Indole derivatives with antibacterial activity, preparation method thereof, use thereof, and pharmaceutical composition and medical device prepared therefrom

Abstract

The present invention belongs to the field of medical technology, and specifically relates to an indole derivative with antibacterial activity, a preparation method thereof, a use thereof, and a pharmaceutical composition and medical device prepared therefrom. The present invention provides a compound as shown in Formula I by optimizing the structure of a substituent. These compounds have a good inhibitory effect on pathogenic bacteria including Pseudomonas aeruginosa, and are expected to be developed into antibacterial and anti-infective drugs. They can also be used as coating materials for medical devices to exert antibacterial effects, and have good application prospects. Formula I.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to an indole derivative with antibacterial activity, a preparation method thereof, a use thereof, and a pharmaceutical composition and medical device prepared therefrom. Background Art

[0002] Indole compounds are an important class of nitrogen-containing heterocyclic organic compounds, which are composed of a benzene ring and a pyrrole ring. The structural formula of indole is as follows:

[0003]

[0004] Indole and its derivatives are widely used in many industries such as pesticides, medicines, spices, dyes, etc. In the application of the pharmaceutical field, indole and its derivatives show a wide range of biological activities, such as anti-inflammatory, analgesic, antimicrobial, anticonvulsant, antidepressant, antidiabetic, antiparasitic and antiallergic. The diverse biological activities exhibited by compounds containing indole groups.

[0005] Some existing studies have shown that some indole derivatives have antibacterial activity, such as the literature: "Kaur NS S. Recent Developments in the Synthesis and Antimicrobial Activity of Indole and its Derivatives [J]. Current Organic Synthesis, 2019, 16 (1)". However, there is still a need to improve the antibacterial activity of current indole derivatives; in addition, for the sake of drug efficacy and safety, as well as to solve the problem of drug resistance of pathogens, it is also necessary to develop more lead drugs for antibacterial purposes in this field.

[0006] Therefore, how to optimize the substituent structure of indole derivatives and develop more compounds with excellent antibacterial activity remains an important topic in this field. Summary of the invention

[0007] In view of the problems of the prior art, the present invention provides an indole derivative with antibacterial activity, a preparation method thereof, a use thereof, and a pharmaceutical composition and a medical device prepared therefrom.

[0008] The compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystalline form thereof:

[0009]

[0010] Formula I

[0011] R is selected from substituted or unsubstituted C6-C 10aryl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C1-C 10 Alkyl, wherein the substituent is selected from halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, halogen substituted C1-C 10 Alkyl, cyano, amino, C1-C 10 Amine group.

[0012] Preferably, the compound is as shown in Formula II:

[0013]

[0014] Formula II

[0015] Ring A is selected from C6-C 10 Aryl, 5-10 membered heteroaryl;

[0016] n is selected from 0, 1, 2, 3;

[0017] R A Independently selected from halogen, C1-C 10 Alkoxy, C1-C 10 Alkyl, halogen substituted C1-C 10 alkyl.

[0018] Preferably, ring A is selected from phenyl, 6-membered nitrogen-containing heteroaryl; R A Independently selected from F, Cl, C1-C2 alkoxy, trifluoromethyl.

[0019] Preferably, the compound is as shown in Formula III:

[0020]

[0021] Formula III

[0022] M is selected from CR C or N;

[0023] R B Selected from Cl, F;

[0024] R C Selected from methoxy.

[0025] Preferably, R is selected from substituted or unsubstituted C1-C4 alkyl, wherein the substituent is selected from F and Cl.

[0026] Preferably, the compound has the following structural formula:

[0027] , , , , , , , , , , , , , , , .

[0028] The present invention also provides a method for preparing the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystalline form thereof, comprising the following steps:

[0029]

[0030] Step 1, reacting raw material A and raw material B to obtain intermediate A;

[0031] Step 2, removing the amino protecting group of intermediate A to obtain a compound represented by formula II;

[0032] Among them, R D is selected from amino protecting groups.

[0033] Preferably, the amino protecting group is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, tert-butyl, benzoyl, trityl, methoxymethyl, benzyl, allyl, tert-butyldimethylsilyl, tert-butyldimethylsilyl, methylene ether, 9-fluorenylmethoxycarbonyl, tetrahydropyranylmethoxycarbonyl, diphenylphosphoryl, diphenylphosphate, p-nitrobenzyl, p-methoxybenzyl, acetyl, 4-methylbenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2-nitrobenzyl, 2,4-dinitrobenzyl;

[0034] And / or, in step 1, the reaction is carried out under the action of a base, and the base is selected from at least one of K2CO3, K3PO4, Na2CO3, Cs2CO3, t-BuOK, t-BuONa, and triethylamine;

[0035] And / or, in step 1, the reaction is carried out under the action of a ligand and / or a catalyst, the ligand is selected from at least one of PAP ligand, Pcy3, PPh3, t-Bu3P, XPhos, SPhos, and dppf, and the catalyst is selected from at least one of Pd(OAc)2, Pd(dba)2, Pd(PPh3)4, Pd (PPh3)2Cl2, Pd(dppf)Cl2, and Pd(dtpbf)Cl2;

[0036] And / or, in step 1, the reaction solvent is selected from at least one of acetonitrile, 1,4-dioxane, DME, DMSO, DMF, toluene and water;

[0037] And / or, in step 1, the reaction temperature is 30-150° C., and the reaction time is 6-24 hours;

[0038] And / or, in step 2, the reaction is carried out under the action of an acid, and the acid is selected from hydrochloric acid;

[0039] And / or, in step 2, the reaction solvent is selected from at least one of methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane and toluene;

[0040] And / or, in step 2, the reaction temperature is 25-80°C.

[0041] The present invention also provides the use of the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof in the preparation of an anti-pathogenic bacteria and / or anti-infective drug.

[0042] Preferably, the pathogenic bacteria are Gram-negative bacteria and / or Gram-positive bacteria;

[0043] The Gram-negative bacteria are selected from at least one of Pseudomonas aeruginosa, Escherichia coli, Proteus, Shigella dysenteriae, Salmonella typhi, Bordetella pertussis, Vibrio cholerae, Neisseria meningitidis, Haemophilus influenzae, Klebsiella, Salmonella, Shigella, Pasteurella, Parahaemolyticus, and Shigella-like Pyrromonas;

[0044] The Gram-positive bacteria is selected from at least one of Staphylococcus, Streptococcus, Pneumococcus, Bacillus anthracis, Bacillus diphtheriae and Bacillus tetanus.

[0045] The present invention also provides a pharmaceutical composition for use in fighting pathogenic bacteria and / or infection, which is a preparation prepared by using the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof as an active ingredient and adding pharmaceutically acceptable excipients or auxiliary ingredients.

[0046] The present invention also provides use of the above compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof in preparing a coating for a medical device.

[0047] The present invention also provides a medical device, wherein an antibacterial coating is disposed on the surface of the medical device, and the surface or interior of the antibacterial coating comprises the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof.

[0048] The compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0049] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined in this document, the meaning that a person skilled in the art can give them should be given based on the disclosure and context.

[0050] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule.

[0051] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a -C b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C1-C6 alkyl" refers to an alkyl group containing from 1 to 6 carbon atoms.

[0052] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group with 1 to 6 member atoms, such as 1 to 4 member atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) and hexyl. The alkyl group may also be a part of other groups, such as C1-C6 alkoxy.

[0053] "Halogen" is fluorine, chlorine, bromine or iodine.

[0054] "Heteroaryl" refers to an aromatic unsaturated ring containing at least one heteroatom and having a single ring or multiple rings; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom; for example, pyridyl.

[0055] "Alkoxy" refers to an alkyl group attached to the site of attachment through an oxygen atom, for example, methoxy refers to -OCH3.

[0056] "Amine group" refers to a group connected to a linking site through a carbon chain or N, and the carbon chain contains at least one N.

[0057] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form and physiologically compatible with the receptor.

[0058] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final separation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomer, with a certain amount of acid or base appropriately (e.g., equivalent amount). These salts may be precipitated in the solution and collected by filtration, or recovered after solvent evaporation, or obtained by freeze drying after reaction in an aqueous medium. The salts described in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0059] In certain embodiments, one or more compounds of the present invention may be used in combination with each other. It is also possible to select the compounds of the present invention and any other active agent for use in combination to prepare a drug or pharmaceutical composition for regulating cell function or treating a disease. If a group of compounds is used, these compounds may be administered to a subject simultaneously, separately or sequentially.

[0060] The present invention optimizes the structure of indole derivatives and obtains a series of new indole derivatives. These indole derivatives have excellent antibacterial activity and good inhibitory effect on pathogenic bacteria including Pseudomonas aeruginosa. Therefore, the compounds of the present invention are expected to be developed into antibacterial and anti-infective drugs, and can also be used as coating materials for medical devices to play an antibacterial role, and have good application prospects.

[0061] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0062] The following is a further detailed description of the above contents of the present invention through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies implemented based on the above contents of the present invention belong to the scope of the present invention. DETAILED DESCRIPTION

[0063] In the following examples and experimental examples, reagents and raw materials not specifically described are all commercially available products.

[0064] Example 1 Compound 1-5 and its preparation method

[0065] Synthesis method: Compound a (0.2 mmol), different phenylboronic acids (0.4 mmol, 2 eq.), K2CO3 (0.4mmol, 2eq.), PAP ligand (0.01 mmol, 10%mol), Pd(OAc)2 (0.02 mmol, 10%mol) were added to 2 ml of dry acetonitrile under argon atmosphere. Stir at 100 °C for 12 hours. After the reaction was completed, it was cooled to room temperature, 10 ml of EtOAc and 10 ml of saturated ammonium chloride solution were added, the organic phase was extracted, and dried with anhydrous Na2SO4. After the solvent was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography to obtain a compound with BOC. The compound with BOC (0.2 mmol) was dissolved in 2 mL of MeOH, and 0.2 mL of concentrated HCl was added. The mixture was stirred at room temperature and detected by TCL. The target compound was obtained when the raw material disappeared.

[0066] The specific compound structures, yields and product characterization results are as follows:

[0067] (1) Compound 1

[0068]

[0069] Compound 1: 1 H NMR (600 MHz, DMSO-D6) δ 11.15 (s, 1H), 9.42 (s, 2H), 7.78(s, 1H), 7.48 – 7.39 (m, 3H), 7.28 – 7.16(m, 2H), 4.34 (s, 2H), 4.20 (s, 3H), 3.46 (s, 2H), 2.96 (t, J = 6.1 Hz, 2H).

[0070] (2) Compound 2

[0071]

[0072] Compound 2: 1 H NMR (600 MHz, DMSO- D 6) δ 11.28 (s, 1H), 9.71 (s, 2H), 7.87(d, J = 7.7 Hz, 2H), 7.81 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.45 (s, 2H), 4.30 (s, 2H), 3.39 (s, 2H), 2.96 (s, 2H).

[0073] (3) Compound 3

[0074]

[0075] Compound 3: 1 H NMR (600 MHz, DMSO- D 6) δ 11.09 (s, 1H), 9.35 (s, 2H), 7.65 (s, 1H), 7.45 – 7.37 (m, 2H), 6.83 (d, J = 2.3 Hz, 2H), 6.45 (t, J = 2.3 Hz, 1H), 4.65 (s, 2H), 3.89 (s, 6H), 3.79 (s, 2H), 2.82 (s, 2H).

[0076] (4) Compound 4

[0077]

[0078] Compound 4: 1 H NMR (600 MHz, DMSO- D 6) δ 11.19 (s, 1H), 9.53 (s, 2H), 7.79(s, 1H), 7.50 – 7.34 (m, 4H), 4.33 – 4.29 (m, 2H), 3.91 (s, 3H), 3.45 – 3.37(m, 2H), 2.99 – 2.93 (m, 2H).

[0079] (5) Compound 5

[0080]

[0081] Compound 5: 1 H NMR (600 MHz, DMSO- D 6) δ 11.09 (s, 1H), 9.35 (s, 2H), 7.71 (s, 1H), 7.42 – 7.32 (m, 3H), 7.25 – 7.14 (m, 2H), 4.32 (s, 2H), 4.18 (q, J =7.0 Hz, 2H), 3.42 (s, 2H), 2.96 (t, J = 6.1 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H).

[0082] Example 2 Compounds 6, 7, 8 and their preparation methods

[0083] Synthesis method: Compound a (0.2 mmol), different phenylboronic acids (0.4 mmol, 2 eq.), K3PO4 (0.4mmol, 2eq.), Pd(dba)2 (0.02 mmol, 10%mol), Pcy3 (0.04mmol, 20%mol), were added to a mixed solvent of 1.8ml 1,4-dioxane and H2O (volume ratio 2:1) under argon atmosphere. Stir at 100°C for 18 hours. After the reaction was completed, it was cooled to room temperature, 10ml EtOAc and 10ml saturated ammonium chloride solution were added, the organic phase was extracted, and dried with anhydrous Na2SO4. After the solvent was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography to obtain a compound with BOC. The compound with BOC (0.2mmol) was dissolved in 2 mL MeOH, 0.2 mL concentrated HCl was added, stirred at room temperature, and detected by TCL. The target compound was obtained when the raw material disappeared.

[0084] The specific compound structures, yields and product characterization results are as follows:

[0085] (1) Compound 6

[0086]

[0087] Compound 6: 1 H NMR (600 MHz, DMSO- D 6) δ 11.31 (s, 1H), 9.63 (s, 2H), 8.25(d, J = 7.6 Hz, 2H), 8.02 (d, J = 7.7 Hz, 2H), 7.85 (s, 1H), 7.51 (s, 2H), 4.36(s, 2H), 3.35 (s, 2H), 3.01 (s, 2H).

[0088] (2) Compound 7

[0089]

[0090] Compound 7: 1 H NMR (600 MHz, DMSO- D 6) δ 11.36 (s, 1H), 9.66 (s, 2H), 9.10 (s, 1H), 8.92 (d, J= 2.4 Hz, 1H), 8.58 – 8.50 (m, 1H), 8.01 – 7.96 (m, 1H), 7.69 (s, 1H), 7.48 – 7.36 (m, 3H), 4.79 – 4.61 (m, 2H), 3.80 (t, J = 5.6 Hz,2H), 2.86 (t, J = 5.7 Hz, 2H).

[0091] (3) Compound 8

[0092]

[0093] Compound 8: 1 H NMR (600 MHz, DMSO- D 6) δ 11.34 (s, 1H), 9.62 (s, 2H), 8.22– 8.20 (m, 1H), 8.04 – 8.01 (m, 1H), 7.72 –7.69 (m, 1H), 7.61 – 7.57 (m, 1H), 7.50 (s, 1H), 7.48 – 7.43 (m, 1H), 4.35 – 4.30 (m, 2H), 3.44 – 3.37 (m, 2H), 2.98 (t, J = 6.1 Hz, 2H).

[0094] Example 3 Compound 9 and its preparation method

[0095] Synthesis method: Compound a (0.2 mmol), different phenylboronic acids (0.4 mmol, 2 eq.), K3PO4 (0.4mmol, 2eq.), Pd(PPh3)4 (0.02 mmol, 10% mol) were added to a mixed solvent of 2 ml DME and H2O (4:1 by volume ratio) under argon atmosphere. Stir at 60°C for 12 hours. After the reaction was completed, it was cooled to room temperature, 10 ml EtOAc and 10 ml saturated ammonium chloride solution were added, the organic phase was extracted, and dried with anhydrous Na2SO4. After the solvent was evaporated under reduced pressure, the crude product was purified by silica gel column chromatography to obtain a compound with BOC. The compound with BOC (0.2 mmol) was dissolved in 2 mL MeOH, 0.2 mL concentrated HCl was added, stirred at room temperature, and detected by TCL. The target compound was obtained when the raw material disappeared.

[0096] The specific compound structures, yields and product characterization results are as follows:

[0097]

[0098] Compound 9: 1 H NMR (600 MHz, DMSO- D 6) δ 11.17 (s, 1H), 9.47 (s, 2H), 7.65(d, J = 2.2 Hz, 1H), 7.59 (s, 1H), 7.48 (dd, J = 8.5, 2.3 Hz, 1H), 7.36 – 7.29(m, 2H), 6.99 (d, J = 8.5 Hz, 1H), 4.68 (d, J = 27.1 Hz, 2H), 3.93 (s, 3H), 3.80(s, 2H), 2.86 (t, J = 5.7 Hz, 2H).

[0099] Example 4 Compounds 10, 11, 12 and their preparation methods

[0100] Synthesis method:

[0101] A to C: Compound A (1.0 eq.) was dissolved in 8 ml of trifluoroacetic acid and cooled to 0°C. B (1.2 eq.) (1-dimethylamino-2-nitroethylene) was then slowly added and the mixture was moved to room temperature and stirred for 1 h. After the reaction was completed as detected by TLC, saturated sodium bicarbonate was added for neutralization. The organic phase was extracted with DCM and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography to obtain compound C.

[0102] C to D: Under nitrogen atmosphere, nitroolefin C was dissolved in THF solution (10 mL / mmol) and cooled to 0 °C. LiAlH4 solution (6.0 equivalents, 2.5 mmol / ml) was slowly added under vigorous stirring. The mixture was heated to room temperature and stirred for 36 h. After the reaction was completed, the reaction mixture was cooled to 0 °C, H2O was slowly added dropwise to quench the reaction until no more bubbles were generated, and then saturated tartrate solution (30 mL) was added and stirred vigorously for 24 h. After separation, the aqueous layer was extracted with ether, and the collected organic layer was extracted with 2N hydrochloric acid (3×25 mL). The aqueous phase was cooled in an ice bath and the pH was adjusted to about 10 with 3M potassium hydroxide solution. The alkaline mixture was then extracted with ether (3×25 mL), and the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the tryptamine derivative D.

[0103] D to E: Under nitrogen atmosphere, tryptamine derivative D (1 equivalent) was dissolved in acetic acid / methanol mixed solvent (v / v = 2:5), and then paraformaldehyde (1.2 equivalent) was added. The mixture was heated to 80°C for 3 hours and then cooled to 0°C. The pH was adjusted to 9-10 with saturated NaHCO3 aqueous solution (first adjusted to pH 4-5 with NaOH, then adjusted to pH 8 with NaHCO3, and finally a small amount of NaOH solution was added dropwise to pH 9-10). Then, the organic phase was extracted with dichloromethane (DCM, 30 mL × 3). After the organic phases were combined, they were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the target compound.

[0104] The specific compound structures, yields and product characterization results are as follows:

[0105]

[0106] Compound 10 (total yield 15%): 1 H NMR (600 MHz, DMSO- D 6) d = 10.42 (s, 1H), 7.08 –7.03 (m, 2H), 6.74 (d, J = 8.1 Hz, 1H), 3.76 (s, 2H), 2.89 (t, J = 5.6 Hz, 2H),2.49 (t, J = 5.7 Hz, 2H), 2.27 (s, 3H).

[0107] Compound 11 (total yield 17%): 1 H NMR (600 MHz, DMSO-D 6 ) δ = 10.52 (s, 1H), 7.24(s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 7.02 (m, 1H), 4.10 (s, 2H), 3.55 (t, J = 6.2Hz, 2H), 2.90 (t, J = 6.1 Hz, 2H). 1.29 (s, 9H).

[0108] Compound 12 (total yield 12%): 1 H NMR (600 MHz, DMSO-D 6 ) d =11.66 (s, 1H), 7.83 (s, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 4.32 (s, 2H), 3.38(t, J = 6.2 Hz, 2H), 2.96 (t, J = 6.1 Hz, 2H).

[0109] Comparative Example 1

[0110] This comparative example provides a preparation method of reference compound D1.

[0111] Synthesis method: Compound a (1.2 g, 5 mmol, 1 eq) and glyoxylic acid (0.45 g, 6 mmol, 1.2 eq) were dissolved in 15 mL H2O, and then KOH solution (0.3 g, 5 mmol, 1 eq) in 2 mL H2O was added dropwise. The mixture was stirred for 1 h, and the white precipitate was collected by filtration. The precipitate was dissolved in 15 mL H2O, and 12 M HCl (3.6 mL) solution was added at room temperature. After stirring at reflux for 1 h, 3.6 mL 12 M HCl was added again, and stirred at reflux for another 0.5 h. After cooling to rt, light green crystals were obtained, collected by filtration, and then dissolved in 15 mL H2O. The solution was alkalized to pH>13 with 20% KOH, the white precipitate was filtered out, and washed with water 3 times to obtain the target compound.

[0112] The specific compound structures, yields and product characterization results are as follows:

[0113]

[0114] Compound D1: 1 H NMR (600 MHz, DMSO-D6) δ 11.13 (s, 1H), 7.40 (d, J =2.1Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 7.00 (dd, J = 8.5, 2.1 Hz,1H), 4.05 (s,2H), 3.14 (t, J = 5.8 Hz, 2H), 2.70 (t, J = 5.9Hz, 2H).

[0115] The technical solution of the present invention is further illustrated by experiments below.

[0116] Experimental Example 1 Antibacterial activity of compounds

[0117] 1. Experimental Methods

[0118] This experimental example detected the antibacterial activity of various compounds synthesized in Examples 1-4 and compound D1 synthesized in Comparative Example 1.

[0119] Compounds D1 and 1-12 were dissolved in dimethyl sulfoxide to prepare 100 mM stock solutions.

[0120] Sterile saline was used to prepare the overnight culture of Pseudomonas aeruginosa PAO1 into a bacterial solution with OD600nm=1, and the culture medium was inoculated with 1% of the bacterial volume into M9-adenosine (0.1%, w / v, Sigma-Aldrich) medium. The corresponding compounds were added to the M9-adenosine medium in each compound treatment group to make the final concentrations of 0.01 µM, 0.05 µM and 0.1 µM, respectively, and the solvent control group was given an equal amount of dimethyl sulfoxide (i.e., the compound concentration was 0 µM). After the M9-adenosine culture medium was incubated at 37°C for 36 hours, the absorbance of the culture medium was measured at a wavelength of 600 nm.

[0121] 2. Experimental Results

[0122] The effects of 13 compounds on the growth of Pseudomonas aeruginosa PAO1 in M9-adenosine medium are shown in Table 1. In M9-adenosine medium, PAO1 relies on the nucleoside hydrolase Nuh, which is positively regulated by the las quorum sensing system, to decompose and utilize adenosine, the only carbon source in the medium. Therefore, in the quorum sensing selective medium, the inhibition of the growth of PAO1 by the compound reflects its inhibitory activity on the quorum sensing system. Compared with the solvent control group, the addition of various compounds of the present invention can significantly inhibit the growth of PAO1 in the quorum sensing selective medium, and as the concentration of the compound increases, compounds 5 and 9 also have an obvious dose-effect relationship. In addition, it can be seen from the results in Table 1 that the activities of the compounds provided by the present invention are better than those of the control compound D1, and compounds 8 and 9 have the best activity.

[0123] Table 1 Antibacterial activity of compounds

[0124]

[0125]

[0126] Note: Compared with the 0 µM group. Two-tailed t-test. ns, no significant difference; * ，p<0.05。 ** ，p<0.01。 ***, p< 0.001 . Sample size n = 4.

[0127] It can be seen from the above embodiments and experimental examples that the present invention obtains a series of compounds with good antibacterial activity by optimizing the structure of indole derivatives. These compounds are expected to be developed into antibacterial and anti-infective drugs, and can also be used as coating materials for medical devices to play an antibacterial role, and have good application prospects.

Claims

1. A compound represented by formula II or a pharmaceutically acceptable salt thereof: Formula II Ring A is selected from phenyl, 6-membered nitrogen-containing heteroaryl; n is selected from 0, 1, 2, 3; R A Independently selected from F, Cl, C1-C2 alkoxy, trifluoromethyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is shown in formula III: Formula III M is selected from CR C or N; R B Selected from Cl, F; R C Selected from methoxy.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound structural formula is as follows: 、 、 、 、 、 、 、 、 。 4. A method for preparing the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, characterized in that: The steps include: Step 1, reacting raw material A and raw material B to obtain intermediate A; Step 2, removing the amino protecting group of intermediate A to obtain a compound represented by formula II; Among them, R D is selected from an amino protecting group, a ring A, n, R A As described in any one of claims 1 to 3.

5. The preparation method according to claim 4, characterized in that: The amino protecting group is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, tert-butyl, benzoyl, trityl, methoxymethyl, benzyl, allyl, tert-butyldimethylsilyl, tert-butyldimethylsilyl, methylene ether, 9-fluorenylmethoxycarbonyl, tetrahydropyranylmethoxycarbonyl, diphenylphosphoryl, diphenylphosphate, p-nitrobenzyl, p-methoxybenzyl, acetyl, 4-methylbenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2-nitrobenzyl, 2,4-dinitrobenzyl; And / or, in step 1, the reaction is carried out under the action of a base, and the base is selected from at least one of K2CO3, K3PO4, Na2CO3, Cs2CO3, t-BuOK, t-BuONa, and triethylamine; And / or, in step 1, the reaction is carried out under the action of a ligand and / or a catalyst, the ligand is selected from at least one of PAP ligand, Pcy3, PPh3, t-Bu3P, XPhos, SPhos, and dppf, and the catalyst is selected from at least one of Pd(OAc)2, Pd(dba)2, Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, and Pd(dtpbf)Cl2; And / or, in step 1, the reaction solvent is selected from at least one of acetonitrile, 1,4-dioxane, dimethyl ether, dimethyl sulfoxide, N,N-dimethylformamide, toluene and water; And / or, in step 1, the reaction temperature is 30-150° C., and the reaction time is 6-24 hours; And / or, in step 2, the reaction is carried out under the action of an acid, and the acid is selected from hydrochloric acid; And / or, in step 2, the reaction solvent is selected from at least one of methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane and toluene; And / or, in step 2, the reaction temperature is 25-80°C.

6. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of an anti-pathogenic and / or anti-infective drug, characterized in that: The pathogenic bacteria or infection source is Pseudomonas aeruginosa.

7. A pharmaceutical composition for use in fighting pathogenic bacteria and / or infection, characterized in that: The invention relates to a preparation comprising the compound described in any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient and pharmaceutically acceptable adjuvants or auxiliary ingredients.

8. Use of the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of an antibacterial coating for medical devices.

9. A medical device, characterized in that: The surface of the medical device is provided with an antibacterial coating, and the surface or interior of the antibacterial coating comprises the compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

10. Use of a compound or a pharmaceutically acceptable salt thereof in the preparation of an anti-pathogenic and / or anti-infective drug, characterized in that: The pathogenic bacteria or infection source is Pseudomonas aeruginosa, and the compound is selected from: , , .

11. Use of a compound or a pharmaceutically acceptable salt thereof in preparing an antibacterial coating for medical devices, characterized in that: The bacterium is Pseudomonas aeruginosa, and the compound is selected from: 、 、 。 12. A medical device, characterized in that: The surface of the medical device is provided with an antibacterial coating, and the surface or interior of the antibacterial coating includes a compound or a pharmaceutically acceptable salt thereof, and the compound is selected from: 、 、 。

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