A BODIPY compound, preparation method and application thereof

Abstract

The purpose of the present invention is to provide a BODIPY compound, a preparation method and an application thereof, and the BODIPY compound of the present application is applied to photodynamic antibacterial therapy, which has non-invasiveness, broad-spectrum antibacterial activity and low drug resistance. At the same time, the biofilm can also be eliminated by degrading the excretion products of the biofilm.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a BODIPY compound, a preparation method and application thereof. Background Art

[0002] Bacterial infection is one of the most serious health problems, causing millions of people to become ill every year, which poses a serious threat to global public health. Antibiotics play a pivotal role in bacterial infections with their excellent therapeutic effects, but the problems caused by their irrational use are gradually emerging. For example, the emergence of super bacteria has brought a more severe problem to the public health systems of various countries. Photodynamic therapy (PDT) has become an emerging antibacterial treatment method due to its high selectivity, non-invasiveness and almost no bacterial resistance.

[0003] Fluoroboron dipyrrole (BODIPY) fluorescent dyes have excellent photophysical and chemical properties and are a class of functional organic fluorescent dyes that are increasingly gaining widespread attention. Photodynamic antimicrobial therapy (PDAT) is an emerging treatment for bacterial infections. Its mechanism of action is to use the reactive oxygen species (ROS) produced by photosensitizer molecules under the irradiation of an excitation source to efficiently kill pathogenic microorganisms. Photodynamic antimicrobial therapy has been valued by researchers for its many advantages, including non-invasiveness and broad-spectrum antibacterial properties. At the same time, photodynamic antimicrobial therapy has also shown a strong ability to eliminate biofilms by degrading the excretion products of biofilms. More importantly, PDAT therapy has developed into an antibacterial tool. Because it does not require a specific target, pathogenic bacteria basically do not develop resistance to photosensitizers. As a new diagnostic and treatment method, PDAT therapy has played a sufficiently large potential in the treatment of bacterial infections. Summary of the invention

[0004] The object of the present invention is to provide a BODIPY compound, which can generate active oxygen to efficiently kill pathogenic microorganisms, and can be used as a photodynamic antibacterial therapy photosensitizer to achieve photodynamic antibacterial therapy; the above-mentioned BODIPY compound can be obtained by the preparation method of the BODIPY compound of the present application.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A BODIPY compound, the structural formula of which is shown in formula (VII):

[0007]

[0008] Wherein R1, R2, and R3 are each independently hydrogen or (C1-C3) alkyl; X includes I and Br; and n includes 4, 4, and 112.

[0009] Furthermore, in formula (VII), R1, R2, and R3 are each independently (C1-C3) alkyl.

[0010] Furthermore, in formula (VII), R1 is methyl, R2 is ethyl, R3 is methyl, X is Br, and n is 44.

[0011] The preparation method of BODIPY compounds comprises the following steps:

[0012] Preparation of the compound represented by formula (III): reacting the compound represented by formula (II) with copper chloride to obtain the compound represented by formula (III);

[0013] Preparation of the compound represented by formula (IV): reacting the compound represented by formula (III) with a pyrrole ring-containing compound to obtain the compound represented by formula (IV), wherein the pyrrole ring-containing compound includes: pyrrole, 2,4-dimethylpyrrole, and 2,4-dimethyl-3-ethylpyrrole;

[0014] Preparation of the compound represented by formula (V): Modifying the compound represented by formula (IV) by heavy atom to obtain the compound represented by formula (V), wherein the heavy atom comprises I and Br;

[0015] Preparation of the compound represented by formula (VI): reacting the compound represented by formula (V) with NBS in an alkaline environment to obtain the compound represented by formula (VI);

[0016] Preparation of the compound represented by formula (VII): reacting the compound represented by formula (VI) with carboxyl PEG to obtain the compound represented by formula (VII);

[0017] In formula (IV) to formula (VII), R1 is a hydrogen group or a (C1-C3) alkyl group; R2 is a hydrogen group or a (C1-C3) alkyl group; R3 is a hydrogen group or a (C1-C3) alkyl group; in formula (VII), X includes I and Br;

[0018] Preferably, the method for preparing the compound represented by formula (II) comprises:

[0019] Pentafluorobenzaldehyde reacts with pyrrole under acidic conditions to obtain a compound represented by formula (I);

[0020] In a dichloromethane and alkaline environment, the compound represented by formula (I) is contacted with DDQ and boron trifluoride ether to obtain a compound represented by formula (II);

[0021] Preferably, water, pyrrole and hydrochloric acid are added, and pentafluorobenzaldehyde is added after being fully stirred at room temperature, and reacted at room temperature to obtain a compound represented by formula (I); and\or,

[0022] The compound represented by formula (I) is dissolved in dichloromethane, DDQ is added for oxidation for 30 minutes, triethylamine and boron trifluoride ether are added, and the reaction is carried out at room temperature for 5 hours to obtain the compound represented by formula (II);

[0023] Preferably, the volume ratio of pyrrole, hydrochloric acid and pentafluorobenzaldehyde is (1-4):1:1;

[0024] Preferably, the molar ratio of triethylamine to boron trifluoride ether is (1-3):5.

[0025]

[0026] Preparation of the compound represented by formula (III):

[0027] The compound represented by formula (II) is mixed with copper chloride dihydrate and potassium persulfate, and acetonitrile is added to dissolve and react;

[0028] Preferably, the molar ratio of the compound represented by formula (II) to cupric chloride dihydrate is 1:8, and the molar ratio of the compound represented by formula (II) to potassium persulfate is 1:4.

[0029] Preparation of the compound represented by formula (IV):

[0030] Under inert gas protection conditions, the compound represented by formula (III) and the pyrrole ring compound are dissolved in toluene for reaction;

[0031] Preferably, the molar ratio of the compound represented by formula (III) to the pyrrole ring compound is 11:10.

[0032] Preparation of the compound represented by formula (V):

[0033] Under inert gas protection, the compound of formula (IV) is mixed with 4-hydroxymethylphenylboronic acid, tetrakis(triphenylphosphine)palladium and sodium bicarbonate, and toluene, ethanol and water are added to react;

[0034] The molar ratio of the compound of formula (IV) to 4-hydroxymethylbenzeneboronic acid is 1:3, the molar ratio of the compound of formula (IV) to sodium bicarbonate is 1:4, the molar ratio of the compound of formula (IV) to tetrakis(triphenylphosphine)palladium is 10:1, and the volume ratio of the solvent toluene:water:ethanol is (2-5):1:1.

[0035] Preparation of the compound represented by formula (VI):

[0036] The compound represented by formula (V) is dissolved in DCM, and then NBS solution is added dropwise to react at room temperature to obtain the compound represented by formula (VI), wherein the solvent of the NBS solution is DCM;

[0037] Preferably, the molar ratio of the compound represented by formula (V) to NBS is 5:12.

[0038] Preparation of the compound represented by formula (VII):

[0039] The compound represented by formula (VI) is mixed with carboxyl PEG, hydrochloric acid and DMAP, and dichloromethane is added to dissolve and stir to generate a large polar point, and then dissolved in water, and dialyzed to obtain the final target compound;

[0040] Preferably, the molar ratio of the compound represented by formula (VI) to carboxyl-PEG is 5:11.

[0041] A photosensitizer containing the BODIPY compound according to claim 1, wherein the BODIPY compound comprises any one selected from the following structures:

[0042]

[0043] The present invention also provides a BODIPY compound, the structural formula of the compound is:

[0044]

[0045] The preparation method of the above BODIPY compound comprises the following steps:

[0046] Step 1: Add water, pyrrole, and hydrochloric acid, stir well at room temperature, and then add pentafluorobenzaldehyde. React at room temperature for 2 hours, and a large amount of white precipitate is generated. Filter by suction, and wash the filter cake with methanol aqueous solution to obtain a crude product powder, which is then separated and purified by silica gel column chromatography to obtain compound 1;

[0047] Step 2: Compound 1 obtained in step 1 was dissolved in dichloromethane, DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) was added for oxidation for 30 minutes, triethylamine and boron trifluoride ether were added, the mixture was reacted at room temperature for 5 hours, and then sand was made. The solvent was dried under reduced pressure and then separated and purified by silica gel column chromatography to obtain compound 2;

[0048] Step 3: Put compound 2 obtained in step 2, cupric chloride dihydrate and potassium persulfate into a flask, add acetonitrile to dissolve, react at 80°C for one hour, extract with dichloromethane after the reaction is completed, collect the organic phase, wash with water, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product, which is then separated and purified by silica gel column chromatography to obtain compound 3.

[0049] Step 4: Under argon protection, compound 3 obtained in step 3 and 2,4-dimethyl-3-ethylpyrrole were dissolved in toluene, reacted at 50°C for 1 hour, extracted with dichloromethane, the organic phase was collected, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography to obtain compound 4.

[0050] Step 5: Under argon protection, compound 4 obtained in step 4 was placed in a Shrek tube together with 4-hydroxymethylphenylboronic acid, tetrakis(triphenylphosphine)palladium and sodium bicarbonate, and toluene, ethanol and water were added. The mixture was reacted at 110°C for half an hour. After the reaction was completed, it was extracted with dichloromethane, the organic phase was collected, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography to obtain compound 5.

[0051] Step 6: Dissolve the compound 5 obtained in step 5 in DCM and place it in a 50-mL round-bottom flask. Dissolve NBS in DCM and add it dropwise into the round-bottom flask. React at room temperature for 10 minutes. After the reaction is completed, extract with dichloromethane, collect the organic phase, wash with water, dry with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. Separate and purify by silica gel column chromatography to obtain compound 6.

[0052] Step 7: Place compound 6 obtained in step 6, carboxyl PEG, hydrochloric acid and DMAP into a flask, dissolve and stir with dichloromethane, and after generating a large polar point, dissolve in water, dialyze and freeze-dry to obtain the final target compound.

[0053] The preparation method of the above-mentioned photosensitizer with pH responsiveness has a synthetic route as follows:

[0054]

[0055] In step 1, the volume ratio of pyrrole, hydrochloric acid and pentafluorobenzaldehyde is 2:1:1.

[0056] In step 2, the molar ratio of triethylamine to boron trifluoride ether is 3:5.

[0057] In step 3, the molar ratio of compound 2 to cupric chloride dihydrate is 1:8, and the molar ratio of compound 2 to potassium persulfate is 1:4.

[0058] In step 4, the molar ratio of compound 3 to 2,4-dimethyl-3-ethylpyrrole is 11:10.

[0059] In step 5, the molar ratio of compound 4 to 4-hydroxymethylphenylboronic acid is 1:3, the ratio of compound 4 to sodium bicarbonate is 1:4, the molar ratio to tetrakis(triphenylphosphine)palladium is 10:1, and the volume ratio of solvent toluene:water:ethanol is 3:1:1.

[0060] In step 6, the molar ratio of compound 5 to NBS is 5:12.

[0061] In step 7, the molar ratio of compound 6 to carboxyl-PEG is 5:11.

[0062] Beneficial Effects

[0063] (1) The BODIPY compounds of the present invention are applied to photodynamic antibacterial therapy, which is non-invasive and antibacterial. At the same time, the photosensitizer of the present invention also has good water solubility, which helps to improve its biocompatibility and broaden its application range.

[0064] (2) The BODIPY compounds of the present application introduce heavy atoms, which can effectively increase the intersystem crossing of the molecular excited state, improve the active oxygen production rate, and significantly increase the photodynamic force.

[0065] (3) The preparation method of the BODIPY compound of the present application has a simple synthesis route, good reaction selectivity, mild reaction conditions, easy separation and purification, and has universal applicability. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0067] Figure 1 The final product of Example 1 in the specific embodiment of the present invention 1 HNMR spectra;

[0068] Figure 2 The final product of Example 1 in the specific embodiment of the present invention 13 CNMR images;

[0069] Figure 3 The ultraviolet absorption spectrum of the final product of Example 1 in the specific implementation mode of the present invention;

[0070] Figure 4 The fluorescence emission spectrum of the final product of Example 1 in the specific implementation mode of the present invention;

[0071] Figure 5 The UV absorption spectra of the final product of Example 1 at different pH values ​​in the specific implementation mode of the present invention;

[0072] Figure 6 This is an electron microscope spectrum of the final product of Example 1 in a specific embodiment of the present invention;

[0073] Figure 7 This is a dynamic light scattering diagram of the final product of Example 1 in a specific embodiment of the present invention;

[0074] Figure 8 This is a graph showing the antibacterial ability of the final product of Example 1 in a specific embodiment of the present invention. DETAILED DESCRIPTION

[0075] The technical scheme in the embodiment of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiment of the present invention. Obviously, the described embodiment is only a part of the embodiment of the present invention, not all of the embodiments. Based on the embodiment of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0076] Example 1

[0077] Preparation of intermediate 1

[0078] In a 500mL round-bottom flask, add 250mL water, 1mL pyrrole, and 0.5mL HCl, stir well at room temperature, and then add 0.5mL pentafluorobenzaldehyde. React at room temperature for 2h, a large amount of white precipitate is generated, and the filter cake is washed with methanol and water to obtain a crude product powder, and intermediate 1 is obtained as a white powder with a yield of 90% (1.1g).

[0079] Preparation of intermediate 2

[0080] Intermediate 1 (312 mg, 1 mmol) was dissolved in 10 mL CH2Cl2, DDQ (340 mg, 1.5 mmol) was added for oxidation for 30 mins, and then 3 mL Et3N and 5 mL BF3Et2O were added for coordination. After reacting at room temperature for 5 h, the mixture was separated and purified by silica gel column chromatography (300-400 mesh silica gel powder, PE / DCM=100 / 30, V / V) to obtain intermediate 2 as an orange solid with a yield of 80% (286 mg).

[0081] Preparation of compound 3

[0082] The intermediate 2 (358 mg, 1 mmol), cupric chloride dihydrate (1360 mg, 8 mmol), and potassium persulfate (1080 mg, 4 mmol) were placed in a 50 mL round-bottom flask, and 18 mL of acetonitrile was added to dissolve the mixture. The mixture was reacted at 80 °C for 1 h, extracted with dichloromethane (3 × 50 mL), and the organic phase was collected, washed with water (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography (PE / DCM = 3 / 1, V / V) to obtain compound 3 as an orange-red solid 3 with a yield of 35% (128 mg).

[0083] Preparation of compound 4

[0084] Compound 3 (470 mg, 1.1 mmol), 2,4-dimethyl-3-ethylpyrrole (0.13 mL, 0.1 mmol) and 5 mL of toluene as solvent were added to a 50 mL Shrek tube. The mixture was protected by argon and reacted at 50 °C for 1 h. The mixture was extracted with dichloromethane (3 × 50 mL). The organic phase was collected, washed with water (3 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was then separated and purified by silica gel column chromatography (PE / EA = 30 / 1, V / V) to obtain compound 4 as a purple-black solid with a yield of 82% (374 mg).

[0085] Preparation of compound 5

[0086] Compound 4 (256 mg, 0.5 mmol) was added to a Shrek tube, followed by 4-hydroxymethylphenylboronic acid (228 mg, 1.5 mmol), sodium bicarbonate (212 mg, 2 mmol), and tetrakis(triphenylphosphine)palladium (57.8 mg, 0.05 mmol), dissolved in 6 mL of toluene, 2 mL of water and 2 mL of ethanol, and stirred thoroughly. The reaction was followed by TLC. After reacting at 110° C. for 1 h, the mixture was extracted with dichloromethane (3×50 mL), the organic phase was collected, washed with water (3×50 mL), filtered, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography (300-400 mesh silica gel powder, PE / EA=3 / 1, V / V) to obtain compound 5 as a green solid with a yield of 42% (54 mg);

[0087] Preparation of compound 6

[0088] In a 50mL round-bottom flask, compound 5 (292.5mg, 0.5mmol) was added and dissolved in 5mL DCM. NBS (213.6mg, 1.2mmol) was dissolved in 3mL DCM, and the dissolved NBS was added dropwise to the round-bottom flask, stirred thoroughly, and the reaction was tracked by TLC. After reacting at room temperature for 30min, dichloromethane was extracted (3×50mL), the organic phase was collected and washed with water (3×50mL), filtered, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was then separated and purified by silica gel column chromatography (300-400 mesh silica gel powder, PE / EA=3 / 1, V / V) to obtain compound 6 as a blue solid with a yield of 53% (77.5mg);

[0089] Preparation of final product

[0090] In a 50 mL round-bottom flask, compound 6 (370.5 mg, 0.5 mmol), PEG 2000-COOH (1.1 mg, 1.1 mmol), EDC hydrochloric acid (280 mg, 7.6 mmol), DMAP (16 mg, 0.13 mmol), add 16 mL of dichloromethane and stir thoroughly, follow the reaction by TLC, when reacting at room temperature for 30 min, a large polar point is generated, which is soluble in water. Put it into a dialysis bag for 24 h, and freeze-dry it to obtain the final product.

[0091] 1 H NMR (600MHz, CDCl3) δ10.15(d,J=14.8Hz,1H),7.65(d,J=7.9Hz,2H),7.49(d,J=7.9Hz,2H),7.12(d,J=5.1Hz,1 H), 6.70 (d, J = 5.1Hz, 1H), 4.81 (s, 2H), 2.40 (q, J = 7.6Hz, 2H), 2.31 (s, 3H), 2.25 (s, 3H), 1.03 (t, J = 7.6Hz, 3H). 13 C NMR (151MHz, CDCl3) δ152.29,145.19,141.52,141.02,139.74,133.85,131.33,131.06,128.99 ,126.20,124.98,120.06,77.24,77.03,76.81,65.28,29.71,17.23,14.97,13.03,12.79,0.00.

[0092] The final product 1 HNMR diagram, see Figure 1 The final product 13 CNMR images, see Figure 2 ;according to Figure 1-Figure 2 The final product structure is

[0093]

[0094] The UV absorption spectrum of the final product is shown in Figure 3 ; Fluorescence emission spectrum of the final product, see Figure 4 ; UV absorption spectra of the final product at different pH values, see Figure 5 ; Electron microscopy spectrum of the final product, see Figure 6 .

[0095] Example 2

[0096] The difference between Example 2 and Example 1 is only the preparation of Intermediate 1;

[0097] Preparation of Intermediate 1:

[0098] 250 mL of water, 0.5 mL of pyrrole, and 0.5 mL of HCl were added to a 500 mL round-bottom flask, and 0.5 mL of pentafluorobenzaldehyde was added after being stirred at room temperature. The mixture was reacted for 2 h at room temperature, and a large amount of white precipitate was generated. The filter cake was filtered and washed with methanol-water solution to obtain a crude product powder, and intermediate 1 was obtained as a white powder.

[0099] Example 3

[0100] The difference between Example 3 and Example 1 is only the preparation of Intermediate 1;

[0101] Preparation of Intermediate 1:

[0102] 250 mL of water, 2 mL of pyrrole, and 0.5 mL of HCl were added to a 500 mL round-bottom flask, and 0.5 mL of pentafluorobenzaldehyde was added after being fully stirred at room temperature. The mixture was reacted for 2 h at room temperature, and a large amount of white precipitate was generated. The filter cake was filtered and washed with methanol aqueous solution to obtain a crude product powder, and intermediate 1 was obtained as a white powder. The other preparation methods and preparation conditions were consistent with those in Example 1.

[0103] Example 4

[0104] The difference between Example 4 and Example 1 is only the preparation of Intermediate 2;

[0105] Preparation of Intermediate 2:

[0106] The intermediate 1 (1 mmol) was dissolved in 10 mL CH2Cl2, DDQ (1.5 mmol) was added for oxidation for 30 mins, and then 1 mL Et3N and 5 mL BF3Et2O were added for coordination. After reacting at room temperature for 5 h, the intermediate 2 was separated and purified by silica gel column chromatography (300-400 mesh silica gel powder, PE / DCM=100 / 30, V / V) to obtain the intermediate 2 as an orange solid. The other preparation methods and conditions were the same as those in Example 1.

[0107] Example 5

[0108] The only difference between Example 5 and Example 1 is that the pyrrole-containing compound in the preparation of intermediate 4 is pyrrole, and the other preparation methods and preparation conditions are the same as those of Example 1.

[0109] The only difference between Example 6 and Example 1 is that the pyrrole compound in the preparation of intermediate 4 is 2,4-dimethylpyrrole, and the other preparation methods and preparation conditions are the same as those of Example 1;

[0110]

[0111] Example 7

[0112] The difference between Example 7 and Example 1 is that NBS is replaced by iodine reagent and PEG is replaced by2000 -COOH to PEG 5000 -COOH, other preparation methods and preparation conditions are consistent with those in Example 1, and the obtained compound n is 112, and other preparation methods and preparation conditions are consistent with those in Example 1;

[0113]

[0114] Example 8

[0115] The difference between Example 8 and Example 1 is that 2,4-dimethyl-triethylpyrrole is changed to pyrrole, NBS is replaced by iodine reagent, and PEG is replaced by 2000 -COOH to PEG 5000 -COOH, other preparation methods and preparation conditions are consistent with those in Example 1, and the obtained compound n is 112, and other preparation methods and preparation conditions are consistent with those in Example 1;

[0116]

[0117] Test Example 1 Basic Spectra of the Compounds of the Invention

[0118] This test example tests the absorption spectrum and fluorescence spectrum of compound (I) in Example 1 in various solvents. Figure 3 is the absorption spectrum of compound (I) in different solutions. Figure 4 The normalized fluorescence spectra of compound (I) in different solutions under excitation at 650 nm. Figure 5 is the absorption spectrum of compound (I) at different pH. Fluorescence emission ability test example 1:

[0119] 1-1.5 mg of the compound of formula (I) was weighed and dissolved in 2 mL of dichloromethane, and then diluted with toluene, dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N-dimethylformamide and methanol to a molar concentration of 10 -6 mol / L solution; absorption spectrum and emission spectrum test were performed respectively. Experimental Example 2 Characterization of the assembly of the compound of the present invention

[0120] Figure 6 This is a scanning electron microscope image of compound (I), which has a regular appearance and uniform particle size;

[0121] Figure 7 This is the dynamic scattering diagram of compound (I), and the hydrodynamic diameter is about 122 nm.

[0122] Test Example 3 Antibacterial Ability of the Compounds of the Invention

[0123] The photodynamic antibacterial ability test of compound (I) was performed using S. aureus and E. coli bacteria as representatives. The specific steps are as follows:

[0124] After the strain was revived, it was inoculated into LB liquid medium and cultured in a shaker at 37°C and 220 r / min for 16 h. The bacterial solution in the cryopreserved tube was transferred into fresh LB medium and then placed in a shaker overnight (37°C, 220 r / min). The next day, it was diluted to make its OD600 value 0.002, and the corresponding bacterial concentration was 10 -8 CFU, and then diluted 100 times for subsequent antibacterial tests. The diluted bacterial solution was mixed with nanoparticles in a 96-well plate under different conditions, cultured for half an hour, irradiated with a 650nm laser for 15 minutes, and then placed in an incubator for 24 hours. Finally, its survival activity was measured with an ELISA reader, and the control group was set up without co-culture with nanoparticles.

[0125] After the above antibacterial experiment is completed, 100 μL of the supernatant in the 96-well plate is aspirated, and after diluting a certain multiple with PBS, 20 μL is taken for coating the plate, and the sample is evenly dispersed on the sterile solid culture medium, three plates per group, and then the coated plates are placed in a 37°C incubator for static culture for 12 hours, and then photographed to observe their growth.

[0126] Figure 8 Confocal images of bacteria under different pH environments and other conditions and standard plate counts of bacteria. Figure 8 It can be seen that in the absence of light, the compound (I) nanoparticles have no obvious antibacterial effect, while the effect is better under acidic conditions than under neutral conditions. The standard plate count method further confirmed the antibacterial ability of compound (I). It can be seen that the number of bacterial colonies in the non-laser irradiation group is larger, indicating that the survival rate of the non-light group is higher than that of the light group. Obviously, the number of colonies of compound (I) is significantly reduced under laser irradiation. It shows that the nanoparticles can kill most bacteria under light.

[0127] It can be seen from the above embodiments that the water-soluble photosensitizer with a stimulus-responsive BODIPY having broad-spectrum antibacterial activity provided by the present invention has simple synthesis steps and simple separation and purification operations, has good photodynamic killing effects on Gram-positive bacteria and Gram-negative bacteria and related drug-resistant bacteria, and has broad-spectrum antibacterial ability; at the same time, the photosensitizer of the present invention also has good water solubility and can be used to construct a bacterial infection treatment drug with high-efficiency and broad-spectrum antibacterial therapeutic effect.

Claims

1. A BODIPY compound, characterized in that: The structural formula of the compound is shown in formula (VII): Wherein R1, R2, and R3 are each independently a hydrogen group or a (C1-C3) alkyl group; X includes I and Br; and n includes 4, 4, 112.

2. The BODIPY compound according to claim 1, characterized in that: R1, R2, and R3 are each independently (C1-C3) alkyl.

3. The BODIPY compound according to claim 2, characterized in that: R1 is methyl, R2 is ethyl, R3 is methyl, X is Br, and n is 44.

4. A method for preparing the BODIPY compound according to any one of claims 1 to 3, comprising the following steps: Preparation of the compound represented by formula (III): reacting the compound represented by formula (II) with copper chloride to obtain the compound represented by formula (III); Preparation of the compound represented by formula (IV): reacting the compound represented by formula (III) with a pyrrole ring-containing compound to obtain the compound represented by formula (IV), wherein the pyrrole ring-containing compound includes: pyrrole, 2,4-dimethylpyrrole, and 2,4-dimethyl-3-ethylpyrrole; Preparation of the compound represented by formula (V): Under inert gas protection conditions, the compound represented by formula (IV) is mixed with 4-hydroxymethylphenylboronic acid, tetrakis(triphenylphosphine)palladium, and sodium bicarbonate, and toluene, ethanol, and water are added to react; The molar ratio of the compound of formula (IV) to 4-hydroxymethylphenylboronic acid is 1:3, the ratio of the compound of formula (IV) to sodium bicarbonate is 1:4, the molar ratio of the compound of formula (IV) to tetrakis(triphenylphosphine)palladium is 10:1, and the volume ratio of the solvent toluene:water:ethanol is (2-5):1:1; Preparation of the compound represented by formula (VI): reacting the compound represented by formula (V) with NBS in an alkaline environment to obtain the compound represented by formula (VI); Preparation of the compound represented by formula (VII): reacting the compound represented by formula (VI) with carboxyl PEG to obtain the compound represented by formula (VII); In formula (IV) to formula (VII), R1 is a hydrogen group or a (C1-C3) alkyl group; R2 is a hydrogen group or a (C1-C3) alkyl group; R3 is a hydrogen group or a (C1-C3) alkyl group; in formula (VII), X is Br; The preparation method of the compound represented by formula (I) comprises: Add water, pyrrole, and hydrochloric acid, stir thoroughly at room temperature, then add pentafluorobenzaldehyde, and react at room temperature to obtain a compound represented by formula (I); The volume ratio of pyrrole, hydrochloric acid and pentafluorobenzaldehyde is (1-4):1:1; The preparation method of the compound represented by formula (II) comprises: The compound represented by formula (I) is dissolved in dichloromethane, DDQ is added for oxidation for 30 minutes, triethylamine and boron trifluoride ether are added, and the reaction is carried out at room temperature for 5 hours to obtain the compound represented by formula (II); The molar ratio of triethylamine to boron trifluoride ether is (1-3):5; The DDQ is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; 5. The preparation method according to claim 4, characterized in that: Preparation of the compound represented by formula (III): The compound represented by formula (II) is mixed with copper chloride dihydrate and potassium persulfate, and acetonitrile is added to dissolve and react; The molar ratio of the compound represented by formula (II) to cupric chloride dihydrate is 1:8, and the molar ratio of the compound represented by formula (II) to potassium persulfate is 1:

4.

6. The preparation method according to claim 4, characterized in that: Preparation of the compound represented by formula (IV): Under inert gas protection conditions, the compound represented by formula (III) and the pyrrole ring compound are dissolved in toluene for reaction; The molar ratio of the compound represented by formula (III) to the pyrrole ring compound is 11:

10.

7. The preparation method according to claim 4, characterized in that: Preparation of the compound represented by formula (VI): The compound represented by formula (V) is dissolved in DCM, and then NBS solution is added dropwise to react at room temperature to obtain the compound represented by formula (VI), wherein the solvent of the NBS solution is DCM; The molar ratio of the compound represented by formula (V) to NBS is 5:

12.

8. The preparation method according to claim 4, characterized in that: Preparation of the compound represented by formula (VII): The compound represented by formula (VI) is mixed with carboxyl PEG, hydrochloric acid and DMAP, and dichloromethane is added to dissolve and stir to generate a large polar point, and then dissolved in water, and dialyzed to obtain the compound represented by formula (VII); The molar ratio of the compound represented by formula (VI) to carboxyl PEG is 5:

11.

9. A photosensitizer containing the BODIPY compound according to claim 1, characterized in that: The BODIPY compounds include any one selected from the following structures:

Images