Quinolinium-based propane sulfonate salts, methods of making and using the same

Abstract

This invention discloses a quinolinonylpropane sulfonate, its preparation method, and its application. The structural formula of the quinolinonylpropane sulfonate is shown in formula (III). The preparation method is as follows: using 4-methylquinoline and 1,3-propanesulfonic acid lactone as raw materials, a reaction is carried out to obtain product (I); using (4-(diphenylamino)phenyl)boronic acid and 7-bromobenzo[c][1,2,5]thiadiazole-4-carboxaldehyde as raw materials, a coupling reaction is carried out under potassium carbonate and nitrogen atmosphere catalyzed by tetrakis(triphenylphosphine)palladium to obtain product (II); using products (I) and (II) as raw materials, quinolinonylpropane sulfonate (III) is prepared. The quinolinonylpropane sulfonate of this invention exhibits antibacterial activity, especially against Streptococcus pneumoniae, and can be used as an antibacterial agent.

Description

Technical Field

[0001] This invention belongs to the field of antibacterial drug technology, and particularly relates to a quinolinium propane sulfonate, its preparation method and application. Background Technology

[0002] Streptococcus pneumoniae is one of the main pathogens causing pneumonia, and infected patients present with symptoms such as chills, high fever, cough, sputum production, and possibly chest pain. Antibiotics are crucial for treating bacterial pneumonia. However, the problem of drug resistance in Streptococcus pneumoniae is becoming increasingly prominent, especially with a significant increase in resistance rates to commonly used drugs such as β-lactams and macrolides, posing a serious challenge to clinical treatment. Therefore, the development of novel antibiotics has become an urgent need.

[0003] Quinoline derivatives, as an important class of heterocyclic compounds, have shown broad application potential in the field of medicinal chemistry. Studies have shown that structural modification can endow the quinoline skeleton with anti-inflammatory, antibacterial, and antitumor activities. For example, the skeleton of quinolone antibiotics contains quinoline. However, research on quinoline antibacterial agents targeting Streptococcus pneumoniae remains relatively limited.

[0004] Sulfonate compounds, due to their unique hydrophilic and ionic properties, are often used to improve drug solubility and bioavailability. Introducing a sulfonic acid group into the quinoline skeleton may enhance antibacterial activity by strengthening the interaction between the molecule and the bacterial cell membrane. Currently, quinolineonium salts, as quinoline-derived quaternary ammonium compounds, have been preliminarily explored in the antibacterial field, but research on quinolineonium propane sulfonate targeting Streptococcus pneumoniae has not yet been reported. Such compounds, combining the heterocyclic activity of quinoline with the ionic properties of sulfonates, hold promise as highly effective and low-toxicity inhibitors of Streptococcus pneumoniae.

[0005] In conclusion, developing a quinolinium propane sulfonate with definite anti-streptolysinic activity and establishing an efficient preparation method for it will provide novel antibacterial drug candidates for clinical use and is of great significance in combating drug-resistant Streptococcus pneumoniae infections. Summary of the Invention

[0006] The purpose of this invention is to provide a novel quinolinium propane sulfonate with good antibacterial activity against Streptococcus pneumoniae, as well as its preparation method and application.

[0007] To achieve the above objectives, this application adopts the following technical solution:

[0008] In a first aspect, the present invention provides a quinolinium propane sulfonate, the structural formula of which is shown in formula (III):

[0009] .

[0010] Secondly, the present invention provides a method for preparing the above-mentioned quinoline-onyl propane sulfonate, comprising the following steps: using 4-methylquinoline and 1,3-propanesulfonic acid lactone as raw materials, reacting to obtain product (I); using (4-(diphenylamino)phenyl)boronic acid and 7-bromobenzo[c][1,2,5]thiadiazole-4-carboxaldehyde as raw materials, under potassium carbonate and nitrogen atmosphere, a tetra(triphenylphosphine)palladium catalytic coupling reaction is carried out to obtain product (II); using product (I) and product (II) as raw materials, quinoline-onyl propane sulfonate (III) is prepared; the synthetic reaction formula of the quinoline-onyl propane sulfonate is:

[0011] .

[0012] The above technical solution includes the following steps:

[0013] Step 1: Add 4-methylquinoline, 1,3-propanesulfonic acid lactone and toluene to a reactor, heat and stir to react, and obtain product (I);

[0014] Step 2: (4-(diphenylamino)phenyl)boronic acid, 7-bromobenzo[c][1,2,5]thiadiazole-4-carboxaldehyde, potassium carbonate, and tetra(triphenylphosphine)palladium were placed in a solvent of tetrahydrofuran and water, and heated under nitrogen atmosphere at 70°C for 24 hours. After the reaction was completed, the mixture was cooled, rotary evaporated under reduced pressure, extracted with dichloromethane, washed with water, dried with anhydrous magnesium sulfate, filtered, rotary evaporated under reduced pressure, and passed through a silica gel column to obtain product (II).

[0015] Step 3: Add product (I), product (II), morpholine and methanol to the reactor, heat and stir to react, and obtain quinoline-onyl propane sulfonate (III).

[0016] In the above technical solution, in step 1, the molar ratio of 4-methylquinoline and 1,3-propanesulfonic acid lactone is 1:1, and the heating and stirring reaction is carried out at 100°C.

[0017] In the above technical solution, in step 2, the molar ratio of (4-(diphenylamino)phenyl)boronic acid, 7-bromobenzo[c][1,2,5]thiadiazole-4-carboxaldehyde, potassium carbonate and tetra(triphenylphosphine)palladium is 1:1.2:10:0.05.

[0018] In the above technical solution, in step 3, the molar ratio of product (I), product (II) and morpholine is 1:1:1.1; the heating and stirring reaction is carried out at 60°C.

[0019] Thirdly, the present invention provides the application of the above-mentioned quinolinium propane sulfonate in the preparation of antibacterial agents.

[0020] In the above technical solution, the antibacterial agent is an agent against Streptococcus pneumoniae.

[0021] Fourthly, the present invention provides an antibacterial agent containing the above-mentioned quinolinium propane sulfonate as an active ingredient.

[0022] In the above technical solution, the antibacterial agent is an agent against Streptococcus pneumoniae.

[0023] The beneficial effects of this invention are as follows: the synthesis method of the quinoline-onium propane sulfonate of this invention is simple, and it exhibits good antibacterial activity, showing excellent antibacterial activity against Streptococcus pneumoniae. As a novel antibacterial quinoline-onium propane sulfonate, it has great application value in the field of antibacterial technology. Detailed Implementation

[0024] To better illustrate the objectives, technical solutions, and advantages of this invention, the invention will be further described below in conjunction with specific embodiments. This invention can be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the inventive concept to those skilled in the art. This invention will be defined only by the claims.

[0025] Unless otherwise specified, the test methods or experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are obtained from conventional commercial sources or prepared by conventional methods.

[0026] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0027] The synthetic reaction formula for the quinolinium propane sulfonate (III) of this invention is as follows:

[0028]

[0029] The following embodiments are further illustrations of the present invention, but not limitations thereof.

[0030] Example 1:

[0031] Preparation steps of (E)-3-(4-(2-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)vinyl)quinoline-1-onthium-1-yl)propane-1-sulfonate (abbreviated as quinolineonylpropanesulfonate, III):

[0032]

[0033] 50 mmol of 4-methylquinoline, 50 mmol of 1,3-propanesulfonic acid lactone, and 40 mL of toluene were added to a 100 mL flask and stirred at 100 °C for 10 hours. After the reaction was completed, the mixture was cooled, filtered, and the residue was washed with 8 mL of ethanol. The product (I) was then recrystallized from the ethanol, with a yield of 95%.

[0034] 5 mmol of (4-(diphenylamino)phenyl)boronic acid, 6 mmol of 7-bromobenzo[c][1,2,5]thiadiazole-4-carboxaldehyde, 50 mmol of potassium carbonate, and 0.25 mmol of tetra(triphenylphosphine)palladium were placed in 100 mL of tetrahydrofuran / water (10 / 1) solvent and heated under nitrogen atmosphere at 75 °C for 24 hours. After the reaction was completed, the mixture was cooled, rotary evaporated under reduced pressure, extracted with dichloromethane, washed with water, dried over anhydrous magnesium sulfate, filtered, rotary evaporated under reduced pressure, and passed through a silica gel column (hexane:dichloromethane, elution gradient 5:1 to 2:1) to give product (II) in 40% yield.

[0035] 1 mmol of product (I), 1 mmol of product (II), 0.1 mL (1.1 mmol) of morpholine, and 20 mL of methanol were added to a sealed reaction vessel and stirred at 60 °C for 1.5 hours. After the reaction was completed, the product was evaporated under reduced pressure and purified by silica gel column chromatography (200-300 mesh, eluent: methanol:dichloromethane, gradient elution: dichloromethane for 10 min, 0-20% methanol for 20 min, 20% methanol for 10 min, 20-100% methanol for 20 min, methanol for 10 min). The product that absorbed light under 365 nm illumination during the 10 min elution with 20% methanol was collected and evaporated under reduced pressure to obtain the target product (III), with an Rf value of 0.80 (methanol:dichloromethane = 1:6, yield 80%). 1H NMR (600 MHz, DMSO-d6, δ): 9.34 (d, 1H,quinoline), 9.06 (d, 1H, quinoline), 8.65 (d, 1H, quinoline), 8.49 (d, 1H,quinoline), 8.25 (m, 3H, quinoline and vinyl), 8.04 (m, 3H, quinoline andbenzene), 7.87 (d, 2H, benzene), 7.56 (t, 4H, benzene), 7.21 (m, 6H,benzene), 7.08 (d, 2H, benzene), 5.12 (t, 2H, methylene), 2.57 (t, 2H,methylene), 2.28 (m, 2H, methylene). HRMS (ESI): m / z calcd for C 38 H 31 N4O3S2 + :655.1832 [M+H] + ; found: 655.1887.

[0036] Example 2:

[0037] Antibacterial activity test of the target compound:

[0038] The MIC of the target compound was determined by microdilution, and the antibacterial activity of the target compound (quinoline-onyl propane sulfonate prepared in Example 1) against Streptococcus pneumoniae ATCC 49619 was determined.

[0039] The experimental steps for the microdilution method are as follows:

[0040] Add 200 μL of a 1024 μg / mL aqueous solution of the test sample (quinoline-onium propane sulfonate prepared in Example 1) to column 1 of a 96-well plate. Add 100 μL of bovine brain and heart extract culture medium (7.7 g bovine brain extract powder, 9.8 g bovine heart extract powder, 10 g peptone, 2 g glucose, 5 g sodium chloride, 2.5 g disodium hydrogen phosphate, and 1000 mL deionized water) to columns 2-12 respectively. Then, take 100 μL from column 1 and add it to column 2, then take 100 μL from column 2 and add it to column 3, and so on. Finally, take 100 μL from column 9 and add it to column 10, then discard the excess 100 μL. Take 100 μL of a 1024 μg / mL solution. 6Add CFU / mL bacterial culture to each well in columns 1-11, and add 100 μL of culture medium to each well in column 12, for a final volume of 200 μL per well. Column 11 represents bacterial growth control (without culture medium), and column 12 represents sterile control (without culture medium). The concentrations of the test samples in columns 1-10 are 512, 256, 128, 64, 32, 16, 8, 4, 2, and 1 μg / mL, respectively. Each test sample is performed in triplicate. After incubating the 96-well plate at 37°C in a 5% CO2 oven for 24 hours, the OD value is measured using a microplate reader. 600 Value, OD 600 The concentration of wells with values ​​close to those of the sterile blank control is the minimum inhibitory concentration (MIC).

[0041] The results show:

[0042] The MIC of (E)-3-(4-(2-(7-(4-(diphenylamino)phenyl)benzo[c][1,2,5]thiadiazol-4-yl)vinyl)quinoline-1-onthiol-1-yl)propane-1-sulfonate (abbreviated as quinolineonthiol propanesulfonate, III) against Streptococcus pneumoniae is 8 μg / mL.

[0043] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A quinolinium propane sulfonate, characterized in that: Its structural formula is shown in equation (III): 。 2. The method for preparing the quinoline-onyl propane sulfonate according to claim 1, characterized in that: The process includes the following steps: Using 4-methylquinoline and 1,3-propanesulfonic acid lactone as raw materials, a reaction is carried out to obtain product (I); using (4-(diphenylamino)phenyl)boronic acid and 7-bromobenzo[c][1,2,5]thiadiazole-4-carboxaldehyde as raw materials, a tetra(triphenylphosphine)palladium-catalyzed coupling reaction is carried out under potassium carbonate and nitrogen atmosphere to obtain product (II); using products (I) and (II) as raw materials, quinoline-onyl propane sulfonate (III) is prepared; the synthetic reaction formula of the quinoline-onyl propane sulfonate is as follows: 。 3. The preparation method according to claim 2, characterized in that: Includes the following steps: Step 1: Add 4-methylquinoline, 1,3-propanesulfonic acid lactone and toluene to a reactor, heat and stir to react, and obtain product (I); Step 2: (4-(diphenylamino)phenyl)boronic acid, 7-bromobenzo[c][1,2,5]thiadiazole-4-carboxaldehyde, potassium carbonate, and tetra(triphenylphosphine)palladium were placed in a solvent of tetrahydrofuran and water, and heated under nitrogen atmosphere at 70°C for 24 hours. After the reaction was completed, the mixture was cooled, rotary evaporated under reduced pressure, extracted with dichloromethane, washed with water, dried with anhydrous magnesium sulfate, filtered, rotary evaporated under reduced pressure, and passed through a silica gel column to obtain product (II). Step 3: Add product (I), product (II), morpholine and methanol to the reactor, heat and stir to react, and obtain quinoline-onyl propane sulfonate (III).

4. The preparation method according to claim 3, characterized in that: In step 1, the molar ratio of 4-methylquinoline to 1,3-propanesulfonic acid lactone is 1:1, and the reaction is carried out at 100°C with heating and stirring.

5. The preparation method according to claim 3, characterized in that: In step 2, the molar ratio of (4-(diphenylamino)phenyl)boronic acid, 7-bromobenzo[c][1,2,5]thiadiazole-4-carboxaldehyde, potassium carbonate, and tetra(triphenylphosphine)palladium is 1:1.2: 10：0.05。 6. The preparation method according to claim 3, characterized in that: In step 3, the molar ratio of product (I), product (II) and morpholine is 1:1:1.1; the heating and stirring reaction is carried out at 60°C.

7. The use of the quinoline-onyl propane sulfonate according to claim 1 in the preparation of antibacterial agents, characterized in that: The antibacterial agent is an agent that fights Streptococcus pneumoniae.

8. An antibacterial agent, characterized in that: Containing the quinoline-onyl propane sulfonate as described in claim 1 as an active ingredient, the antibacterial agent is an anti-streptolysinic agent.

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