Imidazolyl Schiff base hydrazone ligands and their preparation methods, imidazolyl Schiff base hydrazone metal drugs and their applications

Abstract

This invention belongs to the field of bioinorganic chemistry, specifically relating to imidazole-Schiff base acylhydrazone ligands and their preparation methods, imidazole-Schiff base acylhydrazone metal drugs, and their applications. This invention provides a novel imidazole-Schiff base acylhydrazone ligand, N'-(5-bromo-2-hydroxybenzylmethyl)-4-(1-imidazolium)benzoylhydrazine. The imidazole-Schiff base acylhydrazone ligand is then coordinated with zinc nitrate or europium nitrate to obtain an imidazole-Schiff base acylhydrazone metal drug. Using the method of this invention, a new ligand is obtained, and a new drug with a well-defined structure, low toxicity, and anticancer activity is prepared using this ligand, overcoming the technical defects of existing metal drugs and Schiff base drugs.

Description

Technical Field

[0001] This invention belongs to the field of bioinorganic chemistry technology, specifically relating to imidazole Schiff base hydrazone ligands and their preparation methods, imidazole Schiff base hydrazone metal drugs and their applications. Background Technology

[0002] Since the advent of cisplatin-based drugs, the field of metal-based anti-tumor drug research has seen new developments. However, platinum-based drugs face problems of drug resistance and toxicity. Researchers are working hard to overcome these limitations and seek to develop new potential drug molecules, especially non-platinum metal complexes, in order to reduce side effects and overcome drug resistance, hoping to achieve new breakthroughs in tumor chemotherapy and expand into the treatment of more types of tumors.

[0003] Zinc-based complexes cannot be overlooked when exploring alternatives to platinum-based anticancer drugs. Zinc ions possess a specific equilibrium mechanism in the body, allowing them to be more effectively managed by the body's physiological systems, thereby reducing side effects. Zinc ions also exhibit non-toxicity at higher doses, demonstrating significant biocompatibility, and possessing different targets and mechanisms of action than platinum-based drugs.

[0004] Rare earth elements possess multiple effects, including anti-inflammatory, antibacterial, anticancer, anticoagulant, and analgesic properties. In drug therapy, rare earth complexes, formed by combining rare earth elements with ligands possessing anticancer activity, often exhibit anticancer effects due to the synergistic effect of their components, while also reducing toxicity.

[0005] However, for many years, no new metal drugs have been found that have good anti-tumor effects and can maintain low toxicity to various organs and the body.

[0006] Schiff bases are a class of compounds containing imine or methylimine groups, and are indispensable organic ligands in the synthesis of novel drug molecules. Acylhydrazones, a special type of Schiff base, possess high stability due to the hydrogen bonds formed between their O and N atoms. They can bind to certain substances in the body via hydrogen bonds, thereby inhibiting various physiological and chemical processes and exhibiting good antibacterial, anticancer, antiviral, anti-inflammatory, and antituberculosis activities. However, currently synthesized Schiff base drugs lack a defined structure, have insufficient antitumor activity, or exhibit high levels of toxicity. Summary of the Invention

[0007] To address the shortcomings of the existing technologies, this invention provides an imidazole-Schiff base hydrazone ligand, its preparation method, an imidazole-Schiff base hydrazone metal drug, and its applications. This invention first uses 5-bromo-2-hydroxybenzaldehyde to undergo a nucleophilic addition-elimination reaction with 4-(1H-imidazol-1-yl)benzoylhydrazine to obtain a novel imidazole-Schiff base hydrazone ligand. Then, the imidazole-Schiff base hydrazone ligand is coordinated with zinc nitrate or europium nitrate to obtain an imidazole-Schiff base hydrazone metal drug. Using the method of this invention, a new ligand is obtained, and then a new drug with a well-defined structure, low toxicity, and high anticancer activity is prepared using the ligand, overcoming the technical defects of existing metal drugs and Schiff base drugs.

[0008] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: This invention first designs and synthesizes imidazole-based Schiff base hydrazone ligands, that is, by introducing an imidazole group at one end of the Schiff base hydrazone, making it easy to form a complex with a one-dimensional chain structure with metal ions. The one-dimensional chain molecules can spontaneously self-assemble to form nanoscale aggregates or supramolecular structures. These aggregates or supramolecular structures can improve the in vivo distribution of drugs, prolong the residence time of drugs in the circulatory system, and enhance the tumor targeting of drugs, providing new strategies and methods for drug delivery and treatment.

[0009] The first objective of this invention is to protect an imidazole-based Schiff base hydrazone ligand, the imidazole-based Schiff base hydrazone ligand being N'-(5-bromo-2-hydroxybenzylmethyl)-4-(1-imidazole)benzoylhydrazine, with the following chemical structural formula: .

[0010] The second objective of this invention is to protect a method for preparing an imidazole-based Schiff base acylhydrazone ligand, comprising the following steps: 4-(1H-imidazol-1-yl)benzaldehyde was dissolved in anhydrous ethanol, and then 80 wt% hydrazine hydrate was added dropwise. The mixture was stirred and refluxed at 60℃~80℃ for 4h~12h to obtain 4-(1H-imidazol-1-yl)benzoylhydrazine.

[0011] 4-(1H-imidazol-1-yl)benzoylhydrazide and 5-bromo-2-hydroxybenzaldehyde were dissolved in anhydrous ethanol and subjected to nucleophilic addition-elimination reaction to obtain imidazolyl Schiff base hydrazone ligand.

[0012] Preferably, the nucleophilic addition-elimination reaction is carried out under the following conditions: stirring at 60℃~80℃ for 4h~12h.

[0013] Preferably, the molar ratio of 4-(1H-imidazol-1-yl)benzoylhydrazide to 5-bromo-2-hydroxybenzaldehyde is 1:0.5-2.

[0014] The third objective of this invention is to provide an imidazolium-Schiff base hydrazone metal drug, which is an imidazolium-Schiff base hydrazone zinc complex. The introduction of zinc nitrate further reduces the toxicity of the imidazolium-Schiff base hydrazone zinc complex. It is prepared by a coordination reaction between an imidazolium-Schiff base hydrazone ligand and zinc nitrate, and its structural formula is as follows: .

[0015] Preferably, the unit cell parameters of the imidazole-Schiff base hydrazone zinc complex are a = 7.3584(3) Å, b = 18.1163(8) Å, c = 14.9563(6) Å, β = 95.001(2)°, and the unit cell volume is 1986.19(14) Å. 3 Z=4 D c =1.818g / cm 3 .

[0016] The fourth objective of this invention is to provide an imidazolium-Schiff base hydrazone metal drug, which is an imidazolium-Schiff base hydrazone europium complex. The europium nitrate complex exhibits high fluorescence intensity. The introduction of the molybdenum ion makes it possible to visualize the distribution of the imidazolium-Schiff base hydrazone europium complex within tissues. It is prepared by a coordination reaction between an imidazolium-Schiff base hydrazone ligand and europium nitrate, and its structural formula is as follows: .

[0017] Preferably, the unit cell parameters of the imidazole Schiff base acylhydrazone europium complex are a = 13.1538(11) Å, b = 14.1255(14) Å, c = 14.1709(13) Å, β = 111.855(2)°, and the unit cell volume is 2443.8(4) Å. 3 Z=4 D c =1.993g / cm 3 .

[0018] Preferably, the molar ratio of imidazole Schiff base hydrazone ligand to zinc nitrate is 1:1~2, and the molar ratio of imidazole Schiff base hydrazone ligand to europium nitrate is 1:1~2.

[0019] Preferably, the conditions for the coordination reaction of the imidazole Schiff base hydrazone ligand with europium nitrate are: heating at 60℃~80℃ for 48h~72h.

[0020] Preferably, the conditions for the coordination reaction of the imidazole Schiff base hydrazone ligand with europium nitrate are: heating at 60℃~80℃ for 48h~72h.

[0021] The fifth objective of this invention is to protect the use of imidazole Schiff base hydrazone metal drugs in the preparation of antitumor drugs.

[0022] Preferably, the imidazole Schiff base hydrazone metal complex exhibits significant anticancer activity against human non-small cell lung cancer cell line A549, human breast cancer cell line SKBR3, and human nasopharyngeal carcinoma cell line CNE-2Z. It also shows some toxicity against human breast cancer cell line MDA-MB-231 and human colon cancer cell line HCT116, and its toxicity to normal human ovarian epithelial cells IOSE80 is lower than that of cisplatin.

[0023] Compared with the prior art, the beneficial effects of the present invention are as follows: 0. This invention first provides an imidazole-based Schiff base hydrazone ligand. By introducing an imidazole group at one end of the Schiff base hydrazone, the coordinating active group of the imidazole-based Schiff base hydrazone ligand is increased, making it easier to coordinate with zinc nitrate or europium nitrate, and forming complexes with a one-dimensional chain structure, including imidazole-based Schiff base hydrazone zinc complexes and imidazole-based Schiff base hydrazone europium complexes. Using the imidazole-based Schiff base hydrazone ligand as the ligand unit, the imidazole-based Schiff base hydrazone ligand is reacted with zinc nitrate or europium nitrate using a solvothermal one-pot method to synthesize the imidazole-based Schiff base hydrazone zinc complex or the imidazole-based Schiff base hydrazone europium complex for the first time. This invention explores the anticancer activity of imidazole-Schiff base hydrazone zinc complex and imidazole-Schiff base hydrazone europium complex, studies the relationship between their structure and antitumor activity, and develops new antitumor drugs with high activity and low toxicity, providing a theoretical and experimental basis for the research of new bioinorganic chemical drugs.

[0024] 2. Antitumor activity experiments showed that the imidazole-Schiff base acylhydrazone zinc complex and the imidazole-Schiff base acylhydrazone europium complex exhibited significant anticancer activity against the human non-small cell lung cancer cell line A549, with stronger activity than the positive control drug cisplatin. The inhibition rate of the two complexes against tumor cells was detected using the CCK-8 assay. Both complexes showed significant cytotoxicity against A549 cells, with IC50 values ​​of [missing data]. 50 The value was significantly lower than that of the positive control drug cisplatin. However, the IC50 value for normal cells was significantly lower than that for IOSE80. 50 The value was higher than that of cisplatin, indicating lower toxicity to normal cells (IOSE80). The imidazole Schiff base hydrazone metal drug of this invention is an ideal novel anticancer drug.

[0025] 3. The imidazole-Schiff base hydrazone zinc complex and the imidazole-Schiff base hydrazone europium complex of the present invention have molecular structures that are completely different from those of existing antitumor drugs. The imidazole-Schiff base hydrazone metal drugs have shown superior antitumor activity against human lung cancer cells A549, human breast cancer cells SKBR3, and human nasopharyngeal carcinoma cells CNE-2Z compared to the positive control drug cisplatin, providing new ideas for the development of antitumor drugs.

[0026] 4. The preparation methods of the imidazole-Schiff base acylhydrazone zinc complex and the imidazole-Schiff base acylhydrazone europium complex of the present invention are both carried out under low temperature and anhydrous ethanol solvent conditions, producing imidazole-Schiff base acylhydrazone metal drugs with high purity and high yield. The process is simple, the products are pure, the yield is high, and the post-processing is convenient. In addition, the preparation methods of the imidazole-Schiff base acylhydrazone zinc complex and the imidazole-Schiff base acylhydrazone europium complex employ a one-pot synthesis method, the synthesis solvent is green, no catalyst is required, and the products have well-defined structures. Attached Figure Description

[0027] Figure 1 This is a synthetic route diagram of the imidazole Schiff base hydrazone ligand of the present invention.

[0028] Figure 2 This is a schematic diagram of the structure of the zinc imidazole Schiff base hydrazone complex in Example 1 of the present invention.

[0029] Figure 3 This is a schematic diagram of the structure of the imidazole-Schiff base hydrazone europium complex in Example 2 of the present invention.

[0030] Figure 4 This is a one-dimensional chain structure diagram of the zinc imidazole Schiff base hydrazone complex of Example 1 of the present invention.

[0031] Figure 5 This is a one-dimensional chain structure diagram of the imidazole Schiff base acylhydrazone europium complex of Example 2 of the present invention.

[0032] Figure 6 This is the mass spectrum of the imidazole Schiff base hydrazone ligand in Example 1 of the present invention.

[0033] Figure 7 This is the 1H NMR spectrum of the imidazole Schiff base hydrazone ligand of Example 1 of the present invention.

[0034] Figure 8 The infrared spectrum of the imidazole Schiff base hydrazone ligand in Example 1 of this invention is shown. Detailed Implementation

[0035] The specific embodiments of the present invention are described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention. Unless otherwise specified, the experimental methods described in the embodiments of the present invention are conventional methods.

[0036] Nitrogen-containing heterocyclic imidazole derivatives are an important class of bioactive substances. Imidazole drugs, especially metronidazole, are highly favored in clinical practice due to their wide range of applications. Imidazoles and their derivatives are widely used in agriculture and medicine due to their broad range of activities, such as antibacterial, antitumor, and antiparasitic effects. This invention introduces imidazoles into the ligand structure, providing rich structural diversity for the selection of bioactivity, deepening the study of the structure-activity relationship of imidazole drugs, and also promoting the development of novel imidazole drugs.

[0037] Considering the shortcomings of existing technologies in synthesizing Schiff base drugs, such as the lack of a defined structure, insufficient antitumor activity, and high toxicity, this invention introduces an imidazole group at one end of the Schiff base acylhydrazone, making it easier to form a complex with a one-dimensional chain structure. This increases its retention time in tumor cells, overcoming the problem of multidrug resistance caused by the easy pump-out of traditional small molecules. Furthermore, this invention also has the following advantages:

[0038] Clear Chemical Structure: 1. Through optimized synthesis methods, the imidazole-based Schiff base acylhydrazone metal complex prepared in this invention possesses a clear molecular structure, overcoming the problem of difficult-to-determine Schiff base drug structures in existing technologies and improving the reliability of drug development. 2. Low Toxicity: This invention prioritizes the biocompatibility of the complex during design and synthesis, significantly reducing the toxic side effects of the drug and solving the problem of potentially high toxicity of current Schiff base complexes, thus improving the safety of clinical applications. 3. Excellent Antitumor Activity: Through coordination with zinc and europium metal ions, the imidazole-based Schiff base acylhydrazone metal complex of this invention exhibits excellent antitumor activity, effectively overcoming the problem of insufficient antitumor activity of existing synthetic Schiff base drugs and demonstrating its potential as a novel anticancer drug.

[0039] 5-Bromo-2-hydroxybenzaldehyde, commonly known as 5-bromo-salicylaldehyde, contains a phenolic hydroxyl group and a bromine atom in its molecular structure. This gives it certain acidity and nucleophilicity, making it readily form Schiff bases from amino groups, thus giving it significant application value in the pharmaceutical field. The formation of a Schiff base acylhydrazone structure containing an imidazole group from 5-bromo-2-hydroxybenzaldehyde with 4-(1H-imidazol-1-yl)benzoylhydrazide can significantly enhance its activity; however, this design has not been previously reported.

[0040] The technical solution of the present invention will be studied below using examples. The synthetic route of the imidazole Schiff base hydrazone ligand (HL) in the present invention is as follows: Figure 1 As shown, the specific research methods and results are as follows: Example 1 The preparation method of the imidazole Schiff base acylhydrazone zinc complex includes the following steps: S1. Dissolve 4-(1H-imidazol-1-yl)benzaldehyde in anhydrous ethanol, then add 80 wt% hydrazine hydrate dropwise. The molar ratio of 4-(1H-imidazol-1-yl)benzaldehyde to hydrazine hydrate is 1:1. Stir and reflux at 70 °C for 8 h to obtain 4-(1H-imidazol-1-yl)benzoylhydrazine.

[0041] S2. Dissolve 4-(1H-imidazol-1-yl)benzoylhydrazide and 5-bromo-2-hydroxybenzaldehyde in ethanol at a molar ratio of 1:1.5. Reflux at 78°C for 4 hours, recrystallize to obtain a light yellow solid with a yield of 92%, namely the imidazolyl Schiff base hydrazone ligand N'-(5-bromo-2-hydroxybenzylmethyl)-4-(1-imidazol)benzoylhydrazide, denoted as HL; NMR (e.g., NMR spectroscopy) Figure 7 (as shown) 1 H NMR ( Figure 6 400 MHz d 6 -DMSO) δ : 11.41 (s, 1H), 10.44 (s, 1H), 7.80 (s, 1H), 7.59 (s, 1H), 7.25 (d, J = 5.9 Hz, 2H), 7.07-9.67(m, 4H), 6.60 (d, J = 8.8 Hz, 1H), 6.32 (s, 1H), 6.08 (d, J = 8.8 Hz, 1H). ESI-MS high-resolution mass spectrometry (e.g.) Figure 6 (As shown) [MH] - 385.0289. Fourier transform infrared spectrum (e.g.) Figure 8 As shown, KBr, cm -1): 3502.44(m), 3204.30(w), 3314.67(m), 2359.92(w), 2341.96(w), 1651.68(s), 1613.66(s), 1 577.66(m), 1529.74(s), 1418.96(m), 1457.42(w), 1358.64(m), 1309.67(m), 1295.30(m), 1277 .81(s), 1211.31(m), 1184.01(w), 1082.44(w), 1061.22(m), 969.68(m), 934.64(w), 906.05(w) , 878.08(w), 854.94(m), 824.16(m), 784.39(w), 761.15(w), 727.39(m), 693.79(w), 668.94(m).

[0042] S3. The imidazole-based Schiff hydrazone ligand was mixed with zinc nitrate at a molar ratio of 1:2, and then dissolved in a mixed solvent consisting of 1 mL acetonitrile and 3 mL methanol. The entire mixture was placed in a stainless steel reactor lined with polytetrafluoroethylene and reacted at 70°C for 72 h. The mixture was then slowly cooled to room temperature to obtain colorless blocky crystals. After filtration and drying at room temperature, the imidazole-based Schiff hydrazone zinc complex ZnL was obtained, appearing as orange-yellow flaky crystals with a yield of 57.62%. The molecular formula of ZnL is [ZnLCH3OH]•NO3. Fourier transform infrared spectroscopy (KBr, cm⁻¹) was performed. -1 ): 3502.44(s), 3204.30(w), 2359.92(m), 2341.96(w), 1651.68(s), 1613.66(s), 1577.66(m), 1529.74(s), 1481.96(s), 14 57.42(w), 1436.59(w), 1377.29(w), 1358.64(s), 1309.27(s), 1295.30(s), 1277.81(s), 1211.31(m), 1184.01(m), 1153.9 1(m), 1120.46(w), 1109(w), 1082.44(m), 1061.22(s), 969.68(m), 962.04(s), 934.64(m), 906.05(m), 854.94(s), 824.16( s), 784.39(s), 761.15(mw), 727.39(s), 693.79(m), 668.94(m), 650.51(m), 631.67(m), 562.13(w), 533.19(w), 473.27(w).

[0043] Example 2 The preparation method of imidazole Schiff base acylhydrazone europium complex includes the following steps: S1. Dissolve 4-(1H-imidazol-1-yl)benzaldehyde in anhydrous ethanol, then add 80 wt% hydrazine hydrate dropwise. The molar ratio of 4-(1H-imidazol-1-yl)benzaldehyde to hydrazine hydrate is 1:1. Stir and reflux at 70 °C for 8 h to obtain 4-(1H-imidazol-1-yl)benzoylhydrazine.

[0044] S2. Dissolve 4-(1H-imidazol-1-yl)benzoylhydrazide and 5-bromo-2-hydroxybenzaldehyde in ethanol at a molar ratio of 1:1. Reflux at 78°C for 4 hours and recrystallize to obtain a white solid, namely the imidazolyl Schiff base hydrazone ligand N'-(5-bromo-2-hydroxybenzylmethyl)-4-(1-imidazol)benzoylhydrazide.

[0045] S3. The imidazole-Schiff base hydrazone ligand was mixed with europium nitrate at a molar ratio of 1:2, and then dissolved in a mixture of 1 mL DMF and 3 mL anhydrous ethanol. The entire mixture was placed in a stainless steel reactor lined with polytetrafluoroethylene and reacted at 70°C for 72 h. The mixture was then slowly cooled to room temperature to obtain colorless blocky crystals. After filtration and drying at room temperature, the imidazole-Schiff base hydrazone europium complex EuL was obtained, appearing as orange-yellow flaky crystals with a yield of 59.2%. The molecular formula of EuL is [EuL(NO3)2DMF]. Fourier transform infrared spectroscopy (KBr, cm⁻¹) showed that... -1 ): 2359.85(m), 2341.90(w), 1654.37(m), 1615.60(m), 1517.95(w), 1558.59(w), 1540.53(w), 1521.46(m), 1507.15(w) , 1490.33(m), 1457.83(m), 1435.27(w), 1384.33(s), 1312.61(m), 1294.90(m), 1277.27(m), 1171.70(w), 1050.07(w).

[0046] Example 3 The preparation method of the imidazole Schiff base acylhydrazone zinc complex includes the following steps: S1. Dissolve 4-(1H-imidazol-1-yl)benzaldehyde in anhydrous ethanol, then add 80 wt% hydrazine hydrate dropwise. The molar ratio of 4-(1H-imidazol-1-yl)benzaldehyde to hydrazine hydrate is 1:1. Stir and reflux at 60 °C for 12 h to obtain 4-(1H-imidazol-1-yl)benzoylhydrazine.

[0047] S2. Dissolve 4-(1H-imidazol-1-yl)benzoylhydrazide and 5-bromo-2-hydroxybenzaldehyde in ethanol at a molar ratio of 1:0.5. Reflux at 80°C for 4 hours and recrystallize to obtain a white solid, namely the imidazolyl Schiff base hydrazone ligand N'-(5-bromo-2-hydroxybenzylmethyl)-4-(1-imidazol)benzoylhydrazide.

[0048] S3. The imidazole-Schiff base hydrazone ligand and zinc nitrate were mixed at a molar ratio of 1:1.5 and then dissolved in a mixed solvent consisting of 1 mL acetonitrile and 3 mL methanol. The entire mixture was placed in a stainless steel reactor lined with polytetrafluoroethylene and reacted at 60°C for 72 h. The mixture was then slowly cooled to room temperature to obtain colorless blocky crystals. After filtration and drying at room temperature, the imidazole-Schiff base hydrazone zinc complex was obtained.

[0049] Example 4 The preparation method of imidazole Schiff base acylhydrazone europium complex includes the following steps: S1. Dissolve 4-(1H-imidazol-1-yl)benzaldehyde in anhydrous ethanol, then add 80 wt% hydrazine hydrate dropwise. The molar ratio of 4-(1H-imidazol-1-yl)benzaldehyde to hydrazine hydrate is 1:1. Stir and reflux at 80 °C for 4 h to obtain 4-(1H-imidazol-1-yl)benzoylhydrazine.

[0050] S2. Dissolve 4-(1H-imidazol-1-yl)benzoylhydrazide and 5-bromo-2-hydroxybenzaldehyde in ethanol at a molar ratio of 1:2. Reflux at 60°C for 12 h and recrystallize to obtain a white solid, namely the imidazolyl Schiff base hydrazone ligand N'-(5-bromo-2-hydroxybenzylmethyl)-4-(1-imidazol)benzoylhydrazide.

[0051] S3. The imidazole-Schiff base hydrazone ligand and europium nitrate were mixed in a 1:1 molar ratio and then dissolved in a mixture of 1 mL DMF and 3 mL anhydrous ethanol. The entire mixture was placed in a stainless steel reactor lined with polytetrafluoroethylene and reacted at 80°C for 48 h. The mixture was then slowly cooled to room temperature to obtain colorless blocky crystals. After filtration and drying at room temperature, the imidazole-Schiff base hydrazone europium complex was obtained.

[0052] Examples 1 to 4 of this invention all yielded imidazole-based Schiff base hydrazone metal drugs with excellent antitumor properties. The following studies use ZnL from Example 1 and EuL from Example 2 as examples, and the specific research methods and results are shown below: Single crystals with good crystalline forms were selected and subjected to single-crystal testing using an X-ray single-crystal diffractometer. The crystal structure was analyzed using Olex2 software, and the results are as follows: Figure 2 and Figure 3 As shown, the chemical formula of the imidazole-Schiff base hydrazone zinc complex is [ZnLCH3OH]•NO3, and the chemical formula of the imidazole-Schiff base hydrazone europium complex is [EuL(NO3)2DMF], where L is the imidazole-Schiff base hydrazone ligand anion. Both belong to the monoclinic crystal system, with space group 1. P 2121. The unit cell parameters of the imidazole Schiff base hydrazone zinc complex are a = 7.3584(3) Å, b = 18.1163(8) Å, c = 14.9563(6) Å, β = 95.001(2)°, and the unit cell volume is 1986.19(14) Å. 3 Z=4 D c =1.818g / cm 3 The molecular formula is C 18 H 16 BrN5O6Zn has a molecular weight of 543.64. The unit cell parameters of the imidazole Schiff base acylhydrazone europium complex are a = 13.1538(11) Å, b = 14.1255(14) Å, c = 14.1709(13) Å, β = 111.855(2)°, and the unit cell volume is 2443.8(4) Å. 3 Z=4 D c =1.993g / cm 3 The molecular formula is C 20 H 19 BrEuN7O9 has a molecular weight of 733.29.

[0053] The bond lengths (Å) and bond angles of the imidazole-Schiff base acylhydrazone zinc complex and the imidazole-Schiff base acylhydrazone europium complex are shown in Table 1. The smallest asymmetric unit of the imidazole-Schiff base acylhydrazone zinc complex contains a zinc ion, a ligand anion, a coordinated methanol molecule, and a nitrate anion. The zinc ion is five-coordinated, bonding with the oxygen atom of the methanol molecule, the phenol oxygen atom of the ligand, the acylhydrazone oxygen atom, and the Schiff base nitrogen atom, respectively. It also bonds with the imidazole nitrogen atom of another ligand, forming a one-dimensional chain structure, such as... Figure 4 As shown, the smallest asymmetric unit of the imidazole-Schiff base hydrazone europium complex contains a europium ion, a ligand anion, two coordinated nitrate anions, and a coordinated DMF molecule. The europium ion is nine-coordinated, bonding with seven oxygen atoms, the Schiff base nitrogen atom, and the imidazole nitrogen atom of the other ligand, forming a one-dimensional chain structure, as shown. Figure 5 As shown.

[0054] Table 1. Bond lengths (Å) and bond angles (°) of imidazole Schiff base hydrazone zinc complexes and europium complexes. Cytotoxicity studies: 5×10 4 cells mL -1 Cells were seeded in 96-well plates (100 µL / well), with different cell types using appropriate culture media. A549 cells were cultured in DMEM / F12 medium, MDA-MB-231 cells in 1640 medium, HCT116 cells in 1640-specific medium, and IOSE80 cells in 1640 medium. Each medium was supplemented with 10 wt% fetal bovine serum. Cells were cultured at 37°C in a 5% CO2 atmosphere for 24 h to allow cell adhesion. The old medium was then removed and replaced with fresh medium containing the test complex (previously dissolved in DMSO) at progressively increasing concentrations (0 µmol / L, 2 µmol / L, 4 µmol / L, 8 µmol / L, 16 µmol / L, 32 µmol / L). Cells were then cultured at 37°C for another 48 h. Each treatment was performed in triplicate in three separate experiments. Forty-eight hours after drug administration, 10 µL of CCK-8 reagent was added to each well and incubated at 37°C for 1-4 hours. The absorbance was then measured at 450 nm using a microplate reader. Cell viability under different concentrations of the complex and the IC50 of each complex sample for different cell types were calculated. 50 The value is determined by selecting the imidazolyl Schiff base hydrazone zinc complex (ZnL), imidazolyl Schiff base hydrazone europium complex (EuL), imidazolyl Schiff base hydrazone ligand (HL), or cisplatin.

[0055] The cytotoxicity of ligands HL, cisplatin, ZnL, and EuL against five tumor cell lines (A549, MDA-MB-231, SKBR3, HCT116, and CNE-2Z) and human normal cell line IOSE80 was determined using the CCK-8 assay. The results are shown in Table 2. The results demonstrate that ZnL and EuL exhibited the strongest activity against lung cancer A549 cells, with IC50 values ​​exceeding 100%. 50 The values ​​were only 4.60±0.3µmol / L and 3.86±0.4µmol / L, respectively, and were more effective than the positive control drugs cisplatin and ligand HL. ZnL and EuL showed IC50 values ​​for SKBR3 cells and CNE-2Z cells. 50 The values ​​were all lower than the IC50 of the control drug cisplatin. 50 The values ​​were 14.74 ± 0.9 µmol / L and 8.48 ± 1.1 µmol / L. The imidazole Schiff base acylhydrazone zinc complex and the imidazole Schiff base acylhydrazone europium complex of the present invention showed lower toxicity to normal human ovarian epithelial cells IOSE80 than the control drug cisplatin.

[0056] Table 2. IC50 values ​​of HL, cisplatin, ZnL, and EuL for different tumor cell lines and normal cells at IOSE80. 50 value Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. The embodiments described above are merely preferred embodiments for fully illustrating this invention, and their protection scope is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on this invention are all within the protection scope of this invention, which is defined by the claims.

Claims

1. An imidazolium Schiff base hydrazone complex, characterized in that, The imidazole-based Schiff base acylhydrazone complex is an imidazole-based Schiff base acylhydrazone zinc complex or an imidazole-based Schiff base acylhydrazone europium complex, the chemical structural formula of the imidazole-based Schiff base acylhydrazone zinc complex is: , and the chemical structural formula of the imidazole-based Schiff base acylhydrazone europium complex is: .

2. A method for preparing an imidazole Schiff base acylhydrazone complex, characterized in that, Includes the following steps: 4-(1H-imidazol-1-yl)benzoylhydrazine was prepared using 4-(1H-imidazol-1-yl)benzaldehyde and hydrazine hydrate as raw materials. 4-(1H-imidazol-1-yl)benzoylhydrazide and 5-bromo-2-hydroxybenzaldehyde were dissolved in anhydrous ethanol and subjected to nucleophilic addition-elimination reaction to obtain imidazolyl Schiff base hydrazone ligand; The imidazole-Schiff base hydrazone zinc complex is prepared by a coordination reaction between an imidazole-Schiff base hydrazone ligand and zinc nitrate. The imidazole Schiff base hydrazone europium complex is prepared by a coordination reaction between an imidazole Schiff base hydrazone ligand and europium nitrate.

3. The method for preparing the imidazole-based Schiff base hydrazone complex according to claim 2, characterized in that, The conditions for the nucleophilic addition-elimination reaction are: stirring and refluxing at 60℃~80℃ for 4h~12h.

4. The method for preparing the imidazole-based Schiff base acylhydrazone complex according to claim 2, characterized in that, The molar ratio of 4-(1H-imidazol-1-yl)benzoylhydrazide to 5-bromo-2-hydroxybenzaldehyde is 1:0.5~2.

5. The imidazole Schiff base hydrazone complex according to claim 1, characterized in that, The unit cell parameters of the imidazole-Schiff base hydrazone zinc complex are a = 7.3584(3) Å, b = 18.1163(8) Å, c = 14.9563(6) Å, β = 95.001(2)°, and the unit cell volume is 1986.19(14) Å. 3 Z=4 D c =1.818g / cm 3 .

6. The imidazole Schiff base hydrazone complex according to claim 1, characterized in that, The unit cell parameters of the imidazole Schiff base hydrazone europium complex are a = 13.1538(11) Å, b = 14.1255(14) Å, c = 14.1709(13) Å, β = 111.855(2)°, and the unit cell volume is 2443.8(4) Å. 3 Z=4 D c =1.993g / cm 3 .

7. The method for preparing the imidazole-based Schiff base hydrazone complex according to claim 2, characterized in that, The conditions for the coordination reaction are: heating at 60~80℃ for 48h~72h.

8. The use of the imidazole Schiff base hydrazone complex according to claim 1 in the preparation of antitumor drugs.

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