A thiazolidinone compound, and a preparation method and application thereof

Abstract

The application discloses a thiazolidinone compound and a preparation method and application thereof, and the structural formula of the thiazolidinone compound is shown as formula (II). The preparation method comprises the following steps: 4-bromophenyl isothiocyanate and pyridine-4-formyl hydrazine are used as raw materials, and a product (I) is obtained through reaction; and the product (I) and chloroacetic acid are used as raw materials to prepare the thiazolidinone compound (II). The thiazolidinone compound has antibacterial activity, especially good antibacterial activity on Haemophilus influenzae, 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 thiazolidinone compound, its preparation method, and its application. Background Technology

[0002] The main pathogens causing bacterial pneumonia include Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Symptoms of Haemophilus influenzae pneumonia include low-grade fever, cough with purulent sputum, and it easily leads to bronchopneumonia. Commonly used treatments include penicillins, cephalosporins, and fluoroquinolones. However, with the overuse and misuse of antibiotics, drug-resistant bacteria are increasing. Therefore, the development of novel antibacterial drugs has become an urgent need.

[0003] Linezolid, launched in 2000, has an oxazolidinone skeleton. Thiazolidinones have similar structures to oxazolidinones, suggesting that thiazolidinone compounds may possess antibacterial potential. Currently, no research has been reported on thiazolidinone compounds targeting Haemophilus influenzae. Therefore, developing a thiazolidinone compound with definite anti-Haemophilus influenzae activity and establishing an efficient preparation method will provide novel antibacterial drug candidates for clinical use and is of great significance in combating drug-resistant Haemophilus influenzae infections. Summary of the Invention

[0004] The purpose of this invention is to provide a thiazolidinone compound with a novel structure and good antibacterial activity against Haemophilus influenzae, as well as its preparation method and application.

[0005] To achieve the above objectives, this application adopts the following technical solution:

[0006] In a first aspect, the present invention provides a thiazolidinone compound with the structural formula shown in formula (II):

[0007] .

[0008] Secondly, the present invention provides a method for preparing the above-mentioned thiazolidinone compounds, comprising the following steps: reacting 4-bromophenyl isothiocyanate and pyridine-4-formylhydrazine as raw materials to obtain product (I); using product (I) and chloroacetic acid as raw materials to prepare thiazolidinone compound (II); the synthetic reaction formula of the thiazolidinone compound is as follows:

[0009] .

[0010] The above technical solution includes the following steps:

[0011] Step 1: Add 4-bromophenyl isothiocyanate, pyridine-4-formylhydrazine and methanol to the reactor, heat and stir to react, and obtain product (I);

[0012] Step 2: Add product (I), chloroacetic acid, sodium acetate and methanol to the reactor, heat and stir to react, and obtain thiazolidinone compound (II).

[0013] In the above technical solution, in step 1, the molar ratio of 4-bromophenyl isothiocyanate and pyridine-4-formylhydrazine is 1:1, and the heating and stirring reaction is carried out at 60°C.

[0014] In the above technical solution, in step 2, the molar ratio of product (I), chloroacetic acid, and sodium acetate is 1:1.1:1.2, and the heating and stirring reaction is carried out at 60°C.

[0015] Thirdly, the present invention provides the application of the above-mentioned thiazolidinone compounds in the preparation of antibacterial agents.

[0016] In the above technical solution, the antibacterial agent is an agent against Haemophilus influenzae.

[0017] Fourthly, the present invention provides an antibacterial agent containing the above-mentioned thiazolidinone compounds as active ingredients.

[0018] In the above technical solution, the antibacterial agent is an agent against Haemophilus influenzae.

[0019] The beneficial effects of this invention are as follows: the synthesis method of the thiazolidinone compounds of this invention is simple, and they exhibit good antibacterial activity, showing excellent antibacterial activity against Haemophilus influenzae. As a novel antibacterial thiazolidinone compound, it has great application value in the field of antibacterial technology. Detailed Implementation

[0020] 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.

[0021] 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.

[0022] 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.

[0023] The synthetic reaction formula for the thiazolidinone compound (II) of this invention is as follows:

[0024]

[0025] The following embodiments are further illustrations of the present invention, but not limitations thereof.

[0026] Example 1:

[0027] Preparation steps of (Z)-N'-(3-(4-bromophenyl)-4-oxothiazolidin-2-yl)isonicotinamide (hereinafter referred to as thiazolidinone compound, II):

[0028]

[0029] 10 mmol of 4-bromophenyl isothiocyanate, 10 mmol of pyridine-4-carboxyhydrazide, and 40 mL of methanol were added to a 100 mL flask and stirred at 60 °C for 4 hours. After the reaction was completed, the solution was concentrated to 4 mL, and three times the volume of ethyl acetate was added. The solid precipitated, filtered, and air-dried to obtain product (I) with a yield of 95%.

[0030] 5 mmol of product (I), 5.5 mmol of chloroacetic acid, 6 mmol of sodium acetate, and 10 mL of methanol were added to a 50 mL flask and stirred at 60 °C for 4 hours. After the reaction was complete, an equal volume of water was added, and a solid precipitated. The solid was filtered, dried, and the target product (II) was obtained with a yield of 95%. 1 H NMR (600 MHz, DMSO-d6, δ): 10.81 (s, 1H, -NH-), 8.71 (d,2H, pyridinyl), 7.88 (d, 2H, pyridinyl), 7.65 (m, 4H, benzene), 3.83 (s, 2H,methylene). HRMS (ESI): m / z calcd for C 15 H 12 BrN4O2S + : 390.9859, 392.9839 [M+H] + ;found: 390.9893, 392.9877.

[0031] Example 2:

[0032] Antibacterial activity test of the target compound:

[0033] The MIC of the target compound was determined by microdilution, and the antibacterial activity of the target compound (the thiazolidinone compound prepared in Example 1) against Haemophilus influenzae ATCC 49766 was determined.

[0034] The experimental steps for the microdilution method are as follows:

[0035] Add 200 μL of the test sample aqueous solution (thiazolidinone compound prepared in Example 1) with a concentration of 1024 μg / mL to column 1 of a 96-well plate. Add 100 μL of Haemophilus test medium (Solution A: 2g beef extract powder, 1.5g soluble starch, 17.5g casein hydrolysate, 5g yeast extract powder, 900mL deionized water, sterilized at 121℃ for 20 minutes; Solution B: 15mg heme chloride (dissolved in approximately 1.0 mL of 1 equivalent sodium hydroxide solution), 15mg nicotinamide adenine dinucleotide, 100mL deionized water, filtered for sterilization; then mix solutions A and B together under aseptic conditions and adjust the pH to 7.3 to obtain the final medium) to column 2. 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, until finally taking 100 μL from column 9. After adding μL to column 10 and mixing, discard 100 μL of the excess liquid. Take 100 μL to achieve a concentration of 10. 6 Add 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).

[0036] The results show:

[0037] The MIC of (Z)-N'-(3-(4-bromophenyl)-4-oxothiazolidin-2-yl)isonicotinamide (hereinafter referred to as thiazolidinone compound, II) against Haemophilus influenzae is 32 μg / mL.

[0038] 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 thiazolidinone compound, characterized in that: Its structural formula is shown in formula (II): 。 2. The method for preparing the thiazolidinone compound according to claim 1, characterized in that: The process includes the following steps: using 4-bromophenyl isothiocyanate and pyridine-4-formylhydrazine as raw materials, a reaction is carried out to obtain product (I); using product (I) and chloroacetic acid as raw materials, a thiazolidinone compound (II) is prepared; the synthetic reaction formula of the thiazolidinone compound is as follows: .

3. The preparation method according to claim 2, characterized in that: Includes the following steps: Step 1: Add 4-bromophenyl isothiocyanate, pyridine-4-formylhydrazine and methanol to the reactor, heat and stir to react, and obtain product (I); Step 2: Add product (I), chloroacetic acid, sodium acetate and methanol to the reactor, heat and stir to react, and obtain thiazolidinone compound (II).

4. The preparation method according to claim 3, characterized in that: In step 1, the molar ratio of 4-bromophenyl isothiocyanate to pyridine-4-formylhydrazine is 1:1, and the reaction is carried out at 60°C with heating and stirring.

5. The preparation method according to claim 3, characterized in that: In step 2, the molar ratio of product (I), chloroacetic acid, and sodium acetate is 1:1.1:1.2, and the heating and stirring reaction is carried out at 60°C.

6. The use of the thiazolidinone compound of claim 1 in the preparation of antibacterial agents, characterized in that: The antibacterial agent is an agent that combats Haemophilus influenzae.

7. An antibacterial agent, characterized in that: The active ingredient is a thiazolidinone compound as described in claim 1, and the antibacterial agent is an agent against Haemophilus influenzae.

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