CN118561797A - Benzopyran antibacterial peptide mimics with broad-spectrum antibacterial activity, and preparation method and application thereof - Google Patents

Abstract

The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to benzopyran antimicrobial peptide mimetics with broad-spectrum antimicrobial activity, and preparation methods and applications thereof. In vitro antimicrobial activity verification shows that the benzopyran antimicrobial peptide mimetics provided by the present invention exhibit good antimicrobial activity against both Gram-positive and Gram-negative bacteria, and have the characteristics of rapid bactericidal activity and low resistance to drug resistance, which is expected to provide a new approach to solving the problem of bacterial resistance. A benzopyran antimicrobial peptide mimetic with broad-spectrum antimicrobial activity or a pharmaceutically acceptable salt thereof, the structural formula of the benzopyran antimicrobial peptide mimetic is shown in formula (I):

Description

Benzopyran antimicrobial peptide mimetics with broad-spectrum antimicrobial activity and preparation method and application thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a benzopyran antimicrobial peptide mimetic with broad-spectrum antimicrobial activity and a preparation method and application thereof.

Background Art

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

Due to the large-scale use and abuse of antibiotics worldwide, various "multi-drug resistant bacteria" continue to emerge, posing a severe challenge to human health and becoming one of the biggest threats to global public health. However, the development of new antibiotics is very slow, especially the lack of new antibiotics with new antibacterial mechanisms. In the past 30 years, no antibacterial drugs with new antibacterial mechanisms have appeared on the market. Humanity is about to face a major crisis of no antibiotics available.

Antimicrobial peptides are hydrophilic and lipophilic natural peptides with positive charge that are widely found in multicellular organisms. They are the first line of defense of the immune system against microbial infection. Antimicrobial peptides have common structural characteristics: hydrophilic positive charge and lipophilic side chain, which form a spatial conformation with one side of the same molecule being the hydrophilic part and the other side being the lipophilic part. This spatial structure is considered to be the basis for the antimicrobial activity of antimicrobial peptides. There are structural differences between bacterial cell membranes and mammalian cell membranes. Phosphatidylethanolamine, sphingomyelin and phosphatidylcholine in eukaryotic cell membranes are electrically neutral under physiological conditions. The bacterial phospholipid bilayers of Gram-positive and Gram-negative bacteria are rich in negatively charged phospholipid molecules such as cardiolipin, phosphatidylglycerol and phosphatidylserine. Lipopolysaccharide on the Gram-positive bacterial membrane and teichoic acid in the cell wall of Gram-negative bacteria make the bacteria negatively charged as a whole. The differences in the composition and structure of eukaryotic and bacterial cell membranes make antimicrobial peptides more easily adsorbed on the surface of bacterial cell membranes, thus showing the bactericidal selectivity of antimicrobial peptides. After the antimicrobial peptides with cationic groups are adsorbed onto the negatively charged bacterial surface through electrostatic adsorption, the lipophilic end of the antimicrobial peptide will be inserted into the phospholipid bilayer of the bacterial cell membrane through hydrophobic force, thereby changing the composition of the bacterial cell membrane, destroying the integrity of the bacterial cell membrane, causing bacterial membrane rupture, leading to leakage of internal cell substances, membrane depolarization and cell death. Compared with traditional antimicrobial agents, antimicrobial peptides have novel mechanisms of action, strong antimicrobial properties, fast bactericidal speed, broad antimicrobial spectrum and low resistance to drug resistance. Therefore, as a new type of highly effective antimicrobial agent, antimicrobial peptides have great potential and have received widespread attention from researchers around the world.

Although antimicrobial peptides show excellent antibacterial activity against both Gram-positive and Gram-negative bacteria, they also have some defects, which restrict their clinical application. First, the potential toxicity of antimicrobial peptides: the target of antimicrobial peptides is the bacterial cell membrane. While exerting their antibacterial properties, they also have hemolytic side effects on normal mammals. Second, antimicrobial peptides have poor stability under physiological conditions: due to the widespread presence of proteolytic enzymes in the human body, antimicrobial peptides that enter the human body are very easily degraded by these enzymes and lose their antimicrobial activity. In addition, the high synthesis cost is also a factor that limits the clinical application of antimicrobial peptides. In response to the problems of antimicrobial peptide drugs, medicinal chemists have tried to achieve the goals of high activity, low cytotoxicity, high protease stability, and low synthesis cost through the research of antimicrobial peptide mimetics. So far, only vancomycin, daptomycin, and polymyxin have been approved for clinical use, and there are three mimetics that have advanced to the clinical research stage, namely PMX-30063, LTX-109, and CA-13. Therefore, it is urgent to further expand the types of antimicrobial peptide mimetics.

Summary of the invention

In order to overcome the above problems, the purpose of the present invention is to provide a series of benzopyran antimicrobial peptide mimetics with strong antibacterial properties, fast sterilization speed and broad antibacterial spectrum, and to provide a preparation method and application thereof.

In the first aspect of the present invention, a benzopyran antimicrobial peptide mimetic or a pharmaceutically acceptable salt thereof having broad-spectrum antimicrobial activity is provided. The structural formula of the benzopyran antimicrobial peptide mimetic is shown in formula (I):

Wherein, X is selected from -CH ₂ - or -CO-, n is an integer of 1 to 2, and R is an amino derivative.

In one or more embodiments, the structural formula of the benzopyran antimicrobial peptide mimetic is as shown in Formula (II) to Formula (V):

Wherein, R ¹ is selected from methylamino, ethylamino, dimethylamino, diethylamino, pyridyl, morpholinyl, thiomorpholinyl, 2,6-dimethylmorpholinyl, 1-acetylpiperazinyl, N,N-dimethylethylenediamino, trimethyl-1,3-propylenediamino, N,N-ethyl-1,3-propylenediamino, N,N,2,2-tetramethyl-1,3-propylenediamino, 3-(dibutylamino)propylamino, 1-(3-aminopropyl)pyrrolidinyl, 1-(3-aminopropyl)-4-methylpiperazinyl, 3,3'-iminobis(N,N-dimethylpropylamino);

Wherein, R ² is selected from diethylamino, N,N-dimethylethylenediamino, 3-(dibutylamino)propylamino, 1-(3-aminopropyl)pyrrolidinyl, aminopropylmorpholinyl, 1-(3-aminopropyl)-4-methylpiperazinyl;

Wherein, ^R3 is selected from dimethylamino, diethylamino, morpholinyl, thiomorpholinyl, 2,6-dimethylmorpholinyl, N,N-dimethylethylamino, N,N-dimethylethylenediamino, N,N-ethyl-1,3-propylenediamino, 3-(dibutylamino)propylamino, 1-(3-aminopropyl)pyrrolidinyl, aminopropylmorpholinyl, 1-(3-aminopropyl)-4-methylpiperazinyl, 3,3'-iminobis(N,N-dimethylpropylamino);

Wherein, R ⁴ is selected from N,N-dimethylethylamino, N,N-dimethylethylenediamino, trimethyl-1,3-propylenediamino, N,N-ethyl-1,3-propylenediamino, 3-(dibutylamino)propylamino, 1-(3-aminopropyl)pyrrolidinyl, 1-(3-aminopropyl)-4-methylpiperazinyl.

Preferably, the compound of formula (II) is selected from any of the following structures:

Preferably, the compound of formula (III) is selected from any of the following structures:

Preferably, the compound of formula (IV) is selected from any of the following structures:

Preferably, the compound of formula (V) is selected from any of the following structures:

The second aspect of the present invention provides a method for preparing a benzopyran antimicrobial peptide mimetic having broad-spectrum antimicrobial activity.

Wherein, the preparation method of the compound described in formula (II) comprises:

2,4-dihydroxyacetophenone and citral dimethyl acetal undergo cyclization reaction to generate compound a1, and then compound a1 undergoes bromination reaction with 1,3-dibromopropane to obtain compound a2; finally, compound a2 undergoes substitution reaction with different amine compounds to obtain corresponding target compounds A1-A17;

The specific synthetic route is:

Preferably, the amine compounds used in the synthesis of A1 to A17 are: methylamine, ethylamine, dimethylamine, diethylamine, pyridine, morpholine, thiomorpholine, 2,6-dimethylmorpholine, 1-acetylpiperazine, N,N-dimethylethylenediamine, trimethyl-1,3-propylenediamine, N,N-ethyl-1,3-propylenediamine, N,N,2,2-tetramethyl-1,3-propylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine, 1-(3-aminopropyl)-4-methylpiperazine and 3,3'-imidobis(N,N-dimethylpropylamine).

The preparation method of the compound of formula (III) comprises:

Compound b1 undergoes a substitution reaction with ethyl bromoacetate to generate compound b2; compound b2 is then hydrolyzed under alkaline conditions to obtain compound b3; and compound b3 is finally subjected to an amide condensation reaction with different amine compounds to obtain the corresponding target compounds B1-B6;

The specific synthetic route is:

Preferably, the amine compounds used in the synthesis of B1-B6 are: diethylamine, N,N-dimethylethylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine, aminopropylmorpholine and 1-(3-aminopropyl)-4-methylpiperazine.

The preparation method of the compound of formula (IV) comprises:

2,4,6-trihydroxyacetophenone and citral dimethyl acetal undergo cyclization reaction to generate compound c1; compound c1 then undergoes bromination reaction with 1,3-dibromopropane to obtain compound c2; finally, compound c2 undergoes substitution reaction with different amine compounds to obtain corresponding target compounds C1-C13;

The specific synthetic route is:

Preferably, the amine compounds used in the synthesis of C1-C13 are: dimethylamine, diethylamine, morpholine, thiomorpholine, 2,6-dimethylmorpholine, N,N-dimethylethylamine, N,N-dimethylethylenediamine, N,N-ethyl-1,3-propylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine, aminopropylmorpholine, 1-(3-aminopropyl)-4-methylpiperazine and 3,3'-imidobis(N,N-dimethylpropylamine).

The preparation method of the compound of formula (V) comprises:

Compound d1 undergoes a substitution reaction with ethyl bromoacetate to generate compound d2; compound d2 is hydrolyzed to obtain compound d3; compound d3 is subjected to an amide condensation reaction with different amine compounds to obtain target compounds D1-D7;

The specific synthetic route is:

Preferably, the amine compounds used in the synthesis of D1-D7 are: N,N-dimethylethylamine, N,,N-dimethylethylenediamine, trimethyl-1,3-propylenediamine, N,N-ethyl-1,3-propylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine and 1-(3-aminopropyl)-4-methylpiperazine.

The third aspect of the present invention provides the use of benzopyran antimicrobial peptide mimetics or pharmaceutically acceptable salts thereof having broad-spectrum antimicrobial activity in the preparation of drugs for treating bacterial infections.

The beneficial effects of the present invention are:

(1) The benzopyran antimicrobial peptide mimetics provided by the present invention exhibited good antibacterial activity against both Gram-positive and Gram-negative bacteria, especially compounds A14, C2 and C5-C7 exhibited good antibacterial activity against Staphylococcus aureus, Bacillus subtilis and Escherichia coli, with minimum inhibitory concentration values ranging from 1 to 8 μg/mL. The antibacterial activity of some compounds was better than that of the positive control drugs vancomycin and colistin.

(2) The present invention selected the most active compounds A14 and C5 for further study and found that they have the characteristics of rapid bactericidal activity and are not easy to develop drug resistance, which is expected to provide a new idea for solving the problem of bacterial resistance.

BRIEF DESCRIPTION OF THE DRAWINGS

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

Figure 1 shows the time-killing curves of compounds A14 and C5 against Staphylococcus aureus and Escherichia coli, a is A14, b is C5;

Figure 2 shows the evaluation of the induced resistance of compounds A14 and C5 to Staphylococcus aureus and Escherichia coli, a is A14, and b is C5.

DETAILED DESCRIPTION

It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and/or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and/or combinations thereof.

In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

Example 1 Synthesis of Compounds A1 to A17

1.1 Preparation of compound a1

2,4-dihydroxyacetophenone (5.00 g, 32.86 mmol), citral dimethyl acetal (13.03 g, 65.72 mmol), and pyridine (30.00 mL) were added to a round-bottom flask. The reaction mixture was stirred at 150°C for 14 h. After the reaction was completed by TLC, the reaction was cooled to room temperature, concentrated under reduced pressure to remove excess pyridine, diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain 5.55 g of a colorless oil with a yield of 59%.

1.2 Preparation of compound a2

Compound a1 (5.00 g, 17.46 mmol), 1,3-dibromopropane (15.86 g, 78.57 mmol), cesium carbonate (8.53 g, 26.19 mmol), and acetonitrile (50 mL) were added to a round-bottom flask. The reaction mixture was stirred at 65°C for 10 h. After the reaction was completed by TLC, the reaction was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain 5.83 g of a colorless oil with a yield of 82%.

1.3 Preparation of Compounds A1 to A17

Compound a2 (200 mg, 0.49 mmol) was dissolved in 5 mL of acetonitrile, and the corresponding amine compound (1.96 mmol) and cesium carbonate (Cs ₂ CO ₃ , 1.23 mmol) were added, and the mixture was stirred at 65° C. for 6 h. After the reaction was completed by TLC detection, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography to obtain target compounds A1-A17. The amine compounds used in the synthesis of A1 to A17 are: methylamine, ethylamine, dimethylamine, diethylamine, pyridine, morpholine, thiomorpholine, 2,6-dimethylmorpholine, 1-acetylpiperazine, N,N-dimethylethylenediamine, trimethyl-1,3-propylenediamine, N,N-ethyl-1,3-propylenediamine, N,N,2,2-tetramethyl-1,3-propylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine, 1-(3-aminopropyl)-4-methylpiperazine and 3,3'-imidobis(N,N-dimethylpropylamine).

The specific synthetic route is:

A1: ¹ H NMR (500MHz, CDCl ₃ ) δ7.60 (d, J = 8.7Hz, 1H), 6.65-6.58 (m, 2H), 5.65 (d, J = 10.2Hz,

1H),5.08(dddd,J＝7.1,5.7,2.9,1.4Hz,1H),3.91(t,J＝5.8Hz,2H),3.09(t,J＝6.3Hz,2H),2.68(s,3H ),2.56(s,3H),2.25-2.17(m,2H),2.10-2.04(m,2H),1.76(ddd,J＝14.0,10.0,6.6Hz,1H),1.69-1.64(m,4H ), 1.56 (d, J = 1.4Hz, 3H), 1.41 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ )δ198.51,158.87,154.87,132.10,132.03,130.06,123.64,116.69,115.37,112.49,79.79,77.30,77.05,76.79,74.10,49.19,41.47,35.07,29 .42,28.14,26.89,25.64,22.62,17.62.HRMS (ESI)C ₂₂ H ₃₂ NO ₃ [M+H] ⁺ calcd = 358.2377; found [M+H] ⁺ = 358.2374.

A2: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.54 (d, J = 8.6 Hz, 1H), 6.61 (dd, J = 21.5, 9.4 Hz, 2H), 5.62 (d, J

＝10.1 Hz,1H),5.08(ddt,J＝7.3,5.8,1.5 Hz,1H),3.90(t,J＝6.3 Hz,2H),2.89(t,J＝6.9 Hz,2H),2.74(q ,J＝7.1 Hz,2H),2.58(s,3H),2.07(dq,J＝23.8,6.2 Hz,4H),1.78-1.73(m,1H),1.69-1.62(m,4H),1.56( d, J＝1.3 Hz, 3H), 1.41 (s, 3H), 1.16 (t, J＝7.1 Hz, 3H). ¹³ C NMR (125 MHz, CDCl ₃ )δ198.34,158.32,155.44,131.99,131.30,129.59,123.75,117.08,115.02,112.35,79.39,74.50,46.67,44.16,41.39,29.96,26.76,25.66,22 .64,17.62,14.99.HRMS(ESI)C ₂₃ H ₃₄ NO ₃ [M+H] ⁺ calcd = 372.2533; found [M+H] ⁺ = 372.2538.

A3: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.54 (d, J = 8.6 Hz, 1H), 6.67-6.53 (m, 2H), 5.63 (d, J = 10.1 Hz,

1H),5.08(tp,J＝7.2,1.5 Hz,1H),3.89(t,J＝6.4 Hz,2H),2.58(s,5H),2.33(s,6H),2.06(dp,J＝26.8 ,6.9,6.4 Hz,4H),1.79-1.63(m,5H),1.56(s,3H),1.41(s,3H). ¹³ CNMR(125 MHz,CDCl ₃ )δ198.25,158.21,155.46,131.97,131.17,129.53,125.17,123.76,117.13,114.98,112.33,79.32,74.07,56.07,45.16,41.38,30.03,26.72,2 5.65,22.64,17.62.HRMS(ESI)C ₂₃ H ₃₄ NO ₃ [M+H] ⁺ calcd = 372.2533; found [M+H] ⁺ = 372.2536.

A4: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.53 (d, J = 8.6 Hz, 1H), 6.66 (d, J = 10.1 Hz, 1H), 6.58 (d, J = 8.6

Hz,1H),5.62(d,J＝10.1 Hz,1H),5.08(tdd,J＝7.1,3.1,1.5 Hz,1H),3.87(t,J＝6.5 Hz,2H),2.69(q,J ＝7.4 Hz,2H),2.59(d,J＝6.4 Hz,7H),2.10(tt,J＝11.9,6.9Hz,2H),2.00(p,J＝6.9 Hz,2H),1.75(ddd,J ＝14.0,10.2,6.4 Hz,1H),1.69-1.61(m,4H),1.41(s,3H),1.06(t,J＝7.2 Hz,6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ198.35,158.18,155.65,131.95,131.08,129.38,125.25,123.78,117.27,114.91,112.30,79.28,74.62,49.51,46.74,41.37,30.13,27.58,2 6.72,25.66,22.64,17.61,11.49.HRMS(ESI )C ₂₅ H ₃₈ NO ₃ [M+H] ⁺ calcd = 400.2846; found [M+H] ⁺ = 400.2847.

A5: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.54 (d, J = 8.6 Hz, 1H), 6.70 (d, J = 10.1 Hz, 1H), 6.58 (d, J = 8.6

Hz,1H),5.61(d,J＝10.1 Hz,1H),5.08(t,J＝7.1 Hz,1H),3.87(t,J＝6.4 Hz,2H),2.60(s,3H),2.55- 2.49(m,2H),2.41(s,4H),2.10(tt,J＝11.4,6.9 Hz,2H),2.01(p,J＝6.6 Hz,2H),1.80-1.63(m,5H),1.63 -1.58(m,4H),1.56(s,3H),1.45(m,2H),1.41(s,3H). ¹³ C NMR (125MHz, CDCl ₃ )δ198.33,158.20,155.66,131.93,131.06,129.32,125.26,123.79,117.33,114.93,112.32,79.27,74.31,55.37,54.50,41.37,30.16,27.33,2 6.72,25.84,25.65,24.35,22.64,17.61.HRMS (ESI)C ₂₅ H ₃₆ NO ₃ [M+H] ⁺ calcd = 398.2690; found [M+H] ⁺ = 398.2693.

A6: ¹ H NMR (500 MHz, CDCl ₃ )) δ7.54 (d, J = 8.6 Hz, 1H), 6.70 (dd, J = 10.1, 0.7 Hz, 1H), 6.59 (dd,

J＝8.6,0.7 Hz,1H),5.61(d,J＝10.1 Hz,1H),5.08(dddd,J＝8.6,5.7,2.9,1.4Hz,1H),3.89(t,J＝6.3Hz,2H ),3.73(t,J＝4.7 Hz,4H),2.59(s,5H),2.48(s,4H),2.05(dtd,J＝42.0,13.6,13.0,6.6 Hz,4H),1.76(ddd, J＝13.9,10.2,6.3 Hz,1H),1.69-1.63(m,4H),1.57(d,J＝1.4 Hz,3H),1.41(s,3H). ¹³ C NMR (125 MHz, CDCl ₃ )δ198.27,158.19,155.57,131.97,131.10,129.38,125.28,123.76,117.29,114.91,112.37,79.28,73.94,66.98,54.96,53.64,41.37,30.14,2 7.00,26.73,25.65,22.64,17.62.HRMS(ESI )C ₂₅ H ₃₆ NO ₄ [M+H] ⁺ calcd = 414.2639; found [M+H] ⁺ = 414.2641.

A7: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.54 (d, J = 8.6 Hz, 1H), 6.68 (d, J = 10.1 Hz, 1H), 6.59 (d, J = 8.6

Hz,1H),5.62(d,J＝10.1 Hz,1H),5.09(t,J＝7.7 Hz,1H),3.87(t,J＝6.3 Hz,2H),2.82-2.68(m,8H), 2.62(t,J＝6.7 Hz,2H),2.58(s,3H),2.09(dq,J＝12.0,6.3 Hz,2H),2.05-1.96(m,2H),1.82-1.71(m,1H) ,1.71-1.62(m,4H),1.57(s,3H),1.41(s,3H). ¹³ CNMR(125 MHz,CDCl ₃ )δ198.23,158.20,155.51,131.99,131.15,129.43,125.21,123.75,117.26,114.92,112.36,79.30,73.86,55.30,54.99,41.37,30.11,27.89,2 6.74,25.66,22.64,17.63.HRMS(ESI)C ₂₅ H ₃₆ NO ₃ S[M+H] ⁺ calcd=430.2410; found[M+H] ⁺ =430.2410.

A8: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.54 (d, J = 8.6 Hz, 1H), 6.70 (d, J = 10.1 Hz, 1H), 6.59 (d, J = 8.6

Hz,1H),5.61(d,J＝10.1 Hz,1H),5.15-5.02(m,1H),3.89(t,J＝6.3 Hz,2H),3.78-3.63(m,2H),2.75(d ,J＝10.5 Hz,2H),2.59(s,3H),2.54(t,J＝7.2 Hz,2H),2.09(dq,J＝11.8,6.2 Hz,2H),2.01(p,J＝6.6Hz ,2H),1.81-1.72(m,3H),1.71-1.62(m,4H),1.57(s,3H),1.41(s,3H),1.17(d,J＝6.3 Hz,6H). ¹³ CNMR (125 MHz, CDCl ₃ )δ198.27,158.19,155.60,131.97,131.09,129.35,125.28,123.76,117.31,114.90,112.36,79.27,74.00,71.71,59.48,54.56,45.85,41.37,3 0.15,28.66,27.04,26.73,25.65,22.64,19.20 ,17.61.HRMS(ESI)C ₂₇ H ₄₀ NO ₄ [M+H] ⁺ calcd＝442.2952; found[M+H] ⁺ =442.2958.

A9: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.53 (d, J = 8.6 Hz, 1H), 6.69 (d, J = 10.1 Hz, 1H), 6.59 (d, J = 8.6

Hz,1H),5.61(d,J＝10.1 Hz,1H),5.08(t,J＝6.5 Hz,1H),3.90(t,J＝6.3 Hz,2H),3.68-3.59(m,2H), 3.52-3.43(m,2H),2.59(d,J＝4.7 Hz,5H),2.46(dt,J＝16.4,5.0Hz,4H),2.10(s,5H),2.01(p,J＝6.6Hz ,2H),1.81-1.72(m,1H),1.70-1.62(m,4H),1.56(s,3H),1.41(s,3H). ¹³ C NMR (125 MHz, CDCl ₃ )δ198.20,168.94,158.17,155.49,131.96,131.11,129.42,125.24,123.74,117.23,114.89,112.35,79.28,73.81,54.39,53.23,52.72,46.28, 41.39,30.10,27.23,26.73,25.65,22.63,21.32 ,17.61.HRMS(ESI)C ₂₇ H ₃₉ N ₂ O ₄ [M+H] ⁺ calcd＝455.2904; found[M+H] ⁺ ＝455.2909.

A10: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.55 (d, J = 8.7 Hz, 1H), 6.62 (dd, J = 24.8, 9.4 Hz, 2H), 5.62 (d,

J＝10.1 Hz,1H),5.08(ddt,J＝8.5,7.1,1.4 Hz,1H),3.91(t,J＝6.2 Hz,2H),2.93(t,J＝6.9 Hz,2H),2.78( t,J＝6.1 Hz,2H),2.58(s,3H),2.48(t,J＝6.1 Hz,2H),2.21(s,6H),2.07(tt,J＝13.1,6.5 Hz,4H), 1.81-1.63(m,5H),1.56(d,J＝1.4 Hz,3H),1.41(s,3H). ¹³ C NMR (125 MHz, CDCl ₃ )δ198.17,158.30,155.42,131.92,131.29,129.55,124.85,123.73,117.07,115.00,112.32,79.37,74.42,58.60,47.18,46.91,45.52,41.37,3 0.05,29.92,26.74,25.65,22.62,17.61.HRMS (ESI)C ₂₅ H ₃₉ N ₂ O ₄ [M+H] ⁺ calcd = 415.2955; found [M+H] ⁺ = 415.2951.

A11: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.53 (d, J = 8.6 Hz, 1H), 6.62 (dd, J = 33.3, 9.4 Hz, 2H), 5.62 (d,

J＝10.1 Hz,1H),5.08(ddp,J＝7.3,6.1,1.5 Hz,1H),3.87(t,J＝6.5 Hz,2H),2.57(d,J＝13.0 Hz,5H),2.45- 2.37(m,2H),2.36-2.29(m,2H),2.25(s,9H),2.09(dh,J＝14.2,7.8 Hz,2H),2.03-1.94(m,2H),1.79-1.64( m, 7H), 1.56 (d, J = 1.4 Hz, 3H), 1.41 (s, 3H). ¹³ C NMR (125 MHz, CDCl ₃ )δ198.33,158.16,155.65,131.93,131.05,129.39,125.28,123.77,117.24,114.88,112.31,79.25,74.47,57.78,55.65,54.30,45.37,41.96,4 1.36,30.16,27.89,26.71,25.65,25.40,22.63 ,17.61.HRMS(ESI)C ₂₇ H ₄₃ N ₂ O ₃ [M+H] ⁺ calcd＝443.3268; found[M+H] ⁺ ＝443.3273.

A12: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.54 (d, J = 8.6 Hz, 1H), 6.61 (dd, J = 21.6, 9.4 Hz, 2H), 5.62 (d,

J＝10.1 Hz,1H),5.08(tq,J＝7.2,1.5 Hz,1H),3.90(t,J＝6.3 Hz,2H),2.86(t,J＝6.9 Hz,2H),2.71(t, J＝7.0 Hz,2H),2.58(s,3H),2.55-2.47(m,6H),2.09(dp,J＝12.5,7.0,6.5 Hz,2H),2.02(q,J＝6.6 Hz,2H ), 1.78-1.64 (m, 7H), 1.56 (s, 3H), 1.41 (s, 3H), 1.01 (t, J = 7.1 Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ198.26,158.24,155.51,131.98,131.20,129.53,123.76,117.13,114.96,112.34,79.33,74.52,51.33,48.91,46.85,46.81,41.38,30.03,26 .73,25.66,22.64,17.62,11.63.HRMS(ESI )C ₂₈ H ₄₅ N ₂ O ₃ [M+H] ⁺ calcd＝457.3425; found[M+H] ⁺ ＝457.3427.

A13: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.55 (d, J＝8.6 Hz, 1H), 6.66 (d, J＝10.1 Hz, 1H), 6.59 (d, J＝

8.6 Hz, 1H), 5.62 (d, J = 10.1 Hz, 1H), 5.08 (t, J = 7.1 Hz, 1H), 3.91 (t, J = 6.3 Hz, 2H), 2.86 (t, J = 6.8 Hz ,2H),2.59(s,3H),2.50(s,2H),2.27(s,6H),2.18(s,2H),2.10(tt,J＝12.0,7.4 Hz,2H),2.02(p, J＝6.5Hz,2H),1.82-1.62(m,5H),1.56(s,3H),1.41(s,3H),0.92(s,6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ198.27,158.21,155.64,131.95,131.12,129.45,123.77,117.24,114.93,112.31,79.29,74.55,69.51,59.60,48.74,47.44,41.38,30.11,26 .72,25.65,24.93,22.64,17.61.HRMS(ESI )C ₂₉ H ₄₇ N ₂ O ₃ [M+H] ⁺ calcd＝471.3581; found[M+H] ⁺ ＝471.3580.

A14: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.55 (d, J = 8.6 Hz, 1H), 6.61 (dd, J = 23.8, 9.4 Hz, 2H), 5.62 (d,

J＝10.1 Hz,1H),5.08(t,J＝7.1 Hz,1H),3.90(t,J＝6.3 Hz,2H),3.11(s,1H),2.87(t,J＝6.9 Hz,2H) ,2.72(t,J＝6.9 Hz,2H),2.58(s,3H),2.48(t,J＝7.0 Hz,2H),2.43-2.36(m,4H),2.06(dp,J＝26.6,6.3 Hz,4H),1.80-1.62(m,7H),1.56(s,3H),1.40(q,J＝7.5 Hz,7H),1.29(dq,J＝14.6,7.2 Hz,4H),0.90(t ,J＝7.3 Hz,6H). ¹³ C NMR (125 MHz, CDCl ₃ ) δ198.20,158.27,155.48,131.97,131.25,129.55,125.03,123.75,117.11,114.99,112.34,79.35,74.48,53.79,52.62,4 8.93,46.89,41.39,29.98,29.09, 26.74,25.65,22.64,20.76,17.62,14.11.HRMS(ESI)C ₃₂ H ₅₂ N ₂ O ₃ [M+H] ⁺ calcd＝513.4051; found[M+H] ⁺ ＝513.4055.

A15: ¹ H NMR (500MHz, CDCl ₃ ) δ7.55 (d, J = 8.6 Hz, 1H), 6.69-6.54 (m, 2H), 5.63 (d, J = 10.1 Hz,

1H),5.08(ddq,J＝8.6,5.7,1.4Hz,1H),3.89(t,J＝6.2Hz,2H),2.92(t,J＝6.7Hz,2H),2.80(t,J＝6.9 Hz,2H),2.58(s,3H),2.55-2.43(m,6H),2.08(dp,J＝23.6,7.0,6.5Hz,4H),1.84-1.69(m,7H),1.68-1.60( m, 4H), 1.56 (d, J = 1.4Hz, 3H), 1.41 (s, 3H). ¹³ CNMR (125MHz, CDCl ₃ )δ198.11,158.36,155.33,132.00,131.42,129.71,124.73,123.72,116.98,115.12,112.36,79.47,74.43,54.84,54.21,47.00,41.41,29.71,2 6.79,25.66,23.38,22.63,17.63.HRMS(ESI )C ₂₈ H ₄₃ N ₂ O ₃ [M+H] ⁺ calcd＝455.3268; found[M+H] ⁺ ＝455.3272.

A16: ¹ H NMR (500MHz, CDCl ₃ ) δ7.55 (d, J＝8.6Hz, 1H), 6.62 (dd, J＝18.4, 9.4Hz, 2H), 5.63 (d,

J＝10.1Hz,1H),5.08(t,J＝7.1Hz,1H),3.90(t,J＝6.2Hz,2H),3.36-3.18(m,1H),2.91(t,J＝6.8Hz, 2H),2.78(t,J＝6.8Hz,2H),2.75-2.13(m,16H),2.11-2.01(m,4H),1.82-1.72(m,3H),1.70-1.61(m,4H) ,1.56(s,3H),1.41(s,3H). ¹³ C NMR (125MHz, CDCl ₃ )δ198.16,158.39,155.30,131.99,131.43,129.72,124.72,123.70,117.00,115.10,112.37,79.47,74.42,56.92,55.04,53.20,48.79,47.04,4 5.95,41.40,29.85,26.78,26.21,25.65,22.63 ,17.62.HRMS(ESI)C ₂₉ H ₄₆ N ₃ O ₃ [M+H] ⁺ calcd＝484.3534; found[M+H] ⁺ ＝484.3536.

A17: ¹ H NMR (500MHz, CDCl ₃ ) δ7.51 (d, J＝8.6Hz, 1H), 6.63 (d, J＝10.2Hz, 1H), 6.58 (d, J＝

9.0Hz,1H),5.63(d,J＝10.1Hz,1H),5.12-5.04(m,1H),3.86(t,J＝6.5Hz,2H),2.70-2.63(m,2H),2.57( s,3H),2.54-2.49(m,4H),2.46-2.40(m,4H),2.33(s,12H),2.09(dq,J＝12.7,6.7Hz,2H),2.00-1.93(m, 2H),1.80-1.62(m,9H),1.57(s,3H),1.41(s,3H). ¹³ C NMR (125MHz, CDCl ₃ )δ198.34,158.14,155.52,131.96,131.07,129.54,125.19,123.75,117.16,114.90,112.25,79.31,74.50,57.51,51.62,50.67,44.98,41.36,3 0.09,27.60,26.71,25.65,24.55,22.63,17.62 .HRMS(ESI)C ₃₁ H ₅₂ N ₃ O ₃ [M+H] ⁺ calcd = 514.4003; found [M+H] ⁺ = 514.4007.

Example 2 Synthesis of Compounds B1-B6

2.1 Preparation of compound b2

Compound b1 (1.30 g, 4.54 mmol), ethyl bromoacetate (1.52 g, 9.08 mmol), cesium carbonate (2.22 g, 6.81 mmol), and acetonitrile (20 mL) were added to a round-bottom flask. The reaction mixture was stirred at 65°C for 10 h. After the reaction was completed by TLC, the reaction was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain 1.44 g of a colorless oil with a yield of 85%.

2.2 Preparation of compound b3

Compound b2 (1.20 g, 3.22 mmol) was dissolved in a mixed solution of methanol and water (1:1, 20 mL), and lithium hydroxide (0.68 g, 16.10 mmol) was added and stirred at room temperature overnight. After the reaction was completed by TLC, it was concentrated under reduced pressure to remove excess methanol, diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain 1.02 g of a yellow oil with a yield of 92%.

2.3 Preparation of Compounds B1-B6

Compound b3 (0.20 g, 0.58 mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (0.19 g, 1.45 mmol) were dissolved in acetonitrile (10 mL), stirred in an ice bath for 10 min, and then N,N-diisopropylethylamine (DIEA, 0.24 g, 0.64 mmol) and the corresponding amine compound (2.32 mmol) were added and the mixture was stirred at room temperature for 3 h. After the reaction was completed by TLC, the reaction was cooled to room temperature, concentrated under reduced pressure to remove acetonitrile, extracted with ethyl acetate, washed with dilute hydrochloric acid (2 mol/L), 5% sodium bicarbonate solution, and saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain the target compounds B1-B6. The amine compounds used in the synthesis of B1-B6 are: diethylamine, N,N-dimethylethylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine, aminopropylmorpholine and 1-(3-aminopropyl)-4-methylpiperazine.

The specific synthetic route is:

B1: ¹ H NMR (500MHz, CDCl ₃ ) δ7.52 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 10.2 Hz, 1H), 6.61 (d, J = 8.6

Hz,1H),5.64(d,J＝10.2Hz,1H),5.08(tt,J＝7.1,1.4Hz,1H),4.56(d,J＝1.0Hz,2H),3.44(q,J＝7.1 Hz,2H),3.33(q,J＝7.1Hz,2H),2.58(s,3H),2.08(q,J＝8.6,6.2Hz,2H),1.79-1.62(m,5H),1.56(s ,3H),1.41(s,3H),1.18(dt,J=8.9,7.1Hz,6H). ¹³ C NMR (125MHz, CDCl ₃ )δ198.06,166.49,158.23,154.67,131.93,131.11,129.89,125.00,123.72,117.08,115.17,112.52,79.49,73.13,41.39,40.21,29.88,26.77, 25.66,22.62,17.61,14.36,12.91.HRMS(ESI )C ₂₄ H ₃₄ NO ₄ [M+H] ⁺ calcd = 400.2482; found [M+H] ⁺ = 400.2484.

B2: ¹ H NMR (500MHz, CDCl ₃ ) δ7.81 (t, J＝4.7Hz, 1H), 7.56 (dd, J＝8.7, 6.9Hz, 1H), 6.58 (ddd,

J＝21.3,9.4,5.6Hz,2H),5.66(dd,J＝10.1,3.3Hz,1H),5.12-5.02(m,1H),4.34(d,J＝7.4Hz,2H),3.65(d ,J＝5.3Hz,2H),3.16-3.01(m,2H),2.74(d,J＝11.4Hz,6H),,2.50(d,J＝7.7Hz,3H),2.13-1.99(m,2H ),1.74(ddt,J＝16.2,11.5,6.0Hz,1H),1.70-1.61(m,4H),1.56(d,J＝2.8Hz,3H),1.39(d,J＝5.5Hz,3H) ^.13C NMR (125MHz, CDCl ₃ ) δ198.70,170.42,158.82,153.88,132.42,132.09,130.54,123.59,122.99,116.51,115.36,112.68,79.84,73.43,58.36,44.42 ,41.34,35.49,29.34,26.69,25.65,22.61 ,17.63.HRMS(ESI)C ₂₄ H ₃₅ N ₂ O ₄ [M+H] ⁺ calcd＝415.2591; found[M+H] ⁺ ＝415.2596.

B3: ¹ H NMR (500MHz, CDCl ₃ ) δ8.11 (t, J = 5.8Hz, 1H), 7.61 (d, J = 8.7Hz, 1H), 6.67-6.60 (m,

1H),6.60-6.53(m,1H),5.68(d,J＝10.1Hz,1H),5.08(ddq,J＝8.6,5.9,1.4Hz,1H),4.37(s,2H),3.51(q ,J＝6.2Hz,2H),3.01(t,J＝7.7Hz,2H),2.83(t,J＝8.2Hz,4H),2.54(s,3H),2.08(tp,J＝12.5,7.2, ¹³ CNMR (125MHz, CDCl ₃ )δ197.31,168.90,158.71,153.96,132.31,132.05,130.36,123.54,122.95,116.61,115.14,112.51,79.69,73.75,52.48,50.85,41.26,36.64, 29.31,26.63,25.60,25.58,24.33,22.57,20.23 ,17.59,13.60.HRMS(ESI)C ₃₁ H ₄₉ N ₂ O ₄ [M+H] ⁺ calcd＝513.3687; found[M+H] ⁺ ＝513.4600.

B4: ¹ H NMR (500MHz, CDCl ₃ ) δ8.57 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 6.64 (d, J = 8.6Hz, 1H),

6.54(d,J＝10.1Hz,1H),5.67(d,J＝10.1Hz,1H),5.13-5.03(m,1H),4.35(s,2H),3.50(q,J＝5.9Hz,2H ),2.66(t,J＝6.7Hz,2H),2.54(d,J＝7.5Hz,7H),2.08(tq,J＝14.2,7.8Hz,2H),1.87-1.73(m,3H),1.70 -1.63(m,8H),1.56(s,3H),1.41(s,3H). ¹³ C NMR (125MHz, CDCl ₃ )δ196.82,168.04,158.53,153.89,132.02,131.90,130.33,123.70,123.56,116.51,114.81,112.70,79.56,73.84,54.91,54.10,41.24,38.88, 29.52,27.29,26.59,25.62,23.37,22.57,17.60 .HRMS(ESI)C ₂₈ H ₄₁ N ₂ O ₄ [M+H] ⁺ calcd = 455.2904; found [M+H] ⁺ = 455.2908.

B5: ¹ H NMR (500MHz, CDCl ₃ ) δ8.27 (t, J = 5.5 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 6.65 (d, J = 8.7

Hz,1H),6.54(d,J＝10.1Hz,1H),5.67(d,J＝10.1Hz,1H),5.08(tt,J＝7.1,1.4Hz,1H),4.36(s,2H), 3.67(t,J＝4.7Hz,4H),3.49(q,J＝6.1Hz,2H),2.55(d,J＝16.0Hz,9H),2.07(qq,J＝14.7,8.6,8.1Hz,2H ), 1.84 (p, J = 6.6 Hz, 2H), 1.80-1.62 (m, 5H), 1.54 (s, 3H), 1.42 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ )δ196.83,168.28,158.61,153.81,132.18,130.44,123.55,123.41,116.51,115.02,112.65,79.64,73.84,66.59,57.36,53.67,41.26,38.36,2 9.32,26.63,25.63,25.17,22.59,17.62.HRMS (ESI)C ₂₇ H ₃₉ N ₂ O ₅ [M+H] ⁺ calcd = 471.2853; found [M+H] ⁺ = 471.2852.

B6: ¹ H NMR (500MHz, CDCl ₃ ) δ8.47 (t, J = 5.4Hz, 1H), 7.62 (d, J = 8.7Hz, 1H), 6.65 (d, J = 8.7

Hz,1H),6.54(d,J＝10.1Hz,1H),5.68(d,J＝10.2Hz,1H),5.08(ddt,J＝8.7,7.2,1.4Hz,1H),4.37(s,2H ),3.49(q,J＝6.0Hz,2H),2.54(d,J＝5.1Hz,13H),2.14-2.04(m,5H),1.84-1.63(m,7H),1.56(d,J＝ 1.4Hz, 3H), 1.42 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ )δ196.72,168.15,158.55,153.69,132.03,130.42,123.65,123.50,116.50,114.95,112.66,79.61,73.68,57.07,54.55,52.82,45.44,41.23,3 8.84,29.41,25.60,25.21,22.55,17.58.HRMS (ESI)C ₂₈ H ₄₂ N ₃ O ₄ [M+H] ⁺ calcd = 484.3170; found [M+H] ⁺ = 484.3177.

Example 3 Synthesis of Compounds C1-C13

3.1 Preparation of compound c1

2,4,6-trihydroxyacetophenone (5.00 g, 29.73 mmol), citral dimethyl acetal (23.58 g, 118.93 mmol), and pyridine (30.00 mL) were added to a round-bottom flask. The reaction mixture was stirred at 150°C for 14 h. After the reaction was completed by TLC, the reaction was cooled to room temperature, concentrated under reduced pressure to remove excess pyridine, diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by silica gel chromatography to obtain 7.17 g of a colorless oil with a yield of 50%.

3.2 Preparation of compound c2

The raw materials used are compound c1 and 1,3-dibromopropane, and the specific preparation method is the same as the preparation of compound a2 in Example 1.

3.3 Preparation of Compounds C1-C13

The raw materials used are compound c2 and the corresponding amino compound, and the preparation method is the same as the preparation of compounds A1 to A17 in Example 1.

The amine compounds used in the synthesis of C1-C13 are: dimethylamine, diethylamine, morpholine, thiomorpholine, 2,6-dimethylmorpholine, N,N-dimethylethylamine, N,N-dimethylethylenediamine, N,N-ethyl-1,3-propylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine, aminopropylmorpholine, 1-(3-aminopropyl)-4-methylpiperazine and 3,3'-imidobis(N,N-dimethylpropylamine).

The specific synthetic route is:

C1: ¹ H NMR (500MHz, CDCl ₃ ) δ6.63 (d, J = 10.0Hz, 1H), 6.51 (d, J = 10..0Hz, 1H), 5.55-5.43 (m,

2H),5.17-5.04(m,2H),3.87(tt,J＝6.4,3.1Hz,2H),2.49(d,J＝11.6Hz,5H),2.28(s,6H),2.08(ddt,J ＝16.0,11.7,7.0Hz,4H),1.95-1.87(m,2H),1.79-1.62(m,10H),1.43-1.35(m,6H). ¹³ C NMR (125MHz, CDCl ₃ )δ200.84,152.59,151.65,150.62,131.87,126.74,126.51,123.87,,117.39,117.30,117.28,116.68,108.13,106.05,79.60,79.09,74.48,56. 17,45.26,41.39,41.01,32.71,28.04,25.66, 22.80,22.57,17.61.HRMS(ESI)C ₃₃ H ₄₈ NO ₄ [M+H] ⁺ calcd＝522.3518; found[M+H] ⁺ =522.3582.

C2: ¹ H NMR (500MHz, CDCl ₃ ) δ6.63 (d, J = 10.1Hz, 1H), 6.52 (d, J = 10.0Hz, 1H), 5.51-5.44 (m,

2H),5.08(dt,J＝6.9,3.5Hz,2H),3.86(td,J＝6.3,3.3Hz,2H),2.65-2.56(m,6H),2.50(s,3H),2.09(t ,J＝15.0Hz,4H),1.90(dt,J＝13.8,6.4Hz,2H),1.79-1.63(m,10H),1.57(s,6H),1.42-1.35(m,6H),1.06( t, J=7.2Hz, 6H). ¹³ C NMR (125MHz, CDCl ₃ )δ200.90,152.66,151.60,,150.59,131.86,131.79,126.66,126.48,123.92,123.87,117.36,116.69,108.10,108.09,106.00,105.97,79.57,7 9.10,79.08,74.73,49.44,46.74,41.38,41.07, 41.01,32.71,27.32,26.36,26.33,,26.27,25..66,22.80,22.61,22.58,17.61,11.47.HRMS(ESI)C ₃₅ H ₅₂ NO ₄ [M+H] ⁺ calcd = 550.3891; found [M+H]] ⁺ = 550.3896.

C3: ¹ H NMR (500MHz, CDCl ₃ ) δ6.63 (d, J＝10.1Hz, 1H), 6.56 (d, J＝10.0Hz, 1H), 5.47 (d, J＝

10.1Hz,2H),5.08(t,J＝6.3Hz,2H),3.95-3.83(m,2H),3.72(t,J＝4.5Hz,4H),2.48(d,J＝18.9Hz,9H) ¹³ C NMR (125MHz, CDCl ₃ )δ200.72,152.57,151.59,150.56,131.74,126.62,123.92,117.43,116.66,108.11,105.99,79.57,79.05,74.20,67.00,55.10,53.63,41.37,4 1.00,32.69,26.96,26.36,26.34,26.28,25.66 ,22.78,22.60,22.56,17.60.HRMS(ESI)C ₃₅ H ₅₀ NO ₅ [M+H] ⁺ calcd＝564.3684; found[M+H] ⁺ ＝564.3684.

C4: ¹ H NMR (500 MHz, CDCl ₃ ) δ6.63 (d, J = 10.1 Hz, 1H), 6.54 (d, J = 10.0 Hz, 1H), 5.47 (dd, J =

10.1,2.2 Hz,2H),5.08(t,J＝6.4 Hz,2H),3.92-3.80(m,2H),2.72(d,J＝6.5Hz,4H),2.68(dd,J＝5.7,3.7 Hz,4H),2.51(d,J＝14.4 Hz,5H),2.08(hept,J＝8.1 Hz,4H),1.88(p,J＝6.5 Hz,2H),1.79-1.60(m,10H), 1.57(s,6H),1.42-1.35(m,6H). ¹³ C NMR (126 MHz, CDCl ₃ )δ200.78,152.59,151.62,150.58,131.86,131.81,130.91,126.64,126.52,123.92,123.87,117.43,117.39,116.67,108.10,106.04,106.01,7 9.60,7 9.11,79.08,74.23,55.42,54.96,41.40,41.08,41.03,28.04,26.96,26.40,26.38,26.36,26.30,25.67,22.80,22.61,22.58,17.62,17.60.HRMS (ESI)C ₃₅ H ₅₀ NO ₄ S[M+H] ⁺ calcd＝580.3455; found[M+H] ⁺ ＝580.3455.

C5: ¹ H NMR (500 MHz, CDCl ₃ ) δ6.63 (d, J = 10.1 Hz, 1H), 6.55 (d, J = 10.0 Hz, 1H), 5.51-5.43 (m,

2H),5.08(tdt,J＝7.2,3.1,1.5 Hz,2H),3.91-3.82(m,2H),3.67(dtd,J＝12.4,6.1,2.0 Hz,2H),2.95(s,1H) ,2.88(s,1H),2.78-2.73(m,2H),2.49(d,J＝10.8 Hz,5H),2.09(tq,J＝15.9,9.4,8.6 Hz,4H),1.94-1.86(m ,2H),1.74(ddt,J＝15.8,11.9,5.4 Hz,4H),1.66(d,J＝2.0 Hz, 6H), 1.42-1.36 (m, 6H), 1.17 (d, J = 6.3 Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ200.74,162.47,152.58,151.58,150.55,131.81,126.61,126.49,123.91,123.90,123.86,117.42,116.66,108.10,106.01,79.57,79.05,74. 25,71.67,59.48,54.70,41.37,41.05,41.00,36.44 ,31.39,26.98,26.34,26.27,25.65,22.78,22.59,22.56,19.19,17.59,17.58.HRMS(ESI)C ₃₇ H ₅₄ NO ₅ [M+H] ⁺ calcd＝592.3997; found [M+H] ⁺ ＝592.4001.

C6: ¹ H NMR (500 MHz, CDCl ₃ ) δ6.63 (d, J = 10.1 Hz, 1H), 6.49 (d, J = 10.0 Hz, 1H), 5.55-5.43

(m,2H),5.09(dtt,J＝8.7,5.2,1.7 Hz,2H),3.98-3.81(m,2H),2.91(t,J＝6.7Hz,2H),2.83(t,J＝6.2 Hz,2H),2.51(d,J＝9.7 Hz,5H),2.24(s,6H),2.04(dtd,J＝38.9,12.1,11.1,7.0 Hz,6H),1.82-1.61(m,10H) ,1.57(s,6H),1.4-1.33(m,6H). ¹³ C NMR (125MHz, CDCl ₃ )δ200.70,152.58,151.06,131.94,131.86,126.98,126.53,123.88,123.81,117.11,116.65,108.20,106.15,79.83,79.36,74.36,46.88,46.82 ,45.46,41.46,41.12,32.87,26.45,26.38,25.65 ,22.85,22.58,17.61.HRMS(ESI)C ₃₅ H ₅₂ N ₂ O ₄ [M+H] ⁺ calcd＝565.4000; found[M+H] ⁺ ＝565.4004.

C7: ¹ H NMR (500 MHz, CDCl ₃ ) δ6.63 (d, J = 10.1 Hz, 1H), 6.50 (d, J = 10.0 Hz, 1H), 5.50-5.47 (m,

1H),5.47-5.45(m,1H),5.13-5.05(m,2H),3.94-3.84(m,2H),3.35(s,1H),2.86(t,J＝6.9 Hz,2H),2.79 (t,J＝6.2 Hz,2H),2.50(s,3H),2.48(d,J＝6.2 Hz,2H),2.23(s,6H),2.14-2.01(m,4H),2.00-1.94( m, 2H), 1.80-1.63 (m, 10H), 1.57 (s, 6H), 1.39 (d, J = 5.8Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ200.78,152.57,151.96,150.84,131.88,131.80,126.86,126.50,123.90,117.19,117.08,116.65,108.15,106.10,79.71,79.21,74.46,58.4 7,47.09,46.80,45.50,41.42,41.05,32.78,29.78 ,26.42,25.64,22.81,22.56,17.60.HRMS(ESI)C ₃₅ H ₅₃ N ₂ O ₄ [M+H] ⁺ calcd＝565.4000; found[M+H] ⁺ =565.3995.

C8: ¹ H NMR (500 MHz, CDCl ₃ ) δ6.63 (d, J = 10.1 Hz, 1H), 6.49 (d, J = 10.0 Hz, 1H), 5.51-5.44 (m,

2H),5.08(tt,J＝9.1,7.4,3.3 Hz,2H),3.88(q,J＝5.7 Hz,2H),2.80(t,J＝6.9Hz,2H),2.71(t,J＝6.9 Hz,2H),2.58-2.43(m,9H),2.07(tq,J＝14.8,8.2,7.3 Hz,4H),1.95(h,J＝6.6 Hz,2H),1.81-1.63(m,12H) ,1.39(d,J＝6.7 Hz,6H),1.02(t,J＝7.2 Hz,6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ200.80,152.53,151.77,150.71,131.85,126.79,126.48,123.90,117.25,116.65,108.11,106.06,79.65,79.14,74.49,51.30,48.81,46.70, 41.40,41.02,32.73,30.00,26.69,26.39,26.34 ,26.27,25.64,22.80,22.59,22.55,17.59,11.53.HRMS(ESI)C ₃₈ H ₅₉ N ₂ O ₄ [M+H] ⁺ calcd=607.4469; found[M+H] ⁺ =607.4476.

C9: ¹ H NMR (500 MHz, CDCl ₃ ) δ6.63 (d, J = 10.1 Hz, 1H), 6.50 (d, J = 10.0 Hz, 1H), 5.50-5.45 (m,

2H),5.08(t,J＝6.2 Hz,2H),3.88(q,J＝5.8 Hz,2H),2.79(t,J＝6.9 Hz,2H),2.68(t,J＝7.0 Hz,2H) ,2.49(d,J＝8.4 Hz,5H),2.43-2.37(m,4H),2.16-2.00(m,4H),1.93(p,J＝6.5 Hz,2H),1.81-1.64(m,12H ), 1.57 (s, 6H), 1.40 (dd, J = 15.4, 7.8 Hz, 10H), 1.32-1.25 (m, 4H), 0.90 (t, J = 7.3 Hz, 6H). ¹³ C NMR (125 MHz ,CDCl ₃ )δ200.80,152.55,151.70,150.67,131.77,126.75,126.47,123.90,123.89,123.84,117.32,117.24,117.22,116.66,108.11,106.04,106.01,7 9.61,79.11,74.5 9,53.78,52.54,48.85,46.79,41.39,41.06,41.01,32.71,30.19,29.09,27.04,26.38,26.33,26.27,25.65,22.80,22.59,22.56,20.75,17.59 ,14.11.HRMS(ESI)C ₄₂ H ₆₇ N2O ₄ [M+H] ⁺ calcd＝663.5095; found [M+H] ⁺ ＝663.5090.

C10: ¹ H NMR (500 MHz, CDCl ₃ ) δ6.64 (d, J = 10.1 Hz, 1H), 6.47 (d, J = 10.1 Hz, 1H), 5.55-5.45

(m,2H),5.09(tdt,J＝7.1,3.4,1.6 Hz,2H),3.87(tt,J＝9.3,4.7 Hz,2H),2.97(q,J＝6.2 Hz,4H),2.66( t,J＝6.7 Hz,2H),2.61-2.54(m,4H),2.51(s,3H),2.08(pd,J＝11.9,9.3,5.1 Hz,6H),1.92(p,J＝6.7 Hz ,2H),1.83-1.62(m,14H),1.56(s,6H),1.39(dd,J=4.2,2.5 Hz,6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ200.36,153.05,152.28,151.60,132.02,131.89,127.51,126.63,123.65,116.70,116.54,115.95,108.33,106.36,80.14,79.67,73.70,54.9 7,53.95,49.10,46.69,41.48,41.15,33.13,27.11 ,26.54,26.46,25.63,24.50,23.32,22.88,22.57,22.53,17.59.HRMS(ESI)C ₃₈ H ₅₇ N ₂ O ₄ [M+H] ⁺ calcd＝605.4313; found[M+H] ⁺ ＝605.4316.

C11: ¹ H NMR (500 MHz, CDCl ₃ ) δ6.63 (d, J = 10.1 Hz, 1H), 6.49 (d, J = 10.0 Hz, 1H), 5.51-5.44

(m,2H),5.08(dt,J＝7.0,3.6 Hz,2H),3.88(tt,J＝9.1,4.7 Hz,2H),3.67(t,J＝4.6 Hz,4H),2.82(dt, J＝24.1,6.8 Hz,4H),2.50(s,3H),2.44(t,J＝7.0 Hz,6H),2.16-2.03(m,4H),1.99(dt,J＝11.4,5.7 Hz,2H ), 1.83-1.62 (m, 12H), 1.57 (s, 6H), 1.39 (d, J = 7.1 Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ200.79,152.45,152.15,151.02,131.96,131.87,127.08,126.56,123.87,123.78,117.05,117.05,117.03,116.63,108.19,106.21,106.17,7 9.83,7 9.36,79.34,74.39,66.95,57.39,53.75,48.72,46.88,41.45,41.13,41.08,32.86,26.45,26.41,26.34,25.65,22.84,22.61,22.57,17.61.HRMS (ESI)C ₃₈ H ₅₆ N ₂ O ₄ [M+H] ⁺ calcd＝621.4262; found[M+H] ⁺ ＝621.4267.

C12: ¹ H NMR (500MHz, CDCl ₃ ) δ6.64 (d, J = 10.1Hz, 1H), 6.49 (d, J = 10.1Hz, 1H), 5.57-5.43

(m,2H),5.08(dddt,J＝7.5,5.9,3.8,1.8Hz,2H),3.89(dtd,J＝7.9,6.0,5.3,2.6Hz,2H),2.90(dt,J＝11.0, 6.6Hz,4H),2.51(s,3H),2.47(t,J＝6.8Hz,3H),2.23(s,3H),2.07(qd,J＝11.8,10.6,4.8Hz,6H),1.85( p, J＝6.8Hz, 2H), 1.80-1.62 (m, 10H), 1.57 (s, 6H), 1.43-1.35 (m, 6H). ¹³ C NMR (126MHz, CDCl ₃ )δ200.72,152.41,151.10,131.95,131.85,127.10,126.56,123.80,123.73,117.03,116.73,116.59,108.18,106.18,79.87,79.39,79.36,74.2 4,56.96,54.97,53.11,48.90,46.80,45.88,41.43 ,41.12,41.07,32.89,28.90,26.44,26.42,25.64,25.25,22.83,22.55,17.59,17.58.HRMS(ESI)C ₃₈ H ₅₈ N ₃ O ₄ [M+H] ⁺ calcd = 620.4422; found [M+H] ⁺ = 634.4594.

C13: ¹ H NMR (500MHz, CDCl ₃ ) δ6.63 (d, J = 10.1Hz, 1H), 6.48 (d, J = 9.9Hz, 1H), 5.53-5.44 (m,

2H),5.08(dtdq,J＝7.4,6.0,2.9,1.3Hz,2H),3.85(td,J＝6.4,1.6Hz,2H),2.63(dt,J＝21.7,7.7Hz,6H),2.54 (t,J＝7.0Hz,4H),2.49(s,15H),2.16-2.00(m,4H),1.89-1.78(m,6H),1.77-1.60(m,10H),1.57(d,J =2.8Hz, 6H), 1.42-1.35 (m, 6H). ¹³ C NMR (125MHz, CDCl ₃ )δ201.02,152.57,151.68,150.69,131.92,131.84,126.94,126.49,123.90,123.81,117.15,117.11,116.65,108.00,106.00,105.97,79.71,79 .22,74.25,57.07,51.37,50.45,44.36,41.42,41.11 ,41.06,32.81,27.33,,26.39,26..37,25.64,23.77,22.81,22.61,22.57,17.60.HRMS(ESI)C ₄₁ H ₆₆ N ₃ O ₄ [M+H] ⁺ calcd＝664.5048; found[M+H] ⁺ ＝664.5051.

Example 4 Synthesis of Compounds D1-D7

4.1 Preparation of compound d2

The raw materials used are compound d1 and ethyl bromoacetate, and the preparation method is the same as the preparation of compound b2 in Example 2.

4.2 Preparation of compound d3

The raw materials used are compound d3 and lithium hydroxide, and the preparation method is the same as the preparation of compound b3 in Example 2.

4.3 Preparation of Compounds D1-D7

The raw materials used are compound d3 and the corresponding amino compound, and the preparation method is the same as the preparation of compounds B1-B6 in Example 2.

The amine compounds used in the synthesis of D1-D7 are: N,N-dimethylethylamine, N,N-dimethylethylenediamine, trimethyl-1,3-propylenediamine, N,N-ethyl-1,3-propylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine and 1-(3-aminopropyl)-4-methylpiperazine.

The specific synthetic route is:

D1: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.48 (t, J＝5.8 Hz, 1H), 6.63 (d, J＝10.1 Hz, 1H), 6.44 (d, J＝

10.1 Hz,1H),5.57-5.48(m,2H),5.13-5.04(m,2H),4.37(s,2H),3.62(dtt,J＝15.0,9.3,4.5 Hz,2H),3.10-3.03 (m,2H),2.73(d,J＝1.5 Hz,6H),2.53(s,3H),2.08(dt,J＝15.9,7.4 Hz,4H),1.83-1.63(m,10H),1.39( d, J＝8.7 Hz, 6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ201.78,170.26,153.12,151.68,132.05,127.81,126.79,123.65,116.61,115.71,108.04,106.60,80.34,79.65,74.00,58.27,44.46,41.53, 41.09,35.57,32.98,26.57,26.38,26.28,25.64 ,22.92,22.60,22.54,17.62.HRMS(ESI)C ₃₄ H ₄₉ N ₂ O ₅ [M+H] ⁺ calcd＝565.3636; found[M+H] ⁺ =565.3639.

D2: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.39 (d, J = 5.6 Hz, 1H), 6.64 (d, J = 10.1 Hz, 1H), 6.43 (d, J =

10.0 Hz,1H),5.54-5.47(m,2H),5.08(dddt,J＝6.0,4.6,3.3,1.9 Hz,2H),4.37(d,J＝4.8 Hz,2H),3.47(q,J ＝6.1 Hz,2H),2.55(t,J＝6.3 Hz,2H),2.52(s,3H),2.32(s,6H),2.10(dq,J＝22.4,8.8,8.0 Hz,4H),1.83 -1.65(m,10H),1.57(q,J＝1.9 Hz,6H),1.43-1.37(m,6H). ¹³ C NMR(125 MHz, CDCl ₃ )δ200.33,168.41,152.58,151.59,151.24,131.95,127.54,126.77,123.78,123.69,116.84,116.81,116.52,116.42,107.71,106.48,80.11,79 .42,74.37,57.84,45.19,41.53,41.03,40.95,36.49 ,32.77,26.55,26.29,26.20,25.64,22.87,22.61,22.56,17.61.HRMS(ESI)C ₃₄ H ₄₉ N ₂ O ₅ [M+H] ⁺ calcd＝565.3636; found[M+H] ⁺ ＝565.3638.

D3: ¹ H NMR (500 MHz, CDCl ₃ ) δ6.63 (d, J = 11.3 Hz, 1H), 6.51-6.44 (m, 1H), 5.58 (dd, J = 10.1,

3.8 Hz, 1H), 5.51 (d, J = 9.8 Hz, 1H), 5.08 (s, 2H), 4.54 (t, J = 5.4 Hz, 2H), 3.50 (hept, J = 7.2 Hz, 2H), 3.07 (t,J＝7.0 Hz,2H),2.93(s,3H),2.79(s,6H),2.49(s,3H),2.04(dd,J＝16.2,8.9 Hz,6H),1.79(tt, J＝11.0,5.7 Hz,2H),1.67(d,J＝7.1 Hz,8H),1.57(s,6H),1.43-1.35(m,6H). ¹³ C NMR (125 MHz, CDCl ₃ )δ200.54,169.93,152.95,151.54,151.24,132.06,131.89,128.42,126.95,123.80,123.65,116.45,116.03,108.46,106.99,80.32,79.85,72. 74,55.26,45.13,43.53,41.56,41.18,38.60,34.30 ,26.61,26.48,26.40,25.65,22.92,22.62,22.56,22.51,17.61.HRMS(ESI)C ₃₆ H ₅₃ N ₂ O ₅ [M+H] ⁺ calcd＝593.3949; found [M+H] ⁺ ＝593.3954.

D4: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.67 (t, J＝6.4 Hz, 1H), 6.64 (d, J＝10.1 Hz, 1H), 6.43 (d, J＝

10.1 Hz,1H),5.57(dd,J＝10.1,2.5 Hz,1H),5.52(d,J＝10.1 Hz,1H),5.13-5.04(m,2H),4.40(s,2H),3.49( q,J＝6.5 Hz,2H),3.34-3.21(m,6H),2.52(s,3H),2.16-2.01(m,6H),1.86-1.63(m,10H),1.57(d,J＝ 4.5 Hz, 6H), 1.45-1.33 (m, 12H). ¹³ C NMR (125MHz, CDCl ₃ )δ201.01,171.27,153.01,151.43,131.88,127.93,126.85,123.66,116.51,115.77,107.97,106.64,80.31,79.63,73.72,49.60,47.22,41.51, 41.04,40.96,38.58,35.48,32.86,26.56,26.33 ,26.23,25.63,24.40,22.90,22.58,22.52,17.60,8.69.HRMS(ESI)C ₃₇ H ₅₅ N ₂ O ₅ [M+H] ⁺ calcd＝607.4105; found[M+H] ⁺ ＝607.4100.

D5: ¹ H NMR (500 MHz, CDCl ₃ ) δ7.76-7.70 (m, 1H), 6.64 (d, J = 10.1 Hz, 1H), 6.40 (d, J = 10.0 Hz,

1H),5.55-5.49(m,2H),5.08(ddddq,J＝8.6,5.6,4.2,2.8,1.4Hz,2H),4.42-4.33(m,2H),3.45(q,J＝6.2Hz, 2H),2.83(t,J＝6.9Hz,2H),2.68(t,J＝7.9Hz,4H),2.52( s,3H),2.09(pt,J＝14.8,7.0Hz,4H),1.90(p,J＝6.8Hz,2H),1.82-1.65(m,10H),1.60-1.51(m,10H),1.44 -1.38(m,6H),1.33(q,J＝7.4Hz,4H),0.91(t,J＝7.4Hz,6H). ¹³ C NMR (125MHz, CDCl ₃ ) δ200.25,152.90,151.65,151.45,132.06,127.63,126.76,123.67,116.77,116.50,116.06,107.70,106.53,80.23,79.49, 74.29,53.31,51.84,41.55,40.98,37.33 ,32.88,27.49,26.58,25.64,22.90,22.61,20.43,17.61,13.85.HRMS(ESI)C ₄₁ H ₆₃ N ₂ O ₅ [M+H] ⁺ calcd=663.4731; found[M+H] ⁺ =663.4724.

D6: ¹ H NMR (500MHz, CDCl ₃ ) δ7.83 (t, J＝5.5Hz, 1H), 6.64 (d, J＝10.1Hz, 1H), 6.41 (d, J＝

10.0Hz,1H),5.59-5.47(m,2H),5.14-5.05(m,2H),4.38(s,2H),3.48(q,J＝6.1Hz,2H),3.14-3.03(m,6H ),2.52(s,3H),2.17-2.03(m,4H),1.98(dt,J＝6.9,3.2Hz,6H),1.83-1.65(m,10H),1.56(s,6H),1.40( d, J＝8.9Hz, 6H). ¹³ C NMR (126MHz, CDCl ₃ )δ200.68,170.16,153.05,151.54,132.08,127.78,126.81,123.65,116.65,116.47,115.83,107.81,106.59,80.31,79.58,74.02,54.13,53.28 ,41.56,41.07,41.00,36.62,32.93,26.60,26.55 ,26.35,26.26,25.64,23.24,22.90,22.61,22.55,17.62.HRMS(ESI)C ₃₇ H ₅₃ N ₂ O ₅ [M+H] ⁺ calcd=605.3949; found[M+H] ⁺ =605.3950.

D7: ¹ H NMR (500MHz, CDCl ₃ ) δ7.84 (t, J＝5.5Hz, 1H), 6.56 (d, J＝10.1Hz, 1H), 6.33 (d, J＝

10.1Hz,1H),5.50(dd,J＝10.1,2.3Hz,1H),5.45(d,J＝10.1Hz,1H),5.07-4.95(m,2H),4.29-4.21(m,2H), 3.36(q,J＝5.9Hz,2H),3.03(s,4H),2.85(s,4H),2.68(t,J＝6.3Hz,2H),2.51(s,3H),2.44(s,3H ¹³ CNMR (125MHz, CDCl ₃ )δ200.48,175.45,169.10,152.92,151.45,151.12,148.22,131.97,128.08,126.99,123.68,116.37,115.89,107.76,106.68,80.35,79.68,73. 93 ,55.40,53.48,50.50,43.91,41.49,41.03,40.98,37.64,32.88,26.53,26.34,26.24,25.64,24.77,22.88,22.56,22.51,21.65,17.61.HRMS(ESI)C ₃₈ H ₅₆ N ₃ O ₅ [M+H] ⁺ calcd＝634.4214; found[M+H] ⁺ ＝634.4219.

Experimental Example 1

In vitro antimicrobial activity test

Microbroth dilution method: Add fresh nutrient broth medium into a 96-well plate, add a certain amount of sterile water or DMSO solution (2560μg/mL, m/V) of the test compound and control drug to the No. 1 well of each row A-H of the 96-well plate in turn and dilute by two-fold dilution, then inoculate an appropriate amount of bacterial solution with a certain turbidity, incubate at 37℃ for 24h, observe the bacterial growth in each well, and read the minimum inhibitory concentration (MIC) of the drug. Observe with the naked eye that there is no bacterial growth in the tube with the lowest drug concentration, which is the MIC of the test strain.

The experimental results are shown in Tables 1 and 2.

Table 1 Antibacterial activity of benzopyran antimicrobial peptide mimetics against Gram-positive bacteria

COMP=compounds,VAM=vancomycin,COS=colistin

Table 2 Antibacterial activity of benzopyran antimicrobial peptide mimetics against Gram-negative bacteria

COMP=compounds,VAM=vancomycin,COS=colistin

Tables 1 and 2 show the MIC values of the corresponding compounds against 10 common clinical bacteria (4 Gram-negative bacteria and 6 Gram-positive bacteria). In general, the target compounds have broad-spectrum antibacterial activity, but according to the MIC data, it is found that the antibacterial activity of these compounds against Gram-positive bacteria is better than that against Gram-negative bacteria. Compounds A14, C1, C2, C6-C13, D1-D5 all show broad-spectrum bactericidal activity, and the MIC values against Gram-positive bacteria can reach 1-8 μg/mL. At the same time, they also showed good activity against Gram-negative bacteria. The minimum inhibitory activity of compound A14 against Escherichia coli ATCC25922, Klebsiella pneumoniae ATCC10031 and Acinetobacter baumannii ATCC19606 was 4 μg/mL, and the minimum inhibitory activity of compound C12 against Escherichia coli ATCC25922 and Acinetobacter baumannii ATCC19606 could reach 2 μg/mL. All compounds showed poor or moderate antibacterial activity against Pseudomonas aeruginosa ATCC27853.

Experimental Example 2

Bactericidal kinetics test

Staphylococcus aureus and Escherichia coli were cultured overnight, diluted to a certain multiple, and a certain amount of bacterial solution was taken and cultured in a shaking table.

Allow the bacteria to grow to the logarithmic phase, and add different concentrations of the test compound or control drug. At 0h, 1h, 3h, 5h, 7h, and 9h after drug addition, take 100μL from each group with different compounds and concentrations to a 96-well plate, centrifuge for 3min, discard the supernatant, resuspend the bacteria in 100μL of 1×PBS, and dilute tenfold, take 10μL and drop it on the MHA agar plate, three parallels for each concentration, and incubate the agar plate in an incubator for 24h. Calculate the number of colonies according to the dilution multiple.

Compounds A14 and C12 with good preliminary antibacterial activity were selected as research objects to study their bactericidal effects on Staphylococcus aureus and Escherichia coli at different concentrations over time, as shown in Figure 1. The results showed that compounds A14 and C12 had rapid bactericidal effects, and when the compound concentration was 8 μg/mL, all Staphylococcus aureus could be killed within 6 hours.

Experimental Example 3

Resistance induction test

First, the MIC values of the compound and the positive control drug (norfloxacin) against Staphylococcus aureus and Escherichia coli were determined. The compound and the control drug were added to the agar solution to a final concentration of 1/2 MIC. Staphylococcus aureus and Escherichia coli were then cultured on agar plates containing different drugs, and the surviving bacteria were inoculated into the next new plate for several days, and then the MIC values of the compound and the positive drug against the bacteria on the agar plate were determined.

Compounds A14 and C12 were also selected to study their evaluation of inducing drug resistance in Staphylococcus aureus and Escherichia coli. The results showed that compounds A14 and C12 performed well in inhibiting bacterial drug resistance. The MIC of the two compounds against Staphylococcus aureus and Escherichia coli remained basically stable when the drug MIC/2 concentration was induced for 20 generations, while the MIC of the control drug norfloxacin against bacteria increased by 256 times, as shown in Figure 2, indicating that compounds A14 and C12 have the characteristics of antimicrobial peptides that are not easy to produce bacterial resistance.

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

Claims (10)

1. A benzopyran antimicrobial peptide mimetic or a pharmaceutically acceptable salt thereof having broad-spectrum antimicrobial activity, wherein the structural formula of the benzopyran antimicrobial peptide mimetic is as shown in formula (I): Wherein, X is selected from -CH ₂ - or -CO-, n is an integer of 1 to 2, and R is an amino derivative. 2. The benzopyran antimicrobial peptide mimetic with broad-spectrum antimicrobial activity or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structure of the benzopyran antimicrobial peptide mimetic is as shown in formula (II): Wherein, ^R1 is selected from methylamino, ethylamino, dimethylamino, diethylamino, pyridyl, morpholinyl, thiomorpholinyl, 2,6-dimethylmorpholinyl, 1-acetylpiperazinyl, N,N-dimethylethylenediamino, trimethyl-1,3-propylenediamino, N,N-ethyl-1,3-propylenediamino, N,N,2,2-tetramethyl-1,3-propylenediamino, 3-(dibutylamino)propylamino, 1-(3-aminopropyl)pyrrolidinyl, 1-(3-aminopropyl)-4-methylpiperazinyl, 3,3'-iminobis(N,N-dimethylpropylamino) group. 3. The benzopyran antimicrobial peptide mimetic with broad-spectrum antimicrobial activity or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structure of the benzopyran antimicrobial peptide mimetic is as shown in formula (III): Wherein, ^R2 is selected from diethylamino, N,N-dimethylethylenediamino, 3-(dibutylamino)propylamino, 1-(3-aminopropyl)pyrrolidinyl, aminopropylmorpholinyl, 1-(3-aminopropyl)-4-methylpiperazinyl. 4. The benzopyran antimicrobial peptide mimetic with broad-spectrum antimicrobial activity or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structure of the benzopyran antimicrobial peptide mimetic is as shown in formula (IV): Wherein, ^R3 is selected from dimethylamino, diethylamino, morpholinyl, thiomorpholinyl, 2,6-dimethylmorpholinyl, N,N-dimethylethylamino, N,N-dimethylethylenediamino, N,N-ethyl-1,3-propylenediamino, 3-(dibutylamino)propylamino, 1-(3-aminopropyl)pyrrolidinyl, aminopropylmorpholinyl, 1-(3-aminopropyl)-4-methylpiperazinyl, 3,3'-iminobis(N,N-dimethylpropylamino) group. 5. The benzopyran antimicrobial peptide mimetic with broad-spectrum antimicrobial activity or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structure of the benzopyran antimicrobial peptide mimetic is as shown in formula (V): Wherein, R ⁴ is selected from N,N-dimethylethylamino, N,N-dimethylethylenediamino, trimethyl-1,3-propylenediamino, N,N-ethyl-1,3-propylenediamino, 3-(dibutylamino)propylamino, 1-(3-aminopropyl)pyrrolidinyl, 1-(3-aminopropyl)-4-methylpiperazinyl. 6. The benzopyran antimicrobial peptide mimetic with broad-spectrum antimicrobial activity or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, characterized in that the compound of formula (II) is selected from any of the following structures: The compound of formula (III) is selected from any of the following structures: The compound of formula (IV) is selected from any of the following structures: The compound of formula (V) is selected from any of the following structures: 7. The method for preparing the benzopyran antimicrobial peptide mimetic with broad-spectrum antimicrobial activity according to any one of claims 1 to 6, characterized in that the method for preparing the compound of formula (II) comprises: 2,4-dihydroxyacetophenone and citral dimethyl acetal undergo cyclization reaction to generate compound a1, and then compound a1 undergoes bromination reaction with 1,3-dibromopropane to obtain compound a2; finally, compound a2 undergoes substitution reaction with different amine compounds to obtain corresponding target compounds A1-A17; The specific synthetic route is: The preparation method of the compound of formula (III) comprises: Compound b1 undergoes a substitution reaction with ethyl bromoacetate to generate compound b2; compound b2 is then hydrolyzed under alkaline conditions to obtain compound b3; and compound b3 is finally subjected to an amide condensation reaction with different amine compounds to obtain the corresponding target compounds B1-B6; The specific synthetic route is: The preparation method of the compound of formula (IV) comprises: 2,4,6-trihydroxyacetophenone and citral dimethyl acetal undergo cyclization reaction to generate compound c1; compound c1 then undergoes bromination reaction with 1,3-dibromopropane to obtain compound c2; finally, compound c2 undergoes substitution reaction with different amine compounds to obtain corresponding target compounds C1-C13; The specific synthetic route is: The preparation method of the compound of formula (V) comprises: Compound d1 undergoes a substitution reaction with ethyl bromoacetate to generate compound d2; compound d2 is hydrolyzed to obtain compound d3; compound d3 is subjected to an amide condensation reaction with different amine compounds to obtain target compounds D1-D7; The specific synthetic route is: 8. The preparation method according to claim 7, characterized in that the amine compounds used in the synthesis of A1 to A17 are respectively: methylamine, ethylamine, dimethylamine, diethylamine, pyridine, morpholine, thiomorpholine, 2,6-dimethylmorpholine, 1-acetylpiperazine, N,N-dimethylethylenediamine, trimethyl-1,3-propylenediamine, N,N-ethyl-1,3-propylenediamine, N,N,2,2-tetramethyl-1,3-propylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine, 1-(3-aminopropyl)-4-methylpiperazine and 3,3'-iminobis(N,N-dimethylpropylamine); Alternatively, the amine compounds used in the synthesis of B1-B6 are: diethylamine, N,N-dimethylethylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine, aminopropylmorpholine and 1-(3-aminopropyl)-4-methylpiperazine. 9. The preparation method as claimed in claim 7, characterized in that the amine compounds used in the synthesis of C1-C13 are: dimethylamine, diethylamine, morpholine, thiomorpholine, 2,6-dimethylmorpholine, N,N-dimethylethylamine, N,N-dimethylethylenediamine, N,N-ethyl-1,3-propylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine, aminopropylmorpholine, 1-(3-aminopropyl)-4-methylpiperazine and 3,3'-iminobis(N,N-dimethylpropylamine); Alternatively, the amine compounds used in the synthesis of D1-D7 are: N,N-dimethylethylamine, N,N-dimethylethylenediamine, trimethyl-1,3-propylenediamine, N,N-ethyl-1,3-propylenediamine, 3-(dibutylamino)propylamine, 1-(3-aminopropyl)pyrrolidine and 1-(3-aminopropyl)-4-methylpiperazine. 10. Use of the benzopyran antimicrobial peptide mimics with broad-spectrum antimicrobial activity or pharmaceutically acceptable salts thereof according to any one of claims 1 to 6 and/or the benzopyran antimicrobial peptide mimics with broad-spectrum antimicrobial activity prepared by the method for preparing the benzopyran antimicrobial peptide mimics with broad-spectrum antimicrobial activity according to any one of claims 7 to 9 in the preparation of drugs for treating bacterial infections.