Ferrocene derivative and application thereof

Abstract

The invention discloses a ferrocene derivative and application thereof, the structural formula of the ferrocene derivative is # imgabs0 #, and the ferrocene derivative has a rhodamine structure fused with ferrocene, has an obvious inhibitory effect on staphylococcus aureus, and has no toxicity to human cells.

Description

Technical Field

[0001] The invention belongs to the technical field of medicinal compounds, and in particular relates to a ferrocene derivative and application thereof. Background Art

[0002] Bacteria are one of the oldest and most diverse microorganisms on earth, and are widely present in the environment around us, including soil, water, air, and every corner of our body surface and inside. In the long history of coexistence between humans and microorganisms, bacterial infection has always been a health issue that has received much attention and has a far-reaching impact.

[0003] In early human society, poor living conditions and lack of hygiene knowledge created extremely favorable conditions for the growth and spread of bacteria. Once a bacterial infection occurred, it would spread rapidly among the population, causing severe infectious diseases such as cholera and typhoid fever, bringing huge disasters to the entire community, causing a large number of people to become ill or even die, and seriously hindering the development of society and human reproduction.

[0004] With the advancement of the times and the acceleration of urbanization, the population density has further increased, and people's interactions have become more frequent, which has also increased the risk of bacterial infection transmission to a certain extent. At the same time, although modern medical technology has made great progress, such as the discovery of penicillin by Fleming, which once gave humans an advantage in the fight against bacterial infections, bacteria have also shown amazing adaptability and mutation capabilities. They continue to evolve and develop drug resistance, making the originally effective antibiotics gradually lose their effectiveness, resulting in some bacterial infections that were once easily cured becoming a difficult medical problem again, bringing new and severe challenges to global public health.

[0005] Today, bacterial infection is still one of the important factors causing various diseases worldwide, ranging from common respiratory tract infections and urinary tract infections to more serious sepsis, which constantly threatens the health of people of different ages and regions. This situation has prompted the scientific and medical communities to continue to conduct in-depth research in order to seek more effective prevention, control and treatment strategies. Summary of the invention

[0006] The present invention aims to overcome the defects of the prior art and provide a ferrocene derivative and its application.

[0007] Another object of the present invention is to provide a method for preparing the above-mentioned ferrocene derivatives.

[0008] Another object of the present invention is to provide applications of the above ferrocene derivatives.

[0009] The technical solution of the present invention is as follows:

[0010] A ferrocene derivative having the structural formula

[0011] The preparation method of the above ferrocene derivatives, the synthetic route is:

[0012]

[0013] In a preferred embodiment of the present invention, the steps are as follows:

[0014] (1) Dissolve the S1 in dichloromethane and stir, add the DMTMM and stir at room temperature for 8-12 minutes, then add the S2 and stir at room temperature for reaction;

[0015] (2) The material obtained in step (1) is diluted with dichloromethane, and then washed with a dilute hydrochloric acid solution, followed by separation to obtain an organic phase, which is then washed with deionized water and separated to collect the organic phase, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove dichloromethane, and the obtained solid is separated and purified using a silica gel chromatography column to obtain the ferrocene derivative.

[0016] Further preferably, in step (1), the mass ratio of S1, DMTMM and S2 is 1:0.8-0.9:0.3-0.4.

[0017] Use of the ferrocene derivative in preparing an anti-Gram-positive bacteria composition.

[0018] In a preferred embodiment of the present invention, the anti-Gram-positive bacteria composition has an inhibitory effect on the growth of Staphylococcus aureus.

[0019] An anti-Gram-positive bacteria composition, the active ingredient of which includes the above-mentioned ferrocene derivative.

[0020] In a preferred embodiment of the present invention, the active ingredient is the above-mentioned ferrocene derivative.

[0021] In a preferred embodiment of the present invention, it has an inhibitory effect on the growth of Staphylococcus aureus.

[0022] The beneficial effects of the present invention are as follows: the present invention has a rhodamine structure fused with ferrocene, has an obvious inhibitory effect on Staphylococcus aureus, and has no toxicity to human cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the inhibitory effect of Fc-Rd on Staphylococcus aureus at a concentration of 8 μM in Example 2 of the present invention.

[0024] Figure 2 The figure shows the effect of co-incubation of cells with different concentrations of Fc-Rd on cell activity in Example 2 of the present invention. DETAILED DESCRIPTION

[0025] The technical solution of the present invention is further illustrated and described below through specific implementation modes in combination with the accompanying drawings.

[0026] Example 1 Synthesis of ferrocene derivative Fc-Rd.

[0027] The synthetic route of the present embodiment is as follows:

[0028]

[0029] The specific steps include:

[0030] (1) Preparation of compound S1 (see Fleming, Rev. Infect. Dis. 1980, 2, 129-139).

[0031] (2) 1 g of compound S1 (1.49 mmol) was dissolved in 10 mL of dichloromethane and stirred. 825 mg of compound 4-(4,6-dimethoxytriazine-2-yl)-4-methylmorpholine hydrochloride (DMTMM) was added and stirred at room temperature for 10 min. Then 390 mg of tert-butyl 2-(methylamino)ethylcarbamate (S2) was added and stirred at room temperature for 2 h until the reaction was complete.

[0032] (3) The material obtained in step (2) was diluted with dichloromethane and then washed thoroughly with a 1 mol / L dilute hydrochloric acid solution. The organic phase was separated and then washed twice with deionized water. The organic phase was collected and dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the organic solvent. The solid was separated and purified using a 100-200 mesh silica gel column (eluent polarity: dichloromethane / methanol, 20:1) to obtain 871 mg of the ferrocene derivative Fc-Rd with a yield of 80.3%.

[0033] The characterization data of the ferrocene derivative Fc-Rd are as follows:

[0034] 1H NMR(500MHz,Chloroform-d)δ8.21(s,1H),7.59(tt,J=13.8,7.4Hz,2H),7.29–7.14(m,2H),7.08(t,J=7.2Hz,1H),5.30(s,1H ),4.94–4.66(m,3H),4.32(d,J=5.9Hz,3H),3.66(ddt,J=41.0,13.6,6.8Hz,3H),3.40–3.24(m,1H),3.14(dt,J=31.3,6.8Hz, 1H),3.05(s,1H),2.89–2.73(m,1H),2.61(ddd,J=52.0,15.4,6.6Hz,1H),2.43(dd,J=15.4,8.5Hz,1H),1.85(dt,J=9.0,4.9H z,1H),1.43(d,J=4.4Hz,2H),1.41(s,4H),1.35(q,J=7.7,7.0Hz,5H),1.27(d,J=14.7Hz,4H),0.87(q,J=12.7,9.6Hz,1H).13C NMR (151MHz, CDCl3) δ169.24,168.93,162.91,158.01,156.16,154.93,144.37,134.75,1 32.18,130.03,129.70,129.37,128.74,127.79,123.37,122.66,116.60,116.24,96.50,7 9.71,79.38,77.29,77.08,76.86,73.78,72.68,70.68,70.56,47.43,46.05,38.55,38.2 6,37.94,31.51,29.69,28.41,27.04,26.34,22.69,21.09,14.13,12.67,0.01.MALDI-TOF MS calculated for C 43 H 50 FeN3O4 + (M) m / z 728.313, found 729.337.

[0035] Example 2

[0036] (1) Incubate Staphylococcus aureus in LB medium at 37°C until OD 600 Use fresh culture medium to dilute the bacterial solution to OD 600 ~0.05.

[0037] (2) Using the bacterial solution incubated without adding the compound as a control, Staphylococcus aureus was incubated with LB medium containing Fc-Rd (8 μM) prepared in Example 1 for 4 h. Next,

[0038] (3) The Staphylococcus aureus solution obtained in step (2) was diluted with PBS by 10 3 Then, 10 μL of the bacterial solution was spread on LB medium and incubated at 37°C for 18-24 h.

[0039] All experiments were performed in triplicate. The antibacterial activity of Fc-Rd was evaluated by the number of colony-forming units of Staphylococcus aureus. Figure 1 As shown, the number of colonies on the culture medium with added Fc-Rd was significantly less than that in the control group, proving that Fc-Rd has an inhibitory effect on the growth of Staphylococcus aureus.

[0040] Example 3

[0041] (1) The standard solution of Fc-Rd prepared in Example 1 was mixed with the cell culture solution at a volume ratio of 1:2000, 1:1000, and 1:500, respectively, to obtain cell culture solutions containing 5 μM, 10 μM, and 20 μM Fc-Rd, respectively. The culture solution without Fc-Rd was used as a blank control.

[0042] (2) The culture medium with different Fc-Rd contents and the culture medium of the blank control group were incubated with A549 cells (human lung adenocarcinoma cells) in a 24-well culture plate for 6 h, and then the cells were washed and the cell density was detected using CCK-8 (Cell Counting Kit-8).

[0043] The results are as follows Figure 2 As shown, the cell activities incubated with 0 μM, 5 μM, 10 μM and 20 μM Fc-Rd were 100%, 98%, 95% and 93%, respectively, indicating that Fc-Rd had no obvious killing effect on cells under short-term culture.

[0044] The above description is only a preferred embodiment of the present invention, and therefore cannot be used to limit the scope of the present invention. That is, equivalent changes and modifications made according to the patent scope of the present invention and the contents of the specification should still fall within the scope of the present invention.

Claims

1. A ferrocene derivative, characterized in that: Its structural formula is 2. The method for preparing the ferrocene derivative according to claim 1, characterized in that: Its synthetic route is 3. The preparation method according to claim 2, characterized in that: The steps include: (1) Dissolve the S1 in dichloromethane and stir, add the DMTMM and stir at room temperature for 8-12 minutes, then add the S2 and stir at room temperature for reaction; (3) The material obtained in step (2) is diluted with dichloromethane, and then washed with a dilute hydrochloric acid solution, followed by separation to obtain an organic phase, which is then washed with deionized water and separated to collect the organic phase, dried over anhydrous sodium sulfate, and then distilled under reduced pressure to remove dichloromethane, and the obtained solid is separated and purified using a silica gel chromatography column to obtain the ferrocene derivative.

4. The preparation method according to claim 3, characterized in that: In the step (1), the mass ratio of S1, DMTMM and S2 is 1:0.8-0.9:0.3-0.

4.

5. Use of the ferrocene derivative according to claim 1 in preparing an anti-Gram-positive bacteria composition.

6. The use according to claim 5, characterized in that: The anti-Gram-positive bacteria composition has an inhibitory effect on the growth of Staphylococcus aureus.

7. An anti-Gram-positive bacteria composition, characterized in that: The effective component thereof comprises the ferrocene derivative described in claim 1.

8. An anti-Gram-positive bacteria composition according to claim 7, characterized in that: The active ingredient is the ferrocene derivative.

9. An anti-Gram-positive bacteria composition according to claim 7 or 8, characterized in that: It has an inhibitory effect on the growth of Staphylococcus aureus.

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