TB derivatives with photodynamic antibacterial and anti-tumor activity and synthesis method thereof

Abstract

The invention provides a TB derivative with photodynamic antibacterial and anti-tumor activity and a synthesis method thereof, the derivative comprises a carbazole-TB-thiophene-pyridinium derivative, the structural formula of the derivative is shown in the specification, and the four derivatives have good viscosity response and aggregation-induced emission property and can efficiently and synchronously generate I-type and II-type active oxygen. The TB-CB-1, the TB-TPA-1 and the TB-TPA-2 have good photodynamic antibacterial activity on tested gram positive bacteria (G + bacteria), and the antibacterial rates of the TB-CB-1, the TB-TPA-1 and the TB-TPA-2 on the three kinds of G + bacteria are all larger than 90% when the concentration of the TB-CB-1, the TB-TPA-1 and the TB-TPA-2 is 2 mol. L <-1 >. The four compounds have strong photodynamic anti-tumor activity and large light and dark toxicity difference, the IC50 values of the TB-CB-1 to MCF-7, A549 and HepG2 cells are all greater than 100 [mu] g.mL <-1 > in the absence of illumination, and the IC50 values are respectively reduced to 1.53 [mu] g.mL <-1 > and 0.28 [mu] g.mL <-1 > under illumination; the IC50 of the TB-TPA-2 to A549 cells under a dark condition is greater than 200 [mu] g.mL <-1 >, and the illumination is reduced to 2.01 [mu] g.mL <-1 >. The invention provides a new thought for design and synthesis of a novel photodynamic antibacterial / antitumor photosensitizer.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to the synthesis method of carbazole (triphenylamine)-Tröger's base (TB)-(thiophene)-pyridinium derivatives and their application in the field of photodynamic antibacterial / antitumor. Background Technology

[0002] Carbazole possesses excellent hole transport capabilities, a wide band gap, multiple modifiable sites, and good thermal and photochemical stability. Its large steric hindrance and twisted molecular configuration allow for effective separation of its HOMO and LUMO, thereby reducing ΔE. ST Therefore, carbazole and its derivatives are among the most widely used electron donors in photosensitizer design.

[0003] The central nitrogen atom in triphenylamine gives it a large electron-donating ability, while its large Stokes shift and high fluorescence quantum yield make it more widely used than carbazole in photosensitizer design. More importantly, triphenylamine is a flexible, propeller-shaped molecule that readily exhibits AIE (Alternating Electron Induction) properties. This allows compounds containing the triphenylamine group to be widely used in fluorescent materials, bioimaging, optoelectronics, drug delivery, and therapeutic diagnostics.

[0004] Thiophene is an aromatic ring containing a sulfur atom. The sulfur atom has two pairs of n electrons outside the nucleus and a large atomic radius, making it easy to polarize. Introducing a thiophene group into an organic molecule can increase the length of the conjugated system and increase the electron cloud density of the system, thereby improving the ISC efficiency and ROS generation capacity of the entire molecule and further enhancing its aPDT activity.

[0005] Tröger's base (TB) possesses a V-shaped, non-planar, rigid structure, which avoids intermolecular π-π stacking; it has eight π electrons and two lone pairs of electrons, making it an excellent electron donor. Theoretical calculations show that the TB framework has multiple triplet levels (T1) with energies close to the singlet level (S1). n The potential for intersystem crossing is high, leading to a high probability of ROS generation. Therefore, theoretically, TB possesses both aggregation-induced emission (AIE) properties and high ROS generation efficiency, making it an advantageous framework for designing and synthesizing highly efficient aPDT photosensitizers. However, to date, there are no reports of AIE-based photosensitizers using TB as the framework.

[0006] Therefore, this invention synthesized two products using carbazole or triphenylamine as electron donors, TB backbone as electron donor and bridging group, and pyridinium as electron acceptor, respectively. To investigate the effect of thiophene on aPDT activity, a thiophene was introduced between TB and pyridinium, synthesizing two carbazole / triphenylamine-TB-(thiophene)-pyridinium compounds. The optical properties, AIE properties, and ROS generation capacity of all products were determined. Their aPDT activity against Staphylococcus aureus, MRSA, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus biofilms was detected under low-energy white light irradiation. By examining the effects of photosensitizers on bacteria before and after aPDT, such as changes in bacterial surface zeta potential, bacterial morphology (SEM), and intrabacterial ROS levels (CLSM), and combining the LogP of the photosensitizers, the aPDT mechanism of the products was explored. Preliminary tests were conducted on their photodynamic antitumor activity against A549, MCF-7, and HepG2. Summary of the Invention

[0007] Technical Problem: The purpose of this invention is to provide a class of TB derivatives with photodynamic antibacterial and antitumor activities and their synthesis method. By introducing carbazole or triphenylamine and a pyridinium group into the TB backbone, a carbazole (triphenylamine)-TB-thiophene-pyridinium derivative was designed and synthesized, and applied to the fields of photodynamic antibacterial and photodynamic antitumor activities. The excellent optical properties, aPDT activity against drug-resistant bacteria, and PDT antitumor activity of the product make it of great development value in the fields of hospital wastewater treatment, non-invasive antitumor drugs, viscosity probes, cell imaging, and organelle localization.

[0008] Technical solution: One type of TB derivative with photodynamic antibacterial and antitumor activity of the present invention is a carbazole or triphenylamine, TB, thiophene or pyridinium derivative, and its structural formula is shown as the following: first derivative TB-CB-1, second derivative TB-TPA-1, third derivative TB-CB-2 and fourth derivative TB-TPA-2: .

[0009] The method for synthesizing the first derivative TB-CB-1 includes the following steps: Step 1: 4-Bromoaniline reacts with paraformaldehyde to give the first intermediate, as shown in the following reaction formula:

[0010] Step 2: The first intermediate reacts with DMF to obtain the second intermediate, as shown in the following reaction formula:

[0011] Step 3: 4-Methylpyridine reacts with iodomethane to give the third intermediate, as shown in the following reaction formula:

[0012] Step 4: The second intermediate reacts with N-phenyl-3-carbazoleboric acid to give the fourth intermediate, as shown in the following reaction formula:

[0013] Step 5: The fourth intermediate reacts with the third intermediate to give the first derivative TB-CB-1, as shown in the following reaction formula: .

[0014] The method for synthesizing the second derivative TB-TPA-1 includes the following steps: Step 6: The second intermediate reacts with triphenylamine 4-boronic acid to give the fifth intermediate, as shown in the following reaction formula:

[0015] Step 7: The fifth intermediate reacts with the third intermediate to yield the second derivative TB-TPA-1, as shown in the following reaction formula: .

[0016] The method for synthesizing the third derivative TB-CB-2 includes the following steps: Step 8: The first intermediate reacts with N-phenyl-3-carbazoleboric acid to give the sixth intermediate, as shown in the following reaction formula:

[0017] Step 9: The sixth intermediate reacts with 5-aldehyde-2-thiopheneboronic acid to give the seventh intermediate, as shown in the following reaction formula:

[0018] Step 10: The seventh intermediate reacts with the third intermediate to give the third derivative TB-CB-2, as shown in the following reaction formula: .

[0019] The synthesis method of the fourth derivative TB-TPA-2 includes the following steps: Step 11: The first intermediate reacts with triphenylamine 4-boronic acid to obtain the eighth intermediate, as shown in the following reaction formula:

[0020] Step 12: The eighth intermediate reacts with 5-aldehyde-2-thiopheneboronic acid to give the ninth intermediate, as shown in the following reaction formula:

[0021] Step 13: The ninth intermediate reacts with the third intermediate to give the fourth derivative TB-TPA-2, as shown in the following reaction formula:

[0022] The application of the derivatives of the present invention with photodynamic antibacterial and antitumor activity lies in the application of TB-CB-1, TB-TPA-1, TB-CB-1 and TB-TPA-2 in the preparation of viscosity probes.

[0023] The application of TB-CB-1, TB-TPA-1, TB-CB-1 and TB-TPA-2 in the preparation of aggregation-induced emission materials.

[0024] The application of TB-CB-1, TB-TPA-1, TB-CB-1 and TB-TPA-2 in the preparation of photodynamic antibacterial drugs.

[0025] The application of TB-CB-1, TB-TPA-1, TB-CB-1 and TB-TPA-2 in the preparation of photodynamic antitumor drugs.

[0026] The antibacterial properties described are inhibition against Staphylococcus aureus, MRSA, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa; The anti-tumor effect is specifically targeting the inhibition of HepG2, A549, and MCF-7.

[0027] Beneficial effects: The carbazole (triphenylamine)-TB-thiophene-pyridinium derivative of the present invention has the following advantages: 1. A carbazole (triphenylamine)-TB-thiophene-pyridinium photosensitizer was synthesized for the first time. The synthesis method is simple and the post-processing is convenient. 2. The product has good viscosity response capability and has the potential to become a viscosity response probe; it has significant AIE properties and is expected to realize imaging-guided PDT.

[0028] 3. The product has a stronger ROS generation capacity than commercially available photosensitizers, and can generate both type I and type II ROS simultaneously. The synergistic effect of type I and type II ROS in the tumor microenvironment can overcome the problem of low PDT activity in the tumor microenvironment of most photosensitizers that can only generate type II ROS.

[0029] 4. The synthesized photosensitizer has strong light absorption and conversion efficiency, and can be used in LED white light with light intensity far below the literature average. Achieving G under the stimulation + It exhibits highly effective inhibition of bacteria and possesses high biosafety.

[0030] 5. The synthesized photosensitizer has a positive effect on G. + The bacteria exhibited good aPDT effect under low-power illumination (LED white light, 1.89 mW / cm²) far below the literature values. 2Under these conditions, a 2 μmol / L photosensitizer drug was used to treat three tested G... + All bacteria showed an inhibition rate of over 90%, including methicillin-resistant Staphylococcus aureus (MRSA).

[0031] 6. All synthesized photosensitizers exhibit strong photodynamic antitumor activity and show significant differences in phototoxicity and dark toxicity: TB-CB-1 showed an IC50 of 1 against MCF-7, A549, and HepG2 cells in the absence of light. 50 Values ​​all >100 μg·mL -1 Under light, the concentration decreased to 1.53 μg·mL. -1 and 0.28 μg·mL -1 TB-TPA-2 effect on IC50 of A549 cells under dark conditions 50 >200μg·mL -1 The light intensity decreased to 2.01 μg·mL -1 PDT's antitumor activity far exceeds that of most type I antitumor photosensitizers currently reported, and it has significant value for further research.

[0032] 7. The excellent optical properties, drug-resistant aPDT activity, and PDT antitumor activity of the two products make them of great development value in the fields of non-invasive antitumor drugs, viscosity probes, cell imaging, and organelle localization. Attached Figure Description

[0033] Figure 1 The fluorescence emission spectra (a) and broken line graphs (b) of compound TB-CB-1 at different viscosities are shown. Figure 2 The fluorescence emission spectra (c) and broken line graphs (d) of compound TB-TPA-1 at different viscosities are shown. Figure 3 The fluorescence emission spectra (a) and broken line graphs (b) of compound TB-CB-2 at different viscosities are shown. Figure 4 The fluorescence emission spectra (c) and broken line graphs (d) of compound TB-TPA-2 at different viscosities are shown. Figure 5 The bactericidal ability of different concentrations of TB-CB-1 against Staphylococcus aureus (A), Escherichia coli (B), and MRSA (C) is measured using the plate count method. Figure 6 The bactericidal activity of different concentrations of TB-TPA-1 against Staphylococcus aureus (A), Escherichia coli (B), and MRSA (C) (plate count method). Figure 7The bactericidal activity of different concentrations of TB-TPA-2 against Staphylococcus aureus (A), Escherichia coli (B), and MRSA (C) (plate count method). Figure 8 It is the fourth intermediate 1 H NMR spectrum; Figure 9 It is the fourth intermediate 13 C NMR spectrum; Figure 10 It is the fifth intermediate 1 H NMR spectrum; Figure 11 It is the fifth intermediate 13 C NMR spectrum; Figure 12 It is the sixth intermediate 1 H NMR spectrum; Figure 13 It is the sixth intermediate 13 C NMR spectrum; Figure 14 It is the seventh intermediate 1 H NMR spectrum; Figure 15 It is the seventh intermediate 13 C NMR spectrum; Figure 16 It is the eighth intermediate 1 H NMR spectrum; Figure 17 It is the eighth intermediate 13 C NMR spectrum; Figure 18 It is the ninth intermediate 1 H NMR spectrum; Figure 19 It is the ninth intermediate 13 C NMR spectrum; Figure 20 It is compound TB-CB-1 1 H NMR spectrum; Figure 21 It is compound TB-CB-1 13 C NMR spectrum; Figure 22 It is compound TB-TPA-1 1 H NMR spectrum; Figure 23 It is compound TB-TPA-1 13 C NMR spectrum; Figure 24 It is compound TB-CB-2 1 H NMR spectrum; Figure 25 It is compound TB-CB-2 13 C NMR spectrum; Figure 26 It is compound TB-TPA-2 1 H NMR spectrum; Figure 27 It is compound TB-TPA-2 13 C10 NMR spectrum. Detailed Implementation

[0034] This invention designs and synthesizes carbazole (triphenylamine)-TB-(thiophene)-pyridinium derivatives by introducing carbazole or triphenylamine, thiophene, and pyridinium groups into the TB backbone. The invention then applies these derivatives to the preparation of viscosity probes, aggregation-induced emission materials, photodynamic antibacterial drugs, and photodynamic antitumor drugs. The antibacterial effect is the inhibition of Staphylococcus aureus, MRSA, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa; the antitumor effect is the inhibition of HepG2, A549, and MCF-7.

[0035] The present invention will be further described below with reference to the embodiments.

[0036] The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Those skilled in the art will understand that various changes and modifications can be made to the present invention without departing from the spirit and scope thereof.

[0037] The structural formulas of the synthesized carbazole (triphenylamine)-TB-(thiophene)-pyridinium derivatives are shown in Table 1:

[0038] Example 1: Synthesis of the product of the present invention In this embodiment, 4-bromoaniline, 4-bromo-3-methoxyaniline, paraformaldehyde, and pyridine-4-boronic acid were selected as raw materials. Carbazole or triphenylamine and pyridinium groups were introduced onto the synthesized TB skeleton through a simple reaction, resulting in the synthesis of four carbazole (triphenylamine)-TB-(thiophene)-pyridinium derivatives. The steps included: 1. Synthesis of the first intermediate 3 4-Bromoaniline (50.0 mmol) and paraformaldehyde (100.0 mmol) were added sequentially to a 200.0 mL round-bottom flask, which was then placed in a cryogenic bath and heated to -15 °C. Trifluoroacetic acid (100.0 mL, added dropwise over approximately 30 min) was slowly added dropwise with stirring, and the mixture was allowed to react at room temperature for 7 days. After the reaction was complete (tracked by TLC), the mixture was poured into ice water, the pH was adjusted to 9-10 with ammonia, and the mixture was cooled to room temperature. The mixture was then extracted with dichloromethane. The crude product was obtained by rotary evaporation. Acetone was added, and the mixture was heated until the crude product was completely dissolved. The product was recrystallized at room temperature, filtered, and washed with acetone to obtain the first intermediate 3.

[0039]

[0040] 2. Synthesis of the second intermediate 4 10.0 mmol of the first intermediate 3 was weighed into a 250 mL pear-shaped flask (prepared by igniting with a three-wick lamp to remove water before use). After purging with argon three times, 40 mL of freshly distilled tetrahydrofuran (THF) was added. The reaction mixture was then transferred to a Dewar flask at -78 °C (dry ice and acetone). Under argon protection, 10.0 mmol of n-butyllithium was added, and the reaction was allowed to proceed for 0.5 h. After this, 10.0 mmol of DMF was added, the Dewar flask was removed, and the mixture was stirred at room temperature for 12 h. The reaction was monitored by TLC until complete. After quenching with water, the mixture was extracted with DCM (50 mL, three times). The organic phase was collected, and the product was purified by column chromatography (PE:EA = 2:1) to obtain the second intermediate 4.

[0041]

[0042] 3. Synthesis of the third intermediate 7 1.0 mmol of 4-methylpyridine 5 was weighed into a 50 mL single-necked flask and stirred in an ice-water bath for 0.5 h. Then, 1.1 mmol of iodomethane was slowly added dropwise, during which a white solid was produced. After the addition was completed, the reaction was continued for 4 h (a large amount of solid precipitated). An appropriate amount of diethyl ether was added and stirred for 0.5 h. The mixture was then filtered, and the filter cake was washed with 20 mL of diethyl ether and dried to give the third intermediate 7, with a yield of 92%.

[0043]

[0044] 4. Synthesis of the fourth intermediate 9 and the fifth intermediate 11 Weigh 1.0 mmol of the second intermediate 4, 2.0 mmol of N-phenyl-3-carbazoleboronic acid 8 (or triphenylamine 4-boronic acid 10), 0.2 mmol of tetrakis(triphenylphosphine)palladium, and 5.0 mmol of anhydrous potassium carbonate into a 50 mL two-necked flask. Add 16 mL of toluene, 4 mL of ethanol, and 2 mL of deionized water as a mixed solvent. After purging the flask three times with argon gas, place it at 80 °C. o The reaction was carried out in an oil bath for 12 h, and TLC was monitored until the reaction was complete. After quenching with water, the reaction was extracted with DCM. The organic phase was collected, and the product was purified by column chromatography (PE:EA = 2:1). After drying, it was weighed to obtain the fourth intermediate 9 (or the fifth intermediate 11), with a yield of 62% (79%).

[0045]

[0046]

[0047] 5. Synthesis of the sixth intermediate 12 and the eighth intermediate 15 Weigh 1.0 mmol of first intermediate 3 (1.5 mmol), second intermediate 4 (or 0.2 mmol of triphenylamine 4-borate 10), tetrakis(triphenylphosphine)palladium, and 5.0 mmol of anhydrous potassium carbonate into a 50 mL two-necked flask. Add 16 mL of toluene, 4 mL of ethanol, and 2 mL of deionized water as a mixed solvent. After purging the flask three times with argon gas, place it at 80°C. o The reaction was carried out in an oil bath for 12 h, and TLC was monitored until the reaction was complete. After quenching with water, the reaction was extracted with DCM. The organic phase was collected, and the product was purified by column chromatography (PE:EA = 3:1). After drying, it was weighed to obtain the sixth intermediate 12 (or the eighth intermediate 15), with a yield of 47% (54%).

[0048]

[0049]

[0050] 6. Synthesis of the seventh intermediate 14 and the ninth intermediate 16 Weigh 1.0 mmol of intermediate 12 (or intermediate 15), 2.0 mmol of compound 13, 0.2 mmol of 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride, and 5.0 mmol of anhydrous potassium carbonate into a 50 mL two-necked flask. Add 10 mL of methanol and 10 mL of toluene as a mixed solvent. After purging the flask three times with argon, place it at 80°C. o The reaction was carried out in an oil bath for 12 hours, monitored by TLC until complete, quenched with water, and extracted with DCM. The organic phase was collected, and the product was purified by column chromatography (PE: EA = 2:1). After drying, it was weighed to obtain the seventh intermediate 14 (or the ninth intermediate 16), with a yield of 71% (74%).

[0051]

[0052]

[0053] 7. Synthesis of products TB-CB-1 and TB-TPA-1 Weigh 1.0 mmol of the fourth intermediate 9 (or the fifth intermediate 11) and 0.95 mmol of compound 7 into a 50 mL two-necked flask, add 5 mL of methanol and 5 mL of toluene respectively, purge the gas three times with argon, and then place the flask at 100 °C. o The reaction was carried out in an oil bath for 12 h. During the process, a yellow solid was precipitated. After the reaction was completed, when the temperature dropped to room temperature, 5 mL of diethyl ether was added and stirred for 0.5 h. The mixture was filtered, and the filter cake was washed with 20 mL of diethyl ether. If the final product was not pure, the filter cake could be washed with about 1 mL of methanol. The product was dried and weighed to obtain product TB-CB-1 (or TB-TPA-1), with a yield of 76% (81%).

[0054]

[0055]

[0056] 8. Synthesis of products TB-CB-2 and TB-TPA-2 Weigh 0.5 mmol of the seventh intermediate 14 (or the ninth intermediate 16) and 0.45 mmol of compound 7 into a 50 mL two-necked flask, add 5 mL of methanol and toluene respectively, purge the gas three times with argon, and then place in a 100 mL container. o The reaction was carried out in an oil bath for 12 h. During the process, a red solid was precipitated. After the reaction was completed, when the temperature dropped to room temperature, 5 mL of diethyl ether was added and stirred for 0.5 h. The mixture was filtered, and the filter cake was washed with 20 mL of diethyl ether. If the final product was not pure, the filter cake could be washed with about 1 mL of methanol. The product was dried and weighed to obtain TB-CB-2 (or TB-TPA-2), with a yield of 78% (81%).

[0057]

[0058]

[0059] First derivative (TB-CB-1) Chemical formula: C 41 H 33 IN4 The Chinese name is: 1-methyl-4-(2-(8-(9-phenyl-9-) H -carbazole-3-yl)-6 H ,12 H -5,11-methyldibenzo[ b,f [1,5]diazoazine-2-yl)vinyl)pyridine-1-iodide The English name is: 1-methyl-4-(2-(8-(9-phenyl-9H-carbazol-3-yl)-6 H ,12 H -5,11-methanodibenzo[ b,f ][1,5]diazocin-2-yl)vinyl)pyridin-1-ium iodide Appearance: Yellow solid Melting point: 221.3-221.9℃ 1H NMR spectrum: 1 H NMR (400 MHz, DMSO- D 6) δ 8.80 (d, J = 8.0 Hz, 2H, N + -α-H), 8.47 (s, 1H, Ar-H), 8.30 (d, J = 8.0 Hz, 1H, Ar-H), 8.13 (d, J = 8.0Hz, 2H, N + -β-H), 7.89 (d, J = 16.0 Hz, 1H, Ar-H), 7.69 (t, J = 8.0 Hz, 2H,Ar-H), 7.63 (t, J = 8.0 Hz, 3H, Ar-H), 7.54 (d, J = 16.0 Hz, 3H, Ar-H), 7.41-7.28 (m, 9H, ), 4.76 (t, J = 16.0 Hz, 2H, bridge -CH2-), 4.33 (m, 4H, -CH2-), 4.24 (d, 3H, -CH3). Carbon NMR spectrum: 13 C NMR (100 MHz, DMSO- D6) δ 153.09, 151.42, 147.21,145.49, 141.06, 140.94, 139.91, 137.31, 136.66, 132.69, 130.90, 130.76,129.41, 129.03, 128.25, 127.64, 127.54, 127.16, 127.00, 126.15, 125.97,125.76, 125.50, 125.47, 123.85, 123.68, 123.40, 122.26, 121.30, 120.69, 118.76, 110.44, 110.24, 66.74, 58.98, 58.66, 47.32. Mass spectrometry: HRMS (ESI) m / z : calcd for [C 41 H 33 N4] [M] + found (expected):581.2707 (581.2705). Second derivative (TB-TPA-1) Chemical formula: C 41 H 35 IN4 The Chinese name is: 4-(2-(8-)4-(diphenylamino)phenyl)-6 H ,12 H -5,11-methyldibenzo[ b,f [1,5]diazozinin-2-yl)vinyl)-1-methylpyridine-1-iodide The English name is: 4-(2-(8-(4-(diphenylamino)phenyl)-6 H ,12 H -5,11-methanodibenzo[ b,f ][1,5]dia-zocin-2-yl)vinyl)-1-methylpyridin-1-ium iodide Appearance: Yellow solid Melting point: 209.6-210.4℃ 1H NMR spectrum: 1 H NMR (400 MHz, DMSO- D 6) δ 8.81 (d, J = 8.0 Hz, 2H, N +-α-H), 8.14 (d, J = 8.0 Hz, 2H, N + -β-H), 7.90 (d, J = 16.0 Hz, 1H, Ar-H), 7.55 (d, J = 8.0 Hz, 1H, Ar-H), 7.47 (d, J = 8.0 Hz, 2H, Ar-H), 7.41 (d, J = 8.0Hz, 1H, Ar-H), 7.38 (s, 1H, Ar-H), 7.35 - 7.16 (m, 8H, 6Ar-H + 2C=CH), 7.02(m, 8H, Ar-H), 4.78 - 4.66 (m, 2H, bridge -CH2-), 4.26 (m, 7H, ). Carbon NMR spectrum: 13 C NMR (100 MHz, DMSO- D 6) δ 153.10, 151.36, 147.59,147.46, 146.82, 145.50, 140.94, 135.46, 134.45, 130.89, 130.12, 129.45,129.36, 128.98, 128.75, 127.83, 127.63, 127.54, 125.94, 125.87, 125.74,125.59, 125.11, 124.53, 123.95, 123.68, 122.27, 66.67, 58.89, 58.59, 47.34. Mass spectrometry: HRMS (ESI) m / z : calcd for [C 41 H 35 N4] + [M] + found (expected):583.2863 (583.2862). Third derivative (TB-CB-2) Chemical formula: C 45 H 35 IN4S The Chinese name is: 1-methyl-4-(2-(5-(9-(9-phenyl-9) H -carbazole-3-yl)-6 H ,12 H -5,11-methyldibenzo[ b,f[1,5]diazoazine-3-yl)thiophene-2-yl)vinyl)pyridine-1-iodonium The English name is: 1-methyl-4-(2-(5-(9-(9-phenyl-9H-carbazol-3-yl)-6 H ,12 H -5,11-methanodibenzo[ b,f ][1,5]diazocin-3-yl)thiophen-2-yl)vinyl)pyridin-1-iumiodide Appearance: Red solid Melting point: 241.2-241.6℃ 1H NMR spectrum: 1 H NMR (400 MHz, DMSO- D 6) δ 8.79 (d, J = 8.0 Hz, 2H, N + -α-H), 8.47 (s, 1H, Ar-H), 8.30 (d, J = 8.0 Hz, 1H, Ar-H), 8.15 (d, J = 8.0Hz, 2H, N + -β-H), 7.68 (q, J = 8.0 Hz, 3H, Ar-H), 7.63 (d, J = 8.0 Hz, 3H, Ar-H), 7.60 - 7.50 (m, 3H, Ar-H), 7.50 - 7.45 (m, 2H, Ar-H), 7.43 (d, J = 8.0Hz, 1H, Ar-H), 7.41 - 7.35 (m, 4H, Ar-H), 7.29 (t, J = 8.0 Hz, 1H, Ar-H), 7.25 (d, J = 8.0 Hz, 2H, C=CH), 7.10 (d, J = 16.0 Hz, 1H, Ar-H), 4.75 (t, J= 16.0 Hz, 2H, bridge -CH2-), 4.35 – 4.23 (m, 4H, -CH2-), 4.21 (s, 3H, N + -CH3). Carbon NMR spectrum: 13 C NMR (100 MHz, DMSO- D6) δ 152.67, 149.65, 147.65,147.30, 145.36, 141.07, 139.92, 139.51, 137.33, 136.68, 134.24, 133.99,132.74, 130.75, 129.70, 129.00, 128.66, 128.24, 127.16, 126.98, 126.15,125.78, 125.54, 125.48, 125.13, 124.78, 123.86, 123.52, 123.41, 121.91, 121.29, 120.68, 118.77, 110.43, 110.23, 66.80, 58.94, 58.68, 47.29. Mass spectrometry: HRMS (ESI) m / z : calcd for [C 45 H 35 N4S] + [M] + found (expected):663.2584 (663.2582). Fourth derivative (TB-TPA-2) Chemical formula: C 45 H 37 IN4S The Chinese name is: 4-(2-(5-(9-(4-(diphenylamino)phenyl)-6 H ,12 H -5,11-methyldinitrobenzo[ b,f [1,5]diazoazine-3-yl)thiophene-2-yl)vinyl)-1-methylpyridine-1-iodonium iodide The English name is: 4-(2-(5-(9-(4-(diphenylamino)phenyl)-6 H ,12 H -5,11-methanodibenzo[ b,f ][1,5]diazocin-3-yl)thiophen-2-yl)vinyl)-1-methylpyridin-1-ium iodide Appearance: Red solid Melting point: 220.9-221.6℃ 1H NMR spectrum: 1 H NMR (400 MHz, DMSO- D6) δ 8.80 (d, J = 8.0 Hz, 2H, N + -α-H), 8.15 (d, J = 8.0 Hz, 2H, N + -β-H), 7.51 (d, J = 8.0 Hz, 1H, Ar-H), 7.47(d, J = 8.0 Hz, 4H, Ar-H), 7.41 (d, J = 8.0 Hz, 1H, Ar-H), 7.34 (s, 1H, Ar-H), 7.30 (t, J = 8.0 Hz, 4H, Ar-H), 7.21 (d, J = 4.0 Hz, 2H, Ar-H), 7.18 (d,J = 8.0 Hz, 1H, Ar-H), 7.11 (d, J = 16.0 Hz, 1H, Ar-H), 7.01 (m, 8H, ), 4.77 - 4.64 (m, 2H, bridge -CH2-), 4.32-4.16 (m, 7H, ). Carbon NMR spectrum: 13 C NMR (100 MHz, DMSO- D 6) δ 152.67, 149.59, 147.63, 147.59, 147.54, 146.81, 145.37, 139.51, 135.47, 134.48, 134.24, 134.00, 130.12, 129.65, 128.96, 128.63, 127.83, 126.13, 125.77, 125.59, 125.12, 124.75, 124.53, 123.94, 123.66, 123.52, 121.92, 66.71, 58.83, 58.60, 49.14, 47.30. Mass spectrometry: HRMS (ESI) m / z : calcd for [C 45 H 37 N4S] + [M] + found (expected):665.2742 (665.2739). Example 2: Viscosity response of the product of the present invention Abnormal cells often have a higher viscosity than normal cells. The high viscosity within these cells restricts the movement of chemical bonds, making it easier for molecules to aggregate.

[0060] Take 0.1 mL of a concentration of The working solution was diluted to 10 mL with glycerol:water solutions in ratios of 1:9 and 9:1, respectively, and its fluorescence emission spectrum was measured. Figure 1-4 ).

[0061] As shown in the figure, the RFI of TB-CB-1 and TB-TPA-1 peaked at glycerol contents of 70% and 80%, respectively, representing increases of 50.1-fold and 4.7-fold, both exhibiting viscosity responsiveness. The relative fluorescence intensity (RFI) of TB-CB-2 and TB-TPA-2 peaked at glycerol contents of 60% and 70%, respectively, both also exhibiting viscosity responsiveness.

[0062] Example 3: In vitro photodynamic antibacterial activity of the product of the present invention The aPDT activities of TB-CB-1, TB-TPA-1, and TB-TPA-2 against five bacteria were tested using the plate colony counting method (see table below). Figure 5-7 ).

[0063] Table 2. Inhibition rate (%) of compound TB-TPA-1 against five bacteria under dark or light conditions. a

[0064] a Experimental conditions: LED white light Irradiate for 20 minutes; b It has no antibacterial activity.

[0065] Table 3. Inhibition rate (%) of compound TB-CB-1 against five bacteria under dark or light conditions. a

[0066] a Experimental conditions: LED white light Irradiate for 20 minutes; b It has no antibacterial activity.

[0067] Table 4. Inhibition rate (%) of compound TB-TPA-2 against five bacteria under dark or light conditions. a

[0068] a Experimental conditions: LED white light Irradiate for 20 minutes;b It has no antibacterial activity.

[0069] From Table 2-4 and Figure 5 - 7 shows that: 1. TB-CB-1 and TB-TPA-1 at 2 µmol·L -1 Both exhibited inhibition rates exceeding 90% against Staphylococcus aureus. Compared to RB, although its ROS production was higher, its aPDT activity was slightly reduced. TB-TPA-1 and TB-CB-1 at 4 µmol·L⁻¹ -1 or 2µmol·L -1 The inhibition rates against MRSA were 96.4% and 95.8%, respectively, indicating high aPDT activity. Under light irradiation, TB-CB-1, TB-TPA-1, and TB-TPA-2 all showed good inhibition rates at a concentration of 2 µmol·L⁻¹. -1 The four compounds showed an inhibition rate of over 99% against Bacillus subtilis. They also showed no aPDT activity against Escherichia coli and Pseudomonas aeruginosa.

[0070] 2. The concentration of TB-CB-2 reached 16 µmol·L⁻¹. -1 No aPDT activity was found in any of the five bacteria, which is inconsistent with the ROS assay results. Further investigation is needed to determine the specific reasons.

[0071] 3. Although TB-CB-2 and TB-TPA-2 have higher ROS production than TB-CB-1 and TB-TPA-1, their aPDT activity is actually lower. This may be because the introduction of electron-rich thiophene disperses some of the positive charge, affecting the binding degree of TB-CB-2 and TB-TPA-2 to the bacterial membrane.

[0072] Example 4: In vitro photodynamic antitumor activity of the product of the present invention Given the excellent ROS generation capacity of the four compounds, their PDT antitumor activity against HepG2, A549 and MCF-7 cells was tested (see Table 6).

[0073] Table 6. IC50 of four compounds on test cells in the dark or under light. 50 Value (μg·mL) -1 )

[0074] Table 6 shows that TB-TPA-1 has an IC50 value for MCF-7 cells. 50 The value was 1.36 μg·mL -1 For HepG2 cells, the concentration was 0.35 μg / mL. -1 However, it also has strong dark toxicity to these two types of tumor cells.

[0075] TB-CB-1 IC50 of these two tumor cell types under dark conditions 50 The values ​​were all greater than 100, indicating very low dark toxicity, which decreased to 1.53 μg·mL under light conditions. -1 and 0.28 μg·mL -1 TB-TPA-2 effect on IC50 of A549 cells under dark conditions 50 Greater than 200 μg·mL -1 The light intensity decreased to 2.01 μg·mL -1 Both are excellent PDT antitumor photosensitizers and have great value for further research.

[0076] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A class of TB derivatives having photodynamic antibacterial and antitumor activity, characterized in that The derivative is a carbazole or triphenylamine, TB, thiophene or pyridine onium derivative, and the structural formula is shown in the first derivative TB-CB-1, the second derivative TB-TPA-1, the third derivative TB-CB-2 and the fourth derivative TB-TPA-2 as follows: 。 2. A method for synthesizing a class of TB derivatives having photodynamic antibacterial and antitumor activity according to claim 1, characterized in that, The synthesis method of the first derivative TB-CB-1 comprises the following steps: Step 1: 4-bromoaniline (1) reacts with paraformaldehyde (2) to obtain a first intermediate (3), and the reaction formula is as follows: ； Step 2: The first intermediate (3) reacts with DMF to obtain a second intermediate (4), and the reaction formula is as follows: ； Step 3: 4-methylpyridine (5) reacts with iodomethane (6) to obtain a third intermediate (7), and the reaction formula is as follows: ； Step 4: The second intermediate (4) reacts with N-phenyl-3-carbazole boronic acid (8) to obtain a fourth intermediate (9), and the reaction formula is as follows: ； Step 5: The fourth intermediate (9) reacts with the third intermediate (7) to obtain the first derivative TB-CB-1, and the reaction formula is as follows: 。 3. The method of synthesis of a class of TB derivatives having photodynamic antibacterial and antitumor activity according to claim 2, characterized in that, The synthesis method of the second derivative TB-TPA-1 comprises the following steps: Step 6: The second intermediate (4) reacts with 4-boronic acid triphenylamine (10) to obtain a fifth intermediate (11), and the reaction formula is as follows: ； Step 7: The fifth intermediate (11) reacts with the third intermediate (7) to obtain the second derivative TB-TPA-1, and the reaction formula is as follows: 。 4. The method of synthesis of a class of TB derivatives having photodynamic antibacterial and antitumor activity according to claim 3, characterized in that, The synthesis method of the third derivative TB-CB-2 comprises the following steps: Step 8: The first intermediate (3) reacts with N-phenyl-3-carbazole boronic acid (8) to obtain a sixth intermediate (12), and the reaction formula is as follows: ； Step 9: The sixth intermediate (12) reacts with 5-aldehyde-2-thiophene boronic acid (13) to obtain a seventh intermediate (14), and the reaction formula is as follows: ； Step 10: The seventh intermediate (14) reacts with the third intermediate (7) to obtain the third derivative TB-CB-2, and the reaction formula is as follows: 。 5. The method of synthesis of a class of TB derivatives having photodynamic antibacterial and antitumor activity according to claim 4, characterized in that, The synthesis method of the fourth derivative TB-TPA-2 comprises the following steps: ； Step 11: The first intermediate (3) reacts with 4-boronic acid triphenylamine (10) to obtain an eighth intermediate (15), and the reaction formula is as follows: ； Step 12: The eighth intermediate (15) reacts with 5-aldehyde-2-thiophene boronic acid (13) to obtain a ninth intermediate (16), and the reaction formula is as follows: 。 6. The use of a TB derivative of the class having photodynamic antibacterial and antitumor activity according to claim 1, characterized in that Step 13: The ninth intermediate (16) reacts with the third intermediate (7) to obtain the fourth derivative TB-TPA-2, and the reaction formula is as follows:

7. The use of a derivative of TB having photodynamic antibacterial and antitumor activity according to claim 6, characterized in that The TB-CB-1, TB-TPA-1, TB-CB-1 and TB-TPA-2 are applied to prepare a viscosity probe.

8. The use of a derivative of TB having photodynamic antibacterial and antitumor activity according to claim 7, characterized in that The TB-CB-1, TB-TPA-1, TB-CB-1 and TB-TPA-2 are applied to prepare an aggregation-induced emission material.

9. The use of a derivative of TB having photodynamic antibacterial and antitumor activity according to claim 8, characterized in that The TB-CB-1, TB-TPA-1, TB-CB-1 and TB-TPA-2 are applied to prepare a photodynamic antibacterial drug. The TB-CB-1, TB-TPA-1, TB-CB-1 and TB-TPA-2 are applied to prepare a photodynamic antitumor drug.

10. The use of a derivative of TB having photodynamic antibacterial and antitumor activity according to claim 9, characterized in that, The antibacterial is inhibition to Staphylococcus aureus, MRSA, Bacillus subtilis, Escherichia coli and Pseudomonas aeruginosa; the antitumor is inhibition to HepG2, A549 and MCF-7.

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