Ion-type chalcogen five-membered heterocyclic conjugated oligomer and preparation method and application thereof

Abstract

This invention discloses an ionic chalcogenide five-membered heterocyclic conjugated oligomer, its preparation method, and its applications. To address the problems of commonly used Type-II photosensitizing drugs' high oxygen dependence, making it difficult to maintain high activity sustainably; and the unclear molecular design mechanism of Type-I photosensitizing drugs, leading to low photosensitization activity, low reactive oxygen species (ROS) production, and insufficient antibacterial activity, this invention discloses an ionic photosensitizing drug based on a chalcogenide five-membered heterocyclic conjugated oligomer structure. This drug significantly increases the generation of ROS, demonstrating improved Type-I photodynamic response performance. Furthermore, the antibacterial activity of the conjugated oligomer of this invention is significantly enhanced, requiring significantly lower effective concentrations; nanomolar doses are sufficient to rapidly inactivate methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, and Escherichia coli. The photosensitizing drug described in this invention possesses excellent antibacterial properties and biofriendliness, and is expected to become one of the candidate drugs for photodynamic antibacterial therapy in clinical applications.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to a photosensitive antibacterial agent, specifically an ionic chalcogenide five-membered heterocyclic conjugated oligomer, its preparation method, and its application. Background Technology

[0002] The discovery and widespread use of antibiotics have effectively controlled the spread of bacterial diseases. However, most of the new antibiotics approved in recent decades are derivatives developed based on the core structures of antibiotics from the 1980s. Furthermore, the long-term irrational use of antibiotics, coupled with the resurgence and spread of unknown pathogens due to the worsening greenhouse effect, has led to a global pandemic of multidrug-resistant bacteria. Therefore, there is an urgent need to develop new methods and drugs. Photodynamic therapy (PDT), as an important method for combating bacterial resistance, has demonstrated unique advantages, but still faces many challenges, particularly the high oxygen dependence and insufficient activity persistence of widely used Type-II photosensitizing drugs, which severely limit further clinical application and development. Type-I photosensitizing drugs can recycle oxygen and generate free radicals such as highly toxic hydroxyl radicals in situ, while also possessing high activity and adaptability to hypoxic environments, potentially improving the activity and duration of current PDT. However, the variety of Type-I photosensitizing drugs is currently very limited. More importantly, the molecular design principles and potential photochemical mechanisms of Type-I photosensitizing drugs are unclear, making it difficult to achieve breakthroughs in photosensitization efficiency. Therefore, developing efficient and universally applicable Type-I photosensitizing drugs is an important scientific issue in the field of antibacterial and anti-infective drugs, and it needs to be solved urgently. Summary of the Invention

[0003] The technical problems to be solved by this invention are: (1) commonly used Type-II photosensitizing drugs are highly dependent on oxygen, making it difficult to maintain high activity continuously; (2) the molecular design mechanism of Type-I photosensitizing drugs is unclear, resulting in low photosensitization activity, low production of reactive oxygen free radicals, and insufficient antibacterial activity. In order to solve these problems, this invention discloses an ionic photosensitizing drug based on a chalcogenide five-membered heterocyclic conjugated oligomer structure.

[0004] The present invention adopts the following technical solution.

[0005] An ionic chalcogenide five-membered heterocyclic conjugated oligomer has the following chemical structural formula:

[0006] ;

[0007] Wherein, X and Y are selected from any one of sulfur (S), selenium (Se), and tellurium (Te), and X=Y or X≠Y are both true; m and n are independently selected from 0 to 1, preferably m and n are 0 or 1 respectively, and m≠n; R is selected from one of the following chemical structural formulas:

[0008] , , .

[0009] This invention discloses a method for preparing the above-mentioned ionic chalcogen five-membered heterocyclic conjugated oligomers, comprising the following steps: using compounds of formula V and formula VI as raw materials, reacting to obtain ionic chalcogen five-membered heterocyclic conjugated oligomers; or using compounds of formula X and formula XI as raw materials, reacting to obtain ionic chalcogen five-membered heterocyclic conjugated oligomers.

[0010] The chemical structural formulas of compounds V, VI, X, and XI are as follows:

[0011]

[0012]

[0013] The substituents refer to ionic chalcogenide five-membered heterocyclic conjugated oligomers; s and q take values ​​from 0 to 1 and s ≠ q.

[0014] In this invention, the molar ratio of compound V to compound VI is 1:2.5 to 4; compound V and compound VI are reacted at room temperature under nitrogen for 10 to 20 hours to obtain ionic chalcogen five-membered heterocyclic conjugated oligomers; further, after the reaction is completed, the product is separated and purified to obtain ionic chalcogen five-membered heterocyclic conjugated oligomers.

[0015] Preferably, piperidine is used as a catalyst and compounds of formula V and formula VI are used as raw materials to react and obtain ionic chalcogenide five-membered heterocyclic conjugated oligomers; more preferably, the molar ratio of compound V to piperidine is 1:1~2.

[0016] In this invention, the molar ratio of compound X to compound XI is 1:2.5~4; compound X and compound XI are reacted under nitrogen at 60~90℃ for 15~30 hours to obtain ionic chalcogen five-membered heterocyclic conjugated oligomers; further, after the reaction is completed, the product is separated and purified to obtain ionic chalcogen five-membered heterocyclic conjugated oligomers.

[0017] Preferably, bis(triphenylphosphine)palladium dichloride and cuprous iodide are used as catalysts, and compounds of formula X and formula XI are used as raw materials to react and obtain ionic chalcogenide five-membered heterocyclic conjugated oligomers; more preferably, the amount of bis(triphenylphosphine)palladium dichloride is 0.1 to 0.15 equivalents, the amount of cuprous iodide is 0.1 to 0.3 equivalents, and the amount of compound of formula X is 1 equivalent.

[0018] Preferably, the ionic chalcogenide five-membered heterocyclic conjugated oligomer has the structure described in Formula II:

[0019]

[0020] Preferably, the ionic chalcogenide five-membered heterocyclic conjugated oligomer has the structure described in Formula III:

[0021]

[0022] Preferably, the ionic chalcogenide five-membered heterocyclic conjugated oligomer has the structure described in Formula IV:

[0023]

[0024] This invention discloses the application of the above-mentioned ionic chalcogenide five-membered heterocyclic conjugated oligomers in the preparation of pharmaceuticals.

[0025] This invention discloses the application of the above-mentioned ionic chalcogenide five-membered heterocyclic conjugated oligomers in the preparation of antibacterial drugs.

[0026] This invention discloses the application of the above-mentioned ionic chalcogenide five-membered heterocyclic conjugated oligomers in the preparation of photodynamic antibacterial drugs.

[0027] This invention discloses the application of the above-mentioned ionic chalcogenide five-membered heterocyclic conjugated oligomers as photosensitizing drugs in the preparation of photodynamic antibacterial drugs.

[0028] This invention discloses a drug whose active ingredient is the above-mentioned ionic chalcogenide five-membered heterocyclic conjugated oligomer.

[0029] This invention provides an ionic chalcogenide five-membered heterocyclic conjugated oligomer, its preparation method, and its applications. First, the chalcogenide atoms, conjugation length, and ionic substituents in the conjugated oligomer skeleton were adapted and optimized, resulting in a series of novel conjugated oligomer photosensitive drugs. Second, these conjugated oligomers can effectively generate reactive oxygen species under light irradiation, with a significant increase in the generation of reactive oxygen free radicals, demonstrating improved Type-I photodynamic response performance. Finally, the antibacterial activity of these conjugated oligomers is significantly enhanced, and the effective concentration is significantly reduced; nanomolar doses are sufficient to rapidly inactivate methicillin-resistant Staphylococcus aureus, Staphylococcus aureus, and Escherichia coli. The photosensitive drugs described in this invention possess excellent antibacterial properties and biofriendliness, and are expected to become candidate drugs for clinical application of photodynamic antibacterial therapy. Attached Figure Description

[0030] Figure 1 The photodynamic properties of conjugated oligomer (Formula II) Type-I were evaluated, including (a) hydroxyl radical generation evaluation and (b) superoxide anion generation evaluation.

[0031] Figure 2 The photodynamic anti-Staphylococcus aureus activity of the conjugated oligomer (Formula II) was observed.

[0032] Figure 3 The photodynamic activity of the conjugated oligomer (Formula II) against drug-resistant Staphylococcus aureus was demonstrated.

[0033] Figure 4 Comparison of photodynamic anti-Escherichia coli activity of OTS (a) and conjugated oligomer (Formula II) (b). Detailed Implementation

[0034] This invention provides an ionic chalcogenide five-membered heterocyclic conjugated oligomer, its preparation method, and its application. The ionic chalcogenide five-membered heterocyclic conjugated oligomer has the structure described in Formula I:

[0035]

[0036] Wherein, X and Y are selected from any one of sulfur (S), selenium (Se), and tellurium (Te), and X=Y or X≠Y are both true; m and n are independently selected from 0 to 1, preferably m and n are 0 or 1 respectively, and m≠n; R is selected from one of the following chemical structural formulas:

[0037] , , .

[0038] The ionic chalcogen five-membered heterocyclic conjugated oligomer of Formula I, when m=1 and n=0, is synthesized as follows: using ethanol as solvent and piperidine as catalyst, compounds of Formula V and Formula VI are reacted at room temperature under nitrogen for 10-20 hours in a molar ratio of 1:2.5-4, and the product is separated and purified to obtain the conjugated oligomer shown in Formula VII; the molar ratio of compound V to piperidine is 1:1-2; in Formula V, s is 1 and q is 0.

[0039]

[0040] The method for synthesizing the conjugated oligomer of Formula V is as follows: using methanol and toluene (preferably in equal volumes) as solvents, potassium carbonate and bis(diphenylphosphine)ferrocene palladium dichloride as catalysts, the compounds of Formula VIII and Formula IX are reacted at a molar ratio of 1:2.5~4 under nitrogen at 60~90℃ for 10~20 hours, and the products are separated and purified to obtain the conjugated oligomer of Formula V; wherein the amount of potassium carbonate is 4~8 equivalents, the amount of bis(diphenylphosphine)ferrocene palladium dichloride is 0.1~0.25 equivalents, and the amount of compound of Formula VIII is 1 equivalent.

[0041]

[0042] Preferably, the ionic chalcogenide five-membered heterocyclic conjugated oligomer has the structure described in Formula II:

[0043]

[0044] Preferably, the ionic chalcogenide five-membered heterocyclic conjugated oligomer has the structure described in Formula III:

[0045]

[0046] The ionic chalcogen five-membered heterocyclic conjugated oligomer of Formula I, when m=0 and n=1, is synthesized as follows: using triethylamine and N,N-dimethylformamide (preferably in equal volumes) as solvents, and bis(triphenylphosphine) palladium dichloride and cuprous iodide as catalysts, compounds of Formula X and Formula XI are reacted at a molar ratio of 1:2.5~4 under nitrogen atmosphere at 60~90℃ for 15~30 hours. The product is then separated and purified to obtain the conjugated oligomer of Formula XII; wherein the amount of bis(triphenylphosphine) palladium dichloride is 0.1~0.15 equivalents, the amount of cuprous iodide is 0.1~0.3 equivalents, and the amount of compound X is 1 equivalent.

[0047]

[0048] The method for synthesizing the conjugated oligomer of Formula X is as follows: using triethylamine and tetrahydrofuran (preferably in a volume ratio of 1:2) as solvents, and bis(triphenylphosphine) palladium dichloride and cuprous iodide as catalysts, Formula XIII and trimethylsilylacetylene are reacted at a molar ratio of 1:2-4 under nitrogen atmosphere at a temperature of 60-90°C for 15-24 hours. After the reaction, the crude product is concentrated and treated with 1 mol / L... -1 The tetrabutylammonium fluoride was deprotected in a tetrahydrofuran solution, and the product was separated and purified to obtain the conjugated oligomer shown in Formula X; wherein the amount of bis(triphenylphosphine)palladium dichloride was 0.1~0.15 equivalents, the amount of cuprous iodide was 0.1~0.3 equivalents, and the amount of compound XIII was 1 equivalent.

[0049]

[0050] The method for synthesizing the conjugated oligomer of formula XIII is as follows: using carbon tetrachloride as solvent, formula V and bromosuccinimide are reacted under reflux at a molar ratio of 1:3~6 for 12~24 hours, and the product is separated and purified to obtain the conjugated oligomer shown in formula XIII. In formula V, s=q=0.

[0051] Preferably, the ionic chalcogenide five-membered heterocyclic conjugated oligomer has the structure described in Formula IV.

[0052]

[0053] In the above chemical structural formula, the choice of substituents or letters is the same as that of compound I. When m=1 and n=0, q and s take values ​​of 0 or 1 and q≠s; when m=0 and n=1, q=s=0.

[0054] Preferably, when the above-mentioned ionic chalcogenide five-membered heterocyclic conjugated oligomer is used as a photosensitizing drug for photodynamic antibacterial activity, the generation of superoxide anion free radicals and hydroxyl free radicals increases by approximately 3 and 17 times, respectively, through Type-I photodynamic reaction.

[0055] Preferably, the bacterial strains used in the photodynamic antibacterial application are *Escherichia coli* (ATCC25922) and *Staphylococcus aureus* (ATCC25923), and methicillin-resistant *Staphylococcus aureus* (ATCC43300), with a bacterial cell count of 5–9 × 10⁻⁶. 7 CFU mL -1 .

[0056] Preferably, the illumination conditions for photodynamic antibacterial treatment are as follows: the light source is a xenon lamp, and the wavelength range is controlled within 400–700 nm using a filter; the illumination time is 30 minutes; and the irradiance is 30 mW / cm². -2 .

[0057] Preferably, when the conjugated oligomer described in Formula I is used as a photosensitizing drug, the minimum dosage is only 20 nM to achieve an antibacterial rate of over 95%.

[0058] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Obviously, the following embodiments are provided to better understand the present invention and are not intended to limit the scope of the preferred embodiments. They do not constitute a limitation on the content and scope of protection of the present invention. Any product identical or similar to the present invention derived by any person under the guidance of the present invention or by combining the features of the present invention with other prior art falls within the scope of protection of the present invention. The chemical reagents used in the embodiments of the present invention are all conventional reagents and pharmaceuticals. Unless otherwise specified, the experimental data of the bacterial experiments are the average values ​​of three repeated experiments.

[0059] Example 1: Using X=Y=S, m=1, n=0 and R= in Equation I Taking the conjugated oligomer (Formula II) as an example, the preparation process and specific preparation method are as follows:

[0060]

[0061] Synthesis of Intermediate 3: In a 50 mL round-bottom flask, 1 equivalent of starter 1, 4 equivalents of starter 2, and 5 equivalents of catalyst potassium carbonate were dissolved in a mixed solvent of methanol and toluene (volume ratio 1:1). After degassing the reaction mixture, 0.1 equivalents of bis(diphenylphosphine)ferrocene palladium dichloride were added, and the mixture was reacted at 75 °C under nitrogen protection for 12 hours. The reaction mixture was then cooled to room temperature, extracted, dried, concentrated, and separated by column chromatography (petroleum ether:dichloromethane = 20:1, v:v) to obtain Intermediate 3 (yield 70%).

[0062] Synthesis of Formula II: In a 50 mL round-bottom flask, 1 equivalent of intermediate 3 and 2.4 equivalents of starting material 4 were dissolved in ethanol. After degassing the reaction mixture, 2 equivalents of piperidine were added, and the mixture was reacted overnight at 78 °C under nitrogen protection. The reaction mixture was then brought to room temperature, concentrated, and separated by column chromatography (dichloromethane:methanol = 40:1, v:v) to obtain the product of Formula II (yield 55%). 1 HNMR (400 MHz, DMSO- d 6) δ 8.82 (d, J = 6.4 Hz, 4H), 8.26 – 8.12 (m, 6H), 7.51(s, 6H), 7.18 (d, J = 15.9 Hz, 2H), 4.23 (s, 6H).

[0063] Example 2: Using X=Se, Y=S, m=1, n=0 and R= in Equation I Taking the conjugated oligomer (Formula III) as an example, the preparation process and specific preparation method are as follows:

[0064]

[0065] Synthesis of intermediate 6: In a 100 mL round-bottom flask, 1 equivalent of starting material 5 and 2.1 equivalents of catalyst N,N,N',N'-tetramethylethylenediamine (TMEDA) were dissolved in anhydrous and oxygen-free n-hexane. After mixing, 2.1 equivalents of sec-butyllithium solution were added dropwise using a constant-pressure dropping funnel at 0 °C, and the reaction was carried out at 65 °C for 1 h. Finally, the reaction mixture was cooled to -78 °C, and 2 equivalents of 1,2-dibromotetrachloroethane in diethyl ether solution were added. The mixture was then restored to room temperature and reacted for 12 h. The crude product was extracted, dried, and concentrated, and then separated by column chromatography (petroleum ether) to obtain intermediate 6 (yield 22%).

[0066] Synthesis of intermediate 8: In a 50 mL round-bottom flask, 1 equivalent of intermediate 6, 4.5 equivalents of raw material 7, and 5 equivalents of catalyst potassium carbonate were dissolved in a mixed solvent of methanol and toluene (volume ratio 1:1). After degassing the reaction mixture, 0.15 equivalents of bis(diphenylphosphine)ferrocene palladium dichloride were added, and the mixture was reacted overnight at 75 °C under nitrogen protection. The reaction mixture was then cooled to room temperature, extracted, dried, and concentrated, and then separated by column chromatography (petroleum ether: dichloromethane = 40:1, v:v) to obtain intermediate 8 (yield 72%).

[0067] Synthesis of intermediate 10: In a 50 mL round-bottom flask, 1 equivalent of intermediate 8 and 2.5 equivalents of starting material 9 were dissolved in chloroform. After degassing the reaction mixture, 2 equivalents of piperidine were added, and the mixture was reacted at 78 °C under nitrogen protection for 12 hours. The reaction mixture was then brought to room temperature, concentrated, and separated by column chromatography (petroleum ether: dichloromethane = 40:1, v:v) to obtain intermediate 10 (yield 62%).

[0068] Synthesis of Formula III: In a 50 mL round-bottom flask, 1 equivalent of intermediate 10 was dissolved in tetrahydrofuran. Then, a solution of acetonitrile in nitrosamine hexafluorophosphate (2 equivalents) was added to the reaction mixture through a constant-pressure dropping funnel, and the reaction was carried out at room temperature for 1 h. The crude product liquid was added dropwise to ice water, and the precipitate was collected by filtration. The precipitate was washed three times with an equal volume mixture of methanol and water, and then dried under vacuum to obtain product of Formula III (yield 80%). 1 H NMR (500 MHz, DMSO- d 6) δ 8.15 (s, 2H), 7.30 (d, J= 6.2 Hz, 2H), 7.23 – 7.18 (m, 2H), 6.66 – 6.59 (m, 2H), 6.19 –6.11 (m, 2H), 4.50 – 4.47 (m, 4H), 4.42 – 4.39 (m, 4H), 4.16 (s, 10H).

[0069] Example 3: Using X=S, Y=Se, m=0, n=1 and R= in Equation I Taking the conjugated oligomer (Formula IV) as an example, the preparation process and specific preparation method are as follows:

[0070]

[0071] Synthesis of Intermediate 13: In a 50 mL round-bottom flask, 1 equivalent of starting material 11, 3 equivalents of starting material 12, and 5 equivalents of catalyst potassium carbonate were dissolved in a mixed solvent of methanol and toluene (volume ratio 1:1). After degassing the reaction mixture, 0.1 equivalents of bis(diphenylphosphine)ferrocene palladium dichloride were added, and the reaction was carried out at 75 °C under nitrogen protection for 12 hours. The reaction mixture was then cooled to room temperature, extracted, dried, concentrated, and separated by column chromatography (petroleum ether:dichloromethane = 20:1, v:v) to obtain Intermediate 13 (yield 65%).

[0072] Synthesis of Intermediate 14: In a 50 mL round-bottom flask, 1 equivalent of Intermediate 13 and 4 equivalents of bromosuccinimide (NBS) were refluxed in carbon tetrachloride solution for 12 hours. The reaction mixture was brought to room temperature, extracted, dried, concentrated, and then separated by column chromatography (petroleum ether:dichloromethane = 50:1, v:v) to give Intermediate 14 (yield 84%).

[0073] Synthesis of Intermediate 16: In a 50 mL round-bottom flask, 1 equivalent of intermediate 14 and 2.2 equivalents of starting material 15 were dissolved in a mixed solvent of triethylamine and tetrahydrofuran (volume ratio 1:2). After degassing the reaction mixture, 0.1 equivalents of catalyst bis(triphenylphosphine)palladium dichloride and 0.2 equivalents of cuprous iodide were added, and the mixture was refluxed under nitrogen protection for 12 hours. The reaction mixture was brought to room temperature, concentrated, and then 1 M tetrabutylammonium fluoride (TBAF) in tetrahydrofuran solution was added to the crude product. The mixture was reacted at room temperature for 1 hour, and then concentrated again. Intermediate 16 was obtained by column chromatography (petroleum ether) (yield 64%).

[0074] Synthesis of Formula IV: In a 50 mL round-bottom flask, 1 equivalent of intermediate 16 and 2.5 equivalents of starting material 17 were dissolved in a mixed solvent of triethylamine and N,N-dimethylformamide (volume ratio 1:1). After degassing the reaction mixture, 1.1 equivalents of catalyst bis(triphenylphosphine)palladium dichloride and 1.1 equivalents of cuprous iodide were added, and the reaction was carried out at 70 °C for 20 h under nitrogen protection. The reaction mixture was then cooled to room temperature, concentrated, and separated by column chromatography (dichloromethane:methanol = 40:1, v:v) to obtain product of Formula IV (yield 52%). 1 H NMR (500 MHz, DMSO- d 6) δ 8.22 – 8.16 (m, 4H), 7.73 (d, J = 5.1 Hz, 2H), 7.66 – 7.56 (m, 6H), 7.45 (s, 2H).

[0075] Example 4

[0076] The Type-I photodynamic reactivity of the conjugated oligomer (Formula II) was evaluated by characterizing the production of superoxide anion radicals and hydroxyl radicals. The generation of radicals was quantitatively characterized using a fluorescent probe method. Specifically, conventional techniques were employed, with DHR123 (5 μM) used to detect superoxide anions and HPF (5 μM) used to detect hydroxyl radicals. The conjugated oligomer (Formula II) was excited using a xenon lamp (with wavelengths controlled between 400 and 700 nm via filters), and the increase in fluorescence intensity of the fluorescent probes over time was recorded, with a monitoring time range of 1–5 min. See [link to relevant documentation]. Figure 1 Experiments show that the generation of hydroxyl radicals (a) and superoxide anion radicals (b) increases by about 17 and 3 times, respectively, through the Type-I photodynamic reaction of conjugated oligomers (Formula II).

[0077] Following standard methods, cryopreserved bacterial strains (Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus, purchased from the China Industrial Microbial Culture Collection Center) were activated by streaking on LB solid medium. Single colonies were selected and cultured in LB liquid medium for 18 hours by shaking. After incubation, the medium was discarded, and the culture was resuspended in physiological saline. The bacterial cell count was quantified by reading the turbidity value (OD600) at 600 nm using a microplate reader. The OD600 reading was controlled at 0.1 to ensure a bacterial cell count of 1 × 10⁻⁶. 8 CFU mL -1Using a xenon lamp as a light source (with the wavelength controlled at 400-700 nm via filters), conjugated oligomers (Formula II) are excited to initiate a photodynamic reaction. Highly efficient antibacterial activity is achieved through free radicals generated via the Type-I pathway, with an irradiance of 30 mW cm⁻¹. -2 The light exposure time is 30 minutes. Drug concentration is expressed as its concentration in physiological saline.

[0078] See Figure 2 Experiments show that the conjugated oligomer (Formula II) achieves an antibacterial rate of over 95% against Staphylococcus aureus with only 20 nM (IC50: 2 nM) via Type-I photodynamic reaction; compared with the reported photosensitizer OT-Se ( Chinese Chemical Letters , 2024, 35 Compared to OT-Se (108535.), the amount of drug required to achieve an antibacterial effect of over 95% is reduced to two-fifths (OT-Se requires 50 nM); compared to the previously reported photosensitizer OTE ( ACS Appl. Mater. Interfaces 2016, 8 Compared to , 1019.), the amount of drug required to achieve an antibacterial effect of over 95% is reduced to one-quarter (OTE requires 80 nM, IC50: 10 nM), and the irradiance is reduced to one-third (OTE requires 90 mW cm⁻¹ irradiance). -2 The antibacterial activity was greatly enhanced.

[0079] See Figure 3 Further investigation was conducted on the antibacterial activity of the conjugated oligomer (Formula II) against methicillin-resistant Staphylococcus aureus, and an antibacterial rate of over 95% was achieved with only 150 nM (IC50: 46 nM).

[0080] See Figure 4 Further parallel experiments were designed to synthesize the molecule named OTS, as described in the reported patent (CN2015104159384), with structural formula m=0, n=3, and R selected from -N + (CH3)3I － The photodynamic antibacterial activity of OTS and the conjugated oligomer (Formula II) against Escherichia coli was compared under the same experimental conditions. The results showed that the conjugated oligomer (Formula II) of this invention, at a concentration of 200 nM (IC50: 40 nM), could inactivate more than 95% of the bacteria, while OTS (IC50: 378 nM) had an antibacterial rate of less than 50% under the same conditions, further demonstrating the excellent antibacterial properties of the photosensitizing drug disclosed in this invention.

[0081] Antimicrobial resistance is one of the world's top ten public health crises and a hot scientific issue at the forefront of global science and technology. Although the problem of antimicrobial resistance has received widespread attention, the extensive and unregulated use of alcohol, chlorine-based disinfectants, and antibiotics is exerting selective pressure on bacteria. If effective measures are not taken, this will accelerate the deterioration of the problem. Furthermore, with the intensifying greenhouse effect and the large-scale melting of glaciers worldwide, the risk of releasing unknown pathogenic bacteria, frozen for tens or hundreds of thousands of years, into the environment is increasing. To address the potential pandemics of infectious diseases caused by worsening antimicrobial resistance, photodynamic therapy (PDT) stands out due to its high efficiency, broad spectrum, low toxicity, and low tendency to induce resistance. However, this method has not yet reached its ideal state for clinical application. The main reason is the lack of high-performance photosensitizing drugs with novel photodynamic response mechanisms. Therefore, developing novel photosensitizing drugs, improving the various shortcomings exposed in the clinical application of PDT, or reserving them as candidate drugs to cope with potential pandemics of infectious diseases are of significant research importance and have broad market prospects.

[0082] Bacterial resistance is a major challenge threatening human health. Photodynamic therapy (PDT) is one of the effective strategies to overcome bacterial resistance, but currently widely used Type-II photosensitizing drugs have been found to have problems such as high oxygen dependence and insufficient activity persistence, which greatly limits the widespread clinical application of this therapy. This invention designs a series of novel ionic chalcogen five-membered heterocyclic conjugated oligomer photosensitizing drugs. Through reactive oxygen species generation analysis, it is demonstrated that these photosensitizing drugs can initiate antibacterial treatment through a Type-I photodynamic reaction process, effectively reducing oxygen dependence and enhancing activity persistence. Furthermore, the faster and stronger reactive oxygen species generation performance of these photosensitizing drugs significantly reduces the effective dose to the nanomolar level, further reducing side effects. These photosensitizing drugs possess excellent antibacterial properties and biofriendliness, and are expected to become one of the candidate drugs for clinical application of PDT.

Claims

1. An ionic chalcogen five-membered heterocyclic conjugated oligomer characterized in that, The chemical structural formula is as follows: ； wherein, X, Y are independently selected from any one of sulfur, selenium and tellurium; m, n are independently selected from 0-1, and m≠n; R is selected from one of the following chemical structural formulae: 、 。 2. The ionic chalcogen five-membered heterocyclic conjugated oligomer according to claim 1, characterized in that, X and Y are the same or different.

3. The method for preparing the ionic chalcogen five-membered heterocyclic conjugated oligomer of claim 1 comprises the following steps: using compounds of formula V and formula VI as raw materials, reacting to obtain the ionic chalcogen five-membered heterocyclic conjugated oligomer; or using compounds of formula X and formula XI as raw materials, reacting to obtain the ionic chalcogen five-membered heterocyclic conjugated oligomer; wherein, The chemical structural formulae of the compound of formula V, the compound of formula VI, the compound of formula X and the compound of formula XI are respectively as follows: ； ； s and q are 0-1 and s≠q.

4. The method of claim 3, wherein the ionene pentatomic heterocyclic conjugated oligomer is prepared by the reaction of a quaternary ammonium salt and a quinone. The molar ratio of the compound of formula V and the compound of formula VI is 1:2.5-4, the compound of formula V and the compound of formula VI are reacted under the condition of nitrogen at room temperature for 10-20 hours to obtain the ionic group pentatomic heterocyclic conjugated oligomer; the molar ratio of the compound of formula X and the compound of formula XI is 1:2.5-4, the compound of formula X and the compound of formula XI are reacted under the condition of nitrogen at 60-90℃ for 15-30 hours to obtain the ionic group pentatomic heterocyclic conjugated oligomer.

5. The method of claim 3, wherein the ionene pentatomic heterocyclic conjugated oligomer is prepared by the reaction of a quaternary ammonium salt with a halogenated aromatic compound. The ionic group pentatomic heterocyclic conjugated oligomer is obtained by taking piperidine as a catalyst and taking the compound of formula V and the compound of formula VI as raw materials; the ionic group pentatomic heterocyclic conjugated oligomer is obtained by taking dichlorobis(triphenylphosphine)palladium and cuprous iodide as a catalyst and taking the compound of formula X and the compound of formula XI as raw materials.

6. A medicament, characterized by comprising: The active ingredient is the ionic group pentatomic heterocyclic conjugated oligomer of claim 1.

7. The use of the ionic group pentatomic heterocyclic conjugated oligomer of claim 1 in the preparation of a photodynamic antibacterial drug.

8. The use of the ionic group pentatomic heterocyclic conjugated oligomer of claim 1 as a photosensitive drug in the preparation of a photodynamic antibacterial drug.

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