WO2022177078A1 - Antibacterial agent comprising trifluoromethylated hydroquinone - Google Patents

Abstract

The present invention relates to an antibacterial agent comprising a trifluoromethylated hydroquinone derivative having an excellent antibacterial effect even in a small amount. The antibacterial agent of the present invention has an excellent antibacterial effect even in a small amount, and for this reason, the present invention can exhibit a high antibacterial effect even in a small amount when applied to industrial preservatives and coatings.

Description

Antimicrobials comprising trifluoromethylated hydroquinone derivatives

The present invention relates to an antimicrobial agent comprising a trifluoromethylated hydroquinone derivative.

Industrial preservatives and coatings are applied to paper, paints, wallpaper, paints, etc. to prevent the formation of mold, and as these industrial preservatives, a 2% solution of 1,2-hexanediol has been generally used.

1,2-hexanediol is a liquid compound having a boiling point of 220 to 230°C and is harmless to the human body, but has a problem in that a large amount is required to function as a preservative due to its low antibacterial activity.

On the other hand, hydroquinone (hydroquinone) is a phenol-based aromatic organic compound, which is well soluble in water and has strong reducing power, so it has been used as an antioxidant or polymerization inhibitor in food, rubber, etc. When applied to 1,2-hexanediol, similarly to 1,2-hexanediol, a large amount is required, so there is a problem in that the application of the technology is limited.

One object of the present invention is to provide an antibacterial agent comprising a trifluoromethylated hydroquinone derivative having excellent antibacterial effect even in a small amount.

The antimicrobial agent according to an embodiment of the present invention includes a trifluoromethylated hydroquinone derivative represented by the following Chemical Formula 1:

[Formula 1]

In Formula 1,

R ₁ , R ₂ , R _{3 ,} and R ₄ are each independently selected from hydrogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, halogen, and —CF ₃ , with the proviso that R ₁ , R ₂ any one of , R _{3 ,} and R ₄ is —CF ₃ .

In one embodiment, any one of R ₁ , R ₂ , R _{3 ,} and R ₄ may be —CF ₃ , and the rest may be hydrogen or straight or branched chain alkoxy having 1 to 10 carbon atoms.

In an embodiment, any one of R ₁ , R ₂ , R _{3 ,} and R ₄ may be —CF ₃ , and the remainder may be hydrogen or halogen.

In one embodiment, any one of R ₁ , R ₂ , R _{3 ,} and R ₄ may be —CF ₃ , and the remainder may be hydrogen or a linear or branched alkyl having 1 to 10 carbon atoms.

In one embodiment, the antimicrobial agent may include a trifluoromethylated hydroquinone derivative represented by any one of the following Chemical Formulas 1-1 to 1-14.

[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

[Formula 1-4]

[Formula 1-5]

[Formula 1-6]

[Formula 1-7]

[Formula 1-8]

[Formula 1-9]

[Formula 1-10]

[Formula 1-11]

[Formula 1-12]

[Formula 1-13]

[Formula 1-14]

The antimicrobial agent according to another embodiment of the present invention includes a trifluoromethylated hydroquinone derivative represented by the following Chemical Formula 2:

[Formula 2]

In Formula 2,

R ₁₁ , R ₁₂ , R _{13 ,} and R ₁₄ are each independently selected from hydrogen or halogen, provided that at least one or more of R ₁₁ , R ₁₂ , R _{13 ,} and R ₁₄ is halogen.

In one embodiment, the antimicrobial agent may include a trifluoromethylated hydroquinone derivative represented by the following Chemical Formula 2-1 or 2-2.

[Formula 2-1]

[Formula 2-2]

The trifluoromethylated hydroquinone derivative of the present invention has an effect of remarkably enhancing the antibacterial effect of hydroquinone by introducing a trifluoro group (-CF ₃ ) to hydroquinone.

Therefore, the antibacterial agent of the present invention containing the trifluoromethylated hydroquinone derivative has excellent antibacterial effect even in a small amount, and thus, when applied to industrial preservatives and coatings, it can exhibit a high antibacterial effect even in a small amount, which is an economical advantage There is this.

1 is a result of observing the sterilization effect of each concentration of the compounds added to the culture medium of the yeast Saccharomyces cerevisiae .

Figure 2 is the result of observing the bactericidal effect of each concentration of the compounds added to the culture medium of the fungus Cryptococcus neoformans .

3 is a result of observing the sterilization effect of each concentration of the compounds added to the culture medium of the yeast Candida albicans .

Figure 4 is the result of observing the sterilization effect of each concentration of the compounds added to the culture medium of the fungus Aspergillus niger .

5 is a result of comparing the sterilization effect of each compound concentration for 4 types of cells.

Hereinafter, the present invention will be described in detail.

The terminology used in this application is only used to describe specific embodiments and is not intended to limit the present invention. Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In this specification, when a part "includes", "contains", or "has" a certain component, it means that other components may be further included unless otherwise defined.

As used herein, "substitution" in the expression "substituted or unsubstituted" means that a hydrogen atom in one functional group is replaced by another atom or another functional group (ie, a substituent).

As used herein, "alkyl" may be straight-chain or branched, and may be substituted or unsubstituted. The number of carbon atoms of the alkyl is not particularly limited, but specifically, it may be a straight-chain or branched alkyl having 1 to 10 carbon atoms, more specifically, a straight-chain or branched alkyl having 1 to 4 carbon atoms. Specific examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

In the present specification, the "alkoxy" may be a straight chain, branched chain, or cyclic chain, and may be substituted or unsubstituted. The number of carbon atoms of the alkoxy is not particularly limited, and specifically, it may be a straight-chain or branched-chain alkoxy having 1 to 10 carbon atoms, more specifically, a straight-chain or branched-chain alkoxy having 1 to 4 carbon atoms. Specific examples of the alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, and the like.

As used herein, "halogen" includes F, Cl, Br, and I atoms, and specifically may be F, Cl, or Br atoms.

The antimicrobial agent according to an embodiment of the present invention may include a trifluoromethylated hydroquinone derivative represented by the following Chemical Formula 1:

[Formula 1]

In Formula 1, R ₁ , R ₂ , R _{3 ,} and R ₄ are each independently selected from hydrogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, halogen, and —CF ₃ , any one of R ₁ , R ₂ , R _{3 ,} and R ₄ is —CF ₃ .

Specifically, any one of R ₁ , R ₂ , R _{3 ,} and R ₄ is —CF ₃ , and the remainder is hydrogen or a linear or branched chain alkyl having 1 to 10 carbon atoms, or hydrogen or a straight chain having 1 to 10 carbon atoms. or branched chain alkoxy, or hydrogen or halogen.

Specific examples of the antimicrobial agent containing the trifluoromethylated hydroquinone derivative represented by Formula 1 may include the following Formulas 1-1 to 1-14:

[Formula 1-1]

[Formula 1-2]

[Formula 1-3]

[Formula 1-4]

[Formula 1-5]

[Formula 1-6]

[Formula 1-7]

[Formula 1-8]

[Formula 1-9]

[Formula 1-10]

[Formula 1-11]

[Formula 1-12]

[Formula 1-13]

[Formula 1-14]

Meanwhile, the antibacterial agent according to another embodiment of the present invention may include a trifluoromethylated hydroquinone derivative represented by the following Chemical Formula 2:

[Formula 2]

In Formula 2, R ₁₁ , R ₁₂ , R _{13 ,} and R ₁₄ are each independently selected from hydrogen or halogen, provided that at least one of R ₁₁ , R ₁₂ , R _{13 ,} and R ₁₄ is halogen. .

Specific examples of the antimicrobial agent containing the trifluoromethylated hydroquinone derivative represented by Formula 2 may include Formula 2-1 or Formula 2-2 below:

[Formula 2-1]

[Formula 2-2]

The trifluoromethylated hydroquinone derivative represented by Formula 1 or 2 has an effect of remarkably enhancing the antibacterial effect of hydroquinone by introducing a trifluoro group (-CF ₃ ) to the hydroquinone.

Therefore, the antibacterial agent of the present invention containing the trifluoromethylated hydroquinone derivative has excellent antibacterial effect even in a small amount, and thus, when applied to industrial preservatives and coatings, it can exhibit a high antibacterial effect even in a small amount, which is an economical advantage There is this.

Meanwhile, in one embodiment, the trifluoromethylated hydroquinone derivative represented by Formula 1 or Formula 2 is irradiated with light having a wavelength of 380 nm to 500 nm to the benzoquinone derivative in the presence of a trifluoromethylation reagent in a solvent. It can be prepared by reaction.

In one embodiment, the benzoquinone derivative may be a 1,4-benzoquinone derivative. Specifically, the benzoquinone derivative may be 1,4-benzoquinone unsubstituted or substituted by one or more substituents selected from alkyl, alkoxy, and halogen, and more specifically, unsubstituted 1,4-benzoquinone. It may be quinone, or 1,4-benzoquinone substituted by one or two substituents selected from linear or branched alkyl having 1 to 10 carbon atoms, straight or branched chain alkoxy having 1 to 10 carbon atoms, and halogen. .

In one embodiment, the trifluoromethylation reagent is not particularly limited as long as it is commonly used in organic synthesis as a source of trifluoromethyl groups. Commonly used trifluoromethylation reagents include Togni's reagent, Umemoto's reagent, and Langlois' reagent. Togni's reagent and Umemoto's reagent have the advantage of being stable and easy to handle even at room temperature for a long time, but they have the disadvantage of being expensive. Langlois reagent (CF ₃ SO ₂ Na) is inexpensive, and when used in the preparation of the compound of the present invention, the reaction can proceed smoothly in connection with the starting material, so the use of Langlois reagent as a trifluoromethylation reagent it is preferable

In one embodiment, the solvent may be water, an organic solvent, or a mixed solvent in which water and an organic solvent are mixed. The organic solvent is not particularly limited as long as it does not react with the reactants, and examples thereof include methanol, ethanol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile (MeCN), 2,2,2 -trifluoroethanol (TFE), etc. are mentioned, and these may be used individually or in mixture of two or more. Considering the solubility of reactants, solubility of removal, reaction efficiency, yield, etc., as the solvent, one selected from water, methanol, ethanol, dimethyl sulfoxide, acetonitrile, and 2,2,2-trifluoroethanol more can be used. In terms of production yield, a mixed solvent in which water and an organic solvent are mixed as the solvent, specifically, a mixed solvent in which water and acetonitrile or 2,2,2-trifluoroethanol are mixed is preferable. When mixing water and an organic solvent, their mixing ratio is 1:2 to 2:1 (by volume), specifically 1:1.5 to 1.5:1 (by volume), more specifically 1 It may be a ratio of :1 (by volume).

Hereinafter, the present invention will be described in more detail based on examples. However, the present invention is not limited to these examples.

1. Examples

[Example 1] Preparation of 2-(trifluoromethyl)benzene-1,4-diol

Dissolving 1 mmol of Langlois reagent and 3 mmol of 1,4-benzoquinone in TFE/H ₂ O (1/1, 0.2 M) under an argon (Ar) atmosphere at room temperature and irradiating light with a blue LED (18 W) The reaction was carried out for 6 hours. This gave 2-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 2] Preparation of 3,5-dimethoxy-2-(trifluoromethyl)benzene-1,4-diol

The reaction was carried out in the same manner as in Example 1, except that 2,6-dimethoxybenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 3,5-dimethoxy-2-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 3]

The reaction was carried out in the same manner as in Example 1, except that 2-chlorobenzoquinone was used instead of 1,4-benzoquinone as a starting material. Thus, a compound represented by the following Chemical Formula 1-3 was synthesized. (Existing as a mixture with Example 4)

[Formula 1-3]

[Example 4]

The reaction was carried out in the same manner as in Example 1, except that 2-chlorobenzoquinone was used instead of 1,4-benzoquinone as a starting material. Thus, a compound represented by the following Chemical Formula 1-4 was synthesized. (Existing as a mixture with Example 3)

[Formula 1-4]

[Example 5]

The reaction was carried out in the same manner as in Example 1, except that 2,6-dichlorobenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 2,6-dimethyl-4-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 6] Preparation of 2-chloro-3-(trifluoromethyl)benzene-1,4-diol

The reaction was carried out in the same manner as in Example 1, except that 2-chlorobenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 2-chloro-3-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 7] Preparation of 3,5-dimethyl-2-(trifluoromethyl)benzene-1,4-diol

The reaction was carried out in the same manner as in Example 1, except that 2,6-dimethylbenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 3,5-dimethyl-2-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 8] Preparation of 2,5-dimethyl-2-(trifluoromethyl)benzene-1,4-diol

The reaction was carried out in the same manner as in Example 1, except that 2,5-dimethylbenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 2,5-dimethyl-2-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 9] Preparation of 2-methyl-3-(trifluoromethyl)benzene-1,4-diol

The reaction was carried out in the same manner as in Example 1, except that 2-methylbenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 2-methyl-3-(trifluoromethyl)benzene-1,4-diol (in admixture with 2-methylhydroquinone) as a white solid.

[Example 10] Preparation of 2-methyl-5-(trifluoromethyl)benzene-1,4-diol

The reaction was carried out in the same manner as in Example 1, except that 2-methylbenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave a mixture of 2-methyl-5-(trifluoromethyl)benzene-1,4-diol and 2-methyl-6-(trifluoromethyl)benzene-1,4-diol as a white solid.

[Example 11] Preparation of 3,5-dichloro-4- (trifluoromethoxy) phenol

The reaction was carried out in the same manner as in Example 1, except that 2,5-dichlorobenzoquinone was used instead of 1,4-benzoquinone as a starting material. This gave 3,5-dichloro-4-(trifluoromethoxy)phenol as a white solid.

[Comparative Example 1]

As Comparative Example 1, a hydroquinone compound represented by the following Chemical Formula 3 was prepared.

[Formula 3]

[Comparative Example 2]

As Comparative Example 2, 1,2-hexanediol represented by the following Chemical Formula 4 was prepared.

[Formula 4]

Experimental Example 1: Preparation of cell suspension

In the antibacterial experiments of the compounds of Examples 1 to 6 and Comparative Examples 1 and 2 of the present invention, Saccharomyces cerevisiae B4742, Cryptococcus neoformans H99 (ATCC 208821), Candida albicans (Korea Center for Microorganisms, KCTC 7729), Aspergillus niger (Korea Microorganism Conservation Center) , KCCM 11239) was used as a test cell. S. cerevisiae , C. neoformans , C. albicans strains were cultured in Yeast extract-Peptone-Dextrose (YPD) solid medium (yeast extract 1%, bacto-peptone 2%, glucose 2% and agar 2%) for 48 hours. , A. niger were cultured in Potato Dextrose Agar (PDA, potato dextrose agar) solid medium for 4-5 days before testing. The number of yeast cells was adjusted to account for an OD ₆₀₀ =1.0 equivalent to a cell of 3.0 Х 10 ⁷ .

Fungal cells were harvested from A. niger plate cultures by lifting them with sterile saline containing 0.01% (v/v) Triton X-100 and removing spores from the mycelium using a sterile spreader. The spore-bearing solution was filtered through a cell strainer to separate the mycelium present. The spore count was adjusted to be considered equivalent to 4.3 Х 10 ⁶ spores/mL (Petrikkou E. et al., J. Clin. Microbiol. 2001, 39(4):1345-1347) at OD ₅₃₀ =0.5. The cells thus prepared were maintained at 4 °C until further use.

Experimental Example 2: Analysis of liquid sterilization effect

For the antibacterial sensitivity test by the broth microdilution method, all strains prepared in Experimental Example 1 were used to test according to the regulations of the European Antimicrobial Sensitivity Test Committee (EUCAST).

Examples 1 to 6 antibacterial substances synthesized in the present invention, and the standard solutions of Comparative Examples 1 to 2 were prepared by mixing in the culture solution, and then serially diluted in the culture solution to adjust the final concentration range to 4 - 0.0625 mg/mL did. The culture medium used was YPD broth (1% yeast extract, 2% bacto-peptone, 2% glucose) for yeast species, and Potato Dextrose Broth (PDB) for A. niger .

Specifically, it was cultured using a sterilized test tube so as to overlap three times for each sample. The mixed solution was incubated at 30 °C for 24-48 hours after inoculating the desired number of bacteria per each test tube. The yeast cells of 1.0 Х 10 ⁵ cells per ml were serially diluted and inoculated at 0.1 mL each. On the other hand, the compounds according to the embodiment of the present invention were serially diluted with 1.0 Х 10 ⁴ pieces/ml mold spores and inoculated by 0.1 mL each. Then, the cell concentration was observed at OD ₆₀₀ in order to evaluate the minimum inhibitory concentration by the compound of the present invention.

1 shows the compounds synthesized according to Examples 1 to 6 and Comparative Examples 1 and 2 in various concentrations (0, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 mg/mL) in a culture medium of yeast S. cerevisiae In addition, it shows the result of observing the absorbance at 600 nm to observe the bactericidal effect while culturing for 48 hours.

Referring to FIG. 1, it was confirmed that the sterilizing power of the compounds of the present invention was significantly superior to that of the hydroquinone of Comparative Example 1 and the 1,2-hexanediol of Comparative Example 2.

Figure 2 shows the compounds synthesized according to Examples 1 to 6 and Comparative Examples 1 and 2 at various concentrations (0, 4, 2, 1, 0.5, 0.25, 0.25, 0.125, 0.0625 mg/mL in the culture medium of the fungus C. neoformans ) ), and shows the result of observing the absorbance at 600 nm to observe the sterilization effect while culturing for 48 hours.

As shown in FIG. 2, it was confirmed that the sterilizing power of the compounds of the present invention was somewhat superior to that of the hydroquinone of Comparative Example 1 and the 1,2-hexanediol of Comparative Example 2.

3 shows the compounds synthesized according to Examples 1 to 6 and Comparative Examples 1 to 2 in various concentrations (0, 4, 2, 1, 0.5, 0.25, 0.25, 0.125, 0.0625 mg/mL in a culture medium of yeast C. albicans ) ), and the absorbance was observed at 600 nm to observe the sterilization effect while culturing for 48 hours.

Referring to FIG. 3, it was confirmed that the sterilizing power of the compounds of the present invention was significantly superior to that of hydroquinone and 1,2-hexanediol.

Figure 4 shows the compounds synthesized according to Examples 1 to 6 and Comparative Examples 1 to 2 in various concentrations (0, 4, 2, 1, 0.5, 0.25, 0.25, 0.125, 0.0625 mg/mL in the culture medium of the fungus A. niger ) ) was added and the absorbance was observed at 600 nm to observe the sterilization effect while culturing for 48 hours. could

5 is a graph comparing the sterilization effect by concentration of each compound for four types of cells.

Referring to FIG. 5 , it was confirmed that the sterilizing power of Examples 1 to 6 of the present invention was higher than those of Comparative Examples 1 and 2 for all yeast and mold bacteria. In particular, Example 5 (DS5105) and Example 6 (DS5148) exhibited superior sterilization power compared to Comparative Examples 1 and 2 even at low concentrations, from which a trifluoro group (-CF ₃ ) is introduced into hydroquinone. It was confirmed that there was an effect of remarkably enhancing the antibacterial effect of quinone.

In this experimental example, the sterilization power against two types of yeast bacteria ( S. cerevisiae , C. albicans ) and two types of fungi ( C. neoformans , A. niger ) was examined, but the It is obvious to a person having ordinary knowledge in this field that the same result can be obtained even if it is used for

Although the above has been described with reference to the preferred embodiment of the present invention, those skilled in the art can variously modify and change the present invention without departing from the spirit and scope of the present invention as set forth in the claims below. You will understand that you can.

Claims (7)

1. An antibacterial agent comprising a trifluoromethylated hydroquinone derivative represented by the following formula (1):

   [Formula 1]

   

   In Formula 1,

   R ₁ , R ₂ , R _{3 ,} and R ₄ are each independently selected from hydrogen, alkyl having 1 to 10 carbon atoms, alkoxy having 1 to 10 carbon atoms, halogen, and —CF ₃ , with the proviso that R ₁ , R ₂ any one of , R _{3 ,} and R ₄ is —CF ₃ .
2. According to claim 1,

   Any one of R ₁ , R ₂ , R _{3 ,} and R ₄ is —CF ₃ , and the remainder is hydrogen or a linear or branched alkoxy having 1 to 10 carbon atoms.
3. According to claim 1,

   Any one of R ₁ , R ₂ , R _{3 ,} and R ₄ is —CF ₃ , and the remainder is hydrogen or halogen.
4. According to claim 1,

   Any one of R ₁ , R ₂ , R _{3 ,} and R ₄ is —CF ₃ , and the rest is hydrogen or a straight-chain or branched alkyl having 1 to 10 carbon atoms.
5. According to claim 1,

   An antibacterial agent comprising a trifluoromethylated hydroquinone derivative represented by any one of the following formulas 1-1 to 1-14:

   [Formula 1-1]

   

   [Formula 1-2]

   

   [Formula 1-3]

   

   [Formula 1-4]

   

   [Formula 1-5]

   

   [Formula 1-6]

   

   [Formula 1-7]

   

   [Formula 1-8]

   

   [Formula 1-9]

   

   [Formula 1-10]

   

   [Formula 1-11]

   

   [Formula 1-12]

   

   [Formula 1-13]

   

   [Formula 1-14]

   
6. An antibacterial agent comprising a trifluoromethylated hydroquinone derivative represented by the following formula (2):

   [Formula 2]

   

   In Formula 2,

   R ₁₁ , R ₁₂ , R _{13 ,} and R ₁₄ are each independently selected from hydrogen or halogen, provided that at least one of R ₁₁ , R ₁₂ , R _{13 ,} and R ₁₄ is halogen.
7. The antibacterial agent according to claim 6, characterized in that it comprises a trifluoromethylated hydroquinone derivative represented by the following formula 2-1 or 2-2:

   [Formula 2-1]

   

   [Formula 2-2]

   

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