Phenylpyridinium derivatives, process for their preparation and use

Abstract

The application belongs to the field of new drug compounds, and particularly relates to phenylpyridine quaternary ammonium salt derivatives, and a preparation method and application thereof. The phenylpyridine quaternary ammonium salt derivatives of the application are selected from compounds shown in formula I or formula II or formula III, or pharmaceutically acceptable salts, esters or solvates, tautomers, meso forms, racemates, stereoisomers, metabolites or prodrugs thereof; the compounds shown in the formula I, II and III have the structures shown in the following formula: the phenylpyridine quaternary ammonium salt derivatives are completely different from reported FtsZ inhibitor parent nucleus structures, have different physicochemical properties, and experiments show that the derivatives have the effect of inhibiting FtsZ, can be used as new FtsZ inhibitors, and have good antibacterial activity.

Description

Technical Field

[0001] This invention belongs to the field of new drug compounds and relates to phenylpyridine quaternary ammonium salt derivatives, their preparation methods and applications. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Antimicrobial resistance has become a major global public health crisis, posing a serious threat to human well-being. The emergence of new infectious diseases coupled with antibiotic failure can trigger widespread epidemics, causing significant social and economic consequences worldwide. The development of novel antimicrobial drugs is inherently protracted, involving rigorous clinical trials and regulatory approvals from government agencies. Therefore, the rapid availability of effective treatment modalities during outbreaks of new pathogens or surges in antimicrobial resistance remains limited. Consequently, it is necessary to increase investment in the research and development of innovative antimicrobial drugs with novel mechanisms to revolutionize traditional approaches to bacterial treatment and slow the rate of resistance evolution.

[0004] Filamentous temperature-sensitive protein Z (FtsZ) plays a crucial role in regulating the formation of Z-loop structures essential for bacterial cell division. Early in the division process, FtsZ assembles into a ring-like structure called a Z-loop, strategically positioned at the future site of cell division. This Z-loop serves as the initiation point for cell division, guiding the synthesis of new cell wall and membrane components. Furthermore, FtsZ is widely distributed across bacterial species, suggesting that antimicrobial drugs targeting this protein may possess broad-spectrum antimicrobial activity, thereby enhancing efficacy against different bacterial strains and expanding the therapeutic range. Utilizing the complex mechanisms of FtsZ in bacterial division holds significant potential for developing novel strategies to combat bacterial infections and improve patient outcomes. Summary of the Invention

[0005] To address the shortcomings of existing technologies, the present invention aims to provide phenylpyridine quaternary ammonium salt derivatives, their preparation methods, and applications. These derivatives have completely different core structures from reported FtsZ inhibitors and exhibit different physicochemical properties. Experiments have shown that these derivatives have FtsZ inhibitory effects and can serve as novel FtsZ inhibitors, while also possessing good antibacterial activity.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] In a first aspect, the present invention provides a phenylpyridine quaternary ammonium salt derivative, wherein the phenylpyridine quaternary ammonium salt derivative is selected from compounds of formula I, II or III or their pharmaceutically acceptable salts or esters or solvates, tautomers, mesosomes, racemates, stereoisomers, metabolites or prodrugs;

[0008] The structures of the compounds represented by Formulas I, II and III are shown below:

[0009] ;

[0010] Among them, R 1 Selected from hydrogen, C1-C8 straight-chain or branched alkyl groups and C1-C8 straight-chain or branched alkoxy groups; R 2 Selected from aromatic heteroyl and substituted aromatic heteroyl groups; X is -NH- or -O-; Y is a halogen or benzenesulfonic acid, i.e. It is a halide ion or benzenesulfonic acid anion; Z 1 -N- or -C-; Z 2 -N- or -O-; R 3 It is a C1-C8 straight-chain or branched alkyl group, a C1-C5 straight-chain or branched alkyl group substituted with a cycloalkyl group, or a C1-C5 straight-chain or branched alkyl group substituted with a benzyl group; Z 3 -N- or -C-; R 4 It may be guanidine or absent.

[0011] In some embodiments, R 1 Selected from hydrogen, tert-butyl, hexyloxy, heptoxy, and octyloxy. R 2 In this context, the aromatic heterol group is selected from isoquinoline, benzothiazole, benzoxazole, indole, dihydrobenzofuran, 2,3-dihydro-1H-indene, and thiazole; the substituted aromatic heterol group is an aromatic heterol group substituted with one or more substituents selected from C1-C8 straight-chain or branched alkyl groups, C3-C6 cycloalkyl groups, C1-C3 alkyl-substituted C3-C6 cycloalkyl groups, phenyl groups, and phenyl groups substituted with one or more C1-C5 straight-chain or branched alkyl groups; preferably, R 2Selected from isoquinoline-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-indole-5-yl, 1-octyl-1H-indole-5-yl, 1-(4-tert-butylbenzyl)-1H-indole-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 a halogen, preferably I. R 3 It is 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] Furthermore, formula I has the structure shown in formulas IA, IB, IC, or ID:

[0014]

[0015] In the structure shown in equation IA, n is 0 or 1, and X is -NH- or -O-; R 1 Selected from hydrogen, tert-butyl, hexyloxy, heptoxy, and octyloxy. R 2a The derivative is selected from isoquinoline-7-yl, 2-methylbenzo[d]thiazolyl-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]thiazolyl-2-yl, and thiazolyl-2-yl. Preferably, in the structure of formula IA, n is 1, and R... 2a Selected from benzo[d]thiazol-2-yl and thiazol-2-yl; preferably, in the structure of formula IA, n is 0, R 2aIt is selected from isoquinoline-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-indene-5-yl.

[0016] In the structure shown in equation IB, R 1 Selected from hydrogen, tert-butyl, hexoxy, heptoxy, and octoxy; R 2b Selected from C1-C8 straight-chain or branched alkyl groups and phenyl groups, preferably isobutyl, isopropyl, or phenyl; R 2c It is selected from hydrogen, C1-C8 straight-chain or branched alkyl groups, preferably hydrogen or methyl.

[0017] In the IC structure, R 1 Selected from hydrogen, tert-butyl, hexoxy, heptoxy, and octoxy; R 2d It is selected from hydrogen, C1-C8 straight-chain or branched alkyl and phenyl, preferably hydrogen, isopropyl, n-propyl, n-butyl or phenyl.

[0018] In the ID structure, R 1 Selected from hydrogen, tert-butyl, hexoxy, heptoxy, and octoxy; R 2e The group is selected from hydrogen, C1-C8 straight-chain or branched alkyl, cycloalkyl ethyl and C1-C5 branched or branched alkyl substituted benzyl, 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] Furthermore, the compound represented by Formula II is one of the following:

[0022]

[0023] Furthermore, 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 as shown in Formula III-1; when the Z 3 For C; the R 4 When the group is guanidine, the structure of the compound is shown in Formula III-2.

[0024] .

[0025] Secondly, the present invention provides a method for preparing the above-mentioned phenylpyridine quaternary ammonium salt derivatives, wherein,

[0026] The phenylpyridine quaternary ammonium salt derivative has the structure shown in Formula I, and the preparation method is carried out according to the following reaction route:

[0027] ;

[0028] Among them, R 1 Y, X and R 2 As defined above. If Equation I has the structure shown in Equation IA, Equation IB, Equation IC, or Equation ID, then specifically, as... Figure 1 As shown:

[0029] The preparation method of the compound represented by formula IA is shown in reaction routes I-1 to 18, involving steps a, b, and c, as detailed below:

[0030] The procedure for step a is as follows: Compound 1 is dissolved in a mixed solvent of 1,4-dioxane and H2O. Under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, K2CO3 and a phenylboronic acid analog are added, and the reaction is heated to generate intermediates 2a-2c. Further, the heating temperature is 70-90°C, and the reaction time is 6-12 hours.

[0031] Step b is performed as follows: intermediates 2a-2c are dissolved in a polar aprotic solvent, an excess of iodine-containing reagent is added, and after reacting for a period of time, intermediates 3a-3c are obtained; furthermore, the reaction temperature is preferably 42-80℃;

[0032] Step c is performed as follows: intermediates 3a-3c are dissolved in acetonitrile solvent, commercially available amino aromatic heterocyclic reagents and triethylamine are added, and the mixture is heated to generate compounds 4a-4r, which are compounds represented by formula IA in general formula I.

[0033] The structural formulas of compound 1, intermediates 2a-2c, intermediates 3a-3c, and formula IA are shown below in sequence:

[0034] ; ; ; .

[0035] Furthermore, the preparation method of the compound represented by formula IB is shown in reaction routes I-19~25, involving steps a, b, d, e, and c, as detailed below:

[0036] The procedure for step a is as follows: Compound 1 is dissolved in a mixed solvent of 1,4-dioxane:H2O, and under the catalysis of [1,1'-(diphenylphosphino)ferrocene]palladium dichloride, K2CO3 and a phenylboronic acid analog are added, and the reaction is heated to generate intermediates 2a-2c; further, the heating temperature is 70-90℃, and the reaction time is 6-12 hours;

[0037] Step b is performed as follows: intermediates 2a-2c are dissolved in a polar aprotic solvent, an excess of iodine-containing reagent is added, and after reacting for a period of time, intermediates 3a-3c are obtained; furthermore, the reaction temperature is preferably 42-80℃;

[0038] The procedure for step d is as follows: Compound 5 is dissolved in water, and under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride and triphenylphosphine, Ag2CO3 is added, and the reaction is heated to generate intermediates 6a-6c; furthermore, the heating temperature is 60°C;

[0039] The operation method of step e is as follows: intermediate 6a-6c is dissolved in a mixed solution of ethanol:H2O, Fe powder and NH4Cl are added, and the reaction is heated to generate intermediate 7a-7c; further, the heating temperature is 50℃;

[0040] Step c is performed as follows: intermediate 3a-3c is dissolved in acetonitrile solvent, intermediate 7a-7c and triethylamine are added, and the mixture is heated to produce compound 8a-8g, which is the compound shown in formula IB in general formula I.

[0041] The structural formulas of compound 1, intermediates 2a-2c, 3a-3c, compound 5, intermediates 6a-6c, 7a-7c, and formula IB are shown below in sequence:

[0042] ; ; ; ; ; ; .

[0043] Furthermore, the preparation method of the compound represented by formula IC is shown in reaction routes I-26~39, involving steps a, b, f, g, and c, as detailed below:

[0044] The procedure for step a is as follows: Compound 1 is dissolved in a mixed solvent of 1,4-dioxane and H2O, and under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, K2CO3 and a phenylboronic acid analog are added, and the reaction is heated to generate intermediates 2a-2c; further, the heating temperature is 70-90℃, and the reaction time is 6-12 hours;

[0045] Step b is performed as follows: intermediates 2a-2c are dissolved in a polar aprotic solvent, an excess of iodine-containing reagent is added, and after reacting for a period of time, intermediates 3a-3c are obtained; furthermore, the reaction temperature is preferably 42-80℃;

[0046] The operation method of step f is as follows: compound 9 is dissolved in ethanol, 1,1,1-triethoxybutane analog is added, and under the catalysis of NH4Cl, the mixture is heated to generate intermediate 10a-10d; further, the heating temperature is under reflux conditions;

[0047] The operation method of step g is as follows: intermediate 10a-10d is dissolved in ethanol, and reduced by heating under Pd / C catalysis and H2 atmosphere to generate intermediate 11a-11d; further, the heating temperature is under reflux conditions;

[0048] Step c is performed as follows: intermediates 3a-3c are dissolved in acetonitrile solvent, intermediates 11a-11d and triethylamine are added, and the mixture is heated to generate compounds 12a-12n, which are compounds represented by formula I in general formula I.

[0049] The structural formulas of compound 1, intermediates 2a-2c, intermediates 3a-3c, compound 9, intermediates 10a-10d, 11a-11d, and formula C are shown below in sequence:

[0050] ; ; ; ; ; ; .

[0051] Furthermore, the preparation method of the compound represented by formula ID is shown in reaction routes I-40~45, involving steps a, b, h, i, and c, as detailed below:

[0052] The procedure for step a is as follows: Compound 1 is dissolved in a mixed solvent of 1,4-dioxane and H2O, and under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, K2CO3 and a phenylboronic acid analog are added, and the reaction is heated to generate intermediates 2a-2c; further, the heating temperature is 70-90℃, and the reaction time is 6-12 hours;

[0053] Step b is performed as follows: intermediates 2a-2c are dissolved in a polar aprotic solvent, an excess of iodine-containing reagent is added, and after reacting for a period of time, intermediates 3a-3c are obtained; furthermore, the reaction temperature is preferably 42-80℃;

[0054] The procedure for step h is as follows: Compound 13 is dissolved in anhydrous DMF solvent, a bromoalkane analog is added, and intermediates 14a-14d are generated at low temperature under NaH catalysis; further, the low temperature is 0°C.

[0055] The operation method of step i is as follows: intermediate 14a-14d is dissolved in ethanol, and then reduced by heating under Pd / C catalysis and H2 atmosphere to generate 15a-15d; further, the heating temperature is under reflux conditions;

[0056] Step c is performed as follows: intermediates 3a-3c are dissolved in acetonitrile solvent, intermediates 15a-15d and triethylamine are added, and the mixture is heated to produce compounds 16a-16f, which are compounds represented by formula ID in general formula I.

[0057] The structural formulas of compound 1, intermediates 2a-2c, intermediates 3a-3c, compound 13, intermediates 14a-14d, 15a-15d, and formula ID are shown below in sequence:

[0058] ; ; ; ; ; ; .

[0059] Furthermore, the phenylpyridine quaternary ammonium salt derivative has the structure shown in Formula II, and the preparation method is carried out according to the following reaction route:

[0060] Among them, R 3 Y, Z 1 and Z 2 As defined above.

[0061] The preparation method of the compound represented by Formula II, as shown in reaction routes II-1 to II-5, involves steps a, b, and c, as follows: Figure 2 As shown, the specific preparation method steps are as follows:

[0062] The procedure for step a is as follows: Compound 17 is dissolved in a mixed solvent of 1,4-dioxane:H2O, and K2CO3 and phenylboronic acid are added under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and the reaction is heated to generate intermediate 18; further, the heating temperature is 70-90℃ and the reaction time is 6-12 hours.

[0063] Step b is performed as follows: intermediate 18 is dissolved in a polar aprotic solvent, excess iodine-containing reagent is added, and after reacting for a period of time, intermediate 19 is obtained; furthermore, the reaction temperature is preferably 42-80℃;

[0064] Step c is performed as follows: intermediate 19 is dissolved in acetonitrile solvent, intermediate 11a-11d or 15a-15d and triethylamine are added, and the mixture is heated to produce compound 20, which is the compound shown in general formula II.

[0065] The structural formulas of compounds 17, intermediates 18 and 19, 11a-11d, 15a-15d and formula II are shown below in sequence:

[0066] ; ; ; ; ;

[0067] The preparation method of 15a-15d includes the following steps:

[0068] The procedure for step h is as follows: Compound 13 is dissolved in anhydrous DMF solvent, a bromoalkane analog is added, and intermediates 14a-14d are generated at low temperature under NaH catalysis; further, the low temperature is 0°C.

[0069] The operation method of step i is as follows: intermediate 14a-14d is dissolved in ethanol, and then reduced by heating under Pd / C catalysis and H2 atmosphere to generate 15a-15d; further, the heating temperature is under reflux conditions;

[0070] The structural formulas of compound 13, intermediates 14a-14d and 15a-15d are shown below in sequence:

[0071] ; ; ;

[0072] The preparation method of 11a-11d includes the following steps:

[0073] The operation method of step f is as follows: compound 9 is dissolved in ethanol, 1,1,1-triethoxybutane analog is added, and under the catalysis of NH4Cl, the mixture is heated to generate intermediate 10a-10d; further, the heating temperature is under reflux conditions;

[0074] The operation method of step g is as follows: intermediate 10a-10d is dissolved in ethanol, and then reduced by heating under Pd / C catalysis and H2 atmosphere to generate 11a-11d; further, the heating temperature is under reflux conditions;

[0075] The structural formulas of compound 9, intermediates 10a-10d and 11a-11d are shown below in sequence:

[0076] ; ; ;

[0077] Furthermore, the phenylpyridine quaternary ammonium salt derivative has the structure shown in Formula III, where Formula III is selected from Formula III-1 and Formula III-2:

[0078] The preparation method of Formula III-1 is carried out according to the following reaction route:

[0079] The preparation method of Formula III-2 is carried out according to the following reaction route:

[0080]

[0081] Specifically, the compound represented by Formula III-1, such as Figure 3 As shown, the preparation method includes steps a and b, and the specific steps are as follows:

[0082] Step a is performed as follows: Compound 17 and 1-(2-cyclohexylethyl)-1H-indole-5-amine are dissolved in toluene and subjected to a Buchwald–Hartwig coupling reaction under the conditions of 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), NaOtBu, and bis(dibenzylacetone)palladium, and heated to generate intermediate 21; further, the heating temperature is 100°C;

[0083] Step b is performed as follows: Intermediate 21 is dissolved in a mixed solvent of 1,4-dioxane and H2O. Under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, K2CO3 and phenylboronic acid are added, and the mixture is heated to generate compound 22, i.e., the compound shown in formula III-1. Further, the heating temperature is 70-90℃, and the reaction time is 6-12 hours.

[0084] The structural formulas of compound 17, intermediate 21, and formula III-1 are shown below in sequence:

[0085] ; ; .

[0086] Furthermore, the compound represented by formula III-2, such as Figure 3 As shown, steps c, d, e, f, and g are included. The specific preparation method steps are as follows:

[0087] Step c is performed as follows: Compound 23 is dissolved in toluene with 1-(2-cyclohexylethyl)-1H-indole-5-amine, and a Buchwald–Hartwig coupling reaction is carried out under the conditions of 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), NaOtBu, and bis(dibenzylacetone)palladium, and heated to generate intermediate 24; further, the heating temperature is 100°C;

[0088] The operation method of step d is as follows: intermediate 24 is dissolved in a mixed solvent of 1,4-dioxane:H2O, and K2CO3 and phenylboronic acid are added under the catalysis of [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, and the reaction is heated to generate intermediate 25; further, the heating temperature is 70-90℃, and the reaction time is 6-12 hours;

[0089] The operation method of step e is as follows: intermediate 25 is dissolved in ethanol:H2O=1 / 1, and in the presence of Fe and NH4Cl, it is heated and reduced to generate intermediate 26; further, the heating temperature is under reflux conditions and the temperature is 80°C.

[0090] The procedure for step f is as follows: intermediate 26 is dissolved in chloroform, N,N'-di-Boc-1H-1-guanidinylpyrazole is added, and the reaction generates intermediate 27;

[0091] Step g is performed as follows: intermediate 27 loses its Boc protecting group in the presence of TFA to generate compound 28, namely the compound shown in formula III-2;

[0092] The structural formulas of compound 23, intermediate 24, intermediate 25, intermediate 26, intermediate 27 and formula III-2 are shown below in sequence:

[0093] ; ; ; ; ; .

[0094] The phrase "the heating temperature is under reflux conditions" specifically refers to a reaction heating temperature of 60-80℃, preferably 60℃.

[0095] Thirdly, the present invention provides a composition comprising the phenylpyridine quaternary ammonium salt derivative described in the first aspect, or further comprising excipients.

[0096] The "composition" or "pharmaceutical composition" described in this invention can be used to treat or prevent the diseases described in this invention in subjects, particularly mammals. In the pharmaceutical composition, the phenylpyridine quaternary ammonium salt derivative described in the first aspect serves as the active ingredient, and its dosage should be at a synergistic effective dose. This dosage is within the scope of techniques that can be determined using conventional methods in the art.

[0097] In addition, the active ingredients of the pharmaceutical composition may include other components with antibacterial or auxiliary antibacterial effects, besides the phenylpyridine quaternary ammonium salt derivatives described in the first aspect.

[0098] As described herein, the term "pharmaceutically acceptable" or the interchangeable term "medicinal," for example, in describing "pharmaceutically acceptable salt," indicates that the salt is not only physiologically acceptable to the subject but also refers to a synthetic substance with pharmaceutical value, such as a salt formed as an intermediate in chiral resolution, although such intermediate salt cannot be directly given to the subject but can play a role in obtaining the end product of the present invention.

[0099] The pharmaceutical compositions of the compounds of this invention can be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, vaginal administration, local administration, parenteral administration such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, or intracranial injection or infusion, or via an external reservoir, with oral, intramuscular, intraperitoneal, or intravenous administration being preferred. Specifically, the dosage form of the pharmaceutical composition can be a liquid dosage form or a solid dosage form. Liquid dosage forms can be true solutions, colloids, microparticles, emulsions, or suspensions. Other dosage forms include tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder injections, inclusion complexes, implants, patches, liniments, etc.

[0100] The pharmaceutical compositions of the present invention may also contain commonly used carriers, including, but not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycerol, sorbitol, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin, etc. The carrier content in the pharmaceutical composition can be 1% to 98% by weight, typically approximately 80% by weight. For convenience, local anesthetics, preservatives, buffers, etc., can be directly dissolved in the carrier.

[0101] Fourthly, the present invention provides a formulation comprising the phenylpyridine quaternary ammonium salt derivative described in the first aspect or the composition described in the third aspect.

[0102] Fifthly, the present invention provides the use of the phenylpyridine quaternary ammonium salt derivatives described in the first aspect, the compositions described in the third aspect, or the formulations described in the fourth aspect in the preparation of antibacterial products. The antibacterial products are antimicrobial products.

[0103] The bacteria are both susceptible and drug-resistant, and the susceptible bacteria are Bacillus subtilis (B. subtilis). B. subtilis ATCC9372 is a penicillin-sensitive strain), Bacillus pumilus ( B. pumilus CMCC63202), Staphylococcus aureus ( S. aureus ATCC25923 is an erythromycin-sensitive strain), Streptococcus pyogenes ( S. pyogenes 1. Erythromycin-sensitive strains), Enterococcus faecalis ( E. faecium ATCC19434 is a vancomycin-sensitive strain), Enterococcus faecalis ( E. faecalis ATCC29212 is a vancomycin-sensitive strain), Acinetobacter baumannii ( A. baumannii ATCC19606, standard strain), Pseudomonas aeruginosa ( P. aeruginosa ATCC27853 (a penicillin-sensitive strain) and Escherichia coli ( E. coli ATCC25922 (a penicillin-sensitive strain) or one or more of the following, wherein the drug-resistant bacteria is Staphylococcus aureus ( S. aureus ATCC43300 is a methicillin-resistant strain and Staphylococcus aureus. S. aureus PR (A penicillin-resistant strain), Staphylococcus aureus ( S. aureus CI For clinically isolated drug-resistant strains), Staphylococcus epidermidis ( S. epidermidis (These are penicillin-resistant strains) and drug-resistant streptococci ( S. pyogenes 2, for erythromycin-resistant strains), Enterococcus faecalis ( E. faecalis ATCC51299 (a vancomycin-resistant strain) and Enterococcus faecalis ( E. faecium ATCC51559 (one or more of the vancomycin-resistant strains).

[0104] The antibacterial products include, but are not limited to, one or more of the following: drugs, personal care products, medical devices, kitchenware, food preservatives, and tableware; the personal care products include, but are not limited to, fruit and vegetable cleaners, shampoos, soaps, shower gels, laundry detergents, hand soaps, toilet cleaners, and facial cleansers.

[0105] In a sixth aspect, the present invention provides a method for inhibiting Gram-positive bacteria, the method comprising applying to a surface to be inhibited a phenylpyridine quaternary ammonium salt derivative as described in the first aspect and / or a composition as described in the third aspect and / or an agent as described in the fourth aspect.

[0106] The beneficial effects achieved by one or more of the above technical solutions are as follows:

[0107] (1) The phenylpyridine quaternary ammonium salt derivatives, pharmaceutical compositions, and drug effects on Bacillus subtilis provided by the present invention B. subtilis ATCC9372 is a penicillin-sensitive strain), Bacillus pumilus ( B. pumilus CMCC63202), Staphylococcus aureus ( S. aureus ATCC25923 is an erythromycin-sensitive strain), Streptococcus pyogenes ( S. pyogenes 1. Erythromycin-sensitive strains), Enterococcus faecalis ( E. faecium ATCC19434 is a vancomycin-sensitive strain), Enterococcus faecalis ( E. faecalis ATCC29212 is a vancomycin-sensitive strain), Pseudomonas aeruginosa ( P. aeruginosa ATCC27853 (a penicillin-sensitive strain) and Escherichia coli ( E. coli ATCC25922 is a penicillin-sensitive strain), Acinetobacter baumannii ( A. baumannii ATCC19606, standard strain), Staphylococcus aureus ( S. aureus ATCC43300 is a methicillin-resistant strain and Staphylococcus aureus. S. aureus PR, a penicillin-resistant strain), Staphylococcus aureus ( S. aureus CI, representing clinically isolated drug-resistant strains), Staphylococcus epidermidis ( S. epidermidis (These are penicillin-resistant strains) and drug-resistant streptococci ( S. pyogenes 2, for erythromycin-resistant strains), Enterococcus faecalis ( E. faecalis ATCC51299 (a vancomycin-resistant strain) and Enterococcus faecalis ( E. faecium ATCC51559 (a vancomycin-resistant strain) has a better inhibitory effect and belongs to the broad-spectrum antibacterial active ingredients.

[0108] (2) Several compounds in formulas I, II, and III exhibited superior antibacterial activity against multiple strains compared to the positive compounds. In this series, I-44 demonstrated significant antibacterial activity, with MIC values ​​ranging from 0.0625 to 4 µg / mL against susceptible Gram-positive bacteria, 1 to 4 µg / mL against susceptible Gram-negative bacteria, and 0.25 to 4 µmg / mL against resistant Gram-positive bacteria. Particularly noteworthy is the antibacterial activity of I-44 against... S. aureus ATCC25923 exhibited antibacterial activity of 0.062 µg / mL, significantly exceeding that of other positively charged compounds. [This is in contrast to other compounds.] B. subtilis ATCC9372, the MIC value of I-44 is 0.5 µg / mL, which is comparable to the MIC of linezolid. Furthermore, I-44 has [unclear meaning - possibly related to a specific enzyme or drug]. E. coil ATCC25922 and E. coil The MICs of BW25113 were all 4 µg / mL, indicating their effectiveness against Gram-negative bacteria. Furthermore, among the positive compounds, I-44 showed efficacy against... A. baumannii The MIC value of ATCC19606 reached 1 µg / mL, which was significantly better than linezolid, sanguinarine and berberine.

[0109] (3) Several compounds in formulas I, II, and III also showed good antibacterial activity against MRSA strains. Multiple compounds of 2-phenylpyridine quaternary ammonium salt (I-40, I-41, and I-44) exhibited antibacterial activity of up to 0.5 µg / mL against MRSA strains, which were 32 and 4 times that of ciprofloxacin and linezolid, respectively. I-44, however, showed resistance to penicillin. S. aureus The MIC value of PR was 0.25 µg / mL. Furthermore, I-40, I-41, I-42, and I-44... S. aureus CI exhibited significant antibacterial activity, reaching levels of 0.5 µg / mL. Notably, I-41 showed resistance to vancomycin-resistant bacteria. E. faecalis The antibacterial activity of ATCC51559 (0.5 µg / mL) is 8 times that of linezolid. Attached Figure Description

[0110] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0111] Figure 1 This is the synthetic route for the phenylpyridine quaternary ammonium salt derivatives of general formula I in this invention;

[0112] Figure 2 This is the synthetic route for the phenylpyridine quaternary ammonium salt derivatives of general formula II in this invention;

[0113] Figure 3 This is the synthetic route for the phenylpyridine quaternary ammonium salt derivatives of general formula III in this invention;

[0114] Figure 4 The effect of phenylpyridine quaternary ammonium salt derivatives on the cell morphology of Bacillus subtilis in this invention;

[0115] Figure 5 This invention relates to the effect of phenylpyridine quaternary ammonium salt derivatives on the polymerization of FtsZ protein. Detailed Implementation

[0116] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments and comparative examples.

[0117] Example 1

[0118] Step a: Preparation of 2-(4-(tert-butyl)phenyl)-4-chloropyridine (2a)

[0119]

[0120] 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 was detected 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 give 2a (5.9 g, white solid) in 92% yield. Similarly, 2b and 2c were prepared according to the above method in yields of 95% and 94%, respectively.

[0121] Step b: Preparation of 2-(4-(tert-butyl)phenyl)-4-chloro-1-methylpyridine iodide (3a)

[0122]

[0123] 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, which was then filtered to obtain crude product 3a in 81% yield (1.72 g, yellow solid). Similarly, 3b and 3c were prepared in 80% and 87% yields, respectively, according to the above method.

[0124] Step c: Preparation of 2-(4-(tert-butyl)phenyl)-1-methyl-4-(quinoline-7-amino)pyridine iodide (I-1)

[0125]

[0126] Isoquinoline-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 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 (dichloromethane / methanol = 15:1 as eluent) to give I-1 (82% yield, yellow solid).

[0127] Example 2

[0128] Unlike Example 1, isoquinoline-7-amine in step c was replaced with the same molar amount of 2-methylbenzo[d]thiazol-5-amine to obtain I-2.

[0129] Example 3

[0130] Unlike Example 1, isoquinoline-7-amine in step c was replaced with the same molar amount of benzo[d]oxazol-6-amine to obtain I-3.

[0131] Example 4

[0132] Unlike Example 1, isoquinoline-7-amine in step c was replaced with the same molar amount of 2-phenylbenzo[d]oxazol-6-amine to obtain I-4.

[0133] Example 5

[0134] Unlike Example 1, isoquinoline-7-amine in step c was replaced with the same molar amount of 1H-indole-5-amine to obtain I-5.

[0135] Example 6

[0136] Unlike Example 1, isoquinoline-7-amine in step c was replaced with the same molar amount of 1-octyl-1H-indole-5-amine to obtain I-6.

[0137] Example 7

[0138] Unlike Example 1, isoquinoline-7-amine in step c was replaced with the same molar amount of 2,3-dihydrobenzofuran-5-amine to obtain I-7.

[0139] Example 8

[0140] Unlike Example 1, isoquinoline-7-amine in step c was replaced with the same molar amount of 2,3-dihydro-1H-indene-5-amine to obtain I-8.

[0141] Example 9

[0142] Unlike Example 1, isoquinoline-7-amine in step c was replaced with the same molar amount of benzo[d]thiazol-2-ylmethanol to obtain I-9.

[0143] Example 10

[0144] Unlike Example 1, isoquinoline-7-amine in step c was replaced with the same molar amount of 2-methylbenzo[d]thiazol-5-ol to obtain I-10.

[0145] Example 11

[0146] Unlike Example 1, in step a, 4-tert-butylphenylboronic acid was replaced with the same molar amount of 4-heptoxyphenylboronic acid, resulting in I-11.

[0147] Example 12

[0148] Unlike Example 1, in step a, 4-tert-butylphenylboronic acid was replaced with the same molar amount of 4-heptoxyphenylboronic acid, and in step c, isoquinoline-7-amine was replaced with the same molar amount of 2-methylbenzo[d]thiazol-5-amine, to obtain I-12.

[0149] Example 13

[0150] Unlike Example 1, in step a, 4-tert-butylphenylboronic acid was replaced with the same molar amount of 4-heptoxyphenylboronic acid, and in step c, isoquinoline-7-amine was replaced with the same molar amount of benzo[d]oxazol-6-amine, to obtain I-13.

[0151] Example 14

[0152] Unlike Example 1, in step a, 4-tert-butylphenylboronic acid was replaced with the same molar amount of 4-heptoxyphenylboronic acid, and in step c, isoquinoline-7-amine was replaced with the same molar amount of 2,3-dihydrobenzofuran-5-amine, to obtain I-14.

[0153] Example 15

[0154] Unlike Example 1, in step a, 4-tert-butylphenylboronic acid was replaced with the same molar amount of 4-heptoxyphenylboronic acid, and in step c, isoquinoline-7-amine was replaced with the same molar amount of 2,3-dihydro-1H-indene-5-amine, to obtain I-15.

[0155] Example 16

[0156] Unlike Example 1, in step a, 4-tert-butylphenylboronic acid was replaced with the same molar amount of 4-heptoxyphenylboronic acid, and in step c, isoquinoline-7-amine was replaced with the same molar amount of benzo[d]thiazol-2-ylmethanol, to obtain I-16.

[0157] Example 17

[0158] Unlike Example 1, in step a, 4-tert-butylphenylboronic acid was replaced with the same molar amount of 4-heptoxyphenylboronic acid, and in step e, isoquinoline-7-amine was replaced with the same molar amount of thiazolyl-2-ylmethanol, to obtain I-17.

[0159] Example 18

[0160] Unlike Example 1, in step a, 4-tert-butylphenylboronic acid was replaced with the same molar amount of 4-heptoxyphenylboronic acid, and in step c, isoquinoline-7-amine was replaced with the same molar amount of 2-methylbenzo[d]thiazol-5-ol, to obtain I-18.

[0161] Example 19

[0162] Step d: Preparation of 2-isopropyl-4-methyl-5-(4-nitrophenyl)thiazole (6a)

[0163]

[0164] 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), 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, which was then washed with a 1:1 mixture of acetone and CH2Cl2. After removing the organic solvent by concentration under reduced pressure, a slurry was obtained. CH2Cl2 and water were added for extraction, retaining the organic phase. 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 give 6a (yellow solid, 2.36 g) in 90% yield. Similarly, 6b and 6c were prepared according to the above method in yields of 87% and 89%, respectively.

[0165] Step e: Preparation of 4-(2-isopropyl-4-methylthiazolyl-5-yl)aniline (7a)

[0166]

[0167] 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 of CH3CH2OH / H2O (2:1 ratio). The reaction was detected by thin-layer chromatography. After filtering the reaction solution, the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3:1 as eluent) to give 7a (yellow solid, 1.08 g) in a yield of 67%. Similarly, 7b and 7c were prepared according to the above method, with yields of 75% and 71%, respectively.

[0168] Step c: Preparation of 2-(4-(tert-butyl)phenyl)-4-((4-(2-isopropyl-4-methylthiazolyl-5-yl)phenyl)amino)-1-methylpyridine iodide (8a)

[0169]

[0170] 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 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 (dichloromethane / methanol = 15:1 as eluent) to give I-19.

[0171] Example 20

[0172] Unlike Example 19, in step e, 2-isopropyl-4-methylthiazole was replaced with the same molar amount of 2-isobutylthiazole, resulting in I-20.

[0173] Example 21

[0174] Unlike Example 19, in step e, 2-isopropyl-4-methylthiazole was replaced with the same molar amount of 2-isobutyl-4-methylthiazole, resulting in I-21.

[0175] Example 22

[0176] Unlike Example 19, step c, 3a, was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridine iodide to obtain I-22.

[0177] Example 23

[0178] Unlike Example 19, in step e, 2-isopropyl-4-methylthiazole was replaced with the same molar amount of 2-isobutylthiazole, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridine iodide, to obtain I-23.

[0179] Example 24

[0180] Unlike Example 19, in step e, 2-isopropyl-4-methylthiazole was replaced with the same molar amount of 2-isobutyl-4-methylthiazole, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octyloxy)phenyl)pyridine iodide, to obtain I-24.

[0181] Example 25

[0182] Unlike Example 19, in step e, 2-isopropyl-4-methylthiazole was replaced with 4-(2-phenylthiazol-5-yl)aniline, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octoxy)phenyl)pyridine iodide, to obtain I-25.

[0183] Example 26

[0184] Step f: Preparation of 5-nitro-2-propylbenzo[d]oxazole (10a)

[0185]

[0186] 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.

[0187] Step g: Preparation of 2-propylbenzo[d]oxazol-5-amine (11a)

[0188]

[0189] 10a (2 g, 9.7 mmol) and Pd / C (0.1 g, 0.97 mmol) were dissolved in ethanol and stirred overnight at room temperature under H2 atmosphere. After filtration, the solution was concentrated under reduced pressure to give 11a (black oil, 1.67 g) in 98% purity. Similarly, 11b, 11c, and 11d were prepared according to the above method, with yields of 96%, 95%, and 94%, respectively.

[0190] Step c: Preparation of 2-(4-(tert-butyl)phenyl)-1-methyl-4-((2-propylbenzo[d]oxazol-6-yl)amino)pyridine iodide (12a)

[0191]

[0192] 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 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 (dichloromethane / methanol = 15:1 as eluent) to give I-26.

[0193] Example 27

[0194] Unlike Example 26, triethyl propionate was replaced with triethyl isopropionate in step f to obtain I-27.

[0195] Example 28

[0196] Unlike Example 26, step c, 3a, was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(hexyloxy)phenyl)pyridine iodide, resulting in I-28.

[0197] Example 29

[0198] Unlike Example 26, in step f, triethyl propionate was replaced with triethyl isopropionate, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(hexyloxy)phenyl)pyridine iodide, to obtain I-29.

[0199] Example 30

[0200] Unlike Example 26, in step f, triethyl propionate was replaced with triethyl benzoate, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(hexyloxy)phenyl)pyridine iodide, to obtain I-30.

[0201] Example 31

[0202] Unlike Example 26, in step f, triethyl propionate was replaced with triethyl butyrate, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(hexyloxy)phenyl)pyridine iodide, to obtain I-31.

[0203] Example 32

[0204] Unlike Example 26, step c, 3a, was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(heptoxy)phenyl)pyridine iodide to obtain I-32.

[0205] Example 33

[0206] Unlike Example 26, in step f, triethyl propionate was replaced with triethyl isopropionate, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(heptoxy)phenyl)pyridine iodide, to obtain I-33.

[0207] Example 34

[0208] Unlike Example 26, in step f, triethyl propionate was replaced with triethyl benzoate, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(heptoxy)phenyl)pyridine iodide, to obtain I-34.

[0209] Example 35

[0210] Unlike Example 26, in step f, triethyl propionate was replaced with triethyl butyrate, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(heptoxy)phenyl)pyridine iodide, to obtain I-35.

[0211] Example 36

[0212] Unlike Example 26, step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octoxy)phenyl)pyridine iodide to obtain I-36.

[0213] Example 37

[0214] Unlike Example 26, in step f, triethyl propionate was replaced with triethyl isopropionate, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octoxy)phenyl)pyridine iodide, to obtain I-37.

[0215] Example 38

[0216] Unlike Example 26, in step f, triethyl propionate was replaced with triethyl benzoate, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octoxy)phenyl)pyridine iodide, to obtain I-38.

[0217] Example 39

[0218] Unlike Example 26, in step f, triethyl propionate was replaced with triethyl butyrate, and in step c, 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-(4-(octoxy)phenyl)pyridine iodide, to obtain I-35.

[0219] Example 40

[0220] Step h: Preparation of 1-(4-tert-butylbenzyl)-5-nitro-1H-indole (14a)

[0221]

[0222] 5-Nitro-1H-indole (1.62 g, 10 mmol), 1-bromomethyl-4-tert-butylbenzene (3.39 g, 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 five times with CH3Cl2 and 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 = 20:1 as eluent) to give 14a (white solid, 2.65 g) in 86% yield. Similarly, 14b, 14c, and 14d were prepared according to the above method in yields of 86%, 88%, and 84%, respectively.

[0223] Step i: Preparation of 1-(4-(tert-butyl)benzyl)-1H-indole-5-amine (15a)

[0224]

[0225] 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 solution was concentrated under reduced pressure to give 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.

[0226] Step c: 4-((1-(4-(tert-butyl)benzyl)-1H-indol-5-yl)amino)-2-(4-(tert-butyl)phenyl)-1-methylpyridine iodide

[0227]

[0228] 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 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 (dichloromethane / methanol = 15:1 as eluent) to give I-40.

[0229] Example 41

[0230] Unlike Example 40, 1-bromomethyl-4-tert-butylbenzene in step h was replaced with phenylethyl bromide to obtain I-41.

[0231] Example 42

[0232] Unlike Example 40, step c's 3a was replaced with the same molar amount of 4-chloro-1-methyl-2-phenylpyridine iodide to obtain I-42.

[0233] Example 43

[0234] Unlike Example 40, 1-bromomethyl-4-tert-butylbenzene in step h was replaced with bromooctane, and 3a in step c was replaced with the same molar amount of 4-chloro-1-methyl-2-phenylpyridine iodide, to obtain I-43.

[0235] Example 44

[0236] Unlike Example 40, 1-bromomethyl-4-tert-butylbenzene in step h was replaced with phenylethyl bromide, and 3a in step c was replaced with the same molar amount of 4-chloro-1-methyl-2-phenylpyridine iodide, to obtain I-44.

[0237] Example 45

[0238] Unlike Example 40, the functional group 1-(4-tert-butylbenzyl) in compound 14a in step h is replaced with H (i.e., step h is not required in this example, and 5-nitro-1H-indole can be directly used for the next reduction reaction), and 3a in step c is replaced with the same molar amount of 4-chloro-1-methyl-2-phenylpyridine iodide to obtain I-45.

[0239] The target product of general formula I, i.e., the compounds I-1 to I-45, are as follows: Figure 1 As shown, the relevant NMR information is shown in Table 1.

[0240] Table 1. H from I-1 to I-45 1 NMR information

[0241]

[0242] Example 46

[0243] Step a: Preparation of 2-chloro-4-phenylpyridine (18)

[0244]

[0245] 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 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, 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) in 87% yield.

[0246] Step b: Preparation of 2-chloro-1-methyl-4-phenylpyridine iodide (19)

[0247]

[0248] Dissolve 18 (3.78 g, 20 mmol) in iodomethane and heat the reaction overnight at 80 °C in a sealed tube. After cooling to room temperature, add isopropyl ether to precipitate a yellow solid precipitate. Aspirate the suspension and filter to give crude yellow product 19 in 88% yield (5.82 g, yellow solid).

[0249] Step c: Preparation of 2-((1-(4-(tert-butyl)benzyl)-1H-indole-5-yl)amino)-1-methyl-4-phenylpyridine iodide salt

[0250] 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 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 (dichloromethane / methanol = 15:1 as eluent) to give II-1.

[0251]

[0252] Example 47

[0253] Unlike Example 46, step c involves replacing 15a with the same molar amount of 15b, resulting in II-2.

[0254] Example 48

[0255] Unlike Example 46, 15a in step c is replaced with the same molar amount of 15c, resulting in II-3.

[0256] Example 49

[0257] Unlike Example 46, 15a in step c is replaced with the same molar amount of 13a to obtain II-4.

[0258] Example 50

[0259] Unlike Example 46, step c involves replacing 15a with the same molar amount of 13d to obtain II-5.

[0260] The target product of general formula II, namely the compounds II-1 to II-5, are as follows: Figure 2 As shown in Table 2, the relevant NMR information is as follows.

[0261] Table 2. H from II-1 to II-5 1 NMR information

[0262]

[0263] Example 51

[0264] Step a: Preparation of N-(2-chloropyridin-4-yl)-1-(2-cyclohexylethyl)-1H-indole-5-amine (21)

[0265]

[0266] 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%), and Pd(dba)₂ (1%) were heated to reflux in toluene under a 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 give 21 in 53% yield (white solid, 0.93 g).

[0267] Step b: Preparation of 1-(2-cyclohexylethyl)-N-(2-phenylpyridin-4-yl)-1H-indole-5-amine (III-1)

[0268]

[0269] A solution of 21 (0.2 g, 0.56 mmol), phenylboronic acid (0.082 g, 0.67 mmol), K₂CO₃ (0.155 g, 1.12 mmol), and Pd(PPh₃)₄ (0.064 g, 0.056 mmol) in 1,4-dioxane:H₂O = 10:1 (20 mL) was prepared and heated to 80°C. The reaction 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) in 47% yield.

[0270] Example 52

[0271] Step c: Preparation of 5-(3-chloro-4-nitrobenzyl)-1-(2-cyclohexylethyl)-1H-indole (24)

[0272]

[0273] 4-Bromo-2-chloro-1-nitrobenzene (2 g, 8.39 mmol), 1-(2-cyclohexylethyl)-1h-indole-5-amine (1.8 g, 7.42 mmol), NaOtBu (1.7 g, 17.8 mmol), BINAP (2%), and Pd(dba)₂ (1%) were heated under reflux and stirred in toluene under a 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 low pressure. The residue was purified by vacuum filtration and silica gel column chromatography (petroleum ether / ethyl acetate = 10:1 as eluent) to give 24, in a yield of 62% (yellow solid, 2.06 g).

[0274] Step d: Preparation of 1-(2-cyclohexylethyl)-5-((6-nitro-[1,1'-biphenyl]-3-yl)methyl)-1H-indole (25)

[0275]

[0276] 24 (1.5 g, 3.78 mmol), phenylboronic acid (0.55 g, 4.54 mmol), K₂CO₃ (1.04 g, 7.58 mmol), and 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 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 give 25 (brown solid, 0.761 g) in 46% yield.

[0277] Step e: Preparation of 5-((1-(2-cyclohexylethyl)-1H-indol-5-yl)methyl)-[1,1'-biphenyl]-2-amine (26)

[0278]

[0279] 25 (0.6 g, 1.37 mmol), NH4Cl (0.22 g, 4.11 mmol), and Fe (0.22 g, 4.11 mmol) were reacted in a CH3CH2OH / H2O solution of 2:1 (15 ml) 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 give 26 (white solid, 0.296 g) in 53% yield.

[0280] Step f: Preparation of intermediate 27

[0281]

[0282] 26 (0.25 g, 0.61 mmol) and N,N'-di-boc-1h-pyrazole-1-formamidin (0.38 g, 1.22 mmol) were dissolved in 10 mL CHCl3 (50 °C) for 48 h. The reaction was detected by TCL method. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1 as eluent) to give 27 (white solid, 0.34 g) in 85% yield.

[0283] Step g: Preparation of 1-(5-((1-(2-cyclohexylethyl)-1H-indol-5-yl)methyl)-[1,1'-biphenyl]-2-yl)guanidine (III-2)

[0284]

[0285] 27 (0.30 g, 0.46 mmol) was dissolved in CH2Cl2 (10 mL), and the Boc protecting group was removed under TFA. After adjusting the pH of the solution to neutral, extraction and separation were performed, and the organic phase was concentrated under reduced pressure to give III-2 in 95% yield (brown solid, 0.19 g).

[0286] The target products of general formula III, namely the compounds III-1 and III-2, are as follows: Figure 3 As shown in Table 2, the relevant NMR information is as follows.

[0287] Table 3. H of III-1 and III-2 1 NMR information

[0288]

[0289] Example 53

[0290] In this embodiment, compounds I-1~45, II-1~5 and III-1~2 were selected to detect their inhibitory activity against sensitive and drug-resistant strains. The susceptible strains include eight strains: susceptible Bacillus subtilis (ATCC9372, a penicillin-sensitive strain), Bacillus pumilus (CMCC63202), Staphylococcus aureus (ATCC25923, an erythromycin-sensitive strain), Streptococcus pyogenes (S. 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 strains: drug-resistant Staphylococcus aureus (S. aureus... ATCC43300 (methicillin-resistant strain), Staphylococcus aureus (S. aureus PR, penicillin-resistant strain), Staphylococcus aureus (S. aureus CI, clinically isolated drug-resistant strain), Staphylococcus epidermidis (S. epidermidis, penicillin-resistant strain), Streptococcus pyogenes 2 (erythromycin-resistant strain), Enterococcus faecalis (E. faecalis ATCC51299, vancomycin-resistant strain), and Enterococcus faecium (E. faecium ATCC51559, vancomycin-resistant strain).

[0291] The minimum inhibitory concentrations (MICs) of various phenylpyridine quaternary ammonium salt derivatives (i.e., compounds I-1~45, II-1~5, and III-1~2 of this invention) and sanguinarine (San), berberine (Ber), linezolid (Lin), and ciprofloxacin (Cip) were determined using a serial micropore dilution method. Based on the MIC results, compounds with strong antibacterial activity were screened. Sanguinarine, berberine, linezolid, and ciprofloxacin reference standards were purchased from Anaiji Chemical.

[0292] Table 4. Results of the investigation of antibacterial activity of compounds of general formulas I, II and III of this application against susceptible strains.

[0293]

[0294] Table 5. Results of the investigation of the antibacterial activity of compounds of general formulas I, II and III of this application against drug-resistant strains.

[0295]

[0296] The above experimental results show that phenylpyridine quaternary ammonium salt derivatives possess excellent antibacterial activity against susceptible bacteria. In this series, I-44 exhibited significant antibacterial activity, with MIC values ​​ranging from 0.0625 to 4 µg / mL against susceptible Gram-positive bacteria, 1 to 4 µg / mL against susceptible Gram-negative bacteria, and 0.25 to 4 µmg / mL against resistant Gram-positive bacteria. Particularly noteworthy is the effect of I-44 on… S. aureus ATCC25923 exhibited antibacterial activity of 0.062 µg / mL, significantly exceeding that of other positively charged compounds. [This is in contrast to other compounds.] B. subtilis ATCC9372, the MIC value of I-44 is 0.5 µg / mL, which is comparable to the MIC of linezolid. Furthermore, I-44 has [unclear meaning - possibly related to a specific enzyme or drug]. E. coil ATCC25922 and E. coil The MICs of BW25113 were all 4 µg / mL, indicating their effectiveness against Gram-negative bacteria. Furthermore, among the positive compounds, I-44 showed efficacy against... A. baumannii The MIC value of ATCC19606 reached 1 µg / mL, which was significantly better than linezolid, sanguinarine and berberine.

[0297] Similarly, this series of compounds showed significant inhibitory effects on drug-resistant strains. Several compounds of the 2-phenylpyridine quaternary ammonium salt (I-40, I-41, and I-44) exhibited antibacterial activity of 0.5 µg / mL against MRSA strains, which were 32 and 4 times more potent than those of ciprofloxacin and linezolid, respectively. I-44, however, showed resistance to penicillin. S. aureus The MIC value of PR was 0.25 µg / mL. Furthermore, I-40, I-41, I-42, and I-44... S. aureus CI exhibited significant antibacterial activity, reaching levels of 0.5 µg / mL. Notably, I-41 showed resistance to vancomycin-resistant bacteria. E. faecalis The antibacterial activity of ATCC51559 (0.5 µg / mL) is 8 times that of linezolid.

[0298] Example 54

[0299] Effects of phenylpyridine quaternary ammonium salt derivatives on Bacillus subtilis cell morphology

[0300] This embodiment observed the effect of compounds with excellent antibacterial activity on the bacterial morphology of Bacillus subtilis. The observation results were as follows: Figure 4 Displayed in [the text]. For example... Figure 4As shown, the length of untreated Bacillus subtilis ranged from 1 to 4 μm, while substantial morphological changes occurred between Bacillus 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 Bacillus subtilis ATCC9372 by more than 20 μm. This observed cell extension pattern is characteristic of established FtsZ inhibitors, indicating that these compounds have the potential to inhibit FtsZ function without inducing bacterial cell division.

[0301] Example 55

[0302] Effects of phenylpyridine quaternary ammonium salt derivatives on FtsZ protein polymerization

[0303] This embodiment verifies that the direct effect of the phenylpyridine quaternary ammonium salt derivatives of the present invention on FtsZ protein was characterized by in vitro polymerization experiments. The light scattering intensity of the FtsZ polymerization solution was measured by a fluorescence spectrophotometer, thus reflecting the polymerization kinetics of the protein. DMSO was used as a negative control, and their effect on Bacillus subtilis FtsZ (…) was directly measured in vitro. Bs The effect of FtsZ) polymerization. Figure 5 Figures 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) are depicted. Bs Time-dependent polymerization curves of FtsZ at concentration gradients of 2.5–10 μg / mL. Time-scattering light intensity measurements indicate that these compounds induce polymerization in a concentration-dependent manner. Bs FtsZ polymerization. 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.

[0304] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A phenylpyridine quaternary ammonium salt derivative, characterized in that, The phenylpyridine quaternary ammonium salt derivatives are selected from compounds of formula I, II, or III or their pharmaceutically acceptable salts. The structures of the compounds represented by Formulas I, II and III are shown below: ； Among them, R 1 Selected from hydrogen, C1-C8 straight-chain or branched alkyl groups and C1-C8 straight-chain or branched alkoxy groups; R 2 Selected from aromatic heteroyl and substituted aromatic heteroyl groups; X is -NH- or -O-; Z 1 -N- or -C-; Z 2 -N- or -O-; R 3 Z is a benzyl group substituted with C1-C8 straight-chain or branched alkyl, 1-(2-cyclohexylethyl), or C1-C5 straight-chain or branched alkyl; 3 -N- or -C-; R 4 It may be guanidine or absent; Y is a halogen; The aromatic heterol group is selected from isoquinoline, benzothiazole, benzoxazole, indole, dihydrobenzofuran, 2,3-dihydro-1H-indene, and thiazole; The substituted aromatic heteroyl group is selected from 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, 1-octyl-1H-indol-5-yl, 1-(4-tert-butylbenzyl)-1H-indol-5-yl, 1-(2-cyclohexylethyl)-1H-indol-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.

2. The phenylpyridine quaternary ammonium salt derivative according to claim 1, characterized in that, The R 1 It is selected from hydrogen, tert-butyl, hexoxy, heptoxy, and octoxy.

3. The phenylpyridine quaternary ammonium salt derivative according to claim 1, characterized in that, R 2 Selected from isoquinoline-7-yl, 2,3-dihydrobenzofuran-5-yl, and 2,3-dihydro-1H-indene-5-yl.

4. The phenylpyridine quaternary ammonium salt derivative according to claim 1, characterized in that, Y is I.

5. The phenylpyridine quaternary ammonium salt derivative according to claim 1, characterized in that, R 3 Selected from 1-octyl, 1-(4-tert-butylbenzyl), 2-propyl and 2-butyl.

6. The phenylpyridine quaternary ammonium salt derivative according to claim 1, characterized in that, 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.

7. The phenylpyridine 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: ； In the IA structure, n is 0 or 1, and X is -NH- or -O-; R 1 Selected from hydrogen, tert-butyl, hexoxy, heptoxy, and octoxy; R 2a Selected from isoquinoline-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-indene-5-yl, benzo[d]thiazol-2-yl, and thiazol-2-yl; In the IB structure, R 1 Selected from hydrogen, tert-butyl, hexoxy, heptoxy, and octoxy; R 2b Selected from C1-C8 straight-chain or branched alkyl and phenyl groups; R 2c Selected from hydrogen and C1-C8 straight-chain or branched alkyl groups; In the IC structure, R 1 Selected from hydrogen, tert-butyl, hexoxy, heptoxy, and octoxy; R 2d Selected from hydrogen, C1-C8 straight-chain or branched alkyl groups, and phenyl groups; In the ID structure, R 1 Selected from hydrogen, tert-butyl, hexoxy, heptoxy, and octoxy; R 2e Selected from hydrogen, C1-C8 straight-chain or branched alkyl, cycloalkylethyl and C1-C5 branched alkyl-substituted benzyl groups.

8. The phenylpyridine quaternary ammonium salt derivative according to claim 7, characterized in that, In the IA structure, n is 1, R 2a Selected from benzo[d]thiazolyl-2-yl and thiazolyl-2-yl; In the IA structure, n is 0, R 2a It is selected from isoquinoline-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-indene-5-yl.

9. The phenylpyridine quaternary ammonium salt derivative according to claim 7, characterized in that, In the IB structure, R 2b It is isobutyl, isopropyl, or phenyl.

10. The phenylpyridine quaternary ammonium salt derivative according to claim 7, characterized in that, In the IB structure, R 2c It can be hydrogen or methyl.

11. The phenylpyridine quaternary ammonium salt derivative according to claim 7, characterized in that, In the IC structure, R 2d It can be hydrogen, isopropyl, n-propyl, n-butyl, or phenyl.

12. The phenylpyridine quaternary ammonium salt derivative according to claim 7, characterized in that, R 2e It is hydrogen, n-octyl, 4-tert-butylbenzyl or 2-cyclohexylethyl.

13. The phenylpyridine quaternary ammonium salt derivative according to claim 7, characterized in that, The compound represented by Formula I is one of the following: 。 14. The phenylpyridine quaternary ammonium salt derivative according to claim 7, characterized in that, The compound represented by Formula II is one of the following: 。 15. The phenylpyridine quaternary ammonium salt derivative according to claim 7, characterized in that, The compound represented by Formula III is one of the following: 。 16. A method for preparing the phenylpyridine quaternary ammonium salt derivative according to any one of claims 1-15, characterized in that, The phenylpyridine quaternary ammonium salt derivative has the 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 1-15.

17. The method according to claim 16, characterized in that, The phenylpyridine quaternary ammonium salt derivative has the 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 1-15.

18. The method according to claim 16, characterized in that, The phenylpyridine quaternary ammonium salt derivative has the structure shown in Formula III, where Formula III is selected from Formula III-1 and Formula III-2: The preparation method is carried out according to the following reaction route: ； Alternatively, the preparation method is carried out according to the following reaction route: 。 19. A composition, characterized in that, Includes the phenylpyridine quaternary ammonium salt derivatives according to any one of claims 1-15.

20. The composition according to claim 19, characterized in that, Includes auxiliary materials.

21. A formulation, characterized in that, Includes the phenylpyridine quaternary ammonium salt derivatives according to any one of claims 1-15 or the composition according to claim 19 or 20.

22. The use of the phenylpyridine quaternary ammonium salt derivative of any one of claims 1-15, the composition of claim 19 or 20, or the formulation of claim 21 in the preparation of an antibacterial product; wherein the antibacterial product is an antibacterial product; wherein the bacteria are susceptible bacteria and drug-resistant bacteria, wherein the susceptible bacteria are one or more of susceptible Bacillus subtilis, susceptible Bacillus pumilus, susceptible Staphylococcus aureus, susceptible Streptococcus pyogenes, susceptible Enterococcus faecalis, susceptible Enterococcus faecalis, susceptible Acinetobacter baumannii, susceptible Pseudomonas aeruginosa, and susceptible Escherichia coli strains, and wherein 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 faecalis.

23. The application according to claim 22, characterized in that, The antibacterial product is one or more of the following: medicines and personal care products; the personal care products are one or more of the following: fruit and vegetable cleaners, shampoos, soaps, shower gels, laundry detergents, hand soaps, toilet cleaners, and facial cleansers.

24. A method for inhibiting Gram-positive bacteria in vitro, characterized in that, The method is not intended for the diagnosis or treatment of disease. The method involves applying to the surface to be inhibited a phenylpyridine quaternary ammonium salt derivative according to any one of claims 1-15 and / or the composition according to claim 19 or 20 and / or the formulation according to claim 21.

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