Indole derivative having antibacterial activity, preparation method therefor, use thereof, and pharmaceutical composition and medical device prepared therefrom
By optimizing the substituent structure and synthesis conditions of indole derivatives, compounds with excellent antibacterial activity were prepared, solving the problem of insufficient antibacterial activity of existing indole derivatives, and realizing effective inhibition of Gram bacteria and application of antibacterial coatings in medical devices.
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- CHENGDU PIOLET BIOTECHNOLOGY CO LTD
- Filing Date
- 2025-12-23
- Publication Date
- 2026-07-30
AI Technical Summary
There is room for improvement in the antibacterial activity of existing indole derivatives, and the effectiveness of drugs and the resistance of pathogens must be considered. More compounds with excellent antibacterial activity should be developed to solve this problem.
By optimizing the substituent structure of indole derivatives, indole derivatives with specific substituents are designed, and compounds of Formula I and their pharmaceutically acceptable salts, stereoisomers, solvates or crystal forms are prepared through specific synthetic steps. The reaction is carried out using bases, ligands, catalysts and solvents, and the reaction conditions are optimized to improve antibacterial activity.
A series of indole derivatives with excellent inhibitory effects on Gram-negative and Gram-positive bacteria were obtained, which are suitable for antibacterial coatings of antimicrobial drugs and medical devices, showing good application prospects.
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Figure CN2025144910_30072026_PF_FP_ABST
Abstract
Description
Indole derivatives with antibacterial activity, their preparation methods, their uses, and pharmaceutical compositions and medical devices made from them. Technical Field
[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an indole derivative with antibacterial activity, its preparation method, its uses, and pharmaceutical compositions and medical devices made therefrom. Background Technology
[0002] Indole compounds are an important class of nitrogen-containing heterocyclic organic compounds, formed by the fusion of a benzene ring and a pyrrole ring. The structural formula of indole is as follows:
[0003] Indole and its derivatives have wide applications in numerous industries, including pesticides, pharmaceuticals, fragrances, and dyes. In the pharmaceutical field, indole and its derivatives exhibit a wide range of biological activities, such as anti-inflammatory, analgesic, antimicrobial, anticonvulsant, antidepressant, antidiabetic, antiparasitic, and anti-allergic effects. Compounds containing the indole group exhibit diverse biological activities.
[0004] Some existing studies have shown that some indole derivatives possess antibacterial activity, for example, in 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, considering drug efficacy and safety, as well as addressing the problem of pathogenic bacterial resistance, it is also necessary in this field to develop more lead drugs for antibacterial purposes.
[0005] Therefore, optimizing the substituent structure of indole derivatives and developing more compounds with excellent antibacterial activity remains an important topic in this field. Summary of the Invention
[0006] In view of the problems of the prior art, the present invention provides an indole derivative with antibacterial activity, its preparation method, its use, and pharmaceutical compositions and medical devices made therefrom.
[0007] The compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof:
[0008] R is selected from substituted or unsubstituted C6-C. 10aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C1-C 10 Alkyl groups, wherein the substituents are selected from halogens, C1-C... 10 Alkoxy, C1-C 10 Alkyl or halogen-substituted C1-C 10 Alkyl, cyano, amino, C1-C 10 Amine group.
[0009] Preferably, the compound is as shown in Formula II:
[0010] Ring A is selected from C6-C 10 Aryl, 5-10 heteroaryl;
[0011] n is selected from 0, 1, 2, and 3;
[0012] R A Independently selected from halogens, C1-C 10 Alkoxy, C1-C 10 Alkyl or halogen-substituted C1-C 10 alkyl.
[0013] Preferably, ring A is selected from phenyl or a 6-membered nitrogen-containing heteroaryl group; R A It is independently selected from F, Cl, C1-C2 alkoxy, and trifluoromethyl.
[0014] Preferably, the compound is as shown in Formula III:
[0015] M is selected from CR C Or N;
[0016] R B Selected from Cl and F;
[0017] R C Selected from methoxy groups.
[0018] Preferably, R is selected from substituted or unsubstituted C1-C4 alkyl groups, wherein the substituents are selected from F and Cl.
[0019] Preferably, the compound has the following structural formula:
[0020] The present invention also provides a method for preparing the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, comprising the following steps:
[0021] Step 1: React raw material A and raw material B to obtain intermediate A;
[0022] Step 2: Remove the amino protecting group from intermediate A to obtain the compound shown in Formula II;
[0023] Among them, R D Selected from amino protecting groups, ring A, n, R A As described in any one of claims 2-4 or 6.
[0024] Preferably, the amino protecting group is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, tert-butyl, benzoyl, triphenylmethyl, methoxymethyl, benzyl, allyl, tert-butyldimethylsilyl, tert-butyldimethylsilyl, methylene ether, 9-fluorenylmethoxycarbonyl, tetrahydropyranylmethoxycarbonyl, diphenylphosphoyl, diphenyl phosphate, p-nitrobenzyl, p-methoxybenzyl, acetyl, 4-methylbenzyl, 2-chlorobenzyl, 4-chlorobenzyl, 2-nitrobenzyl, 2,4-dinitrobenzyl;
[0025] And / or, in step 1, the reaction is carried out under the action of a base, the base being selected from at least one of K2CO3, K3PO4, Na2CO3, Cs2CO3, t-BuOK, t-BuONa, and triethylamine;
[0026] And / or, in step 1, the reaction is carried out in the presence of a ligand and / or a catalyst, wherein 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;
[0027] And / or, in step 1, the solvent for the reaction is selected from at least one of acetonitrile, 1,4-dioxane, DME, DMSO, DMF, toluene, and water;
[0028] And / or, in step 1, the reaction temperature is 30-150℃ and the reaction time is 6-24 hours;
[0029] And / or, in step 2, the reaction is carried out in the presence of an acid, selected from hydrochloric acid;
[0030] And / or, in step 2, the solvent for the reaction is selected from at least one of methanol, ethanol, tetrahydrofuran, dioxane, dichloromethane, and toluene;
[0031] And / or, in step 2, the reaction temperature is 25-80℃.
[0032] The present invention also provides the use of the above-mentioned compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or solvates thereof, or crystal forms thereof, in antipathogenic and / or anti-infective applications.
[0033] Preferably, the pathogenic bacteria are Gram-negative bacilli and / or Gram-positive bacilli;
[0034] The Gram-negative bacteria are selected from at least one of the following: Pseudomonas aeruginosa, Escherichia coli, Proteus, Shigella, Salmonella, Bordetella pertussis, Vibrio cholerae, Neisseria meningitidis, Haemophilus influenzae, Klebsiella, Salmonella, Shigella spp., Pasteurella spp., Bacillus parahaemolyticus, and Shigella-like pyridomonas.
[0035] The Gram-positive bacteria are selected from at least one of Staphylococcus, Streptococcus, Streptococcus pneumoniae, Bacillus anthracis, Corynebacterium diphtheriae, and Clostridium tetani.
[0036] The present invention also provides a pharmaceutical composition for anti-pathogenic bacteria and / or anti-infection, which is a formulation made by adding pharmaceutically acceptable excipients or auxiliary ingredients to the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof as the active ingredient.
[0037] The present invention also provides the use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, in the preparation of coatings for medical devices.
[0038] The present invention also provides a medical device having an antibacterial coating on its surface, wherein 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, on its surface or inside.
[0039] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
[0040] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.
[0041] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.
[0042] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a -C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C1-C6 alkyl" refers to alkyl groups containing 1 to 6 carbon atoms.
[0043] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-C6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-C6 alkoxy groups.
[0044] "Halogen" refers to fluorine, chlorine, bromine, or iodine.
[0045] "Heteroaryl" refers to an aromatic unsaturated ring containing at least one heteroatom and having a single or multiple rings; where the heteroatom refers to a nitrogen atom, an oxygen atom, or a sulfur atom; for example, pyridyl.
[0046] "Alkoxy" refers to a group in which an alkyl group is attached to a linker site via an oxygen atom. For example, methoxy is -OCH3.
[0047] "Amino group" refers to a group that is connected to a linking site via a carbon chain or N, and the carbon chain contains at least one N.
[0048] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.
[0049] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.
[0050] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.
[0051] This invention optimizes the structure of indole derivatives, yielding a series of novel indole derivatives. These indole derivatives exhibit excellent antibacterial activity, showing good inhibitory effects against pathogenic bacteria, including Pseudomonas aeruginosa. Therefore, the compounds of this invention hold promise for development into antibacterial and anti-infective drugs, and can also be used as coating materials for medical devices to exert antibacterial effects, demonstrating promising application prospects.
[0052] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.
[0053] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation
[0054] In the following examples and experimental cases, reagents and raw materials not specifically described are all commercially available products.
[0055] Example 1: Compounds 1-5 and their preparation methods
[0056] Synthetic method: Compound a (0.2 mmol), different phenylboronic acids (0.4 mmol, 2 eq.), K₂CO₃ (0.4 mmol, 2 eq.), PAP ligand (0.01 mmol, 10% mol), and Pd(OAc)₂ (0.02 mmol, 10% mol) were added to 2 mL of dry acetonitrile under argon atmosphere. The mixture was stirred at 100 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and 10 mL of EtOAc and 10 mL of saturated ammonium chloride solution were added to extract the organic phase. The extract was dried with anhydrous Na₂SO₄, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound containing BOC. The compound containing 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 TCL was used for detection. The disappearance of the starting material indicated the presence of the target compound.
[0057] The specific compound structures, yields, and product characterization results are as follows:
[0058] (1) Compound 1
[0059] Compound 1: 1 H NMR(600MHz,DMSO-D6)δ11.15(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=6.1Hz,2H).
[0060] (2) Compound 2
[0061] Compound 2: 1 H NMR (600MHz, DMSO-D6) δ11.28(s,1H),9.71(s,2H),7.87(d,J=7.7Hz,2H),7.81(s ,1H),7.73(d,J=7.6Hz,2H),7.45(s,2H),4.30(s,2H),3.39(s,2H),2.96(s,2H).
[0062] (3) Compound 3
[0063] Compound 3: 1 H NMR(600MHz,DMSO-D6)δ11.09(s,1H),9.35(s,2H),7.65(s,1H),7.45–7.37(m,2H),6.83(d ,J=2.3Hz,2H),6.45(t,J=2.3Hz,1H),4.65(s,2H),3.89(s,6H),3.79(s,2H),2.82(s,2H).
[0064] (4) Compound 4
[0065] Compound 4: 1 H NMR(600MHz,DMSO-D6)δ11.19(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).
[0066] (5) Compound 5
[0067] Compound 5: 1H NMR (600MHz, DMSO-D6) δ11.09(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 = 7.0Hz, 2H), 3.42 (s, 2H), 2.96 (t, J = 6.1Hz, 2H), 1.35 (t, J = 7.0Hz, 3H).
[0068] Example 2: Compounds 6, 7, and 8 and their preparation methods
[0069] Synthetic method: Compound a (0.2 mmol), different phenylboronic acids (0.4 mmol, 2 eq.), K3PO4 (0.4 mmol, 2 eq.), Pd(dba)2 (0.02 mmol, 10% mol), and Pcy3 (0.04 mmol, 20% mol) were added to a mixed solvent of 1.8 mL of 1,4-dioxane and H2O (volume ratio 2:1) under argon atmosphere. The mixture was stirred at 100 °C for 18 hours. After the reaction was completed, the mixture was cooled to room temperature, and 10 mL of EtOAc and 10 mL of saturated ammonium chloride solution were added to extract the organic phase. The extract was dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound containing BOC. The compound containing 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 TCL was used for detection. The disappearance of the starting material indicated the presence of the target compound.
[0070] The specific compound structures, yields, and product characterization results are as follows:
[0071] (1) Compound 6
[0072] Compound 6: 1 H NMR (600MHz, DMSO-D6) δ11.31(s,1H),9.63(s,2H),8.25(d,J=7.6Hz,2H),8.02(d ,J=7.7Hz,2H),7.85(s,1H),7.51(s,2H),4.36(s,2H),3.35(s,2H),3.01(s,2H).
[0073] (2) Compound 7
[0074] Compound 7: 1H NMR (600MHz, DMSO-D6) δ11.36(s,1H),9.66(s,2H),9.10(s,1H),8.92(d,J=2.4Hz,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=5.6Hz,2H),2.86(t,J=5.7Hz,2H).
[0075] (3) Compound 8
[0076] Compound 8: 1 H NMR(600MHz,DMSO-D6)δ11.34(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=6.1Hz,2H).
[0077] Example 3 Compound 9 and its preparation method
[0078] Synthetic method: Compound a (0.2 mmol), different phenylboronic acids (0.4 mmol, 2 eq.), K3PO4 (0.4 mmol, 2 eq.), and Pd(PPh3)4 (0.02 mmol, 10% mol) were added to a mixed solvent of DME and H2O (4:1 volume ratio) under argon atmosphere. The mixture was stirred at 60 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature, and 10 ml of EtOAc and 10 ml of saturated ammonium chloride solution were added to extract the organic phase. The extract was dried over anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain the compound containing BOC. The compound containing 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 TCL was used for detection. The disappearance of the starting material indicated the presence of the target compound.
[0079] The specific compound structures, yields, and product characterization results are as follows:
[0080] Compound 9: 1H NMR (600MHz, DMSO-D6) δ11.17(s,1H),9.47(s,2H),7.65(d,J=2.2Hz,1H),7.59(s,1H),7.48(dd,J=8.5,2.3Hz,1H) ,7.36–7.29(m,2H),6.99(d,J=8.5Hz,1H),4.68(d,J=27.1Hz,2H),3.93(s,3H),3.80(s,2H),2.86(t,J=5.7Hz,2H).
[0081] Example 4: Compounds 10, 11, and 12 and their preparation methods
[0082] Synthesis method:
[0083] A to C: Compound A (1.0 eq.) was dissolved in 8 ml of trifluoroacetic acid and cooled to 0 °C. Then, B (1.2 eq.) (1-dimethylamino-2-nitroethylene) was slowly added and stirred at room temperature for 1 h. After the reaction was completed by TLC, saturated sodium bicarbonate was added for neutralization. The organic phase was extracted with DCM, dried with anhydrous Na2SO4, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain compound C.
[0084] C to D: Under a nitrogen atmosphere, nitroolefin C was dissolved in THF solution (10 mL / mmol) and cooled to 0 °C. LiAlH4 solution (6.0 equivalent, 2.5 mmol / mL) was slowly added with vigorous stirring. The mixture was heated to room temperature and stirred for 36 h. After the reaction was complete, the reaction mixture was cooled to 0 °C, and H2O was slowly added dropwise to quench the reaction until no more bubbles were produced. Then, saturated tartrate solution (30 mL) was added, and the mixture was stirred vigorously for 24 h. After separation, the aqueous layer was extracted with diethyl 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 approximately 10 with 3M potassium hydroxide solution. The alkaline mixture was then extracted with diethyl ether (3 × 25 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to give tryptamine derivative D.
[0085] D to E: Under a nitrogen atmosphere, tryptophan derivative D (1 equivalent) was dissolved in a mixed solvent of acetic acid / methanol (v / v = 2:5), and then paraformaldehyde (1.2 equivalents) was added. The mixture was heated to 80°C and reacted for 3 hours, then cooled to 0°C. The pH was adjusted to 9-10 with a saturated aqueous solution of NaHCO3 (first adjusted to pH 4-5 with NaOH, then to pH 8 with NaHCO3, and finally a small amount of NaOH solution was added dropwise to pH 9-10). The organic phase was then extracted with dichloromethane (DCM, 30 mL × 3). The combined organic phases 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.
[0086] The specific compound structures, yields, and product characterization results are as follows:
[0087] Compound 10 (overall yield 15%): 1 H NMR (600MHz, DMSO-D6) δ = 10.42 (s, 1H), 7.08–7.03 (m, 2H), 6.74 (d, J = 8.1Hz, 1H),3.76(s,2H),2.89(t,J=5.6Hz,2H),2.49(t,J=5.7Hz,2H),2.27(s,3H).
[0088] Compound 11 (overall yield 17%): 1 H NMR (600MHz, DMSO-D6) δ = 10.52 (s, 1H), 7.24 (s, 1H), 7.12 (d, J = 8.5Hz, 1H), 7.02 (m,1H),4.10(s,2H),3.55(t,J=6.2Hz,2H),2.90(t,J=6.1Hz,2H).1.29(s,9H).
[0089] Compound 12 (overall yield 12%): 1 H NMR (600MHz, DMSO-D6) δ = 11.66 (s, 1H), 7.83 (s, 1H), 7.52 (d, J = 8.5Hz, 1H), 7. 35(d,J=8.5Hz,1H),4.32(s,2H),3.38(t,J=6.2Hz,2H),2.96(t,J=6.1Hz,2H).
[0090] Comparative Example 1
[0091] This comparative example provides a method for preparing the control compound D1.
[0092] Synthetic 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 of H₂O, and then KOH solution (0.3 g, 5 mmol, 1 eq) was added dropwise to 2 mL of H₂O. The mixture was stirred for 1 h, and the white precipitate was collected by filtration. The precipitate was dissolved in 15 mL of H₂O, and 12 M HCl solution (3.6 mL) was added at room temperature. After stirring under reflux for 1 h, another 3.6 mL of 12 M HCl was added, and the mixture was stirred under reflux for another 0.5 h. After cooling to rt, light green crystals were obtained, which were collected by filtration and then dissolved in 15 mL of H₂O. The solution was alkalized to pH > 13 with 20% KOH, the white precipitate was filtered off, and the solution was washed three times with water to obtain the target compound.
[0093] The specific compound structures, yields, and product characterization results are as follows:
[0094] Compound D1: 1 H NMR (600MHz, DMSO-D6) δ11.13(s,1H),7.40(d,J=2.1Hz,1H),7.29(d,J=8.6Hz,1H),7 .00(dd,J=8.5,2.1Hz,1H),4.05(s,2H),3.14(t,J=5.8Hz,2H),2.70(t,J=5.9Hz,2H).
[0095] The technical solution of this invention will be further explained through experiments below.
[0096] Antibacterial activity of compound in Experiment Example 1
[0097] I. Experimental Methods
[0098] This experiment tested the antibacterial activity of various compounds synthesized in Examples 1-4 and compound D1 synthesized in Comparative Example 1.
[0099] Compounds D1 and 1-12 were dissolved in dimethyl sulfoxide to prepare 100 mM stock solutions.
[0100] Overnight cultured *Pseudomonas aeruginosa* PAO1 was prepared into a bacterial suspension with an OD600nm = 1 using sterile physiological saline and inoculated into M9-adenosine (0.1%, w / v, Sigma-Aldrich) medium at a 1% inoculation rate. For each compound treatment group, the corresponding compound was added to the M9-adenosine medium to achieve final concentrations of 0.01 μM, 0.05 μM, and 0.1 μM, respectively. The solvent control group received an equal volume of dimethyl sulfoxide (i.e., a compound concentration of 0 μM). After static incubation at 37°C for 36 hours, the absorbance of the culture medium was measured at a wavelength of 600 nm.
[0101] II. Experimental Results
[0102] Table 1 shows the effects of 15 compounds on the growth of Pseudomonas aeruginosa PAO1 in M9-adenosine medium. In M9-adenosine medium, PAO1 relies on the nucleoside hydrolase Nuh, which is positively regulated by the las quorum sensing system, to degrade and utilize adenosine, the only carbon source in the medium. Therefore, the inhibitory effect of the compounds on PAO1 growth in quorum-sensing selective medium reflects their inhibitory activity against the quorum sensing system. Compared with the solvent control group, the addition of the various compounds of this invention significantly inhibited the growth of PAO1 in quorum-sensing selective medium, and compounds 5 and 9 showed a clear dose-response relationship with increasing compound concentration. Furthermore, as can be seen from the results in Table 1, the compounds provided by this invention all exhibited superior activity compared to the control compound D1, with compounds 8 and 9 showing the best activity.
[0103] Table 1 Antibacterial activity of the compounds 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.
[0104] As can be seen from the above embodiments and experimental examples, this invention, by optimizing the structure of indole derivatives, has obtained a series of compounds with good antibacterial activity. 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 exert antibacterial effects, showing great application prospects.
Claims
1. The compound represented by Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof: R is selected from substituted or unsubstituted C6-C. 10 aryl, substituted or unsubstituted 5-10 heteroaryl, substituted or unsubstituted C1-C 10 Alkyl, wherein, Substituents are selected from halogens, C1-C 10 Alkoxy, C1-C 10 Alkyl or halogen-substituted C1-C 10 Alkyl, cyano, amino, C1-C 10 Amine group.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that, The compound is shown in Formula II: Ring A is selected from C6-C 10 Aryl, 5-10 heteroaryl; n is selected from 0, 1, 2, and 3; R A Independently selected from halogens, C1-C 10 Alkoxy, C1-C 10 Alkyl or halogen-substituted C1-C 10 alkyl.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that: Ring A is selected from phenyl or a 6-membered nitrogen-containing heteroaryl group; R A It is independently selected from F, Cl, C1-C2 alkoxy, and trifluoromethyl.
4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that, The compound is shown in Formula III: M is selected from CR C Or N; R B Selected from Cl and F; R C Selected from methoxy groups.
5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that: R is selected from substituted or unsubstituted C1-C4 alkyl groups, wherein the substituents are selected from F and Cl.
6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, characterized in that, The compound has the following structural formula:
7. The compound according to any one of claims 2-4 or 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a method for preparing its crystal form, characterized in that, Includes the following steps: Step 1: React raw material A and raw material B to obtain intermediate A; Step 2: Remove the amino protecting group from intermediate A to obtain the compound shown in Formula II; Among them, R D Selected from amino protecting groups, ring A, n, R A As described in any one of claims 2-4 or 6.
8. The preparation method according to claim 7, characterized in that: The amino protecting group is selected from tert-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, tert-butyl, benzoyl, triphenylmethyl, methoxymethyl, benzyl, allyl, tert-butyldimethylsilyl, tert-butyldimethylsilyl, methylene ether, 9-fluorenylmethoxycarbonyl, tetrahydropyranylmethoxycarbonyl, diphenylphosphoyl, diphenyl phosphate, 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, the base being 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 in the presence of a ligand and / or a catalyst, wherein 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 solvent for the reaction is selected from at least one of acetonitrile, 1,4-dioxane, DME, DMSO, DMF, toluene, and water; And / or, in step 1, the reaction temperature is 30-150℃ and the reaction time is 6-24 hours; And / or, in step 2, the reaction is carried out in the presence of an acid, selected from hydrochloric acid; And / or, in step 2, the solvent for the reaction 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℃.
9. The use of the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, for antipathogenic and / or anti-infective purposes.
10. The use according to claim 9, characterized in that: The pathogenic bacteria are Gram-negative bacilli and / or Gram-positive bacilli; The Gram-negative bacteria are selected from at least one of the following: Pseudomonas aeruginosa, Escherichia coli, Proteus, Shigella, Salmonella, Bordetella pertussis, Vibrio cholerae, Neisseria meningitidis, Haemophilus influenzae, Klebsiella, Salmonella, Shigella spp., Pasteurella spp., Bacillus parahaemolyticus, and Shigella-like pyridomonas. The Gram-positive bacteria are selected from at least one of Staphylococcus, Streptococcus, Streptococcus pneumoniae, Bacillus anthracis, Corynebacterium diphtheriae, and Clostridium tetani.
11. A pharmaceutical composition for fighting pathogenic bacteria and / or infection, characterized in that: It is a formulation made by adding pharmaceutically acceptable excipients or auxiliary ingredients to the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof as the active ingredient.
12. Use of the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof, in the preparation of a coating for a medical device.
13. A medical device, characterized in that: The medical device has an antibacterial coating on its surface, and the surface or interior of the antibacterial coating includes the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a solvate thereof, or a crystal form thereof.