Indole antibacterial peptide simulant with antibacterial activity as well as preparation method and application of indole antibacterial peptide simulant

Abstract

The invention provides an indole antibacterial peptide simulant with antibacterial activity and a preparation method and application thereof, and relates to the technical field of medicinal chemistry, the chemical structural formula of the indole antibacterial peptide simulant is shown as the following (I), and n and R in the formula are defined as the specification; in-vitro antibacterial activity experiments prove that the indole antibacterial peptide simulant disclosed by the invention has relatively good antibacterial activity on gram-positive bacteria such as staphylococcus aureus, bacillus subtilis and enterococcus faecalis, and has the characteristics of low cytotoxicity, low hemolysis and difficulty in generating drug resistance; the compound can be applied to preparation of drugs for resisting bacteria or treating bacterial infection. (I)

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and more particularly relates to a kind of indole antibacterial peptide mimics with antibacterial activity and preparation method and application thereof. BACKGROUND

[0002] Due to the widespread use and even abuse of antibiotics, the problem of antimicrobial drug resistance is escalating, and has become one of the most severe global public health challenges in the 21st century. Antimicrobial drug resistance has led to the emergence of various drug-resistant strains in clinical practice. In recent years, infections caused by drug-resistant bacteria have posed an increasingly severe challenge to public health, especially in areas with limited medical resources. The morbidity and mortality of diseases such as sepsis, pneumonia and urinary tract infection associated with drug-resistant pathogens remain high. At the same time, antimicrobial drug resistance is intensifying at an unprecedented rate, and the therapeutic effect of traditional antibiotics in treating infectious diseases is rapidly declining.

[0003] In recent years, even "superbugs" such as Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii have emerged, and these strains have developed resistance to multiple antibiotics, and even have developed pan-resistant strains. The emergence of drug-resistant strains has become a major threat to human health and survival at present and in the future. Finding and developing new antibacterial drugs with new structures and new targets is one of the most effective methods to solve the increasingly severe problem of antimicrobial drug resistance.

[0004] Antibacterial peptides are a class of small molecule compounds composed of 20-50 amino acids, with broad-spectrum antibacterial activity. They are widely present in animals, plants and microorganisms. As the first line of defense against microbial invasion, natural antibacterial peptides play a key role in innate immunity by protecting the host from a variety of pathogenic microorganisms. Most antibacterial peptides exhibit amphiphilic structure, usually containing hydrophilic cationic residues and hydrophobic side chains, which together mediate their targeting of microorganisms and disruption of membrane structure. The positive charge carried by antibacterial peptides is mainly derived from lysine and arginine residues, allowing them to bind to negatively charged bacterial membrane components through electrostatic interactions. Subsequently, the hydrophobic domain of the peptide chain promotes its penetration of the lipid bilayer, disrupting membrane integrity and increasing permeability, ultimately leading to irreversible bacterial death. Because their action does not depend on specific molecular targets, this mechanism reduces the likelihood of bacterial resistance. Despite the potential of antibacterial peptides as a powerful alternative to traditional antibiotics in combating drug-resistant bacterial infections, they still face several challenges that limit their clinical translation. These include poor metabolic stability and short half-life in vivo due to protease degradation; limited antibacterial activity that may not be sufficient to completely clear an infection; potential immunogenicity and hemolytic effects on host cells; and high production costs due to their large molecular size. These problems limit the more widespread therapeutic application of antibacterial peptides.

[0005] Therefore, there is an urgent need to develop new antibacterial agents that retain the advantages of antimicrobial peptides while overcoming their limitations through new strategies. Existing studies have shown that the antibacterial efficacy of antimicrobial peptides is mainly due to their positive charge characteristics and amphiphilic topological structure. To take advantage of this structural feature, researchers have successfully constructed a series of small-molecule antimicrobial peptide mimics over the past decade. These synthetic analogs not only exhibit comparable or superior antibacterial efficacy to natural antimicrobial peptides, but also effectively avoid the inherent defects of natural peptides, including poor stability and potential toxicity. Notably, recent breakthroughs in this field have been made, with three representative peptide mimics (CSA-13, XF-73, and PMX-30063) successfully passing clinical verification, marking the entry of membrane-targeting antimicrobial peptide mimics into the practical treatment development stage. SUMMARY

[0006] To solve the above problems, the purpose of the present application is to provide a series of novel indole-based antimicrobial peptide mimics with strong antibacterial performance and fast killing speed, and to provide a preparation method and application thereof.

[0007] To achieve the above technical purposes, the technical scheme adopted by the present application is as follows: The present application provides an indole-based antimicrobial peptide mimic or a pharmaceutically acceptable salt thereof, and the compound structure is shown as formula (I): (I); Wherein, n = 1, 2 or 3; R is selected from the following groups: ; ; ; ; ; ; ; ; ; ; ; .

[0008] The present application utilizes the structural framework of indole to construct the amphiphilic structural characteristics of antimicrobial peptides, designs and synthesizes a series of indole-based antimicrobial peptide mimics, and verifies their antibacterial activity through in vitro activity experiments, obtaining new antibacterial drugs with strong antibacterial performance, fast killing speed and low resistance.

[0009] Further, the indole-based antimicrobial peptide mimic or the pharmaceutically acceptable salt thereof is selected from the compounds with the following structures: ; ; .

[0010] The indole antimicrobial peptide mimic or its pharmaceutically acceptable salt is prepared by the following method: Compound 1 undergoes a substitution reaction with 1-bromo-3-methyl-2-butene in acetonitrile solution under alkaline conditions to give Compound 2, which is then hydrolyzed under alkaline sodium hydroxide conditions to give Compound 3; Compound 3 undergoes a condensation reaction with an amino-substituted compound under alkaline conditions to give Compound 4; Compound 4 is further deprotected with a Boc protecting group under hydrochloric acid to give Compound 5; Compound 5 reacts with N,N'-bis-Boc-1-guanidinylpyrazole in the presence of N,N-diisopropylethylamine to give Compound 6, which is then deprotected with a Boc protecting group under acidic conditions to give Compound 7; the preparation route of the method is as follows: Among them, compound 1 is 6-bromoindole-3-carboxylic acid; compound 4 includes compounds 4a, 4b, and 4c, with corresponding n values ​​of 1, 2, and 3 in the structural formula, respectively; compound 5 includes compounds 5a, 5b, and 5c, with corresponding n values ​​of 1, 2, and 3 in the structural formula, respectively; compound 6 includes compounds 6a, 6b, and 6c, with corresponding n values ​​of 1, 2, and 3 in the structural formula, respectively; and compound 7 includes compounds 7a, 7b, and 7c, with corresponding n values ​​of 1, 2, and 3 in the structural formula, respectively.

[0011] Further, in the preparation route of the method, reaction conditions and reagents a represent: compound 1 is dissolved in acetonitrile, 1-bromo-3-methyl-2-butene and potassium carbonate are added, and the reaction is carried out at 50-70 °C; b represents: compound 2 is dissolved in an aqueous methanol solution, sodium hydroxide is added, and the reaction is carried out at 50-70 °C; c represents: compound 3 and HATU are dissolved in acetonitrile, N,N-diisopropylethylamine and NH2CH2(CH2) are added. n CH2NHBoc reacts at 50-70 °C; d indicates that compound 4 is dissolved in methanol at room temperature and reacted with hydrochloric acid; e indicates that compound 5 is dissolved in dichloromethane and reacted with N,N-diisopropylethylamine and N,N'-bis-tert-butoxycarbonyl-1-guanidinopyrazole at room temperature.

[0012] Furthermore, the indole antimicrobial peptide mimic or its pharmaceutically acceptable salt is selected from compounds having the structures shown below: ; ; ; ; ; ; ; ; ; .

[0013] Further, compound 11 or compounds 13a-13j are prepared by the following method: Compound 1 reacts with N-(5-aminopentyl)carbamate tert-butyl in acetonitrile solution via amide condensation under the catalysis of HATU to give compound 8; compound 8 is deprotected by the Boc protecting group under hydrochloric acid to give compound 9; compound 9 reacts with N,N'-bis-Boc-1-guanidinylpyrazole under basic conditions of N,N-diisopropylethylamine to give compound 10, which is further deprotected by the Boc protecting group under acidic conditions to give compound 11; or compound 10 reacts with bromides with different substituents under basic conditions of sodium hydride to give compounds 13a-13j; The preparation route of the method is as follows: Furthermore, in the preparation route of the method, the reaction conditions and reagents are as follows: a) Compound A undergoes an amide condensation reaction with N-(5-aminopentyl)carbamate tert-butyl in acetonitrile solution under HATU catalysis at a reaction temperature of 50-70℃; b) Compound 8 reacts at room temperature under hydrochloric acid; c) Compound 9 reacts with N,N'-bis-Boc-1-guanidinopyrazole at room temperature under basic conditions of N,N-diisopropylethylamine; d) Deprotection of the Boc protecting group at room temperature under hydrochloric acid conditions; e) Compound 10 reacts with bromides with different substituents under basic conditions of sodium hydride to obtain compounds 13a-13j at a reaction temperature of 50-70℃.

[0014] This invention provides the use of the above-described indole antimicrobial peptide mimics or pharmaceutically acceptable salts thereof in the preparation of medicaments for the treatment of bacterial infections.

[0015] In a further application, the bacterial infection is caused by Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, or Pseudomonas aeruginosa.

[0016] This invention claims protection for a medicament for the treatment of bacterial infections or for the prevention of bacterial infections, the medicament comprising the above-described indole antimicrobial peptide mimics or pharmaceutically acceptable salts thereof.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The indole antimicrobial peptide mimics described in this invention exhibit good antimicrobial activity against Gram-positive bacteria. In particular, compounds 13e-13j have a minimum inhibitory concentration of 1-16 µg / mL against Staphylococcus aureus, Enterococcus faecalis and Bacillus subtilis. The antimicrobial activity of some compounds is comparable to that of the positive control drug vancomycin, and they can be used in the preparation of antimicrobial or antibacterial drugs.

[0018] (2) Further research on the compound 13e with the best activity in this invention revealed that it has the characteristics of rapid bactericidal effect, low hemolysis, low toxicity and low resistance, which is expected to provide a new approach to solving the problem of bacterial resistance. Attached Figure Description

[0019] 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.

[0020] Figure 1 The time-dependent bactericidal curve of compound 13e against Staphylococcus aureus is shown.

[0021] Figure 2 To evaluate the induction of drug resistance in Staphylococcus aureus by compound 13e.

[0022] Figure 3 Evaluation of the hemolytic toxicity of compound 13e.

[0023] Figure 4 Cytotoxicity evaluation of compound 13e.

[0024] Figure 5 This is the proton NMR spectrum of compound 13e. Detailed Implementation

[0025] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0026] The present invention will be further described in detail below with reference to specific embodiments. It should be noted that the specific embodiments are explanations of the present invention and not limitations thereof. Example

[0027] The compound provided in this embodiment has the following general structural formula I: (I) Wherein, n = 1, 2, 3; R is selected from the following groups:

[0028] More preferably, the compound is selected from: (1) The preparation route for the indole antimicrobial peptide mimic compounds 7a-7c of the present invention is as follows: Reaction conditions: (a) 1-bromo-3-methyl-2-butene, potassium carbonate, acetonitrile, 60 °C; (b) sodium hydroxide, water / methanol, 60 °C; (c) NH₂CH₂(CH₂) n CH2NHBoc, N,N-diisopropylethylamine, HATU, acetonitrile, 60°C; (d) hydrochloric acid, methanol, room temperature; (e) N,N'-bis-tert-butoxycarbonyl-1-guanidinopyrazole, N,N-diisopropylethylamine, dichloromethane, room temperature.

[0029] This can be achieved through the following steps: Intermediate 1 undergoes a substitution reaction with 1-bromo-3-methyl-2-butene under alkaline conditions in acetonitrile solution to give compound 2, which is then hydrolyzed under alkaline sodium hydroxide conditions to give compound 3. Intermediate 3 undergoes a condensation reaction with amino-substituted products of different chain lengths under alkaline conditions to give compounds 4a-4c. Compounds 4a-4c are further deprotected with a Boc protecting group under hydrochloric acid to give 5a-5c. Compounds 5a-5c react with N,N'-bis-Boc-1-guanidinylpyrazole in the presence of N,N-diisopropylethylamine to give the corresponding 6a-6c, which is then deprotected with a Boc protecting group under acidic conditions to give the target compounds 7a-7c.

[0030] (2) The preparation routes for the indole antimicrobial peptide mimics of the present invention, compounds 11 and 13a-13j, are as follows: Reaction conditions: (a) N-(5-aminopentyl)carbamate tert-butyl ester, N,N-diisopropylethylamine, HATU, acetonitrile, 60 °C; (b) hydrochloric acid, methanol, room temperature; (c) N,N'-bis-tert-butoxycarbonyl-1-guanidinylpyrazole, N,N-diisopropylethylamine, dichloromethane, room temperature; (d) hydrochloric acid, methanol, room temperature; (e) bromide, sodium hydride, N,N-dimethylformamide, 60 °C.

[0031] This can be achieved through the following steps: Intermediate 1 reacted with tert-butyl N-(5-aminopentyl)carbamate in acetonitrile solution via amide condensation under the catalysis of HATU to give compound 8; compound 8 was deprotected with a Boc protecting group under hydrochloric acid to give compound 9; compound 9 was reacted with N,N'-bis-Boc-1-guanidinylpyrazole under basic conditions of N,N-diisopropylethylamine to give compound 10, which was further deprotected with a Boc protecting group under acidic conditions to give compound 11; at the same time, compound 10 was reacted with bromides with different substituents under basic conditions of sodium hydride to give target products 13a-13j.

[0032] Example 2 Preparation of compound 2 Compound 1 (5.00 g, 20.83 mmol) was dissolved in acetonitrile (120 mL), followed by the addition of 1-bromo-3-methyl-2-butene (7.76 g, 52.08 mmol) and potassium carbonate (8.64 g, 62.49 mmol). The reaction mixture was stirred at 60 °C for 6 hours. After the reaction was complete, excess acetonitrile was removed by concentration, and the mixture was extracted with ethyl acetate and water, followed by purification by rapid column chromatography to give compound 2 (6.17 g, 82% yield). The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.03 (d, J= 8.5 Hz, 1H), 7.78 (s, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.35 (dd, J = 8.5, 1.7Hz, 1H), 5.50 (ddt, J = 8.6, 7.1, 1.4 Hz, 1H), 5.36 (tp, J = 7.0, 1.5 Hz,1H), 4.82 (d, J = 7.1 Hz, 2H), 4.64 (d, J = 7.0 Hz, 2H), 1.80 (ddd, J = 12.0,6.4, 1.3 Hz, 12H). 13 C NMR (125 MHz, CDCl3) δ 164.83, 138.69, 138.46, 137.33,134.15, 125.78, 125.05, 123.12, 119.27, 117.96, 116.22, 113.13, 107.43,60.84, 44.68, 25.82, 25.73, 18.15.

[0033] Example 3 Preparation of compound 3 Intermediate compound 2 (5.00 g, 13.29 mmol) was dissolved in a 1:1 methanol / water mixture (50 mL), and sodium hydroxide (3.19 g, 79.74 mmol) was added. The mixture was stirred at 60 °C for 8 hours. After the reaction was complete (monitored by TLC), the reaction solution was concentrated under vacuum. The residue was carefully adjusted to pH 2-3 with dilute hydrochloric acid solution, and a solid precipitated. After filtration and drying, a yellow solid 3 (3.60 g, yield 88%) was obtained. The 1H NMR spectrum results are as follows: 1H NMR (500 MHz, CDCl3) δ 8.00 (d,J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.45 (d, J = 1.6 Hz, 1H), 7.32 (dd, J = 8.5,1.7 Hz, 1H), 5.32 (ddt, J = 7.0, 5.5, 1.5 Hz, 1H), 4.59 (d, J = 7.0 Hz, 2H), 1.75 (s, 6H). 13 C NMR (125 MHz, CDCl3) δ 170.15, 139.16, 137.53, 135.40,125.97, 125.46, 123.14, 117.66, 116.49, 113.30, 106.50, 44.79, 25.72, 18.16.

[0034] Example 4 Preparation of compounds 5a-5c Intermediate 3 (0.50 g, 1.62 mmol) and HATU (0.62 g, 1.62 mmol) were dissolved in anhydrous acetonitrile (15 mL) and stirred at 0 °C for 15 min. Then, DIEPA (0.42 g, 3.24 mmol) and amino compounds of different chain lengths (1.62 mmol) were added sequentially, and the reaction was stirred for another 3 h. After the reaction was completed by TLC monitoring, the solvent was removed by concentration, and the residue was extracted with ethyl acetate. The organic phase was washed sequentially with dilute hydrochloric acid and sodium chloride solution, dried, and concentrated to give intermediates 4a-4c (to be used directly in the next reaction). 4a-4c (1.62 mmol) was weighed and dissolved in methanol, and hydrochloric acid (2 mL) was slowly added dropwise, and the reaction was stirred at room temperature for another 24 h. The reaction solution was concentrated, washed with anhydrous diethyl ether, and filtered to give the final products 5a-5c, with yields of 57%-73%.

[0035] Compound 5a is a yellow solid with a yield of 57%. The 1H NMR spectrum results are as follows: 1H NMR (500 MHz, CDCl3) δ 8.22 (s, 3H), 7.71 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.41 (s, 1H), 6.99 (d, J = 8.5 Hz, 1H), 5.08–4.97 (m, 1H), 4.28 (d, J = 6.8 Hz, 2H), 3.34 (q, J = 6.2 Hz, 2H), 3.01–2.90 (m, 2H), 1.88 (d, J = 6.7 Hz, 2H), 1.57 (d, J= 16.3 Hz, 6H). 13 C NMR (125 MHz, CDCl3) δ 166.56, 137.93, 137.03, 131.39,125.26, 124.51, 122.09, 118.14, 115.95, 113.18, 109.21, 44.72, 37.24, 35.90,29.08, 27.52, 25.48, 25.02, 17.91.

[0036] Compound 5b is a yellow solid with a yield of 73%. The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, CDCl3) δ 8.11 (s, 3H), 7.80 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.33 (t, J =5.7 Hz, 1H), 7.08– .00 (m, 1H), 5.03 (t, J = 6.9 Hz, 1H), 4.29 (d, J = 6.8Hz, 2H), 3.27 (p, J = 8.6, 6.7 Hz, 2H), 2.96 (s, 2H), 1.74 (dt, J = 15.4, 7.1Hz, 2H), 1.59 (d, J = 25.7 Hz, 8H). 13 C NMR (125 MHz, CDCl3) δ 165.82, 137.70,136.99, 131.18, 125.38, 124.37, 122.20, 118.29, 115.84, 113.12, 109.70,87.15, 44.69, 39.67, 39.61, 38.81, 26.52, 25.49, 24.97, 24.76, 17.91.

[0037] Compound 5c is a yellow solid with a yield of 71%. The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, MeOD) δ 8.03 (d, J = 8.5 Hz, 1H), 7.86 (s, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.32–7.22 (m, 1H), 5.37 (tp, J = 7.0, 1.5 Hz, 1H), 4.73 (d, J = 7.1 Hz, 2H), 3.39 (t, J = 7.0 Hz, 2H), 2.94 (dd, J = 8.6, 6.7 Hz, 2H), 1.82 (dd, J = 25.5,1.4 Hz, 6H), 1.73–1.64 (m, 4H), 1.48 (td, J = 8.4, 4.1 Hz, 2H). 13 C NMR (125MHz, MeOD) δ 166.25, 137.91, 137.30, 130.50, 125.69, 123.88, 122.31, 118.45,115.61, 115.52, 112.93, 109.92, 44.04, 39.25, 38.47, 28.92, 26.82, 24.44,23.41, 16.72.

[0038] Example 5 Preparation of compounds 7a-7c Under nitrogen protection, dichloromethane solutions of compounds 5a-5c (0.80 mmol) were mixed with DIEPA (0.5 mL, 2.80 mmol), followed by the addition of N,N'-diBoc-1-guanidinopyrazole (0.62 g, 2.00 mmol). The reaction mixture was stirred at room temperature for 12 hours. After the reaction was complete, the system was diluted with ethyl acetate and washed successively with 10% KHSO4 solution, saturated NaHCO3 solution, and brine. The combined organic phases were dried over anhydrous Na2SO4 and concentrated to give intermediates 6a-6c. The Boc protecting group was removed with hydrochloric acid (1.00 mL), followed by rapid chromatographic purification to give target compounds 7a-7c in yields of 43%-56%.

[0039] Compound 7a: white solid, yield 56%. The 1H NMR spectrum results are as follows: 1H NMR (500 MHz, DMSO-d6) δ 8.12–8.05 (m, 2H), 8.00 (s, 1H), 7.77 (dd, J = 6.1, 1.8 Hz, 1H), 7.68(t, J = 6.0 Hz, 1H), 7.27 (dd, J = 8.4, 1.8 Hz, 1H), 5.37 (tt, J = 7.2, 1.7Hz, 1H), 4.80 (d, J = 7.0 Hz, 2H), 3.29 (d, J = 6.3 Hz, 2H), 3.19 (dd, J =8.1, 4.9 Hz, 2H), 1.82 (s, 3H), 1.76 (s, 3H), 1.72 (d, J = 6.8 Hz, 2H). 13 CNMR (125 MHz, DMSO-d6) δ 164.58, 157.35, 137.50, 137.30, 131.21, 126.17,123.99, 123.44, 119.67, 115.33, 113.73, 110.55, 44.33, 39.04, 36.24, 29.57,25.88, 25.41, 18.38.

[0040] Compound 7b: white solid, yield 48%. The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, MeOD)δ 8.03 (d, J = 8.6 Hz, 1H), 7.88 (s, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.28 (dd,J = 8.6, 1.8 Hz, 1H), 5.39 (ddq, J = 8.5, 5.6, 1.5 Hz, 1H), 4.75 (d, J = 7.0Hz, 2H), 3.43–3.39 (m, 2H), 3.25 (tt, J = 6.3, 4.1, 3.5 Hz, 2H), 1.83 (dd, J= 26.5, 1.4 Hz, 6H), 1.67 (ddd, J = 7.1, 5.1, 2.6 Hz, 4H). 13C NMR (125 MHz, MeOD) δ 166.35, 157.25, 137.94, 137.32, 130.56, 125.70, 123.93, 122.30,118.45, 115.53, 112.96, 109.83, 46.50, 44.06, 40.77, 38.06, 26.72, 25.81,24.44, 16.73, 7.81.

[0041] Compound 7c: white solid, yield 43%. The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, MeOD)δ 8.03 (d, J = 8.5 Hz, 1H), 7.86 (s, 1H), 7.59 (d, J = 1.7 Hz, 1H), 7.31–7.24(m, 1H), 5.37 (tp, J = 7.0, 1.5 Hz, 1H), 4.73 (d, J = 7.1 Hz, 2H), 3.39 (t, J= 7.0 Hz, 2H), 2.94 (dd, J = 8.6, 6.7 Hz, 2H), 1.82 (dd, J = 25.5, 1.4 Hz, 6H), 1.73–1.65 (m, 4H), 1.48 (qd, J = 9.5, 8.9, 6.0 Hz, 2H). 13 C NMR (125 MHz, MeOD) δ 166.21, 157.32, 157.27, 137.90, 137.29, 130.48, 125.69, 123.88,122.31, 118.45, 115.51, 112.93, 112.80, 109.95, 44.04, 41.03, 38.63, 29.02, 28.13, 28.03, 24.45, 23.67, 16.74.

[0042] Example 6 Preparation of compound 8 The raw materials used were intermediate compound 1 and tert-butyl N-(5-aminopentyl)carbamate. The preparation method was to react compound 1 with tert-butyl N-(5-aminopentyl)carbamate in acetonitrile solution under the catalysis of condensing agent HATU to obtain compound 8.

[0043] Compound 8 is a yellow solid with a yield of 62%. The 1H NMR spectrum results are as follows: 1H NMR (500 MHz, MeOD)δ 8.01 (d, J = 8.5 Hz, 1H), 7.86 (s, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.25 (dd,J = 8.6, 1.8 Hz, 1H), 3.42–3.34 (m, 2H), 3.05 (t, J = 6.9 Hz, 2H), 1.68–1.61 (m, 4H), 1.55–1.50 (m, 2H), 1.41 (s, 9H). 13 C NMR (125 MHz, MeOD) δ 166.55,137.44, 127.96, 124.81, 123.62, 121.96, 115.38, 114.24, 110.93, 78.45, 39.85,38.89, 29.30, 29.09, 27.39, 23.88.

[0044] Example 7 Preparation of compound 9 Intermediate 8 (0.50 g, 1.18 mmol) was dissolved in ethyl acetate (10 mL), followed by the addition of hydrochloric acid (1 mL). After reacting for 10 hours, the precipitated solid was filtered, and the resulting filter cake was washed with ethyl acetate and dried under vacuum to give a pale yellow solid 9 (0.25 g, 65% yield). The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, MeOD) δ8.11–7.81 (m, 2H), 7.60 (s, 1H), 7.25 (d, J = 6.8 Hz, 1H), 3.41 (s, 2H), 2.96(s, 2H), 1.72 (d, J = 25.0 Hz, 4H), 1.50 (s, 2H). 13 C NMR (125 MHz, MeOD) δ137.44, 128.19, 124.86, 123.64, 121.94, 115.40, 114.32, 110.76, 39.40, 38.47, 28.94, 26.87, 23.44.

[0045] Example 8 Preparation of compound 10 The starting materials used were compound 9 and N,N'-bis-tert-butoxycarbonyl-1-guanidinopyrazole. The preparation method involved the amide condensation reaction of compound 1 with N-(5-aminopentyl)carbamate tert-butyl ester in acetonitrile solution under the catalysis of HATU to obtain compound 8; compound 8 was then deprotected with a Boc protecting group in the presence of hydrochloric acid to obtain compound 9. Compound 9 was a white solid with a yield of 76%. The 1H NMR spectroscopy results are as follows: 1 H NMR (500 MHz, CDCl3) δ 11.48 (s, 1H), 8.36 (d, J =5.3 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.75 (s, 1H), 7.57 (d, J = 1.8 Hz,1H), 7.33–7.28 (m, 1H), 6.43 (t, J = 5.7 Hz, 1H), 3.32 (q, J = 6.8 Hz, 2H), 3.25 (td, J = 7.6, 5.5 Hz, 2H), 1.61–1.50 (m, 4H), 1.47 (d, J = 16.3 Hz,18H), 1.22 (h, J = 7.6, 6.5 Hz, 2H). 13 C NMR (125 MHz, CDCl3) δ 165.59,163.36, 156.30, 153.25, 137.35, 128.09, 124.52, 124.22, 121.70, 116.10,115.03, 105.06, 83.33, 79.62, 40.86, 39.42, 31.24, 29.39, 28.62, 28.26,28.06, 27.98, 24.19.

[0046] Example 9 Preparation of compound 11 The raw materials used were compound 10 and hydrochloric acid. The preparation method involved the amide condensation reaction of compound 1 with N-(5-aminopentyl)carbamate tert-butyl in acetonitrile solution under the catalysis of HATU to obtain compound 8; compound 8 was then deprotected with a Boc protecting group under hydrochloric acid to obtain compound 9; compound 9 was reacted with N,N'-bis-Boc-1-guanidinylpyrazole under basic conditions to obtain compound 10. Compound 10 was a yellow solid with a yield of 47%. The 1H NMR spectroscopy results are as follows: 1H NMR (500 MHz, DMSO-d6) δ 11.71 (d, J = 2.9 Hz, 1H), 8.11–8.02 (m, 2H), 7.98 (t, J = 5.7 Hz, 1H), 7.69 (t, J = 5.6 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.23 (dd, J = 8.5, 1.8 Hz, 1H), 3.25 (q, J = 6.6 Hz, 2H), 3.10 (q, J = 6.7Hz, 2H), 1.62–1.46 (m, 4H), 1.35 (tt, J = 9.7, 6.0 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 164.60, 157.31, 137.45, 128.80, 125.74, 123.61, 123.21, 114.95,114.89, 111.39, 41.22, 38.71, 29.60, 28.69, 24.10.

[0047] Example 10 Preparation of compounds 13a-13j Sodium hydride (25 mg, 1.06 mmol) was added to an 8 mL DMF solution of compound 10 (0.40 g, 0.71 mmol) and the brominated substrate (1.06 mmol), and the reaction mixture was stirred at 80 °C for 8 hours. After the reaction was complete, the solvent was concentrated under reduced pressure to obtain crude product 12a-12j, which was then further processed in diethyl ether with hydrochloric acid (1 mL) to finally obtain the target product 13a-13j.

[0048] Compound 13a is a white solid with a yield of 51%. The 1H NMR spectrum results are as follows: 1H NMR (500 MHz, MeOD) δ 8.04 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 8.5, 1.7 Hz, 1H), 4.16 (t, J = 7.1 Hz, 2H), 3.39 (t, J = 7.1Hz, 2H), 3.19 (t, J = 7.1 Hz, 2H), 1.81 (dq, J = 9.4, 7.1 Hz, 2H), 1.72–1.60(m, 4H), 1.47 (tt, J = 9.4, 6.1 Hz, 2H), 1.36–1.27 (m, 2H), 0.94 (t, J = 7.4Hz, 3H). 13 C NMR (125 MHz, MeOD) δ 166.20, 157.24, 137.35, 131.09, 125.54,123.84, 122.38, 115.58, 112.83, 109.90, 46.07, 41.06, 38.63, 31.79, 29.01,28.13, 23.69, 19.61, 12.63.

[0049] Compound 13b is a white solid with a yield of 58%. The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, MeOD) δ 8.03 (d, J = 8.6 Hz, 1H), 7.92 (s, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 8.6, 1.7 Hz, 1H), 4.16 (t, J = 7.1 Hz, 2H), 3.39 (t, J = 7.1Hz, 2H), 3.19 (t, J = 7.1 Hz, 2H), 1.82 (s, 2H), 1.65 (ddd, J = 16.1, 9.6,7.2 Hz, 4H), 1.47 (qd, J = 7.7, 6.6, 4.3 Hz, 2H), 1.29 (d, J = 4.1 (Hz, 6H), 0.92–0.82 (m, 3H). 13C NMR (125 MHz, MeOD) δ 166.21, 157.24, 137.37, 131.05,125.52, 123.85, 122.36, 115.60, 112.85, 109.92, 46.31, 41.05, 38.62, 31.10,29.67, 29.02, 28.12, 26.10, 23.67, 22.17, 12.93.

[0050] Compound 13c is a white solid with a yield of 68%. The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, MeOD) δ 8.04 (d, J = 8.5 Hz, 1H), 7.95 (s, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.26 (dd, J = 8.6, 1.7 Hz, 1H), 4.15 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 7.0Hz, 2H), 3.19 (t, J = 7.0 Hz, 2H), 1.81 (t, J = 7.1 Hz, 2H), 1.66 (dp, J =10.3, 7.3 Hz, 4H), 1.53–1.42 (m, 2H), 1.34–1.18 (m, 10H), 0.86 (t, J = 7.0Hz, 3H). 13 C NMR (125 MHz, MeOD) δ 166.18, 157.30, 157.25, 137.37, 131.12,125.56, 123.84, 122.41, 115.58, 112.84, 109.92, 51.11, 46.31, 41.06, 38.65,31.50, 29.67, 29.01, 28.86, 28.82, 28.14, 26.39, 23.70, 22.28, 13.07.

[0051] Compound 13d was a white solid with a yield of 66%. The 1H NMR spectrum results are as follows: 1H NMR (500 MHz, MeOD) δ 8.04 (d, J = 8.6 Hz, 1H), 7.93 (s, 1H), 7.64 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 8.6, 1.7 Hz, 1H), 4.16 (t, J = 7.0 Hz, 2H), 3.39 (t, J = 7.1Hz, 2H), 3.19 (t, J = 7.1 Hz, 2H), 1.82 (t, J = 7.1 Hz, 2H), 1.66 (dp, J =9.9, 7.3 Hz, 4H), 1.47 (qd, J = 9.4, 8.8, 5.9 Hz, 2H), 1.31–1.21 (m, 14H),0.88 (t, J = 7.0 Hz, 3H). 13 C NMR (125 MHz, MeOD) δ 166.19, 157.24, 137.38,131.09, 125.55, 123.84, 122.40, 115.59, 112.85, 109.93, 46.31, 41.06, 38.63,31.64, 29.66, 29.18, 29.01, 28.84, 28.12, 26.36, 23.68, 22.32, 13.08.

[0052] Compound 13e is a pale yellow solid with a yield of 66%. Its proton NMR spectrum is shown below. Figure 5 The results of the proton NMR spectrum are shown below: 1 H NMR (500 MHz, MeOD) δ 8.07 (d, J = 8.6 Hz, 1H), 8.00 (s, 1H), 7.62(d, J = 8.1 Hz, 2H), 7.58 (d, J = 1.7 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.29(dd, J = 8.6, 1.7 Hz, 1H), 5.51 (s, 2H), 3.40 (t, J = 7.0 Hz, 2H), 3.19 (t, J= 7.1 Hz, 2H), 1.65 (dq, J = 9.3, 7.3 Hz, 4H), 1.48 (qd, J = 7.4, 6.6, 4.0Hz, 2H). 13C NMR (125 MHz, MeOD) δ 165.95, 157.24, 141.27, 137.44, 131.40,127.30, 125.71, 125.45, 125.43, 124.28, 122.54, 116.04, 113.07, 110.97, 49.29, 41.04, 38.66, 28.97, 28.12, 23.67.

[0053] Compound 13f is a white solid with a yield of 66%. The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, MeOD) δ 8.07 (d, J = 8.6 Hz, 1H), 7.99 (s, 1H), 7.82–7.72 (m, 3H), 7.64 (d, J= 1.8 Hz, 2H), 7.44 (dt, J = 6.9, 3.5 Hz, 2H), 7.28 (dt, J = 8.6, 2.3 Hz, 2H), 5.49 (d, J = 11.1 Hz, 2H), 3.37 (t, J = 7.1 Hz, 2H), 3.16 (t, J = 7.1Hz, 2H), 1.63 (dp, J = 9.5, 7.2 Hz, 4H), 1.50–1.39 (m, 2H). 13 C NMR (125 MHz, MeOD) δ 166.09, 157.22, 137.60, 133.97, 133.38, 133.03, 131.40, 128.47,127.48, 127.35, 126.15, 125.92, 125.82, 125.72, 124.58, 124.15, 122.46,115.88, 113.21, 110.64, 50.06, 41.02, 38.65, 28.97, 28.11, 23.66.

[0054] 13g of the compound was a yellow solid, with a yield of 60%. The 1H NMR spectrum results are as follows: 1H NMR (500 MHz, MeOD) δ 8.07 (d, J = 8.6 Hz, 1H), 8.03–7.99 (m, 1H), 7.60 (dt, J = 3.5, 1.7Hz, 1H), 7.52–7.45 (m, 4H), 7.35 (dddd, J = 8.0, 6.0, 3.8, 1.9 Hz, 2H), 7.27(dt, J = 8.0, 2.0 Hz, 2H), 7.237.18 (m, 2H), 5.34 (dd, J = 7.6, 3.4 Hz, 2H), 3.38 (t, J = 7.0 Hz, 2H), 3.16 (td, J = 7.0, 2.0 Hz, 2H), 1.70 –1.56 (m, 4H), 1.53–1.39 (m, 2H). 13 C NMR (125 MHz, MeOD) δ 166.04, 157.27, 157.22, 140.74,140.25, 137.49, 135.51, 131.46, 128.48, 127.43, 127.11, 127.06, 126.54,125.77, 124.16, 122.50, 115.89, 113.24, 110.58, 49.64, 41.06, 38.69, 28.99,28.12, 23.70.

[0055] The compound was a white solid after 13 hours, with a yield of 57%. The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, MeOD) δ 8.04 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.27 (dd, J = 8.6, 1.7 Hz, 1H), 6.34 (dd, J = 31.7, 2.2 Hz, 3H), 5.27 (s,2H), 3.69 (s, 6H), 3.38 (t, J = 7.1 Hz, 2H), 3.18 (t, J = 7.1 Hz, 2H), 1.64(dq, J = 9.6, 7.3 Hz, 4H), 1.46 (td, J = 8.5, 4.2 Hz, 2H). 13C NMR (125 MHz, MeOD) δ 166.07, 161.38, 157.22, 138.82, 137.53, 131.50, 125.66, 124.11,122.41, 115.81, 113.24, 110.49, 104.93, 99.06, 54.44, 53.45, 49.98, 41.05, 38.67, 28.98, 28.12, 23.69.

[0056] Compound 13i is a white solid with a yield of 71%. The 1H NMR spectrum results are as follows: 1 H NMR (500 MHz, MeOD) δ 7.99 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.24 (dd, J = 8.6, 1.7 Hz, 1H), 7.21 – 7.14 (m, 3H), 7.04 – 6.99 (m, 2H), 4.40 (t, J = 6.9 Hz, 2H), 3.35 (d, J = 5.0 Hz, 2H), 3.18 (t, J = 7.1 Hz, 2H), 3.09 (t, J = 6.9 Hz, 2H), 1.64 (p, J = 7.3 Hz, 4H), 1.45 (tt, J = 9.3, 5.9Hz, 2H). 13 C NMR (125 MHz, MeOD) δ 166.15, 157.24, 138.10, 137.27, 131.21,128.50, 128.19, 126.38, 125.43, 123.84, 122.24, 115.60, 112.95, 109.89, 48.48, 41.05, 38.56, 36.03, 28.97, 28.09, 23.62.

[0057] Compound 13j is a white solid with a yield of 63%. The 1H NMR spectrum results are as follows: 1H NMR (500 MHz, MeOD) δ 7.99 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 7.51 (d, J = 1.7 Hz, 1H), 7.24 (dd, J = 8.5, 1.7 Hz, 1H), 7.03–6.97 (m, 2H), 6.93–6.85 (m, 2H), 4.40 (t, J = 6.8 Hz, 2H), 3.38–3.34 (m, 2H), 3.19 (t, J = 7.1 Hz, 2H), 3.09 (t, J= 6.7 Hz, 2H), 1.65 (p, J = 7.4 Hz, 4H), 1.45 (tt, J = 9.4, 6.0 Hz, 2H). 13 CNMR (125 MHz, MeOD) δ 166.10, 162.83, 160.89, 157.24, 137.26, 134.08, 134.05,131.18, 130.28, 130.21, 125.42, 123.86, 122.26, 115.63, 114.85, 114.68,112.95, 109.96, 48.47, 41.04, 38.54, 35.16, 28.98, 28.09, 23.61.

[0058] Application Example 1: In vitro antibacterial activity test 1. Experimental Methods The minimum inhibitory concentration (MIC) of the target compound obtained in the above examples against bacteria was determined according to the Clinical and Laboratory Standards Institute (CLSI) guidelines, using the microbroth dilution method. The simplified steps are as follows: The test compound was serially diluted twofold in sterile 96-well plates using trypsin-soy broth (TSB) as the growth medium. Subsequently, an equal volume of standardized bacterial suspension was inoculated into each well to achieve a final bacterial concentration of approximately 10⁻⁶. 6 CFU / mL. The culture plates were incubated statically at 37°C for 24 hours. The minimum inhibitory concentration (MIC) was defined as the lowest concentration of the compound required to completely inhibit the growth of visible bacteria. To ensure the reliability and reproducibility of the experiments, all antimicrobial tests were independently repeated three times.

[0059] 2. Experimental Results Table 1 presents the minimum inhibitory concentrations (MICs) of the corresponding indole compounds against six common clinical bacteria (4 Gram-positive and 2 Gram-negative). The clinically marketed drugs vancomycin and polymyxin were used as positive controls. Overall, the target compounds exhibited good antibacterial activity against Gram-positive bacteria. Compounds 13e-13j all showed good antibacterial activity, with MICs ranging from 1 to 16 µg / mL. Among all synthesized indole compounds, compound 13e showed the best antibacterial activity, exhibiting optimal activity against all four tested Gram-positive bacteria. Its MICs against *Staphylococcus aureus* ATCC25923, *Staphylococcus aureus* ATCC43300, *Enterococcus faecalis* ATCC29212, and *Bacillus subtilis* reached 1, 2, 2, and 4 μg / mL, respectively. Its antibacterial activity against *Staphylococcus aureus* ATCC25923 was comparable to that of vancomycin. Furthermore, compound 13e also exhibited moderate antibacterial activity against Gram-negative bacteria (such as Escherichia coli ATCC25922 and Pseudomonas aeruginosa ATCC27853), with MIC values ​​of 16–32 μg / mL. Therefore, we selected compound 13e, which showed the best antibacterial activity, for further evaluation.

[0060] Table 1. Antimicrobial activity of indole antimicrobial peptide mimics (MIC, μg / mL)

[0061] in, S. aureus 25923: Staphylococcus aureus ATCC25923, erythromycin-sensitive strain; S. aureus 43300: Staphylococcus aureus ATCC43300, a methicillin-resistant strain; E. faecalis 29212: Enterococcus faecalis ATCC29212, a vancomycin-sensitive strain; B. subtilis 9372: Bacillus subtilis ATCC9372, a penicillin-sensitive strain; E. coli 25922: Escherichia coli ATCC25922, a penicillin-sensitive strain; P. aeruginosa 27853: Pseudomonas aeruginosa ATCC27853, a penicillin-sensitive strain.

[0062] Application Example 2: Bactericidal Kinetics Test 1. Experimental Methods Staphylococcus aureus ATCC25923 was cultured overnight, and the bacterial suspension was diluted to 1×10⁻⁶. 6CFU / mL. Equal volumes of bacterial suspension were dispensed into sterile test tubes, and compound 13e (concentrations of 1×, 2×, 4×, and 8×MIC) were added to each tube. After incubation, samples were taken at 0.5, 1, 2, 4, 8, 12, and 24 hours. At each time point, 20 μL of bacterial suspension was taken and serially diluted 10-fold with PBS. Appropriate dilutions were plated onto MH plates, inverted, and incubated at 37°C for 18-20 hours. Colony forming units (CFU) were counted, and the colony count was determined. Compound 13e, exhibiting the best antibacterial activity, was selected as the target compound for investigation of its bactericidal efficacy against Staphylococcus aureus ATCC25923 at different concentrations over time.

[0063] 2. Experimental Results like Figure 1 As shown, the results indicate that compound 13e has a rapid bactericidal effect, killing all Staphylococcus aureus within 4 hours at a concentration of 8 µg / mL.

[0064] Application Example 3: Drug Resistance Induction Test 1. Experimental Methods Staphylococcus aureus ATCC25923 was inoculated into MHB broth, and the bacterial suspension concentration was adjusted to 1×10⁻⁶ using sterile MHB. 6 CFU / mL. The standardized bacterial suspension was mixed with the test compound to achieve a final compound concentration of 1 / 2 × MIC, and then incubated at 37°C for 18 hours. This subculture process was repeated daily for 20 consecutive days. The minimum inhibitory concentration (MIC) of compound 13e against the continuously subcultured strains was determined daily.

[0065] 2. Experimental Results Compound 13e was also selected to investigate its effect on inducing resistance in *Staphylococcus aureus* ATCC25923. The results showed that *Staphylococcus aureus* exhibited extremely low bacterial resistance after 20 consecutive passages induced at a sub-concentration (MIC / 2) of 13e. The MIC value of compound 13e against *Staphylococcus aureus* remained relatively stable, while the MIC of the control drug norfloxacin increased 256-fold. Figure 2 As shown, this indicates that the compound is unlikely to induce antibiotic resistance in bacteria.

[0066] Application Example 4: Hemolytic Toxicity Test 1. Experimental Methods Red blood cells were isolated from fresh sheep blood and resuspended in 1× PBS to prepare a 5% (v / v) red blood cell suspension. The test compound was dissolved in PBS to prepare a stock solution with an initial concentration of 5.12 mg / mL. 100 μL of this stock solution was added to a 96-well plate and serially diluted twofold with PBS. Then, 150 μL of the 5% red blood cell suspension was added to each well, bringing the final reaction volume to 250 μL per well. The reaction plate was incubated at 37°C for 1 hour, followed by centrifugation at 3500 rpm for 5 minutes to precipitate intact red blood cells. 100 μL of the supernatant from each well was carefully transferred to a new 96-well plate, and the absorbance of the supernatant was measured at 540 nm using a microplate reader.

[0067] 2. Experimental Results Compound 13e was selected, and its effect on hemolysis of erythrocytes at different concentrations was determined. Figure 3 As shown, compound 13e exhibits extremely low hemolytic activity, and its HC... 50 The concentration value was 95.01 μg / mL, indicating high safety within the concentration range of 1-32 μg / mL. Even at a concentration as high as 64 μg / mL, the hemolytic rate of 13e on erythrocytes was only 9.68%, indicating that compound 13e does not exhibit corresponding hemolytic toxicity within the permitted concentration range.

[0068] Application Example 5: Cytotoxicity Test 1. Experimental Methods The cytotoxicity of compound 13e to LO2 cells was evaluated using the CCK-8 assay. A brief summary of the procedure is as follows: LO2 cells were cultured at 1 × 10⁶ cells per well. 4 Cells were seeded at a density of [number] cells per well in 96-well plates. After cell adhesion, different concentrations of 13e solution were added to the experimental groups, while the negative control group received only complete culture medium without the drug. After culturing for another 24 hours, the supernatant was aspirated, and the cells were gently washed twice with PBS. Subsequently, 100 μL of fresh culture medium containing 10% (v / v) CCK-8 reagent was added to each well, and the plate was incubated at 37°C in the dark for 2 hours. Finally, the absorbance of each well was measured at 450 nm using a multi-mode microplate reader.

[0069] 2. Experimental Results Compound 13e was selected to determine its cytotoxicity against mammalian LO2 cells. For example... Figure 4 As shown, compound 13e exhibits low cytotoxicity, with a C6C value of [missing information]. 50 The concentration was 26.38 μg / mL. After treating LO2 cells with 8 μg / mL of 13e, the cell viability was 89.07%; even when the concentration was increased to 16 μg / mL, the cell viability remained above 80.27%. These results indicate that 13e has almost no toxic effect on mammalian cells within the MIC concentration range.

[0070] Finally, it should be noted that the above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of them. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An indole antimicrobial peptide mimic or a pharmaceutically acceptable salt thereof, characterized in that, Its compound structure is shown in formula (I): （I）； Where n = 1, 2, or 3; R is selected from the following groups:

2. The indole antimicrobial peptide mimicry according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from compounds having the structures shown below:

3. The indole antimicrobial peptide mimicry according to claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, Compound 1 was prepared by the following method: Compound 1 underwent a substitution reaction with 1-bromo-3-methyl-2-butene in an acetonitrile solution under alkaline conditions to obtain Compound 2, which was then hydrolyzed under alkaline sodium hydroxide conditions to obtain Compound 3; Compound 3 underwent a condensation reaction with an amino-substituted compound under alkaline conditions to obtain Compound 4; Compound 4 was further deprotected with a Boc protecting group under hydrochloric acid to obtain Compound 5; Compound 5 reacted with N,N'-bis-Boc-1-guanidinopyrazole in the presence of N,N-diisopropylethylamine to obtain Compound 6, which was then deprotected with a Boc protecting group under acidic conditions to obtain Compound 7; the preparation route of the method is as follows: Among them, compound 1 is 6-bromoindole-3-carboxylic acid; compound 4 includes compounds 4a, 4b, and 4c, with corresponding n values ​​of 1, 2, and 3 in the structural formula, respectively; compound 5 includes compounds 5a, 5b, and 5c, with corresponding n values ​​of 1, 2, and 3 in the structural formula, respectively; compound 6 includes compounds 6a, 6b, and 6c, with corresponding n values ​​of 1, 2, and 3 in the structural formula, respectively; and compound 7 includes compounds 7a, 7b, and 7c, with corresponding n values ​​of 1, 2, and 3 in the structural formula, respectively.

4. The indole antimicrobial peptide mimicry according to claim 3, or a pharmaceutically acceptable salt thereof, characterized in that, In the preparation route described in the method, reaction conditions and reagents a represent: compound 1 is dissolved in acetonitrile, 1-bromo-3-methyl-2-butene and potassium carbonate are added, and the reaction is carried out at 50-70°C; b represents: compound 2 is dissolved in an aqueous methanol solution, sodium hydroxide is added, and the reaction is carried out at 50-70°C; c represents: compound 3 and HATU are dissolved in acetonitrile, N,N-diisopropylethylamine and NH2CH2(CH2) are added. n CH2NHBoc reacts at 50-70°C; d indicates that compound 4 is dissolved in methanol at room temperature and reacted with hydrochloric acid; e indicates that compound 5 is dissolved in dichloromethane and reacted with N,N-diisopropylethylamine and N,N'-bis-tert-butoxycarbonyl-1-guanidinopyrazole at room temperature.

5. The indole antimicrobial peptide mimicry according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Selected from compounds having the structures shown below: #imgpt17#; 6. The indole antimicrobial peptide mimicry according to claim 5, or a pharmaceutically acceptable salt thereof, characterized in that, Compound 11 or compounds 13a-13j are prepared by the following method: Compound 1 reacts with N-(5-aminopentyl)carbamate tert-butyl in acetonitrile solution via amide condensation under the catalysis of HATU to give compound 8; compound 8 is deprotected by the Boc protecting group under hydrochloric acid to give compound 9; compound 9 reacts with N,N'-bis-Boc-1-guanidinylpyrazole under basic conditions of N,N-diisopropylethylamine to give compound 10, which is further deprotected by the Boc protecting group under acidic conditions to give compound 11; or compound 10 reacts with bromides with different substituents under basic conditions of sodium hydride to give compounds 13a-13j; The preparation route of the method is as follows:

7. The indole antimicrobial peptide mimicry according to claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, In the preparation route of the method described above, the reaction conditions and reagents are as follows: a) Compound A undergoes an amide condensation reaction with N-(5-aminopentyl)carbamate tert-butyl in acetonitrile solution under HATU catalysis at a reaction temperature of 50-70℃; b) Compound 8 reacts at room temperature under hydrochloric acid; c) Compound 9 reacts with N,N'-bis-Boc-1-guanidinopyrazole at room temperature under basic conditions of N,N-diisopropylethylamine; d) Deprotection of the Boc protecting group at room temperature under hydrochloric acid conditions; e) Compound 10 reacts with bromides with different substituents under basic conditions of sodium hydride to obtain compounds 13a-13j at a reaction temperature of 50-70℃.

8. The use of any one of the indole antimicrobial peptide mimics of claims 1-7 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of bacterial infections.

9. The application according to claim 8, characterized in that, The bacterial infection mentioned above is an infection caused by Staphylococcus aureus, Bacillus subtilis, Enterococcus faecalis, Escherichia coli, or Pseudomonas aeruginosa.

10. A drug for treating bacterial infections or for antibacterial purposes, characterized in that, It comprises an indole antimicrobial peptide mimic of any one of claims 1-7 or a pharmaceutically acceptable salt thereof.

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