4-cation disubstituted BODIPY compound and preparation method and application thereof
1. A 4-position cation disubstituted BODIPY compound with a structure shown in a formula (I) or (II),
wherein:
r is independently selected from various quaternary ammonium salt cations, including quaternary ammonium salt cations obtained by iodomethanation dimethylamino, iodomethanation diethylamino and iodomethanation pyridine (including all positions in an interproximal manner); iodoethylated dimethylamino, iodoethylated diethylamino, iodoethylated pyridine (including ortho-para positions); bromoethylated dimethylamino, bromoethylated diethylamino, bromoethylated pyridine (including ortho-to meta-positions);
n＝0～6；
x is selected from atoms with heavy atom effect: iodine, bromine, chlorine, sulfur;
R1、R2independently selected from C1-6Alkyl, hydroxy substituted C1-6Alkyl, amino substituted C1-6Alkyl, halogen substituted C1-6Alkyl, aromatic rings connected by double bonds: benzene ring, naphthalene ring, anthracene ring, carbazole ring;
R3、R4independently selected from C1-6Alkyl, hydroxy substituted C1-6Alkyl, amino substituted C1-6Alkyl, halogen substituted C1-6An alkyl group;
R5independently selected from C1-6Alkyl, hydroxy substituted C1-6Alkyl, amino substituted C1-6Alkyl, halogen substituted C1-6Alkyl, phenyl, pyridyl, carboxyl, C1-6Ester group, C1-6An amide.
2. The disubstituted BODIPY compound with a cation at position 4 according to claim 1, wherein R is independently selected from the group consisting of iodomethandimethylamino, iodomethandiethylamino, and quaternary ammonium cations derived from iodomethanpyridine (including meta-and para-positions); n of general formula I is 1-4, and n of general formula II is 1; x is preferably an iodine atom; r1-R4Is methyl.
3. The cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 1 of the structure,
4. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 2 of the structure,
5. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 3 of the following structure,
6. the cationic disubstituted BODIPY compound according to claim 1 or 2, in the 4-position, which is compound 4 of the following structure,
7. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 5 of the structure,
8. the cationic disubstituted BODIPY compound according to claim 1 or 2, in the 4-position, which is compound 6 of the following structure,
9. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 7 of the structure,
10. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 8 of the structure,
11. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 9 of the structure,
12. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 10 of the structure,
13. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 11 having the structure,
14. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 12 having the structure,
15. the cationic disubstituted BODIPY compound according to claim 1 or 2, in the 4-position, which is compound 13 of the structure,
16. the cationic disubstituted BODIPY compound according to claim 1 or 2, wherein said compound is compound 14 of the structure,
17. use of the 4-position cationic disubstituted BODIPY compound of claims 1-16 in the preparation of photodynamic antibacterial medicaments.
18. Use according to claim 17, wherein the antimicrobial agent is a photosensitizer capable of acting as a fluorescent imaging agent and a photodynamic antimicrobial agent.
19. Use according to claim 17, wherein the antibacterial agent is used to inhibit the activity of gram-positive bacteria such as staphylococcus aureus, gram-negative bacteria such as escherichia coli, fungi (candida albicans or clinical resistant bacteria).
20. Use according to claim 17, wherein the antibacterial agent is applied by a route comprising combination with other types of disinfectants such as hydrogen peroxide or medical alcohol.
Background
It has been reported that in recent years, the emergence and spread of "superbacteria" has been caused by the abuse of antibiotics. By "superbacteria" is meant bacteria that are characterized by multiple resistance to current antibiotics, which adds significant difficulty to the treatment of clinical wound infections. And the explosive prevalence of multi-antibiotic resistant superbacteria, while only potentially possible, can be feared as a panic in countries around the world. Therefore, the development of new anti-infection strategies is imminent. Research shows that the photodynamic antibacterial treatment method is one of the most promising new therapies, and has good curative effect on infections caused by bacteria, fungi and viruses, particularly drug-resistant bacterial infections. The photodynamic sterilization is an oxidation damage mechanism based on the synergistic effect of three factors of light, photosensitizer and oxygen, and the problem of drug resistance caused by single drug, photosensitizer concentration, insufficient exposure time and other factors can be avoided.
At present, a great deal of exploration is carried out on the photodynamic inactivation of different bacteria by using different photosensitizers at home and abroad, aiming at finding an ideal photosensitive medicament. It is believed that the ideal antimicrobial photosensitizer should have high efficiency, low toxicity, good selectivity, strong permeability to cell walls, high efficiency in inactivating microorganisms, and less damage to normal tissues.
The BODIPY dye is commonly used for biological imaging, has the advantages of simple synthesis, multiple modifiable sites, high fluorescence quantum yield, good light stability, insensitivity to pH and polarity, relatively small molecular weight, good biocompatibility and the like, is very suitable for biological fluorescence imaging, and is particularly suitable for long-time fluorescence tracking. When the heavy atom at position 2, 6 of BODIPY is substituted, the cross-over probability between systems is increased, the photosensitization efficiency is greatly increased, and the compound can be used as a photosensitizer.
Gram-negative bacteria are reported to be more resistant to photodynamic antibacterial therapy than gram-positive bacteria. As the cell wall of the bacteria is charged with negative charges, cations are introduced into the photosensitizer, the electrostatic interaction between the photosensitizer and the bacteria is enhanced, and the oil-water distribution coefficient of the photosensitizer is adjusted, so that the photosensitizer has amphipathy and can play a role in spectrum antibiosis. In addition, due to the structural difference between microbial cells and host cells (such as mammalian cells), the interaction of the cationic photosensitizer shows obvious difference, so that the selectivity of the photosensitizer to pathogenic microorganisms can be improved by introducing cations, and the harm to the host is reduced.
Based on the basis and the current situation of the prior art, the inventor of the application intends to provide 4-cation disubstituted BODIPY compounds and application thereof, in particular to application of the compounds in preparation of photosensitizers capable of being used as fluorescent imaging agents and photodynamic antibacterial agents.
Disclosure of Invention
The invention aims to provide a novel BODIPY compound with good antibacterial effect and fluorescence labeling microorganism effect and a preparation method thereof based on the basis and the current situation of the prior art. In particular to a 4-cation disubstituted BODIPY compound, a preparation method thereof and application thereof in preparing antibacterial drugs, in particular to application thereof in preparing photosensitizers capable of being used as fluorescent imaging agents and photodynamic antibacterial drugs.
The invention provides a 4-substituted BODIPY compound with a structure shown in a general formula (I) or (II):
wherein:
r is independently selected from various quaternary ammonium salt cations, including quaternary ammonium salt cations obtained by iodomethanation dimethylamino, iodomethanation diethylamino and iodomethanation pyridine (including all positions in an interproximal manner); iodoethylated dimethylamino, iodoethylated diethylamino, iodoethylated pyridine (including ortho-para positions); bromoethylated dimethylamino, bromoethylated diethylamino, bromoethylated pyridine (including ortho-to meta-positions);
n＝0～6；
x is selected from atoms with heavy atom effect (iodine, bromine, chlorine, sulfur, etc.);
R1、R2independently selected from C1-6Alkyl, hydroxy substituted C1-6Alkyl, amino substituted C1-6Alkyl, halogen substituted C1-6Alkyl, aromatic rings (benzene, naphthalene, anthracene, carbazole rings) connected by double bonds;
R3、R4independently selected from C1-6Alkyl, hydroxy substituted C1-6Alkyl, amino substituted C1-6Alkyl, halogen substituted C1-6An alkyl group;
R5independently selected from C1-6Alkyl, hydroxy substituted C1-6Alkyl, amino substituted C1-6Alkyl, halogen substituted C1-6Alkyl, phenyl, pyridyl, carboxyl, C1-6Ester group, C1-6An amide.
In the present invention, the compound has the following structure of compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14:
the invention also aims to provide a preparation method of the 4-cation disubstituted BODIPY compound.
The preparation method of the compound of the invention comprises the following steps:
taking compound 4 as an example, the preparation process of the compound of the present invention is as follows:
taking compound 10 as an example, the preparation process of the compound of the present invention is as follows:
furthermore, the invention provides application of the 4-position cation disubstituted BODIPY compound in preparing antibacterial drugs, in particular application in preparing photosensitizers capable of being used as fluorescent imaging agents and photodynamic antibacterial drugs.
In the invention, the fluorescent developer and the photodynamic antibacterial photosensitizer can be applied to various microorganisms.
The compound of the invention is tested for antibacterial activity, and the result shows that the compound has better microbial inhibitory activity.
The pharmacodynamic test method employed in the present invention is a method well known to those skilled in the art.
In the present invention, the microorganism to be used is commercially available to those skilled in the art.
The invention provides a 4-position cation disubstituted BODIPY compound with good antibacterial effect and fluorescence labeling microorganism effect, tests show that the compound can be attached to microorganisms through electrostatic effect, has good photodynamic antibacterial activity after photodynamic effect, and plays a significant role in inhibiting the growth of microorganisms.
Drawings
Figure 1 is a graph of the results of an antibacterial dose-dependent experiment for compound 10: FIG. 1a is a concentration-dependent curve and a light dose-dependent curve against Staphylococcus aureus; FIG. 1b is a concentration-dependent curve and a light dose-dependent curve against E.coli; FIG. 1c is a concentration-dependent curve and a light dose-dependent curve against Candida albicans; FIG. 1d is a concentration-dependent curve and a light dose-dependent curve of methicillin-resistant Staphylococcus aureus.
Figure 2 is a graph of the antibacterial effect of compound 10 against staphylococcus aureus.
FIG. 3 shows the antibacterial effect of Compound 10 against E.coli.
Figure 4 is the antibacterial effect of compound 10 against candida albicans.
FIG. 5 is a graph showing the antibacterial effect of Compound 10 against methicillin-resistant Staphylococcus aureus.
Detailed Description
The present invention will be described in detail by the following examples, but is not intended to limit the present invention in any way. The described embodiments are only some, but not all embodiments of the invention. All embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without any creative work are within the protection scope of the present invention.
For the followingIn some embodiments, standard procedures and purification methods known to those skilled in the art may be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. The structural formula of the final product is shown by1HNMR、13C NMR and mass spectrometry.
Example 1: synthesis of Compound 1
2I-BDP (100mg,0.2mmol) was dissolved in dry DCM (20ml) under nitrogen, boron trichloride (0.5ml,0.5mmol) was added, stirring was carried out at room temperature for 1.5 hours, diethylaminoethanol (234mg,2mmol) was added, and stirring was carried out at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with DCM and an aqueous solution, DCM and a saturated aqueous solution of sodium chloride, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 100/1, v/v) to give 69.4mg of red solid powder with a yield of 50%.1HNMR(400MHz,CDCl3)δ7.05(s,1H),2.96(t,J＝7.1Hz,4H),2.60(s,6H),2.51–2.36(overlap,12H),2.22(s,6H),0.90(t,J＝6.5Hz,12H).MS(ESI)m/z:[M+2H]2+found 348.1；calcd.694.1.
This red solid powder (69.4mg,0.1mmol) was dissolved in acetonitrile (15ml) under nitrogen atmosphere, excess iodomethane was added and stirred overnight at room temperature, after the reaction was completed, the solvent was dried under reduced pressure, the residue was dissolved in an appropriate amount of methanol and ether was used as a poor solvent and recrystallized to give 190.0mg of compound in 92% yield.1H NMR(400MHz,CD3OD)δ7.72(s,1H),3.40(q,J＝7.1Hz,8H),3.01(s,6H),2.68(s,6H),2.30(s,6H),1.29(t,J＝7.0Hz,12H).13C NMR(151MHz,CD3OD)δ158.29,146.54,135.70,123.75,83.46,62.43,58.55,56.81,16.73,13.91,8.25.HRMS(ESI)m/z:[M-2I]2+found 362.0939；calcd.362.0935.。
Example 2: synthesis of Compound 2
2I-BDP (100mg,0.2mmol) was dissolved in dry DCM (20ml) under nitrogen, boron trichloride (0.5ml,0.5mmol) was added and stirred at room temperature for 1.5 hours, then diethylaminopropanol (262mg,2mmol) was added and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with DCM and an aqueous solution, DCM and a saturated aqueous solution of sodium chloride, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 100/1, v/v) to give 79.5mg of red solid powder with a yield of 55%.1HNMR(400MHz,CDCl3)δ7.07(s,1H),2.88(t,J＝6.5Hz,4H),2.60(s,6H),2.46(dd,J＝13.9,6.9Hz,8H),2.40–2.34(m,4H),2.24(s,6H),1.61–1.52(m,4H),0.96(t,J＝7.0Hz,12H).M2S(ESI)m/z:[M+2H]2+found362.1；calcd.722.2.
This red solid powder (72mg,0.1mmol) was dissolved in acetonitrile (15ml) under nitrogen, excess iodomethane was added, stirred overnight at room temperature, after the reaction was complete, the solvent was spin-dried under reduced pressure, the residue was dissolved in an appropriate amount of methanol, ether was used as a poor solvent, and the compound was recrystallized to yield 290.6mg, 90% yield.1H NMR(400MHz,CD3OD)δ7.67(s,1H),3.37–3.32(m,8H),3.28–3.23(m,4H),3.01(t,J＝5.7Hz,4H),2.96(s,6H),2.62(s,6H),2.29(s,6H),1.79(tt,J＝12.3,6.1Hz,4H),1.31(t,J＝7.0Hz,12H).13C NMR(151MHz,CD3OD)δ158.21,146.03,135.73,123.55,83.02,59.96,59.68,57.78,47.83,25.56,16.41,13.88,8.16.HRMS(ESI)m/z:[M-2I]2+found 376.1089；calcd.376.1092.。
Example 3: synthesis of Compound 3
2I-BDP (100mg,0.2mmol) was dissolved in dry DCM (20ml) under nitrogen, boron trichloride (0.5ml,0.5mmol) was added, stirring was carried out at room temperature for 1.5 hours, dimethylaminoethanol (178mg,2mmol) was added, and stirring was carried out at room temperature overnight. After the reaction is finished, the reaction solution is respectively extracted by DCM and aqueous solution, DCM and saturated aqueous sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 100/1, v/v) to give 70.2mg of red solid powder in 55% yield.1HNMR(400MHz,CDCl3)δ7.04(s,1H),3.03–2.92(m,4H),2.60(s,6H),2.41–2.30(m,4H),2.22(s,6H),2.10(s,12H).MS(ESI)m/z:[M+2H]2+found 320.1；calcd.638.1.
This red solid powder (64mg,0.1mmol) was dissolved in acetonitrile (15ml) under nitrogen, excess iodomethane was added, the mixture was stirred at room temperature overnight, after completion of the reaction, the solvent was dried under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether as a poor solvent to recrystallize 382.1mg, which was 89% yield.1H NMR(400MHz,CD3OD)δ8.72(d,J＝6.2Hz,1H),7.86(d,J＝6.1Hz,1H),7.63(s,1H),4.33(s,2H),3.00(t,J＝6.0Hz,1H),2.96–2.85(m,1H),2.61(s,2H),2.29(s,2H),1.91–1.67(m,1H).13C NMR(151MHz,CD3OD)δ158.35,146.49,135.70,123.58,83.36,68.25,57.40,54.73,16.63,13.84.HRMS(ESI)m/z:[M-2I]2+found334.0626；calcd.334.0622.。
Example 4: synthesis of Compound 4
2I-BDP (100mg,0.2mmol) was dissolved in dry DCM (20ml) under nitrogen, boron trichloride (0.5ml,0.5mmol) was added and stirred at room temperature for 1.5 hours, then dimethylaminopropanol (206mg,2mmol) was added and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with DCM and an aqueous solution, DCM and a saturated aqueous solution of sodium chloride, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 100/1, v/v) to obtain 80.0mg of red solid powder with a yield of 60%.1HNMR(400MHz,CDCl3)δ7.06(s,1H),2.89(t,J＝6.5Hz,4H),2.60(s,6H),2.25–2.18(m,10H),2.13(s,12H),1.57(dt,J＝13.6,6.7Hz,4H).MS(ESI)m/z:[M+2H]2+found 334.1；calcd.666.1.
This red solid powder (67mg,0.1mmol) was dissolved in acetonitrile (15ml) under nitrogen, excess iodomethane was added, the mixture was stirred at room temperature overnight, after the reaction was completed, the solvent was dried under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether as a poor solvent to recrystallize the compound to 472.2mg in 76% yield.1H NMR(400MHz,CD3OD)δ7.66(s,1H),3.42–3.32(m,4H),3.11(s,18H),3.00(t,J＝5.9Hz,4H),2.61(s,6H),2.29(s,6H),1.86(td,J＝12.0,5.9Hz,4H).13C NMR(151MHz,CD3OD)δ156.17,143.92,133.64,121.43,80.92,64.08,57.49,51.69,24.34,14.33,11.82.HRMS(ESI)m/z:[M-2I]2+found 348.0782；calcd.348.0779.。
Example 5: synthesis of Compound 5
2I-BDP (100mg,0.2mmol) was dissolved in dry DCM (20ml) under nitrogen, boron trichloride (0.5ml,0.5mmol) was added, and the mixture was stirred at room temperature for 1.5 hours, followed by 4-hydroxypyridine (190mg,2mmol), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with DCM and an aqueous solution, DCM and a saturated aqueous solution of sodium chloride, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 100/1, v/v) to obtain 65.0mg of red solid powder with a yield of 50%.1HNMR(400MHz,cdcl3)δ8.21(d,J＝4.0Hz,4H),7.40(s,1H),6.39(d,J＝4.2Hz,4H),2.49(s,6H),2.33(s,6H).MS(ESI)m/z:[M+2H]2+found 325.6；calcd.650.0.
This red solid powder (65mg,0.1mmol) was dissolved in acetonitrile (15ml) under nitrogen, excess iodomethane was added, the mixture was stirred at room temperature overnight, after completion of the reaction, the solvent was dried under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether as a poor solvent to recrystallize 574.7mg, 80% yield.1H NMR(600MHz,CD3OD)δ8.45(d,J＝7.3Hz,4H),8.27(s,1H),6.97(d,J＝7.4Hz,4H),4.10(s,6H),2.47(s,6H),2.45(s,6H).13C NMR(151MHz,CD3OD)δ169.17,159.88,150.34,148.48,134.71,125.47,117.44,85.34,47.02,16.43,14.83.HRMS(ESI)m/z:[M-2I]2+found 340.0156；calcd.340.0153.。
Example 6: synthesis of Compound 6
2I-BDP (100mg,0.2mmol) was dissolved in dry DCM (20ml) under nitrogen, boron trichloride (0.5ml,0.5mmol) was added, stirring was carried out at room temperature for 1.5 hours, 4-pyridinemethanol (218mg,2mmol) was added, and stirring was carried out at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with DCM and an aqueous solution, DCM and a saturated aqueous solution of sodium chloride, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 100/1, v/v) to give 91.0mg of red solid powder in 67% yield.1HNMR(400MHz,cdcl3)δ8.45(d,J＝4.5Hz,4H),7.14(d,J＝4.9Hz,4H),4.06(s,4H),2.51(s,6H),2.27(s,6H).MS(ESI)m/z:[M+2H]2+found 339.6；calcd.678.0.
This red solid powder (68mg,0.1mmol) was dissolved in acetonitrile (15ml) under nitrogen, excess iodomethane was added, the mixture was stirred at room temperature overnight, after completion of the reaction, the solvent was dried under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether as a poor solvent to recrystallize 683.6mg, which was 87% yield.1H NMR(600MHz,CD3OD)δ8.76(d,J＝6.6Hz,4H),8.00(d,J＝6.6Hz,4H),7.78(s,1H),4.38(s,4H),4.35(s,6H),2.54(s,6H),2.32(s,6H).13CNMR(151MHz,CD3OD)δ162.97,158.63,146.72,146.02,135.74,126.03,123.91,83.43,63.50,48.30,16.31,13.94.HRMS(ESI)m/z:[M-2I]2+found 354.0313；calcd.354.0309.。
Example 7: synthesis of Compound 7
Under the protection of nitrogen, the mixture is subjected to2I-BDP (100mg,0.2mmol) was dissolved in dry DCM (20ml), boron trichloride (0.5ml,0.5mmol) was added and stirred at room temperature for 1.5 hours, then 4-pyridylethanol (246mg,2mmol) was added and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with DCM and an aqueous solution, DCM and a saturated aqueous solution of sodium chloride, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 100/1, v/v) to obtain 98.8mg of red solid powder with a yield of 70%.1HNMR(400MHz,CDCl3)δ8.40(d,J＝4.0Hz,4H),7.07(s,1H),6.95(d,J＝4.2Hz,4H),3.12(s,4H),2.68(s,4H),2.23-2.21(overlap,12H).MS(ESI)m/z:[M+2H]2+found 354.0；calcd.706.0.
This red solid powder (71mg,0.1mmol) was dissolved in acetonitrile (15ml) under nitrogen, excess iodomethane was added, the mixture was stirred at room temperature overnight, after completion of the reaction, the solvent was dried under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether as a poor solvent to recrystallize 776.2mg, which was a 77% yield compound.1H NMR(400MHz,CD3OD)δ8.73(d,J＝6.2Hz,4H),7.83(d,J＝5.8Hz,4H),7.67(s,1H),4.38(s,6H),3.27(d,J＝5.9Hz,4H),2.95(t,J＝5.9Hz,4H),2.30(s,6H),2.22(s,6H).13C NMR(151MHz,CD3OD)δ160.64,156.04,144.03,143.66,133.47,127.42,121.56,80.87,60.05,46.35,36.74,14.10,11.83.HRMS(ESI)m/z:[M-2I]2+found368.0478；calcd.368.0466.。
Example 8: synthesis of Compound 8
2I-BDP (100mg,0.2mmol) was dissolved in dry DCM (20ml) under nitrogen, boron trichloride (0.5ml,0.5mmol) was added, stirring was carried out at room temperature for 1.5 hours, 4-pyridylpropanol (274mg,2mmol) was added, and stirring was carried out at room temperature overnight. After the reaction, the reaction mixture was extracted with DCM and an aqueous solution, DCM and a saturated aqueous solution of sodium chloride, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 100/1, v/v) to obtain a red colorSolid powder 86.6mg, yield 59%.1H NMR(400MHz,CDCl3)δ8.42(dd,J＝5.3Hz,4H),7.05(s,1H),6.99(dd,J＝5.0Hz,4H),2.89(d,J＝4.0Hz,4H),2.64(s,6H),2.59(d,J＝6.0Hz,4H),2.24(s,6H),1.76–1.67(m,4H).MS(ESI)m/z:[M+2H]2+found 368.0；calcd.734.1.
This red solid powder (73.4mg,0.1mmol) was dissolved in acetonitrile (15ml) under nitrogen atmosphere, excess iodomethane was added and stirred overnight at room temperature, after completion of the reaction, the solvent was dried under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether as a poor solvent and recrystallized to obtain 892.6mg, 91% yield.1H NMR(400MHz,CD3OD)δ8.72(d,J＝6.2Hz,4H),7.86(d,J＝6.1Hz,4H),7.63(s,1H),4.33(s,6H),3.00(t,J＝6.0Hz,4H),2.94–2.87(m,4H),2.61(s,6H),2.29(s,6H),1.84–1.73(m,4H).13C NMR(151MHz,CD3OD)δ156.17,143.92,133.64,121.43,80.92,64.08,57.49,51.69,24.34,14.33,11.82.HRMS(ESI)m/z:[M-2I]2+found 382.0626；calcd.382.0622.。
Example 9: synthesis of Compound 9
2I-BDP (100mg,0.2mmol) was dissolved in dry DCM (20ml) under nitrogen, boron trichloride (0.5ml,0.5mmol) was added, stirring was carried out at room temperature for 1.5 hours, 4-pyridinebutanol (302mg,2mmol) was added, and stirring was carried out at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with DCM and an aqueous solution, DCM and a saturated aqueous solution of sodium chloride, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 100/1, v/v) to give 97.5mg of red solid powder with a yield of 64%.1HNMR(400MHz,CDCl3)δ8.44(d,J＝4.6Hz,4H),7.07(s,1H),7.03(d,J＝5.0Hz,4H),2.84(t,J＝6.1Hz,4H),2.55(s,6H),2.48(t,J＝7.7Hz,4H),2.24(s,6H),1.57(dd,J＝15.3,7.9Hz,4H),1.48–1.39(m,4H).MS(ESI)m/z:[M+2H]2+found 381.8；calcd.762.1.
Under the protection of nitrogen, the red is put intoThe colored solid powder (76mg,0.1mmol) was dissolved in acetonitrile (15ml), excess iodomethane was added, stirring was carried out at room temperature overnight, after completion of the reaction, the solvent was dried by spinning under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether as a poor solvent to obtain 991.0mg of compound by recrystallization in 87% yield.1H NMR(400MHz,CD3OD)δ8.74(d,J＝5.3Hz,4H),7.87(d,J＝5.7Hz,4H),7.61(s,1H),4.31(s,6H),2.92(t,J＝6.0Hz,4H),2.83(t,J＝7.2Hz,4H),2.53(s,6H),2.28(s,6H),1.71–1.60(m,4H),1.50–1.37(m,3H).13CNMR(151MHz,CD3OD)δ164.65,158.13,146.01,145.52,135.73,128.89,123.31,82.64,62.28,48.21,36.26,32.20,27.66,16.23,13.86.HRMS(ESI)m/z:[M-2I]2+found 396.0778；calcd.396.0779.。
Example 10: synthesis of Compound 10
Propargylamine (166mg,2mmol) and ethylmagnesium bromide (2ml,2mmol) were dissolved in dry THF (20ml) under nitrogen atmosphere, reacted at 60 ℃ for 2 hours, and 2I-BDP (100mg,0.2mmol) was added to the reaction solution and stirred overnight. After completion of the reaction, the reaction mixture was dried by spinning, extracted with DCM and saturated aqueous sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 200/1, v/v) to obtain 87.6mg of red solid powder in 70% yield.1H NMR(400MHz,CDCl3)δ6.86(s,1H),2.92(s,4H),2.53(d,J＝12.7Hz,6H),2.01(s,12H),1.98(s,6H).MS(ESI)m/z:[M+2H]2+found 314.1；calcd.626.1.
This red solid powder (63mg,0.1mmol) was dissolved in acetonitrile (15ml) under nitrogen, excess iodomethane was added, the mixture was stirred at room temperature overnight, after completion of the reaction, the solvent was dried under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether as a poor solvent to recrystallize 1081.9mg, which was a 90% yield compound.1H NMR(400MHz,CD3OD)δ7.73(s,1H),4.32(s,4H),3.15(s,18H),2.79(s,6H),2.31(s,6H).13CNMR(151MHz,CD3OD)δ157.86,145.90,132.52,123.64,84.86,83.06,58.33,53.36,49.61,17.81,13.85.HRMS(ESI)m/z:[M-2I]2+found 328.0522；calcd.328.0517.。
Example 11: synthesis of Compound 11
4-alkynyl pyridine (154mg,1.5mmol) and ethylmagnesium bromide (1.5ml,1.5mmol) were dissolved in dry THF (20ml) under nitrogen atmosphere, reacted at 60 ℃ for 2 hours, and 2I-BDP (75mg,0.15mmol) was added to the reaction solution and stirred overnight. After completion of the reaction, the reaction mixture was dried by spinning, extracted with DCM and saturated aqueous sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 200/1, v/v) to obtain 45.6mg of red solid powder with a yield of 45%.1HNMR(400MHz,CDCl3)δ8.50(d,J＝2.2Hz,4H),7.23(d,J＝0.6Hz,5H),2.86(s,6H),2.29(s,6H).MS(ESI)m/z:[M+2H]2+found 338.0；calcd.666.0
This red solid powder (40mg,0.06mmol) was dissolved in acetonitrile (15ml) under nitrogen, excess iodomethane was added, stirred overnight at room temperature, after the reaction was complete, the solvent was spin-dried under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether as a poor solvent and recrystallized to give 1129mg of compound in 51% yield.1HNMR(600MHz,CD3OD)δ8.80(d,J＝6.7Hz,4H),8.00(d,J＝6.8Hz,4H),7.82(s,1H),4.36(s,6H),2.87(s,6H),2.37(s,6H).13C NMR(151MHz,CD3OD)δ156.22,144.46,144.32,140.18,130.56,128.81,128.68,121.70,81.24,47.53,15.57,11.83.HRMS(ESI)m/z:[M-2I]2+found 348.0213；calcd.348.0204.。
Example 12: synthesis of Compound 12
3-alkynyl pyridine (154mg,1.5mmol), ethyl magnesium bromide (1.5ml,1.5mmol) were dissolved in dry THF (20ml) under nitrogen,after 2 hours at 60 ℃ 2I-BDP (75mg,0.15mmol) was added to the reaction solution, and the mixture was stirred overnight. After completion of the reaction, the reaction mixture was dried by spinning, extracted with DCM and saturated aqueous sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, concentrated by rotary evaporation under reduced pressure, and purified by alumina chromatography (DCM/MeOH ═ 200/1, v/v) to give 66mg of red solid powder in 66% yield.1H NMR(400MHz,CDCl3)δ8.61(s,2H),8.45(d,J＝3.8Hz,2H),7.67(d,J＝7.0Hz,2H),7.22(s,1H),7.19(dd,J＝6.9,4.7Hz,2H),2.89(s,6H),2.29(s,6H).MS(ESI)m/z:[M+2H]2+found 338.0；calcd.666.0
This red solid powder (40mg,0.06mmol) was dissolved in acetonitrile (15ml) under nitrogen, excess iodomethane was added, stirred overnight at room temperature, after completion of the reaction, the solvent was dried under reduced pressure, and the residue was dissolved in an appropriate amount of methanol and ether was used as a poor solvent to recrystallize 1238mg, 67% yield.1H NMR(400MHz,D6-DMSO)δ9.13(s,2H),8.88(s,2H),8.56(d,J＝7.1Hz,2H),8.04(s,3H),4.26(s,6H),2.83(s,6H),2.30(s,6H).13C NMR(151MHz,D6-DMSO)δ156.58,151.68,147.25,142.33,137.82,130.47,122.18,120.99,119.99,92.06,81.87,65.24,16.45,13.22.HRMS(ESI)m/z:[M-2I]2+found 348.0211；calcd.348.0204.。
Example 13: measurement of optical parameters of Compounds
The synthesized compound was tested for the maximum absorption wavelength (abs lambda) in acetonitrilemax) Molar extinction coefficient (. epsilon.), fluorescence emission wavelength (. lamda.) (flu. lamda.)max) Fluorescence quantum yield (phi)f) Efficiency of photosensitization: (1O2rate) and the oil-water distribution coefficient (logP) are shown in table 1, and the photosensitization efficiency is referred to Rose Bengal. The result shows that the introduction of a dicationic group at the position 4 of the BODIPY makes the BODIPY amphiphilic, and different substituents have no significant influence on the spectral properties of the dye; the introduction of iodine atoms enables molecular spectrum red shift, molar extinction coefficient change is small, fluorescence quantum yield is reduced, photosensitization efficiency is remarkably improved, and compounds 1-12 have strong photosensitization efficiency and are shown to be excellent photosensitizers.
TABLE 1 Properties of BODIPY dyes
Example 14: antimicrobial Activity test
And (3) culturing microorganisms: the experiment selects staphylococcus aureus (S.aureus, ATCC25923), escherichia coli (E.coli, ATCC25922), candida albicans (C.albicans, ATCC14053) and methicillin-resistant staphylococcus aureus (MRSA, ATCC43300), the culture medium is LB broth culture medium which contains tryptone, yeast extract, NaCl and the like and contains 5% CO at 37 DEG C2Culturing in an incubator.
And (3) activity test: the CFU concentration is 1X 105Bacteria (CFU concentration 1X 10)3Candida albicans) was incubated with the serially diluted compounds for 20min, followed by irradiation with an LED or the like having a maximum emission wavelength of 520nm for 30min at a light intensity of 10mW/cm2Light dose of 18J/cm2And culturing in a constant temperature box at 37 ℃ for 24 hours, observing whether the bacteria solution is clear or turbid, and taking the minimum concentration of the compound corresponding to the clarification of the bacteria solution as the minimum inhibitory concentration. The results are shown in Table 2.
TABLE 2 MIC of photosensitizer
Example 15: dose dependent testing
And (3) culturing microorganisms: the experiment selects staphylococcus aureus (S.aureus, ATCC25923), escherichia coli (E.coli, ATCC25922), candida albicans (C.albicans, ATCC14053) and methicillin-resistant staphylococcus aureus (MRSA, ATCC43300), the culture medium is LB broth culture medium which contains tryptone, yeast extract, NaCl and the like and contains 5% CO at 37 DEG C2Culturing in an incubator.
Concentration dependence test: the CFU concentration was OD600nmThe microorganism of 1.0 was incubated with the serially diluted compound 10 for 10min, followed by irradiation with an LED or the like having a maximum emission wavelength of 520nm at a light intensity of 10mW/cm for 10min2Light dose of 6J/cm2(to the white idea)Bacteria 9J/cm2) The control group was not illuminated, and then the inhibition curves were measured by plate counting, the results being shown in fig. 1 and fig. 2-5.
Light dose dependence test: the CFU concentration was OD600nmIncubating the microorganism of 1.0 with compound 10 of a certain concentration for 10min, and then irradiating the mixture for 0-15 min by using an LED with the maximum emission wavelength of 520nm and the like, wherein the light intensity is 10mW/cm2Light dose is 0-9J/cm2In the control group, compound 10 was not added, and then the inhibition curve was measured by plate counting, and the results are shown in fig. 1 and fig. 2 to 5.
The photosensitizer 10 has no killing ability to the strain, namely, does not show dark toxicity when not being irradiated after being incubated with the strain.
The ability of the photosensitizer 10 to kill staphylococcus aureus, escherichia coli, candida albicans, and methicillin-resistant staphylococcus aureus after incubation with the strain and light exposure increases with increasing compound concentration and light dose.
