Formononetin derivative as well as preparation method and application thereof

Abstract

The invention relates to formononetin derivatives shown in a general formula III in the technical field of organic chemistry, and substituent groups R of the formononetin derivatives are defined in the specification. The formononetin derivative shown in the general formula III can be used for preparing antibacterial or bacteriostatic drugs, has remarkable antibacterial activity on staphylococcus aureus (S.aureus), escherichia coli (E.coli), methicillin-resistant staphylococcus aureus (MRSA) and the like, and is not resistant to drugs.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, specifically to a gentianin derivative and its preparation method and application. Background Technology

[0002] The emergence of bacterial resistance directly weakens the effectiveness of antibiotics. This not only makes infections more difficult to cure but also increases the mortality rate of related diseases. More seriously, it poses a significant threat to modern medical procedures such as surgery and chemotherapy, as these treatments often rely on antibiotics to prevent and control infections, and the presence of resistance greatly increases the risks associated with these procedures.

[0003] Because bacterial resistance poses such a severe challenge, the development of new antibacterial drugs is of paramount importance. The value of new antibacterial drugs lies primarily in two aspects: First, they serve as a last resort against "superbugs" (i.e., multidrug-resistant bacteria), saving patients' lives and filling gaps in clinical treatment when existing antibiotics fail, while simultaneously curbing their further spread by effectively killing drug-resistant bacteria. Second, the emergence of new antibacterial drugs can act as substitutes, reducing dependence on existing antibiotics, thereby limiting their overuse and slowing down the process by which existing antibiotics become ineffective due to frequent use. Summary of the Invention

[0004] Using the natural product gentianin as a raw material, a series of gentianin derivatives were designed and synthesized using theories of medicinal chemistry and drug design for antibacterial activity studies. Results showed that some target compounds exhibited significant antibacterial activity against *Escherichia coli* (E. coli). E. coli It showed better inhibitory effects on fluoroquinolone-resistant Escherichia coli (FREC) than the control drug oxacillin, and did not exhibit drug resistance.

[0005] The main objective of this invention is to provide a gentianin derivative, as shown in general formula III: , Wherein, R is phenyl, substituted phenyl, thiazole ring, isoxazole ring, or coumarin ring.

[0006] The gentianin derivatives of general formula III of this invention can be used to prepare antibacterial or bacteriostatic drugs against Staphylococcus aureus (Staphylococcus aureus). S. aureus ), Escherichia coli ( E. coli It has significant antibacterial activity against bacteria such as methicillin-resistant Staphylococcus aureus (MRSA).

[0007] The active gentianin derivative of general formula III of this invention can be used in combination with clinical antibacterial drugs or with antibacterial active ingredients.

[0008] The following synthetic route describes the preparation of compound III of general formula of the present invention. The synthetic route is as follows: .

[0009] Preparation of Intermediate I: Weigh out 1 mmol of gentianin, 3 mmol of potassium carbonate, 10 mmol of 1,2-dibromoethane, and... N , N Add 10 mL of dimethylformamide to a reaction flask and stir at 40-80 °C. After 8 h, the reaction is complete. Add an appropriate amount of distilled water, extract with ethyl acetate, and purify by column chromatography to obtain intermediate I.

[0010] Preparation of intermediate II: Weigh 0.3 mmol of intermediate I and 5 mL of... N , N Dimethylformamide, 1.5 mmol potassium carbonate, and 1.5 mmol piperazine were added to a reaction flask. After 4 hours, the reaction was complete. An appropriate amount of distilled water was added, and a white solid, namely intermediate II, precipitated.

[0011] Preparation of target compound III: 0.2 mmol of intermediate II, 5 mL of dichloromethane, 0.3 mmol of substituted sulfonyl chloride, and 1 mmol of triethylamine were weighed into a reaction flask and stirred at 0–25 °C. After the reaction was complete, the solvent was concentrated, and the mixture was purified by thin-layer chromatography to obtain target compound III. Detailed Implementation

[0012] The present invention will be further described below with reference to the embodiments. However, the present invention is not limited to the following embodiments. It is foreseeable that various changes may occur in the implementation when those skilled in the art combine it with the prior art.

[0013] Synthetic route of compound III of general formula in this invention: .

[0014] Example 1: Preparation of compound IIIe Preparation of Intermediate I: Weigh out 1 mmol of gentianin, 3 mmol of potassium carbonate, 10 mmol of 1,2-dibromoethane, and... N , N Add 10 mL of dimethylformamide to a reaction flask and stir at 60 °C. After 8 h, the reaction is complete. Add an appropriate amount of distilled water, extract with ethyl acetate, and purify by column chromatography to obtain intermediate I.

[0015] Preparation of intermediate II: Weigh 0.3 mmol of intermediate I and 5 mL of... N , N Dimethylformamide, 1.5 mmol potassium carbonate, and 1.5 mmol piperazine were added to a reaction flask. After 4 hours, the reaction was complete. An appropriate amount of distilled water was added, and a white solid, namely intermediate II, precipitated.

[0016] Preparation of target compound III: 0.2 mmol of intermediate II, 5 mL of dichloromethane, 0.3 mmol of 2-nitrobenzenesulfonyl chloride, and 1 mmol of triethylamine were weighed into a reaction flask and stirred at 0–5 °C. After the reaction was complete, the solvent was concentrated, and the mixture was purified by thin-layer chromatography to obtain target compound IIIe.

[0017] Example 2: Preparation of compound IIIk Preparation of Intermediate I: Weigh out 1 mmol of gentianin, 3 mmol of potassium carbonate, 10 mmol of 1,2-dibromoethane, and... N , N Add 10 mL of dimethylformamide to a reaction flask and stir at 70 °C. After 7 h, the reaction is complete. Add an appropriate amount of distilled water, extract with ethyl acetate, and purify by column chromatography to obtain intermediate I.

[0018] Preparation of intermediate II: Weigh 0.3 mmol of intermediate I and 5 mL of... N , N Dimethylformamide, 1.5 mmol potassium carbonate, and 1.5 mmol piperazine were added to a reaction flask. After 4 hours, the reaction was complete. An appropriate amount of distilled water was added, and a white solid, namely intermediate II, precipitated.

[0019] Preparation of target compound III: 0.2 mmol of intermediate II, 5 mL of dichloromethane, 0.3 mmol of 2-fluorobenzenesulfonyl chloride, and 1 mmol of triethylamine were weighed into a reaction flask and stirred at 5–10 °C. After the reaction was complete, the solvent was concentrated, and the mixture was purified by thin-layer chromatography to obtain target compound IIIk.

[0020] Example 3: Preparation of compound IIIm Preparation of Intermediate I: Weigh out 1 mmol of gentianin, 3 mmol of potassium carbonate, 10 mmol of 1,2-dibromoethane, and... N , N Add 10 mL of dimethylformamide to a reaction flask and stir at 60 °C. After 8 h, the reaction is complete. Add an appropriate amount of distilled water, extract with ethyl acetate, and purify by column chromatography to obtain intermediate I.

[0021] Preparation of intermediate II: Weigh 0.3 mmol of intermediate I and 5 mL of... N , N Dimethylformamide, 1.5 mmol anhydrous potassium carbonate, and 1.5 mmol piperazine were added to a reaction flask. After 4 hours, the reaction was complete. An appropriate amount of distilled water was added, and a white solid, namely intermediate II, precipitated.

[0022] Preparation of target compound III: 0.2 mmol of intermediate II, 5 mL of dichloromethane, 0.3 mmol of 2-methoxyformyl-3-thiazolylsulfonyl chloride, and 1 mmol of triethylamine were weighed into a reaction flask and stirred at 0–5 °C. After the reaction was complete, the solvent was concentrated, and the mixture was purified by thin-layer chromatography to obtain target compound III.

[0023] Example 4: Preparation of Compound IIIo Preparation of Intermediate I: Weigh out 1 mmol of gentianin, 3 mmol of potassium carbonate, 10 mmol of 1,2-dibromoethane, and... N , N Add 10 mL of dimethylformamide to a reaction flask and stir at 80 °C. After 6 h, the reaction is complete. Add an appropriate amount of distilled water, extract with ethyl acetate, and purify by column chromatography to obtain intermediate I.

[0024] Preparation of intermediate II: Weigh 0.3 mmol of intermediate I and 5 mL of... N , N Dimethylformamide, 1.5 mmol potassium carbonate, and 1.5 mmol piperazine were added to a reaction flask. After 4 hours, the reaction was complete. An appropriate amount of distilled water was added, and a white solid, namely intermediate II, precipitated.

[0025] Preparation of target compound III: 0.2 mmol of intermediate II, 5 mL of dichloromethane, 0.3 mmol of substituted coumarin-6-sulfonyl chloride, and 1 mmol of triethylamine were weighed into a reaction flask and stirred at 20–25 °C. After the reaction was complete, the solvent was concentrated, and the mixture was purified by thin-layer chromatography to obtain target compound III.

[0026] The relevant data for target compound III are shown in Table 1: Table 1

[0027] The antibacterial activity test of this invention: using oxacillin as a control drug, the microdilution method was used to determine the antibacterial activity of the compound of general formula III against Staphylococcus aureus (…). S. aureus ), Escherichia coli ( E. coli The minimum inhibitory concentrations (MICs) of methicillin-resistant Staphylococcus aureus (MRSA) and fluoroquinolone-resistant Escherichia coli (FREC) are shown in Table 2.

[0028] Table 2

[0029] The experimental results above clearly demonstrate that the compounds of general formula III protected by this invention possess potential antibacterial activity. Some compounds are effective against *Escherichia coli* (E. coli). E. coli The anti-inhibitory effects of compounds IIIe, IIIm, and IIIo are superior to those of the control drug oxacillin. E. coli The MICs of some compounds were lower than those of the control drug oxacillin; some compounds showed superior activity against fluoroquinolone-resistant Escherichia coli (FREC) compared to oxacillin, such as compounds IIIe, IIIk, IIIm, IIIn, and IIIo, whose MICs against FREC were lower than those of oxacillin. These compounds exhibited significant inhibitory effects against Gram-negative bacteria and drug-resistant Gram-negative bacteria, and did not induce drug resistance. Their potential antibacterial activity could be used to treat... E. coli It is used for the treatment of FREC infectious diseases. It can also be used in combination with other antibacterial active substances.

[0030] The above descriptions are merely embodiments of the present invention, and common knowledge such as specific technical solutions and / or characteristics are not described in detail here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A gentianin derivative, characterized in that: The derivative has the structure shown in general formula III: Where R is phenyl, substituted phenyl, thiazolyl, isoxazolyl, or coumarin ring.

2. The gentianin derivative according to claim 1, characterized in that: The structure shown in Formula III is selected from any of the following: Ⅲe: 、Ⅲf: 、Ⅲg: 、 Ⅲk: 、Ⅲl: 、Ⅲm: 、Ⅲn: 、Ⅲo: 。 3. The method for preparing the gentianin derivative according to claim 1 or 2, characterized in that: It was prepared according to the following synthetic route: 。 4. The method for preparing the gentianin derivative according to claim 3, characterized in that: Includes the following steps: Preparation of Intermediate I: Weigh out gentianin, potassium carbonate, 1,2-dibromoethane and N , N - Dimethylformamide was mixed and stirred until the reaction was complete. Then, an appropriate amount of distilled water was added, and the mixture was extracted with ethyl acetate. The mixture was then purified by column chromatography to obtain intermediate I. Preparation of intermediate II: Weigh intermediate I, N , N Dimethylformamide, potassium carbonate and piperazine are placed in a reaction vessel. After the reaction is complete, an appropriate amount of distilled water is added, and a white solid, namely intermediate II, is precipitated. Preparation of target compound III: Intermediate II, dichloromethane, substituted sulfonyl chloride and triethylamine were weighed into a reaction vessel and stirred to react. After the reaction was completed, the solvent was concentrated and purified by thin-layer chromatography to obtain target compound III.

5. The method for preparing the gentianin derivative according to claim 4, characterized in that: Intermediate I was prepared by stirring at 40-80 °C.

6. The method for preparing the gentianin derivative according to claim 5, characterized in that: The preparation of target compound III was carried out by stirring at 0-25 °C.

7. The use of the gentianin derivative according to claim 1 or 2 in the preparation of antibacterial and / or bacteriostatic drugs.

8. The application according to claim 7, characterized in that: The bacteria are Staphylococcus aureus and / or Escherichia coli.

9. The application according to claim 8, characterized in that: The bacteria are methicillin-resistant Staphylococcus aureus and / or fluoroquinolone-resistant Escherichia coli.

10. The gentianin derivative of claim 1 or 2 is used in combination with antibacterial and / or bacteriostatic active ingredients.

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