A ferrocene derivative and use thereof

Abstract

The application discloses a ferrocene derivative and application thereof, and a structural formula of the ferrocene derivative is shown in the figure. The application has a rhodamine structure fused with ferrocene, has obvious inhibiting effect on staphylococcus aureus, and has no toxicity to human cells.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicinal compounds, and particularly relates to a ferrocene derivative and application thereof. BACKGROUND

[0002] As one of the oldest and most diverse microorganisms on Earth, bacteria are widely present in our surrounding environment, including soil, water, air, and every corner of our body surface and interior. In the long history of human coexistence with microorganisms, bacterial infection has always been a health issue of great concern and far-reaching impact.

[0003] In early human society, due to poor living conditions and lack of health knowledge, bacteria had extremely favorable conditions for breeding and spreading. At that time, once bacterial infection occurred, it would often spread rapidly among the population, causing cholera, typhoid fever and other severe infectious diseases, bringing great disaster to the entire community, causing a large number of population to be ill or even die, and seriously hindering the development of society and the reproduction of human beings.

[0004] With the advancement of the times and the acceleration of urbanization, population density has further increased, and people's communication has become more frequent, which has increased the risk of bacterial infection transmission to some 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 battle against bacterial infection, but bacteria have shown amazing adaptability and variability. They constantly evolve and develop drug resistance, making the originally effective antibiotics gradually lose their effectiveness, thus causing some bacterial infection diseases that were once easily cured to become a thorny medical problem again, bringing new severe challenges to global public health.

[0005] Now, bacterial infection is still one of the important factors leading to various diseases worldwide, from common respiratory tract infections, urinary system infections to more serious sepsis, which threatens the health of people of different ages and different regions at all times. This situation has prompted the scientific and medical communities to conduct in-depth research to seek more effective prevention and treatment strategies. SUMMARY

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

[0007] Another object of the present application is to provide a preparation method of the ferrocene derivative.

[0008] Still another object of the present application is to provide an application of the ferrocene derivative.

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

[0010] A ferrocene derivative has the structural formula

[0011] The preparation method of the above ferrocene derivative, the synthetic route of which is

[0012]

[0013] In a preferred embodiment of the present application, the following steps are included:

[0014] (1) stirring the S1 dissolved in dichloromethane, adding the DMTMM and stirring at room temperature for 8-12 min, then adding the S2 and stirring at room temperature;

[0015] (2) diluting the material obtained in step (1) with dichloromethane, washing with dilute hydrochloric acid solution, then separating the organic phase, washing the organic phase with deionized water, collecting the organic phase, drying with anhydrous sodium sulfate, removing dichloromethane by distillation under reduced pressure, and separating and purifying the obtained solid with a silica gel chromatographic 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] The use of the above ferrocene derivative in the preparation of an anti-Gram-positive bacterial composition.

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

[0019] An anti-Gram-positive bacterial composition, the effective component of which includes the above ferrocene derivative.

[0020] In a preferred embodiment of the present application, the effective component is the above ferrocene derivative.

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

[0022] The beneficial effects of the present application are: the present application has a rhodamine structure fused with ferrocene, which has a significant inhibitory effect on Staphylococcus aureus, and has no toxicity to human cells. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The inhibition effect of Fc-Rd on Staphylococcus aureus at a concentration of 8 μM in Example 2 of the present application.

[0024] Figure 2 The effect of Fc-Rd of different concentrations on cell activity in Example 2 of the present application. DETAILED DESCRIPTION

[0025] The technical solutions of the present application are further described and explained with reference to the specific embodiments in conjunction with the accompanying drawings.

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

[0027] The synthetic route of this example is as follows:

[0028]

[0029] Specifically comprising the following steps:

[0030] (1) Preparation of compound S1 (ref. 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-dimethoxytriazin-2-yl)-4-methylmorpholinium 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, washed with 1 mol / L dilute hydrochloric acid solution, then separated to obtain the organic phase, then the organic phase was washed with deionized water twice, and the organic phase was collected, dried with anhydrous sodium sulfate, and then the organic solvent was removed by distillation under reduced pressure, the obtained solid was separated and purified by a silica gel column with a particle size of 100-200 (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) Staphylococcus aureus was incubated with LB medium at 37°C until OD 600 Reach 0.6. Dilute the bacterial culture with fresh culture medium to OD0.6. 600 ~0.05.

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

[0038] (3) Dilute the Staphylococcus aureus solution obtained in step (2) with PBS in a serial dilution pattern of 10. 3 Then, spread 10 μL of bacterial solution onto LB medium and incubate at 37°C for 18-24 hours.

[0039] All experiments were performed in triplicate. The antibacterial activity of Fc-Rd was assessed by the number of units of Staphylococcus aureus colony formation. Results are as follows: 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 cell culture solution at volume ratios of 1:2000, 1:1000 and 1:500 respectively to obtain cell culture solutions containing 5 μM, 10 μM and 20 μM of 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 blank control group culture medium were incubated with A549 cells (human lung adenocarcinoma cells) in a 24-well plate for 6 hours. Then the cells were washed and the cell density was detected by CCK-8 (Cell Counting Kit-8).

[0043] The results are as follows Figure 2 As shown, the cell viability after incubation with 0μM, 5μM, 10μM and 20μM Fc-Rd was 100%, 98%, 95% and 93%, respectively, indicating that Fc-Rd did not have a significant killing effect on cells under short-term culture.

[0044] The above description is merely a preferred embodiment of the present invention, and therefore should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made in accordance with the scope of the patent 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 as follows 3. The preparation method according to claim 2, characterized in that: Includes the following steps: (1) Dissolve and stir the S1 in dichloromethane, add the DMTMM and stir at room temperature for 8-12 min, then add the S2 and stir at room temperature. (3) The material obtained in step (2) is diluted with dichloromethane, washed thoroughly with dilute hydrochloric acid solution, and then separated to obtain an organic phase. The organic phase is then washed with deionized water and collected by separation. After drying with anhydrous sodium sulfate, dichloromethane is removed by vacuum distillation. The resulting solid is separated and purified by silica gel chromatography column to obtain the ferrocene derivative.

4. The preparation method according to claim 3, characterized in that: In 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 of claim 1 in the preparation of compositions against Gram-positive bacteria.

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

7. A composition for combating Gram-positive bacteria, characterized in that: Its active ingredient includes the ferrocene derivative as described in claim 1.

8. The anti-Gram-positive bacteria composition as described in claim 7, characterized in that: Its active ingredient is the ferrocene derivative mentioned above.

9. A composition against Gram-positive bacteria as described in claim 7 or 8, characterized in that: It has an inhibitory effect on the growth of Staphylococcus aureus.

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