Ionic chalcogenide five-membered heterocyclic conjugated oligomer as well as preparation method and application thereof

Abstract

The invention discloses an ionic chalcogenide five-membered heterocyclic conjugated oligomer as well as a preparation method and application thereof. In order to solve the problems that a common Type-II photosensitive drug has high dependence on oxygen, and high activity is difficult to keep continuously; in order to solve the problems of low photosensitization activity, low reactive oxygen free radical yield and insufficient antibacterial activity caused by undefined molecular design mechanism of the chalcogenide five-membered heterocyclic conjugated oligomer structure and the problems of low photosensitization activity, low reactive oxygen free radical yield and insufficient antibacterial activity of a Type-I photosensitive drug, the invention discloses an ionic photosensitive drug based on a chalcogenide five-membered heterocyclic conjugated oligomer structure, and the generation of reactive oxygen free radicals of the ionic photosensitive drug is remarkably increased. And it is proved that the Type-I photodynamic reaction performance is improved. In addition, the antibacterial activity of the conjugated oligomer is remarkably enhanced, the dosage of effective concentration is remarkably reduced, and methicillin-resistant staphylococcus aureus, staphylococcus aureus and escherichia coli can be quickly inactivated by using the nanomole-level dosage. The photosensitive drug disclosed by the invention has excellent antibacterial property and biological friendliness, and is expected to become one of candidate drugs of a photodynamic antibacterial therapy in clinical application.

Description

Technical Field

[0001] The invention belongs to biomedical technology and relates to a photosensitizing drug antibacterial agent, specifically an ionic sulfide five-membered heterocyclic conjugated oligomer and a preparation method and application thereof. Background Art

[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 parent core structure of antibiotics in the 1980s. The long-term irrational use of antibiotics and the resurgence and spread of unknown pathogens caused by the worsening greenhouse effect have led to a global pandemic of multidrug-resistant bacteria. Therefore, it is urgent to develop new methods and new drugs. Photodynamic antimicrobial therapy, as an important method to combat bacterial resistance, has demonstrated its unique advantages, but it still faces many challenges, especially the high oxygen dependence and insufficient activity sustainability of widely used Type-II photosensitizers, which seriously limit further clinical application and development. Type-I photosensitizers can recycle oxygen and generate free radicals such as highly toxic hydroxyl radicals in situ, while taking into account high activity and adaptability to hypoxic environments, which is expected to improve the activity and persistence of current photodynamic antimicrobial therapy. However, there is a severe shortage of Type-I photosensitizers at present. More importantly, the molecular design principles and potential photochemical mechanisms of Type-I photosensitizers are unclear, making it difficult to achieve a breakthrough in photosensitization efficiency. Therefore, the development of highly effective and universal Type-I photosensitizers is an important scientific issue in the field of antibacterial and anti-infection and needs to be urgently addressed. Summary of the invention

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

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

[0005] An ionic sulfide five-membered heterocyclic conjugated oligomer, the chemical structure of which is as follows: ; 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 valid; m and n are independently selected from 0 to 1, preferably, the values ​​of m and n are 0 or 1 respectively, and m≠n; R is selected from one of the following chemical structural formulas: , , .

[0006] The invention discloses a method for preparing the above-mentioned ionic sulfide five-membered heterocyclic conjugated oligomer, comprising the following steps: using a compound of formula V and a compound of formula VI as raw materials to react to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer; or using a compound of formula X and a compound of formula XI as raw materials to react to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer.

[0007] Wherein, the chemical structural formulas of the compound of formula V, the compound of formula VI, the compound of formula X, and the compound of formula XI are as follows:

[0008]

[0009] Wherein, the substituents refer to the ionic sulfur-based five-membered heterocyclic conjugated oligomer; s and q are 0 to 1 and s≠q.

[0010] In the present invention, the molar ratio of the compound of formula V to the compound of formula VI is 1:2.5-4; the compound of formula V and the compound of formula VI are reacted at room temperature for 10-20 hours under nitrogen conditions to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer, and further, after the reaction is completed, the product is separated and purified to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer.

[0011] Preferably, piperidine is used as a catalyst, and the compound of formula V and the compound of formula VI are used as raw materials to react to obtain an ionic sulfur-containing five-membered heterocyclic conjugated oligomer; further preferably, the molar ratio of the compound of formula V to piperidine is 1:1-2.

[0012] In the present invention, the molar ratio of the compound of formula X to the compound of formula XI is 1:2.5-4; the compound of formula X and the compound of formula XI are reacted at 60-90° C. for 15-30 hours under nitrogen conditions to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer, and further, after the reaction is completed, the product is separated and purified to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer.

[0013] Preferably, bistriphenylphosphine palladium dichloride and cuprous iodide are used as catalysts, and the compound of formula X and the compound of formula XI are used as raw materials to react to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer; further preferably, bistriphenylphosphine palladium dichloride is 0.1 to 0.15 equivalents, cuprous iodide is 0.1 to 0.3 equivalents, and the amount of the compound of formula X is 1 equivalent.

[0014] Preferably, the ionic sulfide five-membered heterocyclic conjugated oligomer has a structure as described in Formula II:

[0015] Preferably, the ionic sulfide five-membered heterocyclic conjugated oligomer has a structure as described in Formula III:

[0016] Preferably, the ionic sulfide five-membered heterocyclic conjugated oligomer has a structure as described in Formula IV:

[0017] The invention discloses application of the ionic sulfide five-membered heterocyclic conjugated oligomer in preparing medicines.

[0018] The invention discloses the application of the ionic sulfide five-membered heterocyclic conjugated oligomer in the preparation of antibacterial drugs.

[0019] The invention discloses the application of the ionic sulfide five-membered heterocyclic conjugated oligomer in the preparation of photodynamic antibacterial drugs.

[0020] The invention discloses the use of the ionic sulfide five-membered heterocyclic conjugated oligomer as a photosensitizer in the preparation of a photodynamic antibacterial drug.

[0021] The invention discloses a medicine, the active component of which is the above-mentioned ionic sulfide five-membered heterocyclic conjugated oligomer.

[0022] The present invention provides an ionic sulfide five-membered heterocyclic conjugated oligomer and its preparation method and application. First, the sulfide atoms, conjugation length and ionic substituents of the conjugated oligomer skeleton are adapted and optimized to obtain a series of conjugated oligomer photosensitizers with a new structure. Secondly, this type of conjugated oligomer can effectively produce reactive oxygen species under light irradiation, among which the generation of reactive oxygen free radicals is significantly increased, proving that the Type-I photodynamic reaction performance is improved. Finally, the antibacterial activity of this type of conjugated oligomer is significantly enhanced, the dosage of the effective concentration is significantly reduced, and the nanomolar dosage can quickly inactivate methicillin-resistant Staphylococcus aureus, Staphylococcus aureus and Escherichia coli. The photosensitizer described in the present invention has excellent antibacterial properties and biofriendliness, and is expected to become one of the candidate drugs for the clinical application of photodynamic antibacterial therapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 Evaluation of Type-I photodynamic performance of conjugated oligomer (Formula II), including (a) hydroxyl radical generation evaluation and (b) superoxide anion generation evaluation.

[0024] Figure 2 The conjugated oligomer (Formula II) has photodynamic activity against Staphylococcus aureus.

[0025] Figure 3 The conjugated oligomer (Formula II) has photodynamic activity against drug-resistant Staphylococcus aureus.

[0026] Figure 4 Comparison of the photodynamic anti-Escherichia coli activity of OTS (a) and conjugated oligomer (Formula II) (b). DETAILED DESCRIPTION

[0027] The present invention provides an ionic sulfide five-membered heterocyclic conjugated oligomer and a preparation method and application thereof. The ionic sulfide five-membered heterocyclic conjugated oligomer has a structure as described in Formula I: 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 valid; m and n are independently selected from 0 to 1, preferably, the values ​​of m and n are 0 or 1 respectively, and m≠n; R is selected from one of the following chemical structural formulas: , , .

[0028] The ionic sulfide five-membered heterocyclic conjugated oligomer described in formula I, when m=1 and n=0, has a synthesis method as follows: using ethanol as a solvent and piperidine as a catalyst, reacting the compounds of formula V and formula VI at a molar ratio of 1:2.5~4 under nitrogen conditions at room temperature for 10 to 20 hours, separating and purifying the product to obtain the conjugated oligomer shown in formula VII; the molar ratio of the compound of formula V to piperidine is 1:1~2; in formula V, s is 1 and q is 0.

[0029]

[0030] The synthesis method of the conjugated oligomer of formula V is as follows: using methanol and toluene (preferably equal volumes) as solvents, potassium carbonate and bis(diphenylphosphino)ferrocenepalladium dichloride as catalysts, reacting the compounds of formula VIII and formula IX at a molar ratio of 1:2.5-4 under nitrogen conditions at 60-90° C. for 10-20 hours, separating and purifying the product to obtain the conjugated oligomer of formula V; wherein the potassium carbonate is 4-8 equivalents, the bis(diphenylphosphino)ferrocenepalladium dichloride is 0.1-0.25 equivalents, and the amount of the compound of formula VIII is 1 equivalent.

[0031]

[0032] Preferably, the ionic sulfide five-membered heterocyclic conjugated oligomer has a structure described by Formula II:

[0033] Preferably, the ionic sulfide five-membered heterocyclic conjugated oligomer has a structure as described in Formula III:

[0034] The ionic sulfide five-membered heterocyclic conjugated oligomer of formula I, when m=0 and n=1, is synthesized by: using triethylamine and N,N-dimethylformamide (preferably equal volumes) as solvents, bistriphenylphosphine palladium dichloride and cuprous iodide as catalysts, reacting the compounds of formula X and formula XI at a molar ratio of 1:2.5-4 under nitrogen conditions at a temperature of 60-90°C for 15-30 hours, separating and purifying the product to obtain the conjugated oligomer of formula XII; wherein the bistriphenylphosphine palladium dichloride is 0.1-0.15 equivalents, the cuprous iodide is 0.1-0.3 equivalents, and the amount of the compound of formula X is 1 equivalent.

[0035]

[0036] The synthesis method of the conjugated oligomer of formula X is as follows: using triethylamine and tetrahydrofuran (preferably in a volume ratio of 1:2) as solvents, bistriphenylphosphine palladium dichloride and cuprous iodide as catalysts, formula XIII and trimethylsilyl acetylene in a molar ratio of 1:2 to 4, heating to 60 to 90°C under nitrogen conditions for reaction for 15 to 24 hours, concentrating the crude product after the reaction and using 1 molL -1 Deprotection is carried out with tetrabutylammonium fluoride tetrahydrofuran solution, and the product is separated and purified to obtain a conjugated oligomer represented by formula X; wherein bistriphenylphosphine palladium dichloride is 0.1 to 0.15 equivalents, cuprous iodide is 0.1 to 0.3 equivalents, and the amount of the compound represented by formula XIII is 1 equivalent.

[0037]

[0038] The synthesis method of the conjugated oligomer of formula XIII is as follows: using carbon tetrachloride as solvent, reacting formula V and bromosuccinimide at a molar ratio of 1:3-6, reflux reaction for 12-24 hours, separating and purifying the product, and obtaining the conjugated oligomer of formula XIII. In formula V, s=q=0.

[0039] Preferably, the ionic sulfide five-membered heterocyclic conjugated oligomer has a structure as described in Formula IV.

[0040]

[0041] In the above chemical structure formula, the selection of substituents or letters is the same as that of the compound of formula I. When m=1 and n=0, q and s are 0 or 1 and q≠s; when m=0 and n=1, q=s=0.

[0042] Preferably, when the above-mentioned ionic sulfur-containing five-membered heterocyclic conjugated oligomer is used as a photosensitizer for photodynamic antibacterial treatment, the generation of superoxide anion radicals and hydroxyl radicals increases by about 3 and 17 times respectively through Type-I photodynamic reaction.

[0043] Preferably, the bacterial species used in the photodynamic antibacterial application are Escherichia coli (ATCC25922), Staphylococcus aureus (ATCC25923), and methicillin-resistant Staphylococcus aureus (ATCC43300), and the number of bacterial cells is 5 to 9×10 7 CFU mL -1 .

[0044] Preferably, the illumination conditions in photodynamic antibacterial treatment are as follows: the light source is a xenon lamp and the wavelength range is controlled within 400-700 nm through a filter, the illumination time is 30 minutes, and the irradiance is 30 mW cm -2 .

[0045] Preferably, the conjugated oligomer of Formula I as a photosensitizer requires a minimum dosage of only 20 nM to achieve an antibacterial rate of more than 95%.

[0046] The present invention is further described in detail below in conjunction with the accompanying drawings and examples. Obviously, the following examples are provided in order to better further understand the present invention, are not limited to the best mode of implementation, and do not limit the content and protection scope of the present invention. Any product identical or similar to the present invention obtained by anyone under the enlightenment of the present invention or by combining the features of the present invention with other prior arts falls within the protection scope of the present invention. The chemical reagents used in the embodiments of the present invention are all conventional reagents and medicines. Unless otherwise specified, the experimental data of the bacterial experiment are the average values ​​of 3 repeated tests.

[0047] Example 1: In Formula I, X=Y=S, m=1, n=0 and R= Taking the conjugated oligomer (Formula II) as an example, the preparation process and specific preparation method are as follows:

[0048] Synthesis of intermediate 3: In a 50 mL round-bottom flask, 1 equivalent of raw material 1, 4 equivalents of raw material 2 and 5 equivalents of catalyst potassium carbonate were dissolved in a mixed solvent of methanol and toluene (volume ratio of 1:1); after the reaction solution was degassed, 0.1 equivalent of bis(diphenylphosphino)ferrocenepalladium dichloride was added, and then reacted at 75°C under nitrogen protection for 12 hours. The reaction mixture was restored to room temperature, extracted, dried and concentrated, and then separated by column chromatography (petroleum ether: dichloromethane = 20:1, v:v) to obtain intermediate 3 (yield 70%).

[0049] Synthesis of formula II: In a 50 mL round-bottom flask, 1 equivalent of intermediate 3 and 2.4 equivalents of raw material 4 were dissolved in ethanol. After the reaction solution was degassed, 2 equivalents of piperidine were added, and then the reaction was carried out overnight at 78°C under nitrogen protection. The reaction mixture was restored 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).

[0050] Example 2: In formula I, X=Se, Y=S, m=1, n=0 and R= Taking the conjugated oligomer (Formula III) as an example, the preparation process and specific preparation method are as follows:

[0051] Synthesis of intermediate 6: In a 100 mL round-bottom flask, 1 equivalent of raw 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 at 0°C using a constant pressure dropping funnel, and the mixture was reacted at 65°C for 1 h. Finally, the reaction mixture was cooled to -78°C, and 2 equivalents of 1,2-dibromotetrachloroethane (1,2-dibromotetrachloroethane) in diethyl ether were added, then the mixture was restored to room temperature and reacted for 12 hours. The crude product was extracted, dried and concentrated, and then separated by column chromatography (petroleum ether) to obtain intermediate 6 (yield 22%).

[0052] 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 of 1:1). After the reaction solution was degassed, 0.15 equivalents of bis(diphenylphosphino)ferrocenepalladium dichloride were added, and then the reaction was carried out at 75°C under nitrogen protection overnight; the reaction mixture was restored 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%).

[0053] Synthesis of intermediate 10: In a 50 mL round-bottom flask, 1 equivalent of intermediate 8 and 2.5 equivalents of raw material 9 were dissolved in chloroform. After the reaction solution was degassed, 2 equivalents of piperidine were added, and then the reaction was carried out at 78°C under nitrogen protection for 12 hours; the reaction mixture was restored to room temperature, concentrated and separated by column chromatography (petroleum ether: dichloromethane = 40:1, v:v) to obtain intermediate 10 (yield 62%).

[0054] Synthesis of formula III: In a 50 mL round-bottom flask, 1 equivalent of intermediate 10 was dissolved in tetrahydrofuran, and then 2 equivalents of nitrosohexafluorophosphate in acetonitrile were added to the reaction solution through a constant pressure dropping funnel and reacted 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 mixed solution of methanol and water, and then vacuum dried to obtain the 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).

[0055] Example 3: In Formula I, X=S, Y=Se, m=0, n=1 and R= Taking the conjugated oligomer (Formula IV) as an example, the preparation process and specific preparation method are as follows:

[0056] Synthesis of intermediate 13: In a 50 mL round-bottom flask, 1 equivalent of raw material 11, 3 equivalents of raw material 12 and 5 equivalents of catalyst potassium carbonate were dissolved in a mixed solvent of methanol and toluene (volume ratio of 1:1). After the reaction solution was degassed, 0.1 equivalent of bis(diphenylphosphino)ferrocenepalladium dichloride was added, and then the reaction was carried out at 75°C under nitrogen protection for 12 hours. The reaction mixture was restored to room temperature, extracted, dried and concentrated, and then separated by column chromatography (petroleum ether: dichloromethane = 20:1, v:v) to obtain intermediate 13 (yield 65%).

[0057] 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 restored to room temperature, extracted, dried and concentrated, and then separated by column chromatography (petroleum ether: dichloromethane = 50:1, v:v) to obtain intermediate 14 (yield 84%).

[0058] Synthesis of intermediate 16: In a 50 mL round-bottom flask, 1 equivalent of intermediate 14 and 2.2 equivalents of raw material 15 were dissolved in a mixed solvent of triethylamine and tetrahydrofuran (volume ratio of 1:2). After the reaction solution was degassed, 0.1 equivalent of catalyst bistriphenylphosphine palladium dichloride and 0.2 equivalent of cuprous iodide were added, and then refluxed for 12 hours under nitrogen protection. The reaction mixture was restored to room temperature, concentrated, and a 1 M tetrabutylammonium fluoride (TBAF) tetrahydrofuran solution was added to the crude product. After reacting at room temperature for 1 h, the reaction solution was concentrated and separated by column chromatography (petroleum ether) to obtain intermediate 16 (yield 64%).

[0059] Synthesis of Formula IV: In a 50 mL round-bottom flask, 1 equivalent of intermediate 16 and 2.5 equivalents of raw material 17 were dissolved in a mixed solvent of triethylamine and N,N-dimethylformamide (volume ratio of 1:1). After the reaction solution was degassed, 1.1 equivalents of catalyst bistriphenylphosphine palladium dichloride and 1.1 equivalents of cuprous iodide were added, and then reacted at 70°C for 20 h under nitrogen protection. The reaction mixture was restored to room temperature, concentrated, and separated by column chromatography (dichloromethane: methanol = 40:1, v:v) to obtain the product of Formula IV (yield 52%). 1 HNMR (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).

[0060] Example 4

[0061] The Type-I photodynamic reaction performance of the conjugated oligomer (Formula II) was evaluated by characterizing the production of superoxide anion radicals and hydroxyl radicals, and the production of free radicals was quantitatively characterized by the fluorescent probe method. Specifically, it is a conventional technology, in which the probe used to detect superoxide anions is DHR123, and the working concentration is 5 μM; the probe used to detect hydroxyl radicals is HPF, and the working concentration is 5 μM. The conjugated oligomer (Formula II) was excited with a xenon lamp as the light source (the band was controlled at 400~700 nm through a filter), and the growth of the fluorescence intensity of the fluorescent probe over time was recorded, and the monitoring time range was 1~5 min. See Figure 1 ,Experiments showed that the generation of hydroxyl radicals (a) and superoxide anion radicals (b) of the conjugated oligomer (Formula II) increased by about 17 and 3 times, respectively, through Type-I photodynamic reaction.

[0062] According to the conventional method, the low-temperature preserved bacteria (Escherichia coli, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus, purchased from the China Industrial Microbiological Culture Collection Center) were streaked and activated on LB solid medium. Single colonies were selected in LB liquid medium and shaken for 18 hours for proliferation culture. After the culture was completed, the medium was discarded and resuspended with physiological saline. The turbidity value (OD600) of the bacterial solution at 600 nm was read by an enzyme reader to quantify the number of bacterial cells. The OD600 reading was controlled at 0.1, so that the number of bacterial cells was 1×10 8 CFU mL -1 A xenon lamp was used as the light source (the wavelength was controlled at 400-700 nm by a filter) to excite the conjugated oligomer (Formula II) to initiate the photodynamic reaction, and the free radicals generated by the Type-I pathway achieved efficient antibacterial activity with an irradiance of 30 mW cm -2 The illumination time is 30 min. Drugs are expressed in concentrations, which refers to their concentrations in physiological saline.

[0063] See also Figure 2 The experiment showed that the conjugated oligomer (Formula II) can achieve an antibacterial rate of more than 95% against Staphylococcus aureus through Type-I photodynamic reaction with only 20 nM (IC50: 2 nM); compared with the reported photosensitizer OT-Se ( Chinese Chemical Letters , 2024, 35 , 108535.) compared to the reported photosensitizer OTE ( ACS Appl. Mater. Interfaces 2016, 8 , 1019.) Compared with the conventional method, the dosage of drug required to achieve more than 95% antibacterial effect was reduced to one-fourth (OTE required 80 nM, IC50: 10 nM), and the irradiance was reduced to one-third (OTE required 90 mW cm -2 ), the antibacterial activity was greatly improved.

[0064] See also Figure 3 , the antibacterial activity of the conjugated oligomer (Formula II) against methicillin-resistant Staphylococcus aureus was further studied, and only 150 nM was required to achieve an antibacterial rate of more than 95% (IC50: 46 nM).

[0065] See also Figure 4, further designed parallel experiments, synthesized the molecule in the reported patent (CN2015104159384) named OTS, with the structural formula m=0, n=3, R selected from -N + (CH 3 ) 3 I － ), and compared the photodynamic antibacterial activity of OTS and conjugated oligomers (Formula II) against Escherichia coli under the same experimental conditions. The results showed that the conjugated oligomer (Formula II) of the present invention could inactivate more than 95% of bacteria at a concentration of 200nM (IC50: 40 nM), while the antibacterial rate of OTS (IC50: 378 nM) was less than 50% under the same conditions, further proving the excellent antibacterial performance of the photosensitizer disclosed in the present invention.

[0066] Bacterial resistance is one of the world's top ten public health crises and a hot scientific issue at the forefront of world science and technology. Although the problem of bacterial resistance has received widespread attention, the large-scale and irregular use of alcohol, chlorine-containing disinfectants and antibiotics is exerting selective pressure on bacteria. If effective measures are not taken, the problem of bacterial resistance will accelerate. In addition, with the continuous intensification of the greenhouse effect, glaciers around the world are melting on a large scale, and the risk of unknown pathogenic bacteria that have been frozen for tens to hundreds of thousands of years being released into the environment is also increasing. In order to cope with the pandemic of infectious diseases that may be caused by the worsening of bacterial resistance, photodynamic antibacterial therapy stands out because of its high efficiency, broad spectrum, low toxicity and low resistance, but this method has not yet reached the ideal state for clinical application. The main reason is the lack of high-performance photosensitizers with a new photodynamic reaction mechanism. Therefore, the development of new photosensitizers, improving the various defects exposed in the clinical application of photodynamic antibacterial therapy, or as a reserve of candidate drugs to cope with possible pandemics of infectious diseases have important research significance and broad market prospects.

[0067] Bacterial resistance is one of the major challenges threatening human health. Photodynamic antimicrobial therapy is one of the effective strategies to overcome the dilemma of bacterial resistance, but the currently widely used Type-II photosensitizers have exposed problems such as high oxygen dependence and insufficient activity sustainability, and the wide clinical application of this therapy is greatly limited. The present invention designs a series of novel ionic sulfur-based five-membered heterocyclic conjugated oligomer photosensitizers. Through the analysis of the generation of reactive oxygen species, it is proved that this type of photosensitizer can initiate antibacterial therapy through the Type-I photodynamic reaction process, effectively reducing the dependence on oxygen and enhancing the activity sustainability; in addition, the faster and stronger reactive oxygen species generation performance of this type of photosensitizer also significantly reduces the effective dose to the nanomolar level, further reducing side effects. This type of photosensitizer has excellent antibacterial properties and biofriendliness, and is expected to become one of the candidate drugs for the clinical application of photodynamic antimicrobial therapy.

Claims

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

3. The method for preparing the ionic sulfide five-membered heterocyclic conjugated oligomer according to claim 1, comprising the following steps: using the compound of formula V and the compound of formula VI as raw materials to react to obtain the ionic sulfide five-membered heterocyclic conjugated oligomer; or using the compound of formula X and the compound of formula XI as raw materials to react to obtain the ionic sulfide five-membered heterocyclic conjugated oligomer; wherein, The chemical structural formulas of the compound of formula V, the compound of formula VI, the compound of formula X, and the compound of formula XI are as follows: ； 。 4. The method for preparing the ionic sulfide five-membered heterocyclic conjugated oligomer according to claim 3, characterized in that: The molar ratio of the compound of formula V to the compound of formula VI is 1:2.5-4, and the compound of formula V and the compound of formula VI react at room temperature for 10-20 hours under nitrogen conditions to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer; the molar ratio of the compound of formula X to the compound of formula XI is 1:2.5-4, and the compound of formula X and the compound of formula XI react at 60-90°C for 15-30 hours under nitrogen conditions to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer.

5. The method for preparing the ionic sulfide five-membered heterocyclic conjugated oligomer according to claim 3, characterized in that: Piperidine is used as a catalyst, and compounds of formula V and VI are used as raw materials to react to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer; bistriphenylphosphine palladium dichloride and cuprous iodide are used as catalysts, and compounds of formula X and XI are used as raw materials to react to obtain an ionic sulfide five-membered heterocyclic conjugated oligomer.

6. A drug, characterized in that The active ingredient is the ionic sulfide five-membered heterocyclic conjugated oligomer described in claim 1.

7. Use of the ionic sulfide five-membered heterocyclic conjugated oligomer according to claim 1 in the preparation of medicines.

8. Use of the ionic sulfide five-membered heterocyclic conjugated oligomer according to claim 1 in the preparation of antibacterial drugs.

9. Use of the ionic sulfide five-membered heterocyclic conjugated oligomer according to claim 1 in the preparation of photodynamic antibacterial drugs.

10. Use of the ionic sulfide five-membered heterocyclic conjugated oligomer according to claim 1 as a photosensitizer in the preparation of photodynamic antibacterial drugs.

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