Phenylpyridine quaternary ammonium salt derivative as well as preparation method and application thereof

Abstract

The invention belongs to the field of novel medicine compounds, and particularly relates to phenylpyridine quaternary ammonium salt derivatives and a preparation method and application thereof. The phenylpyridine quaternary ammonium salt derivative disclosed by the invention is selected from a compound as shown in a formula I or a formula II or a formula III or pharmaceutically acceptable salt or ester or solvate, tautomer, meracemate, racemate, stereoisomer, metabolite or prodrug of the compound, or pharmaceutically acceptable salt or ester or solvate, tautomer, meracemate, racemate, stereoisomer, metabolite or prodrug of the compound. The structure of the compounds shown in the formulas I, II and III is shown in the specification: # imgabs0 is completely different from that of a reported FtsZ inhibitor parent nucleus and has different physicochemical properties, and experiments show that the derivative has an effect of inhibiting FtsZ, can be used as a novel FtsZ inhibitor and also has good antibacterial activity.

Description

Technical Field

[0001] The invention belongs to the field of new drug compounds and relates to phenylpyridine quaternary ammonium salt derivatives and preparation methods and applications thereof. Background Art

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Rapid access to effective treatment modalities during outbreaks of novel pathogens or surges in antimicrobial resistance remains limited. Therefore, there is a need to increase investment in the development of innovative antimicrobials with new mechanisms to revolutionize traditional approaches to bacterial treatment and slow the rate of resistance evolution.

[0004] Filamentous temperature-sensitive protein Z (FtsZ) plays a key role in regulating the formation of the Z-ring structure that is essential for bacterial cell division. Early in the division process, FtsZ assembles into a ring-shaped structure called the Z-ring, which is strategically located at the site of future division within the cell. This Z-ring serves as the starting point for cell division and guides the synthesis of new cell wall and membrane components. In addition, FtsZ is widely distributed among bacterial species, suggesting that antimicrobial drugs targeting this target may have broad-spectrum antimicrobial activity, thereby enhancing efficacy against different bacterial strains and expanding the therapeutic range. Exploiting the complex mechanism of FtsZ in bacterial division has important potential for developing new strategies to combat bacterial infections and improve patient outcomes. Summary of the invention

[0005] In order to solve the deficiencies of the prior art, the present invention aims to provide phenylpyridine quaternary ammonium salt derivatives and preparation methods and applications thereof. The derivatives are completely different from the reported FtsZ inhibitor nucleus structure and have different physical and chemical properties. Experiments have shown that the derivatives have the effect of inhibiting FtsZ, can be used as new FtsZ inhibitors, and also have good antibacterial activity.

[0006] In order to achieve the above object, the technical solution of the present invention is:

[0007] In the first aspect, the present invention provides a phenylpyridinium quaternary ammonium salt derivative, wherein the phenylpyridinium quaternary ammonium salt derivative is selected from the compound represented by Formula I, Formula II or Formula III, or a pharmaceutically acceptable salt or ester or solvate, tautomer, mesomer, racemate, stereoisomer, metabolite or prodrug thereof;

[0008] The structures of the compounds represented by formula I, II and III are as follows:

[0009]

[0010] Among them, R 1 R is selected from hydrogen, C1-C8 straight chain or branched alkyl and C1-C8 straight chain or branched alkoxy; 2 is selected from aromatic hetero groups and substituted aromatic hetero groups; X is -NH- or -O-; Y is halogen or benzenesulfonic acid, that is, is a halogen ion or a benzenesulfonate anion; Z 1 -N- or -C-; Z 2 -N- or -O-; R 3 Z is a C1-C8 straight or branched alkyl, a C1-C5 straight or branched alkyl substituted cycloalkyl, or a C1-C5 straight or branched alkyl substituted benzyl; 3 -N- or -C-; R 4 It is guanidine or none.

[0011] In some embodiments, R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy. 2 wherein the aromatic hetero group is selected from isoquinoline, benzothiazole, benzoxazole, indole, dihydrobenzofuran, 2,3-dihydro-1H-indene and thiazole; the substituted aromatic hetero group is an aromatic hetero group substituted by one or more substituents selected from C1-C8 straight or branched alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted by C1-C3 alkyl, phenyl, phenyl substituted by one or more C1-C5 straight or branched alkyl; preferably, R 2 is selected from the group consisting of isoquinolin-7-yl, 2-methylbenzo[d]thiazol-5-yl, 2-isopropylbenzo[d]oxazol-5-yl, 2-propylbenzo[d]oxazol-5-yl, 2-phenylbenzo[d]oxazol-5-yl, 2-butylbenzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, 1H-indol-5-yl, 1-octyl-1H-indol-5-yl, 1-(4-tert-butylbenzyl)-1H-indol-5-yl, 1- (2-cyclohexylethyl)-1H-indol-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydro-1H-inden-5-yl, benzo[d]thiazol-2-methyl, thiazol-2-methyl, 4-(2-isobutylthiazol-5-yl)phenyl, 4-(2-isopropyl-4-methylthiazol-5-yl)phenyl, 4-(2-isobutyl-4-methylthiazol-5-yl)phenyl and 4-(2-phenylthiazol-5-yl)phenyl. Y is halogen, preferably I. R 3 Selected from 1-octyl, 1-(4-tert-butylbenzyl), 1-(2-cyclohexylethyl), 2-propyl and 2-butyl.

[0012] Preferably, Selected from 1-octyl-1H-indol-6-yl, 1-(4-tert-butylbenzyl)-1H-indol-5-yl, 1-(2-cyclohexylethyl), 2-propylbenzo[d]oxazol-5-yl and 2-butylbenzo[d]oxazol-5-yl.

[0013] Further, Formula I has the structure shown in Formula IA, Formula IB, Formula IC or Formula ID:

[0014]

[0015] In the structure shown in Formula IA, n is 0 or 1, X is -NH- or -O-; R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy. 2a is selected from isoquinolin-7-yl, 2-methylbenzo[d]thiazol-5-yl, benzo[d]oxazol-6-yl, 2-phenylbenzo[d]oxazol-5-yl, 1H-indol-5-yl, 1-octyl-1H-indol-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydro-1H-inden-5-yl, benzo[d]thiazol-2-yl, thiazol-2-yl. Preferably, in the structure of formula IA, n is 1, R 2a is selected from benzo[d]thiazol-2-yl and thiazol-2-yl; preferably, in the structure of formula IA, n is 0, R 2a is selected from isoquinolin-7-yl, 2-methylbenzo[d]thiazol-5-yl, benzo[d]oxazol-6-yl, 2-phenylbenzo[d]oxazol-5-yl, 1H-indol-5-yl, 1-octyl-1H-indol-5-yl, 2,3-dihydrobenzofuran-5-yl and 2,3-dihydro-1H-inden-5-yl.

[0016] Among them, in the structure shown in Formula IB, R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy; R 2b is selected from C1-C8 straight or branched alkyl and phenyl, preferably isobutyl, isopropyl or phenyl; R 2c It is selected from hydrogen, C1-C8 straight or branched chain alkyl, preferably hydrogen or methyl.

[0017] Among them, in the IC structure, R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy; R 2d It is selected from hydrogen, C1-C8 straight or branched alkyl and phenyl, preferably hydrogen, isopropyl, n-propyl, n-butyl or phenyl.

[0018] Among them, in the structure of formula ID, R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy; R 2eBenzyl substituted with C1-C8 straight or branched chain alkyl, cycloalkylethyl and C1-C5 branched or branched chain alkyl, preferably hydrogen, n-octyl, 4-tert-butylbenzyl or 2-cyclohexylethyl.

[0019] Furthermore, the compound represented by formula I is one of the following:

[0020]

[0021]

[0022] Furthermore, the compound represented by formula II is one of the following:

[0023]

[0024] Further, the compound represented by formula III includes formula III-1 and formula III-2, when Z 3 For N, the R 4 , when the site does not have a group, the compound structure is shown in the following formula III-1; when the Z 3 is C; R 4 When it is a guanidine group, the compound structure is shown in the following formula III-2.

[0025]

[0026] In a second aspect, the present invention provides a method for preparing the above-mentioned phenylpyridine quaternary ammonium salt derivatives, wherein:

[0027] The phenylpyridine quaternary ammonium salt derivative has a structure shown in Formula I, and the preparation method is carried out according to the following reaction route:

[0028]

[0029] Among them, R 1 , Y, X, and R 2 As defined above. Formula I has the structure shown in Formula IA, Formula IB, Formula IC or Formula ID, then specifically, Figure 1 As shown:

[0030] The preparation method of the compound represented by Formula IA is shown in reaction schemes I-1 to 18, and is carried out through steps a, b, and c. The specific steps are as follows:

[0031] The operation method of step a is as follows: compound 1 is dissolved in a mixed solvent of 1,4-dioxane:H2O, K2CO3 and phenylboronic acid analogs are added under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and heated to react to generate intermediates 2a-2c; further, the heating temperature is 70-90°C, and the reaction time is 6-12 hours;

[0032] The operation method of step b is as follows: dissolving intermediates 2a-2c in a polar aprotic solvent, adding an excess of an iodine-containing reagent, and reacting for a period of time to obtain intermediates 3a-3c; further, the reaction temperature is preferably 42-80° C.;

[0033] The operation method of step c is as follows: intermediate 3a-3c is dissolved in acetonitrile solvent, commercial amino aromatic heterocyclic reagent and triethylamine are added, and heated to react to generate compound 4a-4r, i.e., compound represented by formula IA in general formula I;

[0034] The structural formulas of the compound 1, intermediates 2a-2c, intermediates 3a-3c and formula IA are shown below in sequence:

[0035]

[0036] Furthermore, the preparation method of the compound represented by formula IB is shown in reaction schemes I-19 to 25, and is carried out through steps a, b and steps d, e, and c. The specific steps are as follows:

[0037] The operation method of step a is as follows: compound 1 is dissolved in a mixed solvent of 1,4-dioxane:H2O, K2CO3 and phenylboronic acid analogs are added under the catalysis of [1,1'-(diphenylphosphino)ferrocene]palladium dichloride, and heated to react to generate intermediates 2a-2c; further, the heating temperature is 70-90°C, and the reaction time is 6-12 hours;

[0038] The operation method of step b is as follows: dissolving intermediates 2a-2c in a polar aprotic solvent, adding an excess of an iodine-containing reagent, and reacting for a period of time to obtain intermediates 3a-3c; further, the reaction temperature is preferably 42-80° C.;

[0039] The operation method of step d is as follows: compound 5 is dissolved in water, and Ag2CO3 is added under the catalytic conditions of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and triphenylphosphine, and heated to react to generate intermediates 6a-6c; further, the heating temperature is 60°C;

[0040] The operation method of step e is as follows: dissolving intermediates 6a-6c in a mixed solution of ethanol:H2O, adding Fe powder and NH4Cl, and heating to react to generate intermediates 7a-7c; further, the heating temperature is 50°C;

[0041] The operation method of step c is as follows: intermediates 3a-3c are dissolved in acetonitrile solvent, intermediates 7a-7c and triethylamine are added, and heated to react to generate compounds 8a-8g, i.e. compounds represented by formula IB in general formula I;

[0042] The structural formulas of the compound 1, intermediates 2a-2c, intermediates 3a-3c, compound 5, intermediates 6a-6c, intermediates 7a-7c and formula IB are shown below in sequence:

[0043]

[0044] Furthermore, the preparation method of the compound represented by Formula IC is shown in reaction schemes I-26 to 39, and is carried out through steps a, b and steps f, g, and c. The specific steps are as follows:

[0045] The operation method of step a is as follows: compound 1 is dissolved in a mixed solvent of 1,4-dioxane:H2O, K2CO3 and phenylboronic acid analogs are added under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and heated to react to generate intermediates 2a-2c; further, the heating temperature is 70-90°C, and the reaction time is 6-12 hours;

[0046] The operation method of step b is as follows: dissolving intermediates 2a-2c in a polar aprotic solvent, adding an excess of an iodine-containing reagent, and reacting for a period of time to obtain intermediates 3a-3c; further, the reaction temperature is preferably 42-80° C.;

[0047] The operation of step f is as follows: dissolving compound 9 in ethanol, adding 1,1,1-triethoxybutane analog, and heating under NH4Cl catalysis to generate intermediates 10a-10d; further, the heating temperature is reflux condition;

[0048] The operation method of step g is as follows: intermediates 10a-10d are dissolved in ethanol, and heated and reduced under Pd / C catalysis and H2 atmosphere to generate intermediates 11a-11d; further, the heating temperature is reflux condition;

[0049] The operation method of step c is as follows: intermediates 3a-3c are dissolved in acetonitrile solvent, intermediates 11a-11d and triethylamine are added, and heated to react to generate compounds 12a-12n, i.e. compounds represented by formula IC in general formula I;

[0050] The structural formulas of the compound 1, intermediates 2a-2c, intermediates 3a-3c, compound 9, intermediates 10a-10d, 11a-11d and formula IC are shown below in sequence:

[0051]

[0052] Furthermore, the preparation method of the compound represented by formula ID is shown in reaction schemes I-40 to 45, and is carried out through steps a, b and steps h, i, and c. The specific steps are as follows:

[0053] The operation method of step a is as follows: compound 1 is dissolved in a mixed solvent of 1,4-dioxane:H2O, K2CO3 and phenylboronic acid analogs are added under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and heated to react to generate intermediates 2a-2c; further, the heating temperature is 70-90°C, and the reaction time is 6-12 hours;

[0054] The operation method of step b is as follows: dissolving intermediates 2a-2c in a polar aprotic solvent, adding an excess of an iodine-containing reagent, and reacting for a period of time to obtain intermediates 3a-3c; further, the reaction temperature is preferably 42-80° C.;

[0055] The operation of step h is as follows: compound 13 is dissolved in anhydrous DMF solvent, a brominated alkane analog is added, and intermediates 14a-14d are generated at low temperature under the catalytic condition of NaH; further, the low temperature is 0°C;

[0056] The operation method of step i is as follows: intermediates 14a-14d are dissolved in ethanol, and heated and reduced under Pd / C catalysis and H2 atmosphere to generate 15a-15d; further, the heating temperature is reflux condition;

[0057] The operation method of step c is as follows: intermediates 3a-3c are dissolved in acetonitrile solvent, intermediates 15a-15d and triethylamine are added, and heated to react to generate compounds 16a-16f, i.e. compounds represented by formula ID in general formula I;

[0058] The structural formulas of the compound 1, intermediates 2a-2c, intermediates 3a-3c, compound 13, intermediates 14a-14d, 15a-15d and formula ID are shown below in sequence:

[0059]

[0060]

[0061] Furthermore, the phenylpyridine quaternary ammonium salt derivative has a structure shown in Formula II, and the preparation method is carried out according to the following reaction route: Among them, R 3 , Y, Z 1 and Z 2 As defined above.

[0062] The preparation method of the compound represented by formula II is as shown in reaction schemes II-1 to II-5, and comprises steps a, b, and c. Figure 2 The specific preparation method steps are as follows:

[0063] The operation method of step a is as follows: compound 17 is dissolved in a mixed solvent of 1,4-dioxane:H2O, K2CO3 and phenylboric acid are added under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and heated to react to generate intermediate 18; further, the heating temperature is 70-90°C, and the reaction time is 6-12 hours;

[0064] The operation of step b is as follows: dissolving the intermediate 18 in a polar aprotic solvent, adding an excess of an iodine-containing reagent, and reacting for a period of time to obtain the intermediate 19; further, the reaction temperature is preferably 42 to 80°C;

[0065] The operation method of step c is as follows: intermediate 19 is dissolved in acetonitrile solvent, intermediate 11a-11d or 15a-15d and triethylamine are added, and heated to react to generate compound 20, i.e., the compound represented by general formula II;

[0066] The structural formulas of the compound 17, intermediate 18, intermediate 19, 11a-11d, 15a-15d and formula II are shown below in sequence:

[0067]

[0068] Wherein, the preparation method of 15a-15d comprises the following steps:

[0069] The operation of step h is as follows: compound 13 is dissolved in anhydrous DMF solvent, a brominated alkane analog is added, and intermediates 14a-14d are generated at low temperature under the catalytic condition of NaH; further, the low temperature is 0°C;

[0070] The operation method of step i is as follows: intermediates 14a-14d are dissolved in ethanol, and heated and reduced under Pd / C catalysis and H2 atmosphere to generate 15a-15d; further, the heating temperature is reflux condition;

[0071] The structural formulas of the compound 13, intermediates 14a-14d and 15a-15d are shown below:

[0072]

[0073] The preparation method of 11a-11d comprises the following steps:

[0074] The operation of step f is as follows: dissolving compound 9 in ethanol, adding 1,1,1-triethoxybutane analog, and heating under NH4Cl catalysis to generate intermediates 10a-10d; further, the heating temperature is reflux condition;

[0075] The operation method of step g is as follows: the intermediates 10a-10d are dissolved in ethanol, and heated and reduced under Pd / C catalysis and H2 atmosphere to generate 11a-11d; further, the heating temperature is reflux condition;

[0076] The structural formulas of the compound 9, intermediates 10a-10d and 11a-11d are shown below:

[0077]

[0078] Furthermore, the phenylpyridine quaternary ammonium salt derivative has a structure shown in Formula III, and Formula III is selected from Formula III-1 and Formula III-2:

[0079] The preparation method of formula III-1 is carried out according to the following reaction route:

[0080]

[0081] The preparation method of formula III-2 is carried out according to the following reaction route:

[0082]

[0083] Specifically, the compound represented by formula III-1 is Figure 3 As shown, the preparation method includes steps a and b, and the specific steps are as follows:

[0084] The operation method of step a is as follows: Compound 17 and 1-(2-cyclohexylethyl)-1H-indol-5-amine are dissolved in toluene, and a Buchwald–Hartwig coupling reaction is carried out under the conditions of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, NaOtBu, and bisdibenzylideneacetone palladium, and the mixture is heated to generate intermediate 21; further, the heating temperature is 100° C.;

[0085] The operation method of step b is as follows: the intermediate 21 is dissolved in a mixed solvent of 1,4-dioxane:H2O, K2CO3 and phenylboric acid are added under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and the reaction is heated to generate compound 22, i.e., the compound represented by formula III-1; further, the heating temperature is 70-90°C, and the reaction time is 6-12 hours;

[0086] The structural formulas of the compound 17, intermediate 21 and formula III-1 are shown below in sequence:

[0087]

[0088] Furthermore, the compound represented by formula III-2 is Figure 3 As shown, it includes steps c, d, e, f and g, and the specific preparation method steps are as follows:

[0089] The operation method of step c is as follows: Compound 23 and 1-(2-cyclohexylethyl)-1H-indol-5-amine are dissolved in toluene, and a Buchwald–Hartwig coupling reaction is carried out under the conditions of 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, NaOtBu, and bisdibenzylideneacetone palladium, and the mixture is heated to generate intermediate 24; further, the heating temperature is 100° C.;

[0090] The operation method of step d is as follows: the intermediate 24 is dissolved in a mixed solvent of 1,4-dioxane:H2O, K2CO3 and phenylboric acid are added under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and the reaction is heated to generate the intermediate 25; further, the heating temperature is 70-90°C, and the reaction time is 6-12 hours;

[0091] The operation of step e is as follows: the intermediate 25 is dissolved in ethanol:H2O=1 / 1, and heated and reduced in the presence of Fe and NH4Cl to generate the intermediate 26; further, the heating temperature is a reflux condition, and the temperature is 80°C;

[0092] The operation of step f is as follows: intermediate 26 is dissolved in chloroform, and N,N'-di-Boc-1H-1-guanidinopyrazole is added to react to generate intermediate 27;

[0093] The operation of step g is as follows: intermediate 27 is deprotected from Boc protecting group in the presence of TFA to generate compound 28, i.e., the compound represented by formula III-2;

[0094] The structural formulas of the compound 23, intermediate 24, intermediate 25, intermediate 26, intermediate 27 and formula III-2 are shown below in sequence:

[0095]

[0096] The above-mentioned "the heating temperature is a reflux condition" specifically refers to a reaction heating temperature of 60-80°C, preferably 60°C.

[0097] In a third aspect, the present invention provides a composition comprising the phenylpyridinium quaternary ammonium salt derivative described in the first aspect, or further comprising an auxiliary material.

[0098] The "composition" or "pharmaceutical composition" of the present invention can be used to treat or prevent the diseases of the present invention in a subject, especially a mammal. In the pharmaceutical composition, the phenylpyridinium quaternary ammonium salt derivative described in the first aspect is used as an active ingredient, which should be a synergistic effective dose, and the drug dose belongs to the technical content of the art that can be determined by conventional technical means.

[0099] In addition, the active ingredients of the pharmaceutical composition may include, in addition to the phenylpyridinium quaternary ammonium salt derivatives described in the first aspect, other ingredients having antibacterial or auxiliary antibacterial effects.

[0100] As described herein, the term "pharmaceutically acceptable" or "pharmaceutically usable" which is used interchangeably therewith, for example, when describing a "pharmaceutically acceptable salt", means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic substance that has pharmaceutical use value, such as a salt formed as an intermediate when performing chiral resolution. Although the salt of this intermediate cannot be directly administered to the subject, the salt can play a role in obtaining the final product of the present invention.

[0101] The pharmaceutical composition of the compound of the present invention can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal or intracranial injection or input, or medication by means of an explanted reservoir, wherein oral, intramuscular, intraperitoneal or intravenous medication is preferred. Specifically, the dosage form of the pharmaceutical composition can be a liquid dosage form or a solid dosage form. The liquid dosage form can be a true solution, a colloid, a microparticle dosage form, an emulsion dosage form, or a suspension dosage form. Other dosage forms include tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, freeze-dried powder injections, inclusion compounds, landfills, patches, liniments, etc.

[0102] The pharmaceutical composition of the present invention may also contain a common carrier, wherein the pharmaceutically acceptable carrier includes but is not limited to: an ion exchanger, aluminum oxide, aluminum stearate, lecithin, serum protein such as human serum protein, a buffer such as phosphate, glycerol, sorbitan, potassium sorbate, a partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silicon oxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin, etc. The content of the carrier in the pharmaceutical composition may be 1% by weight to 98% by weight, usually accounting for about 80% by weight. For convenience, local anesthetics, preservatives, buffers, etc. may be directly dissolved in the carrier.

[0103] In a fourth aspect, the present invention provides a preparation comprising the phenylpyridinium quaternary ammonium salt derivative described in the first aspect or the composition described in the third aspect.

[0104] In a fifth aspect, the present invention provides the use of the phenylpyridinium quaternary ammonium salt derivatives described in the first aspect, the composition described in the third aspect, or the preparation described in the fourth aspect in the preparation of an antibacterial product. The antibacterial product is an antibacterial product.

[0105] The bacteria are sensitive bacteria and drug-resistant bacteria. The sensitive bacteria are Bacillus subtilis ATCC9372 (a penicillin-sensitive strain), Bacillus pumilus CMCC63202), Staphylococcus aureus ATCC25923 (an erythromycin-sensitive strain), Streptococcus pyogenes 1 (an erythromycin-sensitive strain), Enterococcus faecium ATCC19434 (a vancomycin-sensitive strain), Enterococcus faecalis ATCC29212 (a vancomycin-sensitive strain), Acinetobacter baumannii ATCC19606 (a standard strain), Pseudomonas aeruginosa ATCC27853 (a penicillin-sensitive strain) and Escherichia coli ATCC27853 (a penicillin-sensitive strain). ATCC25922, a penicillin-sensitive strain), the resistant bacteria are one or more of Staphylococcus aureus (S.aureus ATCC43300, a methicillin-resistant strain), Staphylococcus aureus (S.aureus PR, a penicillin-resistant strain), Staphylococcus aureus (S.aureus CI, a clinically isolated resistant strain), Staphylococcus epidermidis (S.epidermidis, a penicillin-resistant strain), resistant Streptococcus pyogenes (S.pyogenes 2, an erythromycin-resistant strain), Enterococcus faecalis (E.faecalis ATCC51299, a vancomycin-resistant strain) and Enterococcus faecium (E.faeciumATCC51559, a vancomycin-resistant strain).

[0106] The antibacterial products include but are not limited to one or more of medicines, toiletries, medical devices, kitchen utensils, food preservatives, and dining utensils; the toiletries include one or more of fruit and vegetable cleaners, shampoo, soap, shower gel, laundry detergent, hand soap, toilet cleaner, and facial cleanser.

[0107] In a sixth aspect, the present invention provides a method for inhibiting Gram-positive bacteria, the method comprising applying the phenylpyridinium quaternary ammonium salt derivative described in the first aspect and / or the composition described in the third aspect and / or the preparation described in the fourth aspect to the surface to be inhibited.

[0108] The beneficial effects achieved by one or more of the above technical solutions are as follows:

[0109] (1) The phenylpyridinium quaternary ammonium salt derivatives, pharmaceutical compositions and drugs provided by the present invention are effective against Bacillus subtilis ATCC9372 (a penicillin-sensitive strain), Bacillus pumilus CMCC63202, Staphylococcus aureus ATCC25923 (an erythromycin-sensitive strain), Streptococcus pyogenes 1 (an erythromycin-sensitive strain), Enterococcus faecium ATCC19434 (a vancomycin-sensitive strain), Enterococcus faecalis ATCC29212 (a vancomycin-sensitive strain), Pseudomonas aeruginosa ATCC27853 (a penicillin-sensitive strain) and Escherichia coli ATCC25922 (a penicillin-sensitive strain), Acinetobacter baumannii ATCC25923 (an erythromycin-sensitive strain), and Enterococcus faecium ATCC19434 (a vancomycin-sensitive strain). ATCC19606, standard strain), Staphylococcus aureus (S.aureus ATCC43300, methicillin-resistant strain), Staphylococcus aureus (S.aureus PR, penicillin-resistant strain), Staphylococcus aureus (S.aureus CI, clinically isolated resistant strain), Staphylococcus epidermidis (S.epidermidis, penicillin-resistant strain), resistant Streptococcus pyogenes (S.pyogenes 2, erythromycin-resistant strain), Enterococcus faecalis (E.faecalisATCC51299, vancomycin-resistant strain) and Enterococcus faecium (E.faecium ATCC51559, vancomycin-resistant strain) have better inhibitory effects and are broad-spectrum antibacterial active ingredients.

[0110] (2) The antibacterial activity of multiple compounds in general formula I, II and III against multiple strains is better than that of positive compounds. In this series, I-44 showed significant antibacterial activity, with MIC values ​​of 0.0625 to 4 μg / mL for sensitive Gram-positive bacteria, 1 to 4 μg / mL for sensitive Gram-negative bacteria, and 0.25 to 4 μmg / mL for resistant Gram-positive bacteria. It is particularly noteworthy that the antibacterial activity of I-44 against S. aureus ATCC25923 is 0.062 μg / mL, far exceeding that of other positive compounds. For B. subtilis ATCC9372, the MIC value of I-44 is 0.5 μg / mL, which is comparable to the MIC of linezolid. In addition, the MIC of I-44 against E. coil ATCC25922 and E. coil BW25113 is 4 μg / mL, indicating its effectiveness against Gram-negative bacteria. In addition, among the positive compounds, the MIC value of I-44 against A. baumannii ATCC19606 reached 1 μg / mL, which was significantly better than linezolid, sanguinarine and berberine.

[0111] (3) Several compounds in general formulas I, II and III also have good antibacterial activity against drug-resistant strains. The antibacterial activity of various compounds of 2-phenylpyridinium quaternary ammonium salt (I-40, I-41 and I-44) against MRSA strains can reach 0.5μg / mL, which is 32 and 4 times that of ciprofloxacin and linezolid, respectively, while the MIC value of I-44 against penicillin-resistant S. aureus PR is 0.25μg / mL. In addition, I-40, I-41, I-42 and I-44 showed significant antibacterial activity against S. aureus CI, all reaching the level of 0.5μg / mL. It is worth noting that the antibacterial activity of I-41 against vancomycin-resistant E. faecalis ATCC51559 (0.5μg / mL) is 8 times that of linezolid. BRIEF DESCRIPTION OF THE DRAWINGS

[0112] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

[0113] Figure 1 The synthetic route of the phenylpyridine quaternary ammonium salt derivatives of the general formula I in the present invention;

[0114] Figure 2 The synthetic route of the phenylpyridine quaternary ammonium salt derivatives of the general formula II in the present invention;

[0115] Figure 3 The synthetic route of the phenylpyridine quaternary ammonium salt derivatives of the general formula III in the present invention;

[0116] Figure 4 The effect of the phenylpyridinium quaternary ammonium salt derivatives of the present invention on the cell morphology of Bacillus subtilis;

[0117] Figure 5 This is the effect of the phenylpyridinium quaternary ammonium salt derivatives on the polymerization of FtsZ protein in the present invention. DETAILED DESCRIPTION

[0118] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in combination with specific embodiments and comparative examples.

[0119] Example 1

[0120] Step a: Preparation of 2-(4-(tert-butyl)phenyl)-4-chloropyridine (2a)

[0121]

[0122] 2-Bromo-4-chloropyridine (5 g, 26.18 mmol), 4-tert-butylphenylboronic acid (6.9 g, 39.27 mmol), K2CO3 (7.2 g, 52.36 mmol) and PdCl2(dppf) (0.26 mmol) were dissolved in 1,4-dioxane:H2O=10:1 (100 mL) and heated to 80°C. The reaction process was monitored by thin layer chromatography. The reaction solution was distilled under reduced pressure to remove the solvent. The remaining solution was dissolved in dichloromethane, washed three times with water, and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (using petroleum ether / ethyl acetate=200:1 as eluent) to obtain 2a (5.9 g, white solid) with a yield of 92%. Similarly, 2b and 2c were prepared according to the above method with yields of 95% and 94%, respectively.

[0123] Step b: Preparation of 2-(4-(tert-butyl)phenyl)-4-chloro-1-methylpyridinium iodide (3a)

[0124]

[0125] 2-(4-(tert-butyl)phenyl)-4-chloropyridine (2 g, 8.16 mmol) was dissolved in iodomethane and the reaction solution was heated to 80°C overnight in a sealed tube. After cooling to room temperature, isopropyl ether was added to precipitate a yellow solid and the crude product 3a was obtained by filtration with a yield of 81% (1.72 g, yellow solid). Similarly, 3b and 3c were prepared according to the above method in 80% and 87%.

[0126] Step c: Preparation of 2-(4-(tert-butyl)phenyl)-1-methyl-4-(quinolin-7-amino)pyridinium iodide (I-1)

[0127]

[0128] Isoquinolin-7-amine (53.38 mg, 0.47 mmol), 3a (150 mg, 0.39 mmol) and triethylamine (0.2 ml) were dissolved in acetonitrile (10 ml) and heated to reflux. The reaction process was monitored by thin layer chromatography. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by vacuum filtration and silica gel column chromatography (dichloromethane / methanol = 15:1 as eluent) to give I-1, (yield 82% yellow solid).

[0129] Example 2

[0130] The difference from Example 1 is that in step c, isoquinolin-7-amine is replaced with an equal molar amount of 2-methylbenzo[d]thiazole-5-amine to obtain I-2.

[0131] Example 3

[0132] The difference from Example 1 is that in step c, isoquinolin-7-amine is replaced by an equal molar amount of benzo[d]oxazol-6-amine to obtain I-3.

[0133] Example 4

[0134] The difference from Example 1 is that in step c, isoquinolin-7-amine is replaced with an equal molar amount of 2-phenylbenzo[d]oxazol-6-amine to obtain I-4.

[0135] Example 5

[0136] The difference from Example 1 is that in step c, isoquinolin-7-amine is replaced by an equal molar amount of 1H-indol-5-amine to obtain I-5.

[0137] Example 6

[0138] The difference from Example 1 is that in step c, isoquinolin-7-amine is replaced by an equal molar amount of 1-octyl-1H-indol-5-amine to obtain I-6.

[0139] Example 7

[0140] The difference from Example 1 is that in step c, isoquinolin-7-amine is replaced with 2,3-dihydrobenzofuran-5-amine in an equal molar amount to obtain I-7.

[0141] Example 8

[0142] The difference from Example 1 is that in step c, isoquinolin-7-amine is replaced by an equal molar amount of 2,3-dihydro-1H-indene-5-amine to obtain I-8.

[0143] Example 9

[0144] The difference from Example 1 is that in step c, isoquinolin-7-amine is replaced with an equal molar amount of benzo[d]thiazol-2-ylmethanol to obtain I-9.

[0145] Example 10

[0146] The difference from Example 1 is that in step c, isoquinolin-7-amine is replaced with an equal molar amount of 2-methylbenzo[d]thiazol-5-ol to obtain I-10.

[0147] Embodiment 11

[0148] The difference from Example 1 is that the 4-tert-butylphenylboronic acid in step a is replaced by the same molar amount of 4-heptyloxyphenylboronic acid to obtain I-11.

[0149] Example 12

[0150] The difference from Example 1 is that the 4-tert-butylphenylboronic acid in step a is replaced by the same molar amount of 4-heptyloxyphenylboronic acid, and the isoquinolin-7-amine in step c is replaced by the same molar amount of 2-methylbenzo[d]thiazole-5-amine to obtain I-12.

[0151] Example 13

[0152] The difference from Example 1 is that the 4-tert-butylphenylboronic acid in step a is replaced by the same molar amount of 4-heptyloxyphenylboronic acid, and the isoquinolin-7-amine in step c is replaced by the same molar amount of benzo[d]oxazol-6-amine to obtain I-13.

[0153] Embodiment 14

[0154] The difference from Example 1 is that the 4-tert-butylphenylboronic acid in step a is replaced by the same molar amount of 4-heptyloxyphenylboronic acid, and the isoquinolin-7-amine in step c is replaced by the same molar amount of 2,3-dihydrobenzofuran-5-amine to obtain I-14.

[0155] Embodiment 15

[0156] The difference from Example 1 is that the 4-tert-butylphenylboronic acid in step a is replaced by the same molar amount of 4-heptyloxyphenylboronic acid, and the isoquinolin-7-amine in step c is replaced by the same molar amount of 2,3-dihydro-1H-indene-5-amine to obtain I-15.

[0157] Example 16

[0158] The difference from Example 1 is that the 4-tert-butylphenylboronic acid in step a is replaced by the same molar amount of 4-heptyloxyphenylboronic acid, and the isoquinolin-7-amine in step c is replaced by the same molar amount of benzo[d]thiazol-2-ylmethanol to obtain I-16.

[0159] Embodiment 17

[0160] The difference from Example 1 is that the 4-tert-butylphenylboronic acid in step a is replaced by the same molar amount of 4-heptyloxyphenylboronic acid, and the isoquinolin-7-amine in step e is replaced by the same molar amount of thiazol-2-ylmethanol to obtain I-17.

[0161] Embodiment 18

[0162] The difference from Example 1 is that the 4-tert-butylphenylboronic acid in step a is replaced by the same molar amount of 4-heptyloxyphenylboronic acid, and the isoquinolin-7-amine in step c is replaced by the same molar amount of 2-methylbenzo[d]thiazole-5-ol to obtain I-18.

[0163] Embodiment 19

[0164] Step d: Preparation of 2-isopropyl-4-methyl-5-(4-nitrophenyl)thiazole (6a)

[0165]

[0166] 1-iodo-4-nitrobenzene (2.5 g, 10 mmol), 2-isopropyl-4-methylthiazole (1.69 g, 12 mmol), PdCl2(dppf) (0.36 g, 0.5 mmol) and PPh3 (0.26 g, 1 mmol) and Ag2CO3 (5.52 g, 20 mmol) were dissolved in water (30 mL) and heated to 60 ° C. The reaction mixture was filtered through diatomaceous earth, and then the diatomaceous earth was washed with a 1:1 mixture of acetone and CH2Cl2. After the organic solvent was removed by concentration under reduced pressure, a slurry was obtained. CH2Cl2 and water were added for extraction, and the organic phase was retained. The residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 as eluent) to obtain 6a (yellow solid, 2.36 g) with a yield of 90%. Similarly, 6b and 6c were prepared according to the above method with yields of 87% and 89%, respectively.

[0167] Step e: Preparation of 4-(2-isopropyl-4-methylthiazol-5-yl)aniline (7a)

[0168]

[0169] 6a (1.83 g, 7 mmol), Fe (1.17 g, 21 mmol) and NH4Cl (1.12 g, 21 mol) were stirred at 50 ° C in 50 ml CH3CH2OH / H2O=2:1 solution. The reaction was detected by thin layer chromatography. After filtering the reaction solution, it was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=3:1 as eluent) to obtain 7a (yellow solid, 1.08 g) with a yield of 67%. Similarly, 7b and 7c were prepared according to the above method with yields of 75% and 71%, respectively.

[0170] Step c: Preparation of 2-(4-(tert-butyl)phenyl)-4-((4-(2-isopropyl-4-methylthiazol-5-yl)phenyl)amino)-1-methylpyridinium iodide (8a)

[0171]

[0172] 7a (90.52 mg, 0.47 mmol) and 3a (150 mg, 0.39 mmol) triethylamine (0.2 ml) were dissolved in acetonitrile (10 ml) and heated to reflux. The reaction process was monitored by thin layer chromatography. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by vacuum filtration and silica gel column chromatography (dichloromethane / methanol = 15:1 as eluent) to obtain I-19.

[0173] Embodiment 20

[0174] Different from Example 19, the 2-isopropyl-4-methylthiazole in step e is replaced by the same molar amount of 2-isobutylthiazole to obtain I-20.

[0175] Embodiment 21

[0176] Different from Example 19, the 2-isopropyl-4-methylthiazole in step e is replaced by the same molar amount of 2-isobutyl-4-methylthiazole to obtain I-21.

[0177] Embodiment 22

[0178] Different from Example 19, 3a in step c is replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridinium iodide to obtain I-22.

[0179] Embodiment 23

[0180] Different from Example 19, the 2-isopropyl-4-methylthiazole in step e is replaced by the same molar amount of 2-isobutylthiazole, and 3a in step c is replaced by the same molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridine iodide to obtain I-23.

[0181] Embodiment 24

[0182] Different from Example 19, the 2-isopropyl-4-methylthiazole in step e is replaced with the same molar amount of 2-isobutyl-4-methylthiazole, and the 3a in step c is replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridine iodide to obtain I-24.

[0183] Embodiment 25

[0184] Different from Example 19, the 2-isopropyl-4-methylthiazole in step e is replaced by 4-(2-phenylthiazol-5-yl)aniline, and 3a in step c is replaced by the same molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridine iodide to obtain I-25.

[0185] Embodiment 26

[0186] Step f: Preparation of 5-nitro-2-propylbenzo[d]oxazole (10a)

[0187]

[0188] 2-Amino-4-nitrophenol (2 g, 13 mmol), NH4Cl (0.14 g, 2.6 mmol) and triethyl propionate (5 mL) were dissolved in ethanol (30 mL). The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 3). The yield was 82% (oil, 2.19 g). Similarly, 10b, 10c and 10d were prepared according to the above method with yields of 88%, 83% and 86%, respectively.

[0189] Step g: Preparation of 2-propylbenzo[d]oxazol-5-amine (11a)

[0190]

[0191] 10a (2 g, 9.7 mmol) and Pd / C (0.1 g, 0.97 mmol) were dissolved in ethanol and stirred at room temperature overnight under H2 atmosphere. After filtration, the mixture was concentrated under reduced pressure to obtain a pure product 11a (black oil, 1.67 g) with a yield of 98%. Similarly, 11b, 11c and 11d were prepared according to the above method with yields of 96%, 95% and 94%, respectively.

[0192] Step c: Preparation of 2-(4-(tert-butyl)phenyl)-1-methyl-4-((2-propylbenzo[d]oxazol-6-yl)amino)pyridinium iodonium salt (12a)

[0193]

[0194] 3a (150 mg, 0.39 mmol), 11a (82.76 mg, 0.47 mmol) and triethylamine (0.2 mL) were dissolved in acetonitrile (10 mL) and heated to reflux. The reaction process was monitored by thin layer chromatography. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by vacuum filtration and silica gel column chromatography (dichloromethane / methanol = 15:1 as eluent) to obtain I-26.

[0195] Embodiment 27

[0196] The difference from Example 26 is that triethyl propionate is used to replace triethyl isopropionate in step f to obtain I-27.

[0197] Embodiment 28

[0198] Different from Example 26, 3a in step c is replaced with an equal molar amount of 4-chloro-1-methyl-2-(4-(hexyloxy)phenyl)pyridinium iodide to obtain I-28.

[0199] Embodiment 29

[0200] The difference from Example 26 is that triethyl propionate in step f is replaced with triethyl isopropionate, and 3a in step c is replaced with an equal molar amount of 4-chloro-1-methyl-2-(4-(hexyloxy)phenyl)pyridinium iodide to obtain I-29.

[0201] Embodiment 30

[0202] The difference from Example 26 is that triethyl propionate in step f is replaced with triethyl benzoate, and 3a in step c is replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(hexyloxy)phenyl)pyridine iodide to obtain I-30.

[0203] Embodiment 31

[0204] The difference from Example 26 is that triethyl propionate in step f is replaced with triethyl butyrate, and 3a in step c is replaced with an equal molar amount of 4-chloro-1-methyl-2-(4-(hexyloxy)phenyl)pyridinium iodide to obtain I-31.

[0205] Embodiment 32

[0206] Different from Example 26, 3a in step c is replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(heptyloxy)phenyl)pyridinium iodide to obtain I-32.

[0207] Embodiment 33

[0208] The difference from Example 26 is that triethyl propionate in step f is replaced with triethyl isopropionate, and 3a in step c is replaced with an equal molar amount of 4-chloro-1-methyl-2-(4-(heptyloxy)phenyl)pyridinium iodide to obtain I-33.

[0209] Embodiment 34

[0210] The difference from Example 26 is that triethyl propionate in step f is replaced with triethyl benzoate, and 3a in step c is replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(heptyloxy)phenyl)pyridinium iodide to obtain I-34.

[0211] Embodiment 35

[0212] Different from Example 26, triethyl propionate in step f is replaced with triethyl butyrate, and 3a in step c is replaced with an equal molar amount of 4-chloro-1-methyl-2-(4-(heptyloxy)phenyl)pyridinium iodide to obtain I-35.

[0213] Embodiment 36

[0214] Different from Example 26, 3a in step c is replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridinium iodide to obtain I-36.

[0215] Embodiment 37

[0216] Different from Example 26, triethyl propionate in step f is replaced with triethyl isopropionate, and 3a in step c is replaced with an equal molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridine iodide to obtain I-37.

[0217] Embodiment 38

[0218] The difference from Example 26 is that triethyl propionate in step f is replaced with triethyl benzoate, and 3a in step c is replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridine iodide to obtain I-38.

[0219] Embodiment 39

[0220] Different from Example 26, triethyl propionate in step f is replaced with triethyl butyrate, and 3a in step c is replaced with an equal molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridine iodide to obtain I-35.

[0221] Embodiment 40

[0222] Step h: Preparation of 1-(4-tert-butylbenzyl)-5-nitro-1H-indole (14a)

[0223]

[0224] 5-Nitro-1H-indole (1.62 g, 10 mmol), 1-bromomethyl-4-tert-butylbenzene (3.39, 15 mmol) and NaH (0.48 g, 20 mmol) were present in anhydrous DMF at low temperature. The reaction was detected by thin layer chromatography. The reaction solution was washed with CH3Cl2 and water five times, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by vacuum filtration and silica gel column chromatography (petroleum ether / ethyl acetate = 20: 1 as eluent) to obtain 14a (white solid, 2.65 g) with a yield of 86%. Similarly, 14b, 14c and 14d were prepared according to the above method with yields of 86%, 88% and 84%, respectively.

[0225] Step i: Preparation of 1-(4-(tert-butyl)benzyl)-1H-indol-5-amine (15a)

[0226]

[0227] 14a (2.3 g, 7.4 mmol) and Pd / C (0.78 g, 0.74 mmol) were dissolved in ethanol and stirred overnight at room temperature under H2 atmosphere. After filtration, the mixture was concentrated under reduced pressure to obtain the product 15a with a purity of 93% (oil, 2.21 g). Similarly, 15b, 15c and 15d were prepared according to the above method with yields of 97%, 92% and 93%, respectively.

[0228] Step c: 4-((1-(4-(tert-butyl)benzyl)-1H-indol-5-yl)amino)-2-(4-(tert-butyl)phenyl)-1-methylpyridinium iodide

[0229]

[0230] 3a (150 mg, 0.39 mmol), 15 (130.74 mg, 0.47 mmol) and triethylamine (0.2 ml) were dissolved in acetonitrile (10 ml) and heated to reflux. The reaction process was monitored by thin layer chromatography. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by vacuum filtration and silica gel column chromatography (dichloromethane / methanol = 15:1 as eluent) to obtain I-40.

[0231] Embodiment 41

[0232] The difference from Example 40 is that 1-bromomethyl-4-tert-butylbenzene in step h is replaced by phenylethyl bromide to obtain I-41.

[0233] Embodiment 42

[0234] Different from Example 40, 3a in step c is replaced by an equal molar amount of 4-chloro-1-methyl-2-phenylpyridinium iodide to obtain I-42.

[0235] Embodiment 43

[0236] The difference from Example 40 is that 1-bromomethyl-4-tert-butylbenzene in step h is replaced by bromooctane, and 3a in step c is replaced by the same molar amount of 4-chloro-1-methyl-2-phenylpyridine iodide to obtain I-43.

[0237] Embodiment 44

[0238] The difference from Example 40 is that the 1-bromomethyl-4-tert-butylbenzene in step h is replaced by phenylethyl bromide, and 3a in step c is replaced by the same molar amount of 4-chloro-1-methyl-2-phenylpyridinium iodide to obtain I-44.

[0239] Embodiment 45

[0240] The difference from Example 40 is that 1-bromomethyl-4-tert-butylbenzene in step h is replaced by H, and 3a in step c is replaced by the same molar amount of 4-chloro-1-methyl-2-phenylpyridinium iodide to obtain I-45.

[0241] The target product of general formula I, i.e., the compound formula of I-1 to I-45 is as follows Figure 1 The relevant NMR information is shown in Table 1.

[0242] Table 1. H from I-1 to I-45 1 NMR information

[0243]

[0244]

[0245]

[0246]

[0247]

[0248] Embodiment 46

[0249] Step a: Preparation of 2-chloro-4-phenylpyridine (18)

[0250]

[0251] 4-Bromo-2-chloropyridine (4.75 g, 25 mmol), phenylboronic acid (3.66 g, 30 mmol), K2CO3 (6.91 g, 50 mmol) and PdCl2(dppf) (0.18 g, 0.25 mmol) were dissolved in 1,4-dioxane:H2O=10:1 (200 mL) and heated to 80°C. The reaction process was monitored by TLC. The reactants were distilled under reduced pressure to remove the solvent. The remaining solution was dissolved in dichloromethane, washed three times with water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by vacuum filtration and silica gel column chromatography (petroleum ether / ethyl acetate=200:1 as eluent) to give 18 (4.1 g, white solid) with a yield of 87%.

[0252] Step b: Preparation of 2-chloro-1-methyl-4-phenylpyridinium iodide (19)

[0253]

[0254] 18 (3.78 g, 20 mmol) was dissolved in iodomethane and the reaction was heated to 80 °C overnight in a sealed tube. After cooling to room temperature, isopropyl ether was added to precipitate a yellow solid precipitate. The suspension was aspirated and filtered to give a yellow crude product 19 in 88% yield (5.82 g, yellow solid).

[0255] Step c: Preparation of 2-((1-(4-(tert-butyl)benzyl)-1H-indol-5-yl)amino)-1-methyl-4-phenylpyridine iodide

[0256] 15a (150.21 mg, 0.54 mmol), 19 (150 mg, 0.45 mmol) and triethylamine (0.2 ml) were dissolved in acetonitrile (10 ml) and heated to reflux. The reaction process was monitored by thin layer chromatography. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by vacuum filtration and silica gel column chromatography (dichloromethane / methanol = 15:1 as eluent) to obtain II-1.

[0257]

[0258] Embodiment 47

[0259] Different from Example 46, 15a in step c was replaced with the same molar amount of 15b to obtain II-2.

[0260] Embodiment 48

[0261] Different from Example 46, 15a in step c is replaced by the same molar amount of 15c to obtain II-3.

[0262] Embodiment 49

[0263] Different from Example 46, 15a in step c was replaced with the same molar amount of 13a to obtain II-4.

[0264] Embodiment 50

[0265] Different from Example 46, 15a in step c was replaced with 13d in the same molar amount to obtain II-5.

[0266] The target product of general formula II, i.e., the compound formula of II-1 to II-5 is as follows Figure 2 The relevant NMR information is shown in Table 2.

[0267] Table 2. H of II-1 to II-5 1 NMR information

[0268]

[0269]

[0270] Embodiment 51

[0271] Step a: Preparation of N-(2-chloropyridin-4-yl)-1-(2-cyclohexylethyl)-1H-indol-5-amine (21)

[0272]

[0273] 4-Bromo-2-chloropyridine (1 g, 5.2 mmol), 1-(2-cyclohexylethyl)-1H-indole-5-amine (1.05 g, 4.3 mmol), NaOtBu (1 g, 10.4 mmol), BINAP (2%), Pd(dba)2 (1%) were heated to reflux with stirring in toluene under nitrogen atmosphere. The reaction was detected by thin layer chromatography. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by vacuum filtration and silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 as eluent) to obtain 21 (white solid, 0.93 g) with a yield of 53%.

[0274] Step b: Preparation of 1-(2-cyclohexylethyl)-N-(2-phenylpyridin-4-yl)-1H-indol-5-amine (III-1)

[0275]

[0276] 21 (0.2 g, 0.56 mmol), phenylboronic acid (0.082 g, 0.67 mmol), K2CO3 (0.155 g, 1.12 mmol) Pd(PPh3)4 (0.064 g, 0.056 mmol) in 1,4-dioxane:H2O=10:1 (20 mL) and heated to 80°C. The reaction process was monitored by TLC. The reactants were distilled under reduced pressure to remove the solvent. The remaining solution was dissolved in dichloromethane, washed three times with water, and the organic layer was dried over anhydrous sodium sulfate and filtered. Purification by vacuum filtration and silica gel column chromatography (petroleum ether / ethyl acetate=10:1 as eluent) gave III-1 (0.104 g, brown solid) with a yield of 47%.

[0277] Embodiment 52

[0278] Step c: Preparation of 5-(3-chloro-4-nitrobenzyl)-1-(2-cyclohexylethyl)-1H-indole (24)

[0279]

[0280] 4-Bromo-2-chloro-1-nitrobenzene (2 g, 8.39 mmol), 1-(2-cyclohexylethyl)-1h-indol-5-amine (1.8 g, 7.42 mmol), NaOtBu (1.7 g, 17.8 mmol), BINAP (2%), Pd(dba)2 (1%) were heated to reflux with stirring in toluene under nitrogen atmosphere. The reaction was detected by thin layer chromatography. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dichloromethane. The organic phase was washed 3 times with water, dried over anhydrous sodium sulfate, filtered and concentrated under low pressure. The residue was purified by vacuum filtration and silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 as eluent) to obtain 24 with a yield of 62% (yellow solid, 2.06 g).

[0281] Step d: Preparation of 1-(2-cyclohexylethyl)-5-((6-nitro-[1,1'-biphenyl]-3-yl)methyl)-1H-indole (25)

[0282]

[0283] 24 (1.5 g, 3.78 mmol), phenylboronic acid (0.55 g, 4.54 mmol), K2CO3 (1.04 g, 7.58 mmol) Pd(PPh3)4 (0.042 g, 0.037 mmol) were dissolved in 1,4-dioxane:H2O=10:1 (20 mL) and heated to 80°C. The reaction process was monitored by TLC. The reactants were distilled under reduced pressure to remove the solvent. The remaining solution was dissolved in dichloromethane, washed three times with water, and the organic layer was dried over anhydrous sodium sulfate and filtered. The residue was purified by vacuum filtration and silica gel column chromatography (petroleum ether / ethyl acetate=10:1 as eluent) to obtain 25 (brown solid, 0.761 g) with a yield of 46%.

[0284] Step e: Preparation of 5-((1-(2-cyclohexylethyl)-1H-indol-5-yl)methyl)-[1,1'-biphenyl]-2-amine (26)

[0285]

[0286] 25 (0.6 g, 1.37 mmol), NH4Cl (0.22 g, 4.11 mmol), Fe (0.22 g, 4.11 mmol) were reacted in a CH3CH2OH / H2O=2:1 (15 ml) solution at 50°C. The reaction solution was aspirated and concentrated under low pressure. The residue was purified by vacuum filtration and silica gel column chromatography (petroleum ether / ethyl acetate=3:1 as eluent) to obtain 26 (white solid, 0.296 g) with a yield of 53%.

[0287] Step f: Preparation of intermediate 27

[0288]

[0289] 26 (0.25 g, 0.61 mmol) and N,N'-di-boc-1h-pyrazole-1-carboximidamide (0.38 g, 1.22 mmol) were dissolved in 10 mL CHCl3 (50 ° C) for 48 h. The reaction was detected by TCL. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 as eluent) to obtain 27 (white solid, 0.34 g) with a yield of 85%.

[0290] Step g: Preparation of 1-(5-((1-(2-cyclohexylethyl)-1H-indol-5-yl)methyl)-[1,1'-biphenyl]-2-yl)guanidine (III-2)

[0291]

[0292] After that, extract 2 was taken for 7 minutes (0.30 g, concentrated by 0.46 mol at reduced pressure) and dissolved in an organic phase to obtain C to H 2 IICIl- 2 2 (10 mL yield), 95% (on a brown FA solid, 0.19 Bogc removed). The solution pH was adjusted to neutral

[0293] The target product of general formula III, i.e., the compound formula of III-1 and III-2 is as follows Figure 3 The relevant NMR information is shown in Table 2.

[0294] Table 3. H of III-1 and III-2 1 NMR information

[0295]

[0296] Embodiment 53

[0297] In this example, compounds I-1-45, II-1-5 and III-1-2 were selected to detect the inhibitory activities against sensitive strains and resistant strains. The sensitive strains include eight sensitive strains: sensitive Bacillus subtilis ATCC9372 (a penicillin-sensitive strain), Bacillus pumilus CMCC63202, Staphylococcus aureus ATCC25923 (an erythromycin-sensitive strain), Streptococcus pyogenes 1 (an erythromycin-sensitive strain), Enterococcus faecium ATCC19434 (a vancomycin-sensitive strain), Enterococcus faecalis ATCC29212 (a vancomycin-sensitive strain), Pseudomonas aeruginosa ATCC27853 (a penicillin-sensitive strain) and Escherichia coli ATCC25922 (a penicillin-sensitive strain); the resistant strains include seven resistant strains: resistant Staphylococcus aureus (S.aureus ATCC43300, a methicillin-resistant strain), Staphylococcus aureus (S.aureus PR, a penicillin-resistant strain), Staphylococcus aureus (S.aureus CI, a clinically isolated resistant strain), Staphylococcus epidermidis (S.epidermidis, a penicillin-resistant strain), resistant Streptococcus pyogenes (S.pyogenes 2, an erythromycin-resistant strain), Enterococcus faecalis (E.faecalis ATCC51299, a vancomycin-resistant strain) and Enterococcus faecium (E.faecium ATCC51559, a vancomycin-resistant strain).

[0298] The MIC of each phenylpyridinium quaternary ammonium salt derivative of the present application (i.e., compounds I-1-45, II-1-5 and III-1-2 of the present invention) and sanguinarine (San), berberine (Ber), linezolid (Lin), and ciprofloxacin (Cip) was determined by the continuous micropore two-fold dilution method. Based on the MIC results, compounds with strong antibacterial effects were screened out. The reference substances sanguinarine, berberine, linezolid, and ciprofloxacin were purchased from Anaiji Chemical.

[0299] Table 4. Results of investigation on antibacterial activity of compounds of formula I, II and III against sensitive strains

[0300]

[0301]

[0302] Table 5. Results of investigation on the antibacterial activity of compounds of formula I, II and III against drug-resistant strains

[0303]

[0304]

[0305]

[0306] From the above experimental results, it can be seen that phenylpyridine quaternary ammonium salt derivatives have excellent anti-sensitive bacterial activity. In this series, I-44 exhibited significant antibacterial activity, with MIC values ​​of 0.0625 to 4 μg / mL for sensitive Gram-positive bacteria, 1 to 4 μg / mL for sensitive Gram-negative bacteria, and 0.25 to 4 μmg / mL for resistant Gram-positive bacteria. It is particularly noteworthy that the antibacterial activity of I-44 against S. aureus ATCC25923 is 0.062 μg / mL, far exceeding other positive compounds. For B. subtilis ATCC9372, the MIC value of I-44 is 0.5 μg / mL, which is comparable to the MIC of linezolid. In addition, the MIC of I-44 against E. coil ATCC25922 and E. coil BW25113 is 4 μg / mL, indicating its effectiveness against Gram-negative bacteria. In addition, among the positive compounds, the MIC value of I-44 against A. baumannii ATCC19606 reached 1 μg / mL, which was significantly better than linezolid, sanguinarine and berberine.

[0307] Similarly, this series of compounds showed significant inhibitory effects on drug-resistant strains. The antibacterial activity of various compounds of 2-phenylpyridinium quaternary ammonium salt (I-40, I-41 and I-44) against MRSA strains can reach 0.5μg / mL, which is 32 and 4 times that of ciprofloxacin and linezolid, respectively, while the MIC value of I-44 against penicillin-resistant S.aureus PR is 0.25μg / mL. In addition, I-40, I-41, I-42 and I-44 showed significant antibacterial activity against S.aureus CI, all reaching the level of 0.5μg / mL. It is worth noting that the antibacterial activity of I-41 against vancomycin-resistant E.faecalis ATCC51559 (0.5μg / mL.) is 8 times that of linezolid.

[0308] Embodiment 54

[0309] Effects of phenylpyridinium quaternary ammonium salt derivatives on the cell morphology of Bacillus subtilis

[0310] In this example, the effects of compounds with excellent antibacterial activity on the bacterial morphology of Bacillus subtilis were observed. Figure 4 As shown in Figure 4As shown, the length of untreated B. subtilis ranged from 1 to 4 μm, while substantial morphological changes occurred between B. subtilis and the test compounds. Specifically, at a concentration of 0.5 MIC, I-14, I-41, I-42, and I-44 (I-14, I-41, I-42, and I-44 are 4n, 16b, 16c, and 16e in the figure, respectively) could extend the length of B. subtilis ATCC9372 by more than 20 μm. This observed pattern of cell extension is characteristic of established FtsZ inhibitors, indicating that these compounds have the potential to hinder FtsZ function without inducing bacterial cell division.

[0311] Embodiment 55

[0312] Effects of phenylpyridinium quaternary ammonium salt derivatives on FtsZ protein polymerization

[0313] This example verifies that the direct effect of the phenylpyridinium quaternary ammonium salt derivatives of the present invention on the FtsZ protein is characterized by an in vitro polymerization experiment, and the light scattering intensity value of the FtsZ polymerization solution is measured by a fluorescence spectrophotometer to reflect the polymerization kinetic characteristics of the protein. Using DMSO as a negative control, their effects on the polymerization of Bacillus subtilis FtsZ (BsFtsZ) were directly measured in vitro. Figure 5 The time-dependent polymerization curves of I-14, I-41, I-42, and I-44 (I-14, I-41, I-42, and I-44 are 4n, 16b, 16c, and 16e in the figure, respectively) with BsFtsZ in a concentration gradient of 2.5-10 μg / mL are depicted. The results of time-dependent light scattering intensity measurements showed that these compounds induced BsFtsZ polymerization in a concentration-dependent manner. This differential stimulation of FtsZ polymerization strongly suggests that these compounds exert their antibacterial activity by targeting FtsZ, thereby disrupting the bacterial cell division process.

[0314] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A phenylpyridine quaternary ammonium salt derivative, characterized in that: The phenylpyridinium quaternary ammonium salt derivative is selected from the compounds represented by formula I, formula II or formula III, or pharmaceutically acceptable salts, esters or solvates, tautomers, mesomers, racemates, stereoisomers, metabolites or prodrugs thereof; The structures of the compounds represented by formula I, II and III are as follows: Among them, R 1 R is selected from hydrogen, C1-C8 straight chain or branched alkyl and C1-C8 straight chain or branched alkoxy; 2 is selected from aromatic hetero groups and substituted aromatic hetero groups; X is -NH- or -O-; Z 1 -N- or -C-; Z 2 -N- or -O-; R 3 Z is a C1-C8 straight or branched alkyl, a C1-C5 straight or branched alkyl substituted cycloalkyl, or a C1-C5 straight or branched alkyl substituted benzyl; 3 -N- or -C-; R 4 is guanidine or none; Y is halogen or benzenesulfonic acid.

2. The phenylpyridinium quaternary ammonium salt derivative according to claim 1, characterized in that: The R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy; Preferably, R 2 wherein the aromatic hetero group is selected from isoquinoline, benzothiazole, benzoxazole, indole, dihydrobenzofuran, 2,3-dihydro-1H-indene and thiazole; the substituted aromatic hetero group is an aromatic hetero group substituted by one or more substituents selected from C1-C8 straight or branched alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted with C1-C3 alkyl, phenyl, phenyl substituted with one or more C1-C5 straight or branched alkyl; Preferably, R 2 is selected from the group consisting of isoquinolin-7-yl, 2-methylbenzo[d]thiazol-5-yl, 2-isopropylbenzo[d]oxazol-5-yl, 2-propylbenzo[d]oxazol-5-yl, 2-phenylbenzo[d]oxazol-5-yl, 2-butylbenzo[d]oxazol-5-yl, benzo[d]oxazol-6-yl, 1H-indol-5-yl, 1-octyl-1H-indol-5-yl, 1-(4-tert-butylbenzyl)-1H-indol-5-yl, 1- (2-cyclohexylethyl)-1H-indol-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydro-1H-inden-5-yl, benzo[d]thiazol-2-methyl, thiazol-2-methyl, 4-(2-isobutylthiazol-5-yl)phenyl, 4-(2-isopropyl-4-methylthiazol-5-yl)phenyl, 4-(2-isobutyl-4-methylthiazol-5-yl)phenyl and 4-(2-phenylthiazol-5-yl)phenyl; Preferably, Y is halogen; preferably I; Preferably, R 3 Selected from 1-octyl, 1-(4-tert-butylbenzyl), 1-(2-cyclohexylethyl), 2-propyl and 2-butyl; Preferably, Selected from 1-octyl-1H-indol-6-yl, 1-(4-tert-butylbenzyl)-1H-indol-5-yl, 1-(2-cyclohexylethyl), 2-propylbenzo[d]oxazol-5-yl and 2-butylbenzo[d]oxazol-5-yl.

3. The phenylpyridinium quaternary ammonium salt derivative according to claim 1, characterized in that: Formula I has the structure shown in Formula IA, Formula IB, Formula IC or Formula ID: Wherein, in the structure of Formula IA, n is 0 or 1, X is -NH- or -O-; R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy; R 2a is selected from isoquinolin-7-yl, 2-methylbenzo[d]thiazol-5-yl, benzo[d]oxazol-6-yl, 2-phenylbenzo[d]oxazol-5-yl, 1H-indol-5-yl, 1-octyl-1H-indol-5-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydro-1H-inden-5-yl, benzo[d]thiazol-2-yl and thiazol-2-yl; preferably, in the structure of formula IA, n is 1, R 2a is selected from benzo[d]thiazol-2-yl and thiazol-2-yl; preferably, in the structure of formula IA, n is 0, R 2a is selected from the group consisting of isoquinolin-7-yl, 2-methylbenzo[d]thiazol-5-yl, benzo[d]oxazol-6-yl, 2-phenylbenzo[d]oxazol-5-yl, 1H-indol-5-yl, 1-octyl-1H-indol-5-yl, 2,3-dihydrobenzofuran-5-yl and 2,3-dihydro-1H-inden-5-yl; Among them, in the structure of formula IB, R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy; R 2b is selected from C1-C8 straight or branched alkyl and phenyl, preferably isobutyl, isopropyl or phenyl; R 2c Selected from hydrogen and C1-C8 straight or branched alkyl, preferably hydrogen or methyl; Among them, in the IC structure, R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy; R 2d is selected from hydrogen, C1-C8 straight or branched alkyl and phenyl, preferably hydrogen, isopropyl, n-propyl, n-butyl or phenyl; Among them, in the structure of formula ID, R 1 is selected from hydrogen, tert-butyl, hexyloxy, heptyloxy and octyloxy; R 2e benzyl substituted by a C1-C8 straight or branched chain alkyl, a cycloalkylethyl group, and a C1-C5 branched or branched chain alkyl group, preferably hydrogen, n-octyl, 4-tert-butylbenzyl or 2-cyclohexylethyl; Preferably, the compound represented by formula I is one of the following: Preferably, the compound represented by formula II is one of the following: Preferably, the compound represented by formula III is one of the following:

4. A method for preparing the phenylpyridine quaternary ammonium salt derivative according to any one of claims 1 to 3, characterized in that: The phenylpyridine quaternary ammonium salt derivative has a structure shown in Formula I, and the preparation method is carried out according to the following reaction route: Among them, R 1 , Y, X, and R 2 As defined in any one of claims 1 to 3.

5. The method according to claim 4, characterized in that The phenylpyridine quaternary ammonium salt derivative has a structure shown in Formula II, and the preparation method is carried out according to the following reaction route: Among them, R 3 , Y, Z 1 and Z 2 As defined in any one of claims 1 to 3.

6. The method according to claim 4, characterized in that The phenylpyridine quaternary ammonium salt derivative has a structure shown in Formula III, and Formula III is selected from Formula III-1 and Formula III-2: The preparation method is carried out according to the following reaction scheme: Alternatively, the preparation method is carried out according to the following reaction route:

7. A composition, characterized in that The invention comprises the phenylpyridinium quaternary ammonium salt derivative according to any one of claims 1 to 3; or further comprises auxiliary materials.

8. A preparation, characterized in that The invention comprises the phenylpyridinium quaternary ammonium salt derivative according to any one of claims 1 to 3 or the composition according to claim 7.

9. Use of the phenylpyridinium quaternary ammonium salt derivative according to any one of claims 1 to 3, the composition according to claim 7, or the preparation according to claim 8 in the preparation of an antibacterial product, preferably, the antibacterial product is an antibacterial product; Preferably, the bacteria are sensitive bacteria and drug-resistant bacteria, the sensitive bacteria are one or more of sensitive Bacillus subtilis, sensitive Bacillus pumilus, sensitive Staphylococcus aureus, sensitive Streptococcus pyogenes, sensitive Enterococcus faecium, sensitive Enterococcus faecalis, sensitive Acinetobacter baumannii, sensitive Pseudomonas aeruginosa and sensitive Escherichia coli strains, and the drug-resistant bacteria are one or more of drug-resistant Staphylococcus aureus, drug-resistant Staphylococcus epidermidis, drug-resistant Streptococcus pyogenes, drug-resistant Enterococcus faecalis and drug-resistant Enterococcus faecium; The antibacterial product is one or more of medicines, toiletries, and food preservatives; the toiletries are one or more of fruit and vegetable cleaning agents, shampoo, soap, shower gel, laundry detergent, hand soap, toilet cleaner, and facial cleanser.

10. A method for inhibiting Gram-positive bacteria in vitro, characterized in that: The method comprises applying the phenylpyridinium quaternary ammonium salt derivative according to any one of claims 1 to 3 and / or the composition according to claim 7 and / or the preparation according to claim 8 to the surface to be inhibited from bacteria.

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