, binders, disintegrants, lubricants, antioxidants, colorants, flavoring agents, and the like, and can be used as necessary. In order to achieve sustained release so that it can act for a long time, it can also be coated with a known retarder or the like. Excipients include, for example, sodium carboxymethylcellulose, agar, light anhydrous silicic acid, gelatin, crystalline cellulose, sorbitol, talc, dextrin, starch, lactose, sucrose, glucose, magnesium metasilicate magnesium phosphate, calcium hydrogen phosphate, etc. Can be used. Examples of the binder include gum arabic, sodium alginate, ethyl cellulose, sodium caseinate, sodium carboxymethyl cellulose, agar, purified water, gelatin, starch, tragacanth, and lactose. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, crystalline cellulose, starch, hydroxypropyl starch and the like. Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, talc, hydrogenated oil, sucrose fatty acid ester, waxes and the like. Examples of the antioxidant include tocopherol, gallic acid ester, dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA), ascorbic acid and the like. Other additives and drugs as required, such as antacids (sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, synthetic hydrotalcite, etc.), gastric mucosa protective agents (synthetic aluminum silicate, sucralfate, copper chlorophyllin sodium, etc.) ) May be added.

  When preparing a cosmetic composition, the form is not particularly limited, and is a solution, emulsion, powder, water-oil two-layer system, water-oil-powder three-layer system, gel, tablet or other solid, aerosol, mist, Capsule and sheet can be in any form. In addition, the product form of the cosmetic composition is also arbitrary. For example, skin care cosmetics such as face wash, makeup remover, lotion, cosmetic liquid, pack, milky lotion, cream and sunscreen, foundation, makeup base, lipstick, eye Makeup cosmetics such as shadow, eyeliner, mascara, eyebrow, blusher and nail enamel, hair cosmetics such as hair shampoo, hair rinse, hair styling, hair dye and hair restorer, soap, body soap, deodorant cosmetic and bath preparation And other body cleansing agents, oral cosmetics such as dentifrices and mouthwashes, and aromatic cosmetics such as perfumes. Moreover, this cosmetic may belong to either cosmetics or quasi-drugs in accordance with Japanese Pharmaceutical Affairs Law.

The cosmetic composition includes other components commonly used in cosmetics, quasi drugs and pharmaceuticals, such as powder components, liquid fats and oils, solid fats and oils, waxes, hydrocarbons, higher fatty acids, higher alcohols, esters, silicones, anions. Surfactant, cationic surfactant, amphoteric surfactant, nonionic surfactant, humectant, water-soluble polymer, thickener, film agent, UV absorber, sequestering agent, lower alcohol, polyhydric alcohol , Sugar, amino acids, organic amines, polymer emulsions, pH adjusters, skin nutrients, vitamins, antioxidants, antioxidant auxiliaries, fragrances, water, etc. may be blended as necessary and manufactured by conventional methods. it can.
Examples of other components that can be incorporated into the cosmetic composition include preservatives (ethyl paraben, butyl paraben, etc.), anti-inflammatory agents (eg, glycyrrhizic acid derivatives, glycyrrhetinic acid derivatives, salicylic acid derivatives, hinokitiol, zinc oxide, allantoin, etc. ), Whitening agents (for example, ascorbic acid and its derivatives, placenta extract, saxifrage extract, arbutin, etc.), various extracts (for example, buckwheat, auren, shikon, peonies, assembly, birch, sage, loquat, carrot, aloe , Mallow, iris, grape, yokuinin, loofah, lily, saffron, senkyu, ginger, hypericum, onionis, garlic, capsicum, chimpi, red snapper, seaweed, etc.), activator (eg royal jelly, photosensitizer, cholesterol derivative, etc.) , Blood circulation promoter For example, nonyl acid valenylamide, nicotinic acid benzyl ester, nicotinic acid β-butoxyethyl ester, capsaicin, gingerone, cantalis tincture, ictamol, tannic acid, α-borneol, nicotinic acid tocopherol, inositol hexanicotinate, cyclandrate, cinnarizine , Trazoline, acetylcholine, verapamil, cephalanthin, γ-oryzanol, etc.), antiseborrheic agents (eg, sulfur, thianthol, etc.), anti-inflammatory agents (eg, tranexamic acid, thiotaurine, hypotaurine, etc.) and fungicides (eg, triclosan, Cetylpyridinium chloride, thymols, benzalkonium chloride, etc.).

The pharmaceutical composition and cosmetic composition of the present invention can be applied in the form of an oral composition, an external composition, an internal use composition, etc. Among them, it is applied in the form of an oral composition. preferable.
In addition to the above components, various components can be blended in the oral composition depending on the form. Ingredients that can be incorporated include, for example, abrasives, wetting agents, binders, dentin enhancers, bactericides, pH adjusters, enzymes, anti-inflammatory agents / blood circulation promoters, sweeteners, preservatives, colorants / pigments , Fragrances and the like can be used as appropriate. Specific examples of components that can be blended in the oral composition include dicalcium phosphate, tricalcium phosphate, calcium pyrophosphate, magnesium phosphate, sodium metaphosphate, silicic anhydride, aluminum hydroxide, alumina, hydroxyapatite, Abrasives such as calcium carbonate, magnesium carbonate, calcium sulfate, zeolite, synthetic aluminosilicate, bengara, etc .; granular abrasives granulated with the above abrasives using a binder; glycerin, propylene glycol, butylene glycol, ethylene glycol , Wetting agents such as polyethylene glycol, polypropylene glycol, sorbitol; tooth strengthening agents such as sodium monofluorophosphate, tin fluoride, sodium fluoride; chlorhexidine and its salts, triclosan, cetylpyrichloride Bactericides such as nium, thymols, benzalkonium chloride; pH adjusters such as sodium phosphate; enzymes such as dextranase, amylase, protease, lysozyme, mutanase; sodium chloride, hinokitiol, ε-aminocaproic acid, tranexam Acids, allantoins, tocopherols, octylphthalide, nicotinic esters, dihydrocholesterol, glycyrrhetinic acid, glycyrrhizic acid and its salts, glycerophosphate, chlorophyll, water-soluble inorganic phosphate compounds, azulene, chamomile, assembly, natural , Senkyu, herbal medicines, etc .; anti-inflammatory agents / blood circulation promoters; sweeteners such as saccharin sodium, stevioside, thaumatin, aspartylphenylalanine methyl ester; p-hydroxybenzoic acid, p-hydroxybenzoate Preservatives such as ethyl benzoate, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, sodium benzoate; colorants and pigments such as titanium dioxide; peppermint oil, spearmint oil, menthol, carvone, anethole, eugenol, Methyl salicylate, limonene, ocimene, n-decyl alcohol, citronellol, α-terpineol, methyl acetate, citronellyl acetate, methyl eugenol, cineol, linalool, ethyl linalool, crocodile, thymol, anise oil, lemon oil, orange oil, sage oil Fragrances such as rosemary oil, cinnamon oil, pimento oil, cinnamon oil, winter green oil, clove oil and eucalyptus oil.
The composition for oral cavity can be manufactured by a conventional method by blending the active ingredients. The form of the composition for oral cavity is not particularly limited, and is a powdery toothpaste, a liquid toothpaste, a toothpaste, a toothpaste, a paste-like cleaning agent such as oral pasta, a mouthwash, a liquid cleaning agent such as mouthwash, a gargle tablet, It can be in the form of food such as gingival massage cream, chewing gum, troche and candy.

  When preparing a food composition, the form in particular is not restrict | limited, A drink is also included. In addition to general foods, foods and drinks that indicate the concept of prevention / improvement of infectious diseases, that is, health foods, functional foods, sick foods, foods for specified health use, and the like are also included. Health foods, functional foods, foods for patients and foods for specified health use are specifically formulated in various forms such as fine granules, tablets, granules, powders, capsules, syrups, liquids, and liquid foods. Can be used for these formulations. A food composition in the form of a preparation can be produced in the same manner as a pharmaceutical preparation. The active ingredient and a carrier acceptable as a food, for example, an appropriate excipient (eg, starch, processed starch, lactose, glucose, water, etc.) ) And the like, and then can be produced using conventional means. In addition, food compositions include soups, juices, milk beverages, tea beverages, coffee beverages, cocoa beverages, jelly-like beverages and other liquid food compositions, pudding, yogurt and other semi-solid food compositions, breads, udon Such as noodles such as cookies, chocolate, candy, gum, rice crackers and the like, spreads such as sprinkles, butter, jam and the like. The food also includes feed.

  Food compositions include various food additives such as antioxidants, fragrances, various esters, organic acids, organic acid salts, inorganic acids, inorganic acid salts, inorganic salts, pigments, emulsifiers, preservatives, seasonings Additives such as additives, sweeteners, acidulants, fruit juice extracts, vegetable extracts, nectar extracts, pH adjusters, and quality stabilizers may be used alone or in combination.

  The dose of the active ingredient in the AI-2 inhibitor of the present invention may be an amount that can inhibit AI-2, and can be appropriately determined depending on the administration method, age, symptoms, and the like. For example, based on the mass of the active ingredient, it is usually 0.00001 mg or more, preferably 0.0001 mg or more, usually 1 mg or less, preferably 0.1 mg or less, usually 0.00001 to 1 mg, preferably 0.0001 or more by oral administration per day per kg body weight. ~ 0.1 mg.

  The content of the active ingredient in the AI-2 inhibitor of the present invention can be appropriately determined so as to achieve the above dose. For example, in the AI-2 inhibitor of the present invention, the content of the active ingredient is preferably 0.0001 mass% or more, more preferably 0.001 mass% or more, preferably 1 mass% or less, more preferably 0.1 mass% or less, 0.0001 -1% by mass is preferable, and 0.001-0.1% by mass is more preferable.

  By administering the active ingredient, AI-2 can be inhibited, and thus infectious diseases can be prevented or treated.

  Conventionally, antibiotics have been administered for the prevention and treatment of infectious diseases. However, since bacteria acquire drug resistance, the effectiveness of antibiotics is diminished. On the other hand, if AI-2 is inhibited, it becomes possible to control the quorum sensing system inherent in bacteria and control its pathogenicity. Therefore, the AI-2 inhibitor of the present invention can be expected to have an effect on bacteria having drug resistance.

  The present invention further discloses the following AI-2 inhibitors, pharmaceutical compositions, cosmetic compositions, food compositions, production methods, methods and uses with respect to the above-described embodiments.

<1> An AI-2 inhibitor comprising as an active ingredient at least one compound selected from the group consisting of compounds represented by any one of the general formulas (1) to (4).

(In the general formula (1), R ¹¹ , R ¹² and R ¹³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (preferably 4 or less, more preferably 2 or less).)

(In the general formula (2), R ²¹ and R ²² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (preferably 4 or less, more preferably 2 or less).)

(In General Formula (3), two of R ³¹ , R ³² and R ³³ represent a hydrogen atom, and the remaining one is a hydroxy group or a carbon number of 1 to 6 (preferably 4 or less, more preferably 2 The following represents an alkoxy group.)

(In the general formula (4), R ⁴¹ and R ⁴² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms (preferably 4 or less, more preferably 2 or less), R ⁴³ is a hydroxy group, Represents an alkyl group having 1 to 6 carbon atoms (preferably 4 or less, more preferably 2 or less) or an alkoxy group having 1 to 6 carbon atoms (preferably 4 or less, more preferably 2 or less).

<2> In the general formula (1), R ¹¹ , R ¹² and R ¹³ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms (preferably a hydrogen atom or carbon number). The AI-2 inhibitor according to <1> above, which is a linear or branched alkyl group having 1 or more and 4 or less, more preferably a hydrogen atom or an alkyl group having 1 or 2 carbon atoms.
<3> AI-2 according to <1> or <2>, wherein the compound represented by the general formula (1) is selected from the group consisting of compounds of the following formulas (1-1) to (1-6): Inhibitor.

<4> The AI-2 inhibitor according to <3>, wherein the compound represented by the general formula (1) is selected from the group consisting of the compounds of the formulas (1-2) and (1-5).

<5> In the general formula (2), R ²¹ and R ²² are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms (preferably a hydrogen atom or 1 to 4 carbon atoms). The AI-2 inhibitor according to <1>, which is a linear or branched alkyl group below, more preferably a hydrogen atom or an alkyl group having 1 or 2 carbon atoms.
<6> AI-2 according to <1> or <5>, wherein the compound represented by the general formula (2) is selected from the group consisting of compounds of the following formulas (2-1) to (2-6): Inhibitor.

<7> The AI-2 inhibitor according to <6>, wherein the compound represented by the general formula (2) is a compound represented by the formula (2-3).

<8> In the general formula (3), two of R ³¹ , R ³² and R ³³ are hydrogen atoms, and the remaining one is a hydroxy group or a linear or branched alkoxy group having 1 to 6 carbon atoms ( Preferably, it is a hydroxy group or a linear or branched alkoxy group having 1 to 4 carbon atoms, more preferably a hydroxy group or an alkoxy group having 1 or 2 carbon atoms. Agent.
<9> The AI-2 according to <1> or <8>, wherein the compound represented by the general formula (3) is selected from the group consisting of compounds of the following formulas (3-1) to (3-10): Inhibitor.

<10> The AI according to <9>, wherein the compound represented by the general formula (3) is selected from the group consisting of the compounds of the above formulas (3-3), (3-6), and (3-8). -2 inhibitors.

<11> In the general formula (4), R ⁴¹ and R ⁴² are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms (preferably a hydrogen atom or 1 to 4 carbon atoms). The following linear or branched alkyl group, more preferably a hydrogen atom or an alkyl group having 1 or 2 carbon atoms), and R ⁴³ is a hydroxy group, linear or branched alkyl having 1 to 6 carbon atoms. A linear or branched alkoxy group having 1 to 6 carbon atoms (preferably a hydroxy group, a linear or branched alkyl group having 1 to 4 carbon atoms, or a straight chain having 1 to 4 carbon atoms Or a branched-chain alkoxy group, more preferably a hydroxy group, an alkyl group having 1 or 2 carbon atoms, or an alkoxy group having 1 or 2 carbon atoms). Agent.
<12> AI-2 according to <1> or <11>, wherein the compound represented by the general formula (4) is selected from the group consisting of compounds of the following formulas (4-1) to (4-10): Inhibitor.

<13> The compound represented by the general formula (4) is selected from the group consisting of the compounds of the above formulas (4-2), (4-6), (4-9) and (4-10), The AI-2 inhibitor according to item 12>.

<14> The AI-2 inhibitor according to any one of <1> to <13>, which inhibits a bacterial function caused by quorum sensing between different species via AI-2.
<15> Bacteria with AI-2 receptor bioluminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transfer, pathogenic factor production and spores The AI-2 inhibitor according to any one of <1> to <14>, which inhibits at least one activity selected from the group consisting of formation (preferably a virulence factor producing activity).
<16> Streptococcus mutans, Polyphyromonas gingivalis, Streptococcus oralis, Streptococcus gordonii, Streptococcus sanguinis, Streptococcus mittis, Actinomyces naeslandi, Peptococcus anaerobius, Actinomyces <1> to <15>, which inhibits AI-2 activity against at least one selected from the group consisting of Fusobacterium nucleatum, Beironella parla, Capnocytofaga sputigena, Prevotella intermedia, and Lactobacillus salivarius. The AI-2 inhibitor according to any one of Items.
<17> The AI-2 inhibitor according to any one of <1> to <16>, wherein the AI-2 inhibitor is non-antibacterial.
<18> Any one of <1> to <17>, wherein the content of the active ingredient is 0.0001% by mass or more (preferably 0.001% by mass or more), 1% by mass or less (preferably 0.1% by mass or less). The described AI-2 inhibitor.

<19> A pharmaceutical composition or a cosmetic composition containing the AI-2 inhibitor according to any one of <1> to <18>.
<20> The pharmaceutical composition or cosmetic composition according to <19>, which is applied in the form of an oral composition.
<21> A food composition comprising the AI-2 inhibitor according to any one of <1> to <18>.

<22> Use of at least one compound selected from the group consisting of compounds represented by any one of the general formulas (1) to (4) as an AI-2 inhibitor.
<23> Use of at least one compound selected from the group consisting of compounds represented by any one of the general formulas (1) to (4) for the production of an AI-2 inhibitor.
<24> A method of using at least one compound selected from the group consisting of compounds represented by any one of the general formulas (1) to (4) as an AI-2 inhibitor.
<25> An AI-2 inhibition method using at least one compound selected from the group consisting of compounds represented by any one of the general formulas (1) to (4).
<26> In the general formula (1), R ¹¹ , R ¹² and R ¹³ are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms (preferably a hydrogen atom or carbon number). 1 or more and 4 or less linear or branched alkyl group, more preferably a hydrogen atom or an alkyl group having 1 or 2 carbon atoms), the use or method according to any one of <22> to <25> above .
<27> The compound according to any one of <22> to <26>, wherein the compound represented by the general formula (1) is selected from the group consisting of the compounds of the formulas (1-1) to (1-6). Use or method.
<28> The use or method according to <27>, wherein the compound represented by the general formula (1) is selected from the group consisting of the compounds of the above formulas (1-2) and (1-5).
<29> In the general formula (2), R ²¹ and R ²² are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms (preferably a hydrogen atom or 1 to 4 carbon atoms). The use or method according to any one of <22> to <25> above, which is the following linear or branched alkyl group, more preferably a hydrogen atom or an alkyl group having 1 or 2 carbon atoms.
<30> The compound represented by the general formula (2) is selected from the group consisting of the compounds of the formulas (2-1) to (2-6), according to the items <22> to <25> and <29> Any use or method.
<31> The use or method according to <30>, wherein the compound represented by the general formula (2) is a compound represented by the formula (2-3).
<33> In the general formula (3), two of R ³¹ , R ³² and R ³³ are hydrogen atoms, and the remaining one is a hydroxy group or a linear or branched alkoxy group having 1 to 6 carbon atoms ( Any one of the above <22> to <25>, preferably a hydroxy group or a linear or branched alkoxy group having 1 to 4 carbon atoms, more preferably a hydroxy group or an alkoxy group having 1 or 2 carbon atoms. Use or method according to any of the above.
<34> The compound represented by the general formula (3) is selected from the group consisting of the compounds of the above formulas (3-1) to (3-10), of the <22> to <25> and <33> items Any use or method.
<35> The use according to <34>, wherein the compound represented by the general formula (3) is selected from the group consisting of the compounds of the above formulas (3-3), (3-6) and (3-8). Or method.
<36> In the general formula (4), R ⁴¹ and R ⁴² are each independently a hydrogen atom or a linear or branched alkyl group having 1 to 6 carbon atoms (preferably a hydrogen atom or 1 to 4 carbon atoms). The following linear or branched alkyl group, more preferably a hydrogen atom or an alkyl group having 1 or 2 carbon atoms), and R ⁴³ is a hydroxy group, linear or branched alkyl having 1 to 6 carbon atoms. A linear or branched alkoxy group having 1 to 6 carbon atoms (preferably a hydroxy group, a linear or branched alkyl group having 1 to 4 carbon atoms, or a straight chain having 1 to 4 carbon atoms Or a branched chain alkoxy group, more preferably a hydroxy group, an alkyl group having 1 or 2 carbon atoms, or an alkoxy group having 1 or 2 carbon atoms). The use or method according to any Re.
<37> The compound represented by the general formula (4) is selected from the group consisting of the compounds of the formulas (4-1) to (4-10), according to the items <22> to <25> and <36> Any use or method.
<38> The compound represented by the general formula (4) is selected from the group consisting of the compounds of the above formulas (4-2), (4-6), (4-9) and (4-10), 37> use or method.
<39> The use or method according to any one of <22> to <38>, wherein the function of the bacteria caused by quorum sensing between different species via <39> AI-2 is inhibited.
<40> Bacteria with AI-2 receptor bioluminescence, warming, biofilm formation, proteolytic enzyme production, antibiotic synthesis, gene acceptability development, plasmid conjugation transfer, virulence factor production and spores The use or method according to any one of <22> to <39> above, which inhibits at least one activity selected from the group consisting of formation (preferably a pathogenic factor producing activity).
<41> Streptococcus mutans, Polyphyromonas gingivalis, Streptococcus oralis, Streptococcus gordonii, Streptococcus sanguinis, Streptococcus mittis, Actinomyces naeslandi, Peptococcus anaerobius, Actinomyces <22> to <40>, which inhibits AI-2 activity against at least one selected from the group consisting of Fusobacterium nucleatum, Beironella parla, Capnocytofaga sputigena, Prevotella intermedia and Lactobacillus salivarius. A use or method according to any of the paragraphs.
<42> The use or method according to any one of <22> to <41>, wherein the AI-2 inhibitor is non-antibacterial.
<43> In the AI-2 inhibitor, the content of the compound is 0.0001% by mass or more (preferably 0.001% by mass or more) and 1% by mass or less (preferably 0.1% by mass or less). 42> Use or method according to any of paragraphs 42>.

  EXAMPLES Hereinafter, although this invention is demonstrated further in detail based on an Example, this invention is not limited to this.

Test Example Measurement of AI-2 activity Vibrio Harvey BB170 strain (ATCC BAA-1117) as a reporter strain for the AI-2 bioassay system was obtained at 30 ° C. in Marine Agar 2216 medium (trade name, manufactured by Difco) at 30 ° C. Culture was performed under atmospheric conditions. One platinum loop of Vibrio Harvey BB170 strain cultured in this way was inoculated into 3 mL of Marine Broth 2216 medium (trade name, manufactured by Difco), and shake culture was performed at 30 ° C. and 200 rpm for 8 hours under aerobic conditions. . 200 μL of the bacterial solution was inoculated on AB (Autoinducer Bioassay) medium, and cultured with shaking at 30 ° C. and 200 rpm for 16 hours under aerobic conditions. This bacterial solution was diluted 5000 times with AB medium to obtain a reporter bacterial solution.
Note that AB medium is obtained from Mol. Microbiol., 1993, 9 (4), p. Prepared as follows with reference to 773-786. 0.2% Vitamin-free casamino acids (manufactured by Difco), 0.3M NaCl (manufactured by Wako Pure Chemical Industries, Ltd.), 0.05M MgSO ₄ · 7H ₂ O (manufactured by Wako Pure Chemical Industries, Ltd.) The pH was adjusted to 7.5 with Kojun Pure Chemicals, and the mixture was stored at room temperature after autoclaving. To 1 L of this solution, 1 M potassium phosphate buffer (1 M KH ₂ PO ₄ 21.1 mL + 1 M K ₂ HPO ₄ 28.9 mL) 10 mL, 0.1 M L-arginine (free-base, manufactured by Wako Pure Chemical Industries) 10 mL, 1 mg / ML thiamine HCl (manufactured by Wako Pure Chemical Industries) 1 mL, 10 μg / mL Riboflavin (manufactured by Wako Pure Chemical Industries) 1 mL and glycerol (manufactured by Wako Pure Chemical Industries, Ltd.) 20 mL are thoroughly mixed, and then 42 mL of sterile filtered material is added, A medium was prepared.

This reporter bacterial solution and a 10% by volume ethanol solution of the compound shown in Table 1 were mixed at a ratio (volume ratio) of 9: 1 and preincubated for 10 minutes at room temperature. Next, DPD (manufactured by OMM Scientific) was added to a final concentration of 10 μM, and aerobic shaking culture was performed at 30 ° C. The luminescence intensity after 4 hours was measured with a chemiluminescence meter (Mitharas LB940 (trade name) manufactured by Bertolud), and the AI-2 inhibition rate was measured. Samples were prepared so that the final concentrations of the compounds shown in Table 1 were the concentrations shown in Table 1. Furthermore, the AI-2 inhibition rate is shown as a relative value when the AI-2 inhibition rate when the light emission caused by 10 μM DPD is completely suppressed is 100%. Further, as a positive control, a compound known as an AI-2 inhibitor (4-bromo-5- (4-methoxyphenyl) -2 (5H) -furanone, manufactured by Sigma-Aldrich, final concentration: 10 μM, JP2009 In the same manner, AI-2 inhibitory activity was measured.
The results are shown in Table 1.

  As is clear from the results in Table 1, the AI-2 inhibitor of the present invention has an increased AI-2 inhibitory activity depending on the concentration of the active ingredient, and compared to known AI-2 inhibitory compounds, Has equivalent or higher AI-2 inhibitory activity.

Claims (11)

An autoinducer-2 inhibitor comprising, as an active ingredient, at least one compound selected from the group consisting of compounds represented by any one of the general formulas (1) to (4).

(In the general formula (1), R ¹¹ , R ¹² and R ¹³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.)

(In the general formula (2), R ²¹ and R ²² each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.)

(In General Formula (3), two of R ³¹ , R ³² and R ³³ represent a hydrogen atom, and the remaining one represents a hydroxy group or an alkoxy group having 1 to 6 carbon atoms.)

(In General Formula (4), R ⁴¹ and R ⁴² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁴³ represents a hydroxy group, an alkyl group having 1 to 6 carbon atoms, or a carbon number. Represents an alkoxy group of 1 or more and 6 or less.) The autoinducer-2 inhibitor according to claim 1, wherein the compound represented by the general formula (1) is selected from the group consisting of compounds of the following formulas (1-1) to (1-6).

  The autoinducer-2 inhibitor according to claim 2, wherein the compound represented by the general formula (1) is selected from the group consisting of the compounds of the formulas (1-2) and (1-5). The autoinducer-2 inhibitor according to claim 1, wherein the compound represented by the general formula (2) is selected from the group consisting of compounds of the following formulas (2-1) to (2-6).

  The autoinducer-2 inhibitor of Claim 4 whose compound represented by General formula (2) is a compound represented by the said Formula (2-3). The autoinducer-2 inhibitor according to claim 1, wherein the compound represented by the general formula (3) is selected from the group consisting of compounds of the following formulas (3-1) to (3-10).

  The autoinducer-2 inhibition according to claim 6, wherein the compound represented by the general formula (3) is selected from the group consisting of the compounds of the formulas (3-3), (3-6) and (3-8). Agent. The autoinducer-2 inhibitor according to claim 1, wherein the compound represented by the general formula (4) is selected from the group consisting of compounds of the following formulas (4-1) to (4-10).

  The compound represented by the general formula (4) is selected from the group consisting of the compounds of the above formulas (4-2), (4-6), (4-9) and (4-10). Autoinducer-2 inhibitor.   The pharmaceutical composition or cosmetic composition containing the autoinducer-2 inhibitor in any one of Claims 1-9.   The food composition containing the autoinducer-2 inhibitor in any one of Claims 1-9.