Bithionol derivative, and preparation method therefor and use thereof

Abstract

A bithionol derivative, and a preparation method therefor and a use thereof. The bithionol derivative is as represented by any one of chemical structural formulas I-1 to I-7. The bithionol derivative as represented by the structural formula exhibits better bacteriostatic activity against clinical isolates of gram-positive bacteria such as Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, and Staphylococcus epidermidis and the effect of inhibiting the formation of Staphylococcus aureus biofilms. As compared with bithionol and other bithionol derivatives, the bithionol derivative as represented by the structural formula has a lower inhibitory concentration, a better antibacterial effect, and potential application value in clinical antibacterial infection treatment.

Description

[Corrected 16.05.2024 according to Rule 26] Thiobisdichlorophenol derivatives and their preparation methods and uses Technical Field

[0001] The present invention relates to the field of medical technology, in particular to a thiobisdichlorophenol derivative and a preparation method and application thereof. Background Art

[0002] Gram-positive bacteria such as Staphylococcus aureus, Enterococcus faecalis, and Enterococcus faecium are common pathogens of both community-acquired and nosocomial infections. S. aureus, known as coagulase-positive Staphylococci, produces plasma coagulase and is one of the most pathogenic Staphylococci. Clinically, S. aureus is divided into two categories based on its methicillin sensitivity: methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA). The latest CHINET China Bacterial Resistance Monitoring results released in 2023 pointed out that among the 339,513 bacterial strains isolated clinically, the top three Gram-positive isolates in terms of the number of isolates were Staphylococcus aureus (9.47%), Enterococcus faecium (4.31%) and Enterococcus faecalis (3.60%); the detection rate of MRSA was still 28.7%, and the drug resistance situation was still relatively serious and common, and higher than MSSA; Staphylococcus aureus, as a common pathogen isolated clinically, can cause a variety of clinical infections, from mild skin infections, osteoarthritis, infective endocarditis, prosthetic device infections, and even to severe and fatal tissue infections and sepsis, threatening public health.

[0003] Although a wide range of antimicrobial agents are currently available for Gram-positive bacteria, the widespread use of antibiotics and the lengthy and arduous development of new antimicrobial agents have led to an increasing number of drug-resistant strains in recent years. MRSA, in particular, has become a major cause of infection. While antibiotics can control infections by inhibiting or killing bacteria, they also allow resistant strains to acquire mutations and survive and spread. The spread of drug-resistant bacteria far outpaces the development of new antimicrobial agents. Once bacteria develop resistance to top-tier antibiotics, clinical treatment of infections becomes even more challenging. Traditional antibiotics act by both killing and inhibiting bacteria, primarily by controlling bacterial growth through mechanisms such as affecting cell wall synthesis, preventing bacterial DNA replication, and inhibiting proteins required for growth. Therefore, developing new targets for broad-spectrum antimicrobial activity can provide more options for clinical treatment and facilitate the further development of antimicrobial agents.

[0004] Summary of the Invention

[0005] In response to the above technical problems, the present invention discloses a thiobisdichlorophenol derivative and its preparation method and application. The thiobisdichlorophenol derivative has the effects of effectively resisting the growth of Gram-positive bacteria and inhibiting the biofilm formation of Staphylococcus aureus.

[0006] To this end, the technical solution adopted in the present invention is:

[0007] A thiobisdichlorophenol derivative, which is any one of the following chemical structural formulas I-1 to I-7:

[0008] In this technical solution, compared with thiobisdichlorophenol, the thiobisdichlorophenol derivatives of the chemical structural formulas I-1 to I-7 have better anti-Gram-positive bacteria effects, and the minimum inhibitory concentration is greatly reduced.

[0009] The present invention also discloses a method for preparing the above-mentioned sulfur bis(dichlorophenol) derivative, comprising the following steps:

[0010] Step S1: dissolving bis(dichlorophenol)thiophene or bis(2-hydroxy-5-chlorophenyl)sulfide and K2CO3 in DMF or dichloromethane solvent and stirring for more than 20 minutes; then adding R3-X dropwise to react; wherein, when X=Cl and R3=COCH3, the solvent is dichloromethane and the reaction temperature is room temperature; for other R3-X, the temperature is raised to 55-65°C and the reaction is carried out for more than 4 hours;

[0011] Step S2, monitoring the reaction solution by TLC, cooling to room temperature after the reaction is completed, adding water to the reaction solution, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, drying the organic phase over anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product;

[0012] Step S3, purifying the obtained crude product by column chromatography, separating and purifying to obtain a thiobisdichlorophenol derivative.

[0013] Among them, R3-X corresponding to I-1, I-3, I-4 and I-5 are BrCH2CH2OH, BrCH2CH2Br, CH2CH=CH2Br and CH3I respectively, and R3-X corresponding to I-2, I-6 and I-7 is COCH3Br. After the reaction, TLC was used to monitor the elution and obtain them respectively.

[0014] Furthermore, the elution condition of the column chromatography is V (乙酸乙酯) ∶V (石油醚) =1:400~1:100. Specifically, the elution was monitored by TLC until the product was eluted.

[0015] The invention discloses a composition comprising the above-mentioned thiobisdichlorophenol derivative and a pharmaceutical adjuvant.

[0016] As a further improvement of the present invention, the pharmaceutical adjuvant includes at least one of a diluent, a stabilizer, and a preservative.

[0017] The present invention discloses the application of the above-mentioned thiobisdichlorophenol derivatives, and the thiobisdichlorophenol derivatives are used for preparing antibacterial drugs.

[0018] As a further improvement of the present invention, the antibacterial drug is a drug against Gram-positive bacteria.

[0019] As a further improvement of the present invention, the Gram-positive bacteria is at least one of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Enterococcus faecium.

[0020] The present invention discloses the use of the above-mentioned thiobisdichlorophenol derivatives in preparing antibacterial agents.

[0021] The present invention discloses the application of the above-mentioned sulfur bisdichlorophenol derivative in preparing antibacterial coating.

[0022] The present invention discloses the use of the above-mentioned thiobisdichlorophenol derivative in preparing a disinfectant.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The technical solution of the present invention discloses a thiobisdichlorophenol derivative that exhibits better antibacterial activity against clinical isolates of Gram-positive bacteria including Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Staphylococcus epidermidis, and the like, and inhibits the biofilm formation of Staphylococcus aureus. Compared with thiobisdichlorophenol and other thiobisdichlorophenol derivatives, the thiobisdichlorophenol derivative of the present invention has a lower antibacterial concentration and better antibacterial effect, and has potential application value in the clinical treatment of bacterial infections. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG1 is a diagram of compound I-1 obtained in an embodiment of the present invention. 1 H NMR spectrum.

[0026] Figure 2 is a diagram of compound I-1 obtained in an embodiment of the present invention. 13 C NMR spectrum.

[0027] FIG3 is a graph showing the compound I-2 obtained in an embodiment of the present invention. 1 H NMR spectrum.

[0028] FIG4 is a graph showing the compound I-2 obtained in an embodiment of the present invention. 13 C NMR spectrum.

[0029] Figure 5 is a diagram of compound I-3 obtained in an embodiment of the present invention. 1H NMR spectrum.

[0030] FIG6 is a graph showing the compound I-3 obtained in an embodiment of the present invention. 13 C NMR spectrum.

[0031] FIG7 is a graph showing the compound I-4 obtained in an embodiment of the present invention. 1 H NMR spectrum.

[0032] FIG8 is a graph showing the compound I-4 obtained in an embodiment of the present invention. 13 C NMR spectrum.

[0033] Figure 9 is a diagram of compound I-5 obtained in an embodiment of the present invention. 1 H NMR spectrum.

[0034] Figure 10 is a diagram of compound I-5 obtained in an embodiment of the present invention. 13 C NMR spectrum.

[0035] Figure 11 is a diagram of compound I-6 obtained in an embodiment of the present invention. 1 H NMR spectrum.

[0036] Figure 12 is a diagram of compound I-6 obtained in an embodiment of the present invention. 13 C NMR spectrum.

[0037] Figure 13 is a diagram of compound I-7 obtained in an embodiment of the present invention. 1 H NMR spectrum.

[0038] Figure 14 is a diagram of compound I-7 obtained in an embodiment of the present invention. 13 C NMR spectrum.

[0039] Figure 15 is an analysis diagram of the results of inhibiting the formation of biofilms by Staphylococcus aureus (MSSA (SA113, CHS101), MRSA (YUSA145, YUSA139)) according to an embodiment of the present invention; wherein, (a) is a blank sample, bis(chlorophenoxy)sulfate I-0, bis(chlorophenoxy)sulfate derivatives I-1 and I-2, (b) is a blank sample, bis(chlorophenoxy)sulfate derivatives I-3, I-4, I-5, I-6, I-7, and (c) is a blank sample and comparative example bis(chlorophenoxy)sulfate derivatives I-11, I-12, I-13.

[0040] Figure 16 is an analysis chart showing the results of the inhibition of biofilm formation by Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecalis by thiobisdichlorophenol derivatives at different concentrations in an embodiment of the present invention; wherein, (a) to (n) are I-0, I-1, I-2, I-6, I-0, I-7, I-13, I-14, I-5, I-11, I-12, I-3, I-15, I-4, and I-16, respectively.

[0041] Figure 17 is a graph showing the safety of drugs according to an embodiment of the present invention, wherein a) shows the cytotoxicity of bis(dichlorophene) derivatives at different concentrations on human embryonic kidney 293T cells; b) shows the hemolytic activity of bis(dichlorophene) at different concentrations. DETAILED DESCRIPTION

[0042] The preferred embodiments of the present invention are described in further detail below.

[0043] Example 1 to Example 7

[0044] A sulfur bis(dichlorophenol) derivative, which is one of the following chemical structural formulas I-1 to I-7:

[0045] The preparation route of the above compound is shown in the following reaction formula:

[0046] As shown in the above reaction formula, R1=Cl, and the reactant is Bit-0, namely, bis(dichlorothiophene) (Bithionol).

[0047] R1=H, and the reactant is Bit-2, namely bis-(2-hydroxy-5-chlorophenyl) sulfide.

[0048] The two products obtained by the above reaction formula are: product (1) is a disubstituted product, and product (2) is a monosubstituted product.

[0049] Specifically, it is prepared by the following preparation method:

[0050] Thiobis(dichlorophenol) or bis(2-hydroxy-5-chlorophenyl)sulfide (3 mmol, 3 equiv), potassium carbonate (3 mmol, 3 equiv) and 10 mL of DMF (or dichloromethane) were added to a 50 mL reaction bottle and stirred at room temperature for 30 min. R3-X (1 mmol, 1 equiv) was then slowly added dropwise. After the addition was complete, the reaction system was heated to 60°C and reacted for 6 h (when X = Cl, R3 = COCH3, the solvent was dichloromethane and the reaction temperature was room temperature). The reaction was monitored by TLC (thin layer chromatography). After the reaction was completed, the mixture was cooled to room temperature, 50 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and washed with saturated brine (20 mL × 3). The organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (V (乙酸乙酯) ∶V (石油醚) =1:400~1:100) separation (using TLC to monitor the elution until the monosubstituted product is eluted) and purification to obtain the compound.

[0051] The above R3-X uses:

[0052] X=I,R3=CH3;

[0053] X=Br, R3=CH2CH3, CH2CH=CH2, CH2CH2OH, CH2CH2Br;

[0054] X=Cl, R3=COCH3.

[0055] The general formula of the chemical structures of I-1 to I-7 and the comparative examples is as follows, where R2 is introduced to distinguish between monosubstituted and disubstituted products. The specific structural differences are shown in Table 1:

[0056] Table 1 Differences in chemical structure between Example 1 and Comparative Example 1

[0057] The above steps were used, R3-X was BrCH2CH2OH, reaction, separation (TLC monitoring elution) and purification to obtain the compound I-1 (Bit-9) of Example 1. The obtained compound was then 1 H NMR and 13 The results of C NMR detection are shown in Figures 1 and 2, showing a colorless oil; the recovery rate is 36.8%. 1 H NMR (400MHz, CDCl3) δ7.45 (d, J=2.3Hz, 1H), 7.39 (d, J=2.3Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.17 (s, 1H), 6.79 (d, J=2.3Hz, 1H), 4.33-4.27 (m, 2H), 4.05-4.01 (m, 2H). 13 C NMR (100MHz, CDCl3) δ152.2, 151.2, 134.2, 132.3, 132.0, 130.5, 129.5, 128.8, 128.0, 125.5, 122.3, 118.9, 75.8, 62.4. HRMS(ESI)m / z:C 14 H 11 Cl4O3S + ([M+H] + The compound is 2,4-dichloro-6-((3,5-dichloro-2-(2-hydroxyethoxy)phenyl)thio)phenol, i.e., the compound of chemical formula I-1.

[0058] The above steps were used, R3-X was BrCH2CH2Br, reaction, separation (TLC monitoring elution) and purification were performed to obtain the compound I-3 (Bit-41) of Example 3. The obtained compound was then 1 H NMR and13 The results of C NMR detection are shown in Figures 5 and 6 , indicating a colorless oil; yield: 0.2 g (43.5%). 1 H NMR (400MHz, CDCl3) δ7.46 (d, J=1.8Hz, 1H), 7.40 (s, 1H), 7.27 (s, 1H), 6.71 (d, J=1.6Hz, 1 H), 6.60 (s, 1H), 4.40 (t, J=6.3Hz, 2H), 3.75 (t, J=6.3Hz, 2H). 13 C NMR (100MHz, CDCl3) δ152.0, 150.4, 134.2, 132.3, 132.1, 131.0, 129.2, 129.1, 127.5, 125.8, 122.0, 118.5, 73.1, 29.2. HRMS(ESI)m / z:C 14 H 10 BrCl4O2S + ([M+H] + The calculated result of )464.8211 is 464.8215. The compound is 2-((2-(2-bromoethoxy)-3,5-dichlorophenyl)thio)-4,6-dichlorophenol, that is, the compound of chemical formula I-3.

[0059] The above steps were used, R3-X was CH2CH=CH2Br, reaction, separation (TLC monitoring elution) and purification to obtain the compound I-4 (Bit-43) of Example 4. The obtained compound was then 1 H NMR and 13 C NMR detection results are shown in Figures 7 and 8, showing a white solid with a recovery rate of 49.7% and a melting point of 115-116°C. 1 H NMR (400MHz, CDCl3) δ7.44 (d, J=2.5Hz, 1H), 7.41 (d, J=2.5Hz, 1H), 7.28 (d, J=2.4Hz, 1H), 6.80 (s, 1H), 6.78 (d , J=2.4Hz, 1H), 6.18 (ddt, J=16.4, 10.3, 6.0Hz, 1H), 5.47 (dq, J=17.1, 1.4Hz, 2H), 4.63 (dt, J=6.0, 1.2Hz, 2H). 13 C NMR (100MHz, CDCl3) δ152.2, 151.1, 145.7, 134.2, 132.5, 132.2, 130.6, 129.5, 129.4, 128.1, 125.6, 122.0, 119.9, 118.9, 75.1. HRMS(ESI)m / z:C15 H 11 Cl4O2S + ([M+H] + )396.9216 calculated results, found 396.9212. This compound is 2-((2-(allyloxy)-3,5-dichlorophenyl)thio)-4,6-dichlorophenol, that is, the compound of chemical formula I-4.

[0060] The above steps were used, R3-X was treated with CH3I, and the reaction, separation (TLC monitoring elution) and purification were performed to obtain the compound I-5 (Bit-45) of Example 5. The obtained compound was then 1 H NMR and 13 The results of C NMR detection are shown in Figures 9 and 10, showing a colorless oil; the recovery rate is 29.4%. 1 H NMR (400MHz, CDCl3) δ7.45 (d, J=2.5Hz, 1H), 7.40 (d, J=2.5Hz, 1H), 7.28 (d, J=2.4Hz, 1H), 6.82 (s, 1H), 6.80 (d, J=2.4Hz, 1H), 3.96 (s, 3H). 13 C NMR (100MHz, CDCl3) δ152.4, 152.1, 134.1, 132.1, 131.8, 130.6, 129.6, 129.3, 128.2, 125.6, 122.0, 118.9, 53.6. HRMS(ESI)m / z:C 13 H9Cl4O2S + ([M+H] + )370.8970 calculated result, found 370.8964. This compound is 2,4-dichloro-6-((3,5-dichloro-2-methoxyphenyl)thio)phenol, that is, the compound of chemical formula I-5.

[0061] The above steps were used, the reactant was bis-(2-hydroxy-5-chlorophenyl) sulfide, R3-X was COCH3Br, reaction, separation (TLC monitoring elution) and purification were performed to obtain the compound I-2 (Bit-12) of Example 2, and the obtained compound I-2 (Bit-12) was subjected to 1 H NMR and 13 C NMR detection results are shown in Figures 3 and 4, showing a white solid with a recovery rate of 31.8% and a melting point of 138-140°C. 1 H NMR (400MHz, DMSO) δ7.51 (dd, J=8.6, 2.5Hz, 2H), 7.31 (t, J=5.7Hz, 4H), 2.22 (s, 6H). 13C NMR (100MHz, DMSO) δ168.5, 148.4, 131.8, 130.9, 129.6, 128.3, 125.4, 20.3. HRMS(ESI)m / z:C 16 H 13 Cl2O4S + ([M+H] + The calculated result of ) is 370.9833, totaling 370.9835. The compound is thiobis(4-chloro-2,1-phenylene)diacetate, i.e., the compound of chemical formula I-2.

[0062] The above steps were used, the reactant was thiobisdichlorophenol (Bithionol), R3-X was COCH3Br, reaction, separation (TLC monitoring elution) and purification were performed to obtain the compound I-6 (Bit-46) of Example 6, and the obtained compound I-6 (Bit-46) was subjected to 1 H NMR and 13 C NMR detection results are shown in Figures 11 and 12, showing a white solid with a recovery rate of 24.0% and a melting point of 160-161°C. 1 H NMR (400MHz, CDCl3) δ7.42 (d, J=2.4Hz, 2H), 7.12 (d, J=2.4Hz, 2H), 2.33 (s, 6H). 13 C NMR (100MHz, CDCl3) δ167.6, 145.4, 132.6, 131.0, 130.6, 130.1, 129.4, 20.3. HRMS(ESI)m / z:C 16 H 11 Cl4O4S + ([M+H] + )438.9054 calculated results, found 438.9050. The compound is thiobis(4,6-dichloro-2,1-phenylene)diacetate, that is, the compound of chemical formula I-6.

[0063] The above steps were used, the reactant was thiobisdichlorophenol (Bithionol), R3-X was COCH3Br, reaction, separation (TLC monitoring elution) and purification were performed to obtain the compound I-7 (Bit-47) of Example 7, and the obtained compound I-7 (Bit-47) was subjected to 1 H NMR and 13 C NMR detection results are shown in Figures 13 and 14 , showing a white solid with a yield of 74.5% and a melting point of 168-170°C. 1H NMR (400MHz, CDCl3) δ7.46 (d, J=2.5Hz, 1H), 7.40 (d, J=2.5Hz, 1H), 7.33 (d, J=2.3Hz, 1H), 6.83 (d, J=2.3Hz, 1H), 6.68 (s, 1H), 2.42 (s, 3H). 13 C NMR (100MHz, CDCl3) δ168.4, 151.9, 143.9, 134.1, 132.9, 132.6, 132.3, 131.8, 129.1, 127.9, 125.5, 122.5, 118.2, 20.5. HRMS(ESI)m / z:C 14 H9Cl4O3S + ([M+H] + )398.8919 calculated result, 398.8915 has been found. This compound is 2,4-dichloro-6-((3,5-dichloro-2-hydroxyphenyl)thio)phenyl acetate, that is, the compound of chemical formula I-7.

[0064] In addition, for comparison, other comparative examples of thiobisdichlorophenol derivatives were also prepared, and the differences in their chemical structures are shown in Table 1. Compound I11 was prepared using the following preparation route, with other methods being the same as those in the examples.

[0065] The preparation method of compounds I12-I16 is the same as above, except that the added R3X is changed. The elution is monitored by TLC to obtain compounds I12-I16, as shown in the table below.

[0066] R3X added in the comparative example

[0067] The obtained structural formulas of I12 to I16 are:

[0068] The following experiments were conducted on the sulfur bisdichlorophenol derivatives prepared in Examples 1 to 7 and the comparative example.

[0069] Example 8

[0070] Minimum inhibitory concentration (MIC) testing, including:

[0071] The minimum inhibitory concentration (MIC) was determined by broth microdilution method, with thiobisdichlorophenol as the quality control strain. The thiobisdichlorophenol derivatives of the above examples and comparative examples were operated according to CLSIM100-S27 version.

[0072] The results are shown in Table 2 below. The results in Table 2 show that, compared with thiobisdichlorophenol and the comparative example, the thiobisdichlorophenol derivatives of this embodiment have lower minimum inhibitory concentrations for various Staphylococcus aureus, Staphylococcus epidermidis, Enterobacter faecalis, and Enterococcus faecium, with the lowest MIC being less than 0.78 mg / ml (MIC of thiobisdichlorophenol derivatives of I-6 and I-7 against Staphylococcus epidermidis 1457), and have better antibacterial effects.

[0073] Table 2 Minimum inhibitory concentration (MIC) results of Examples and Comparative Examples

[0074] Table 3 Minimum inhibitory concentration results (MIC) of Examples and Comparative Examples

[0075] *: It is normal for the MIC results to fluctuate by 2 times.

[0076] Example 9

[0077] The biofilm inhibition experiment of sulphur bis-dichlorophenol derivatives at sub-inhibitory concentrations on Staphylococcus aureus specifically includes the following steps:

[0078] Staphylococcus aureus was cultured overnight in TSB medium at 37°C, 220 rpm / min, with shaking for 10-12 hours. The thiobis(dichlorophenol) derivatives described in the above examples and comparative examples were added, and a blank sample was used as a control. The bacterial solution was diluted 1:200 with TSB medium (with or without the antibiotic), and 200 μl was added to each well of a 96-well plate (Costar 3599). Three replicate wells were set up for each strain and incubated at 37°C for 24 hours. The supernatant was discarded, and the cells were washed three times with PBS (200 μl / well / time). After drying at room temperature, the cells were fixed with formaldehyde for 15 minutes (200 μl / well). The formaldehyde was discarded, and after drying at room temperature, 100 μl of 0.5% crystal violet stain was added to each well and stained at room temperature for 10 minutes. The crystal violet stain was gently eluted under clean water until the water was colorless. After drying at room temperature, the OD570 value was read on a microplate reader.

[0079] The above experimental procedures were repeated three times, and the data are expressed as mean ± standard deviation (mean ± SD). The results are shown in Figures 15 and 16. It can be seen that the thiobis(dichlorophenol) derivative I-2 can significantly inhibit the biofilm formation of four strains of Staphylococcus aureus (MSSA (SA113, CHS101) and MRSA (YUSA145, YUSA139)) at subinhibitory concentrations. The thiobis(dichlorophenol) derivative I-1 has a very significant effect in inhibiting the biofilm formation of MSSA (SA113) and MRSA (YUSA145, YUSA139) among Staphylococcus aureus. I-46 and I-47 have a significant inhibitory effect on the biofilm formation of SA113.

[0080] Example 10

[0081] The drug safety test experiment of different concentrations of thiobisdichlorophenol derivatives includes the following steps:

[0082] Adherent cells: Plate target cells in a 96-well plate at 12,500 cells per well. Allow 24 hours for adherence before use. Serially dilute the drug to be tested onto a U-shaped 96-well plate, and set up a blank control without drug, for a total of 100 μl. Discard the medium from the adherent cell culture plate and add 100 μL of the diluted drug. Incubate the plate at 37°C in 5% CO2 for 24 hours. Add 10 μL of CCK8 (MCE) solution to each well (be careful not to create bubbles, as this will affect the results). Continue incubating for 1.5 hours, then measure the absorbance at 450 nm (OD450). Calculate drug cytotoxicity based on the absorbance value using the following formula: Survival rate (%) = (absorbance of experimental group - absorbance of blank group) / (absorbance of control group - absorbance of blank group) * 100%. For suspension cells, plate the cells and drug simultaneously, incubate for 24 hours, and then test. Follow the same steps as above.

[0083] The results are shown in FIG17 . It can be seen that the derivatives have no effect on the activity of human embryonic kidney 293T cells within the normal MIC working concentration range against Gram-positive bacteria, and some derivatives have no hemolytic activity against erythrocytes.

[0084] The above is a further detailed description of the present invention in conjunction with specific preferred embodiments, and the specific implementation of the present invention should not be considered to be limited to these descriptions. For those skilled in the art of the present invention, without departing from the concept of the present invention, several simple deductions or substitutions can be made, which should be considered to fall within the scope of protection of the present invention.

Claims

1. A sulfur bis(dichlorophenol) derivative, characterized in that: It is any one of the following chemical structural formulas I-1 to I-7:

2. The method for preparing a sulfur-bis(dichlorophenol) derivative according to claim 1, wherein The method comprises the following steps: step S1, adding bis(dichlorophenol)thioate or bis(2-hydroxy-5-chlorophenyl)sulfide and K2CO3 into DMF or dichloromethane solvent to dissolve, and stirring for more than 20 minutes; then adding R3-X dropwise to react; wherein, when X=Cl and R3=COCH3, the solvent is dichloromethane and the reaction temperature is room temperature; for other R3-X, the temperature is raised to 55-65°C and the reaction is carried out for more than 4 hours; Step S2, monitoring the reaction solution by TLC, cooling to room temperature after the reaction is completed, adding water to the reaction solution, extracting with ethyl acetate, combining the organic phases, washing with saturated brine, drying the organic phase over anhydrous sodium sulfate, filtering, and concentrating to obtain a crude product; Step S3, purifying the obtained crude product by column chromatography, monitoring the separated liquid by TLC, and separating and purifying to obtain the thiobisdichlorophenol derivative.

3. A composition, characterized in that: The invention comprises the thiobisdichlorophenol derivative as claimed in claim 1 and a pharmaceutical adjuvant.

4. The composition according to claim 3, characterized in that: The pharmaceutical adjuvant includes at least one of a diluent, a stabilizer, and a preservative.

5. The use of the sulfur bis(dichlorophenol) derivative according to claim 1, wherein: The thiobisdichlorophenol derivative is used for preparing antibacterial drugs.

6. The use of the sulfur bis(dichlorophenol) derivative according to claim 5, characterized in that: The antibacterial drug is a drug against Gram-positive bacteria.

7. The use of the sulfur bis(dichlorophenol) derivative according to claim 6, characterized in that: The Gram-positive bacteria is at least one of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, and Enterococcus faecium.

8. Use of the thiobisdichlorophenol derivative as claimed in claim 1 in preparing an antibacterial agent.

9. Use of the thiobisdichlorophenol derivative as claimed in claim 1 for preparing antibacterial coatings.

10. Use of the thiobisdichlorophenol derivative according to claim 1 in preparing a disinfectant.

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