Synthesis and application of an N,N coordinated gallium complex antibacterial agent

Abstract

The present invention provides an N,N coordinated gallium complex antibacterial agent as shown in Formula I, wherein R is -S, or -O or -NH. The novel gallium complex prepared by the present invention has a broad-spectrum antibacterial property and has a good bactericidal effect on both Gram-negative bacteria and Gram-positive bacteria. Formula I

Description

Technical Field

[0001] The invention belongs to the field of complex synthesis, and particularly relates to the synthesis and application of an N,N coordinated gallium complex. Background Art

[0002] Gallium is a post-transition metal that exhibits the unique broad-spectrum and universality of metal antibacterial properties. Therefore, more and more gallium metal derivatives are being developed as potential antibacterial agents.

[0003] Studies have shown that the antibacterial mechanism of gallium may be as follows: many biochemical reactions within bacteria require the participation of iron, especially the formation of biofilms. Gallium and iron have many similarities in properties, and bacteria cannot recognize the two during biochemical reactions. As a result, gallium replaces the action site of iron, making it impossible for bacteria to metabolize normally, leading to bacterial death.

[0004] However, the antibacterial activity of gallium metal is limited. The efficacy can be improved through coordination and synergistic effects of ligands. Therefore, the present invention uses N,N ligands to coordinate with gallium to synthesize complexes with better antibacterial activity, providing a technical reserve for gallium metal antibacterial agents. Summary of the invention

[0005] The purpose of the present invention is to provide a synthesis and application of a gallium complex for antibacterial use.

[0006] The present invention provides an N,N coordinated gallium complex, wherein the molecular structure of the gallium complex is as shown in Formula I:

[0007]

[0008] Wherein, R is -S, or -O or -NH.

[0009] The gallium complex prepared by the present invention uses two ligands, referred to as A and B ligands, A ligand is metformin hydrochloride (as shown in formula II), and B ligand is a heterocyclic ligand (as shown in formula III):

[0010]

[0011] Wherein, R is -S, or -O or -NH.

[0012] The specific steps of preparing the gallium complex are as follows: dissolving the A ligand in 5 mL of an equimolar sodium hydroxide aqueous solution, adding 20 mL of methanol, heating to 70-80° C., slowly dropping 10 mL of an equimolar gallium trichloride methanol solution, dropping for 0.5 h to 1 h, and keeping warm for 2 to 6 h. Then slowly dropping 20 mL of an equimolar hot methanol solution of the B ligand, dropping for 0.5 h to 1 h, keeping warm for 1 h, filtering while hot, and precipitating a yellow-brown product after the solution is cooled.

[0013] The molar amount of the product substance is 0.2-0.5 mmol, and the molar ratio of A ligand: B ligand: NaOH: GaCl3 is 1:1:1:1.

[0014] The gallium complex synthesized by the invention has good antibacterial activity against both Gram-negative bacteria and Gram-positive bacteria and can be used as an antibacterial agent.

[0015] Other features and advantages of the present invention will be described in the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to better understand the preparation method of the gallium (Ga) complex of the present invention, the accompanying drawings provide a reaction flow chart.

[0017] Figure 1 It is a reaction flow chart of the preparation of gallium (Ga) complex of the present invention. Implementation

[0018] The present invention will be described in detail below through specific implementation methods and examples, and the features and advantages of the present invention will be fully and clearly presented. It should be understood that the described specific implementation methods and examples are only a part of the present invention listed, which are only used for explanation and description, but not for limiting the present invention.

[0019] The N,N coordinated gallium complex provided by the present invention is a tetra-coordinated cationic complex, and its molecular structure is shown in Formula I:

[0020]

[0021] Wherein, R is -S, or -O or -NH.

[0022] Preferably, R is -NH.

[0023] The gallium complex prepared by the present invention uses two ligands, referred to as A and B ligands, A ligand is metformin hydrochloride (as shown in formula II), and B ligand is a heterocyclic ligand (as shown in formula III):

[0024]

[0025] Wherein, R is -S, or -O or -NH.

[0026] Preferably, R is -NH.

[0027] Example 1

[0028] Preferably R is -NH. The preparation steps of gallium complex 1c are as follows: 0.25mmol A ligand is dissolved in 5mL 0.05mol / L NaOH aqueous solution, 20mL methanol is added, the temperature is raised to 70°C, 10mL 0.025mol / L GaCl3 methanol solution is slowly added dropwise for about 0.5h, and the temperature is kept for 3h after the addition is completed. Then 20mL 0.0125mol / LB ligand (2-(1H-imidazole-2-yl)quinoline) hot methanol solution is added dropwise for about 0.5h, the temperature is kept for 1h, and the solution is filtered while hot. After the solution is cooled, a yellow-brown product is precipitated, with a yield of 31%. Elemental analysis: calcd(%) for C 16 H 30 N8Cl3Ga:C,38.40;H,4.03;N,22.39;Found(%):C,38.12;H,3.97;N,22.62. In methanol (1×10 -3 M) Molar conductivity Λm (S·cm 2 ·mol -1 ) is 310.

[0029] Example 2

[0030] Preferably R is -S. The preparation steps of gallium complex 2c are as follows: 0.25mmol A ligand is dissolved in 5mL 0.05mol / L NaOH aqueous solution, 20mL methanol is added, the temperature is raised to 75°C, 10mL 0.025mol / L GaCl3 methanol solution is slowly added dropwise for about 0.5h, and the temperature is kept for 3h after the addition is completed. Then 20mL 0.0125mol / LB ligand (2-(quinolin-2-yl)thiazole) hot methanol solution is added dropwise for about 0.5h, the temperature is kept for 1h, and the solution is filtered while hot. After the solution is cooled, a dark yellow-brown product is precipitated, with a yield of 37%. Elemental analysis: calcd(%) for C 16 H 30 N8Cl3Ga:C,37.13;H,3.70;N,18.95;Found(%):C,36.89;H,3.62;N,18.68. In methanol (1×10 -3 M) Molar conductivity Λm (S·cm 2 ·mol -1 ) is 278.

[0031] Example 3

[0032] Preferably R is -O. The preparation steps of gallium complex 3c are as follows: 0.25mmol A ligand is dissolved in 5mL 0.05mol / L NaOH aqueous solution, 20mL methanol is added, the temperature is raised to 78°C, 10mL 0.025mol / L GaCl3 methanol solution is slowly added dropwise for about 1h, and the temperature is kept for 4h after the addition is completed. Then 20mL 0.0125mol / LB ligand (2-(quinolin-2-yl)oxazole) hot methanol solution is added dropwise for about 0.5h, the temperature is kept for 1h, and the solution is filtered while hot. After the solution is cooled, a yellow-brown product is precipitated, with a yield of 44%. Elemental analysis: calcd(%) for C 16 H 30 N8Cl3Ga:C,38.32;H,3.82;N,19.55;Found(%):C,38.72;H,3.74;N,19.25. In methanol (1×10 -3 M) Molar conductivity Λm (S·cm 2 ·mol -1 ) is 297.

[0033] Example 4

[0034] Antibacterial effect test of gallium complexes 1c to 3c. The minimum inhibitory concentration (MIC) of the gallium complexes against Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa), Bacillus subtilis (B. subtilis) and Staphylococcus aureus (S. aureus) was tested by microbroth dilution method. The bacterial solution in the logarithmic growth phase was diluted to 1×10 4 CFU·mL -1 , the bacterial suspension was inoculated into a 96-well plate, and then DMSO solutions of different concentrations of gallium complexes were added according to the two-fold dilution method, and a control group was set up, and each concentration was repeated three times. After culturing overnight, the absorbance value at 590nm was measured with an ELISA instrument, and the MIC value was recorded according to the absorbance value. Table 1 records the MIC values ​​of gallium complexes 1c to 3c synthesized in Examples 1 to 3.

[0035] Table 1 Minimum inhibitory concentration of gallium complexes 1c to 3c

[0036]

[0037] Note: Each concentration group was repeated three times.

[0038] The invention discloses the synthesis and application of an N,N coordinated gallium complex. The gallium complex has a significantly improved antibacterial effect through coordination and synergistic effect of a ligand, has a broad-spectrum antibacterial property and universality, and has an efficacy close to that of commercially available oxazolidinone fungicides.

[0039] Metal gallium complexes have good antibacterial efficacy and can be further developed and utilized as potential antibacterial agents.

Claims

1. An N,N coordinated gallium complex, characterized in that: Its molecular structure is shown in Formula I: Wherein, R is -S, or -O or -NH.

2. A method for preparing the gallium complex according to claim 1, characterized in that: Two ligands are used, referred to as A and B ligands, A ligand is metformin hydrochloride (as shown in formula II), and B ligand is a heterocyclic ligand (as shown in formula III): Wherein, R is -S, or -O or -NH.

3. A method for preparing the gallium complex according to claim 1, characterized in that: The specific preparation steps are: use the A ligand described in claim 2, dissolve it in 5 mL of an equimolar sodium hydroxide aqueous solution, add 20 mL of methanol, heat it to 70-80°C, slowly drop 10 mL of an equimolar gallium trichloride methanol solution, the drop time is 0.5h-1h, keep warm for 2-6h, then slowly drop 20 mL of an equimolar hot methanol solution of the B ligand, the drop time is 0.5h-1h, keep warm for 1h, filter while hot, and precipitate the product after the solution is cooled.

4. A method for preparing a gallium complex according to claim 3, characterized in that: The molar amount of the product substance is 0.2-0.5 mmol, and the molar ratio of A ligand: B ligand: NaOH: GaCl3 is 1:1:1:

1.

5. The N,N coordinated gallium complex according to claim 1, characterized in that: The complex has good bactericidal effects on both Gram-negative bacteria and Gram-positive bacteria and has broad-spectrum bactericidal properties.

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