Imidazolyl Schiff base acylhydrazone ligand, preparation method thereof, imidazolyl Schiff base acylhydrazone metal drug and application of imidazolyl Schiff base acylhydrazone metal drug

Abstract

The invention belongs to the technical field of biological inorganic chemistry, and particularly relates to an imidazolyl Schiff base acylhydrazone ligand, a preparation method of the imidazolyl Schiff base acylhydrazone ligand, an imidazolyl Schiff base acylhydrazone metal drug and application. The invention provides a brand new imidazolyl Schiff base acylhydrazone ligand, the imidazolyl Schiff base acylhydrazone ligand is N '-(5-bromo-2-hydroxybenzylidene)-4-(1-imidazole) benzoyl hydrazine, then the imidazolyl Schiff base acylhydrazone ligand is coordinated with zinc nitrate or europium nitrate, and the imidazolyl Schiff base acylhydrazone metal drug is obtained. A new ligand is obtained by adopting the method disclosed by the invention, a new drug with a clear structure, low toxicity and anticancer activity is prepared by adopting the ligand, and the technical defects of metal drugs and Schiff base drugs in the prior art are overcome.

Description

Technical Field

[0001] The invention belongs to the technical field of bioinorganic chemistry, and in particular relates to an imidazolyl Schiff base acylhydrazone ligand and a preparation method thereof, an imidazolyl Schiff base acylhydrazone metal drug and applications thereof. Background Art

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

[0003] Zinc-based complexes are crucial in the exploration of anticancer alternatives to platinum-based drugs. Zinc ions possess a unique balance within the body, enabling more efficient management by the human physiological system, thereby reducing side effects. Zinc ions exhibit no toxicity even at higher doses, exhibit significant biocompatibility, and possess distinct targets and mechanisms of action compared to platinum-based drugs.

[0004] Rare earth elements (REEs) possess multiple benefits, including anti-inflammatory, antibacterial, anti-cancer, anti-coagulant, and analgesic properties. In pharmacological therapy, rare earth complexes, formed by combining rare earth elements with ligands exhibiting anti-cancer activity, often exhibit anti-cancer effects through synergistic action of the components, while also reducing toxicity.

[0005] However, no new metal drug with good anti-tumor effect and low toxicity to organs and the body has been found for many years.

[0006] Schiff bases are a class of compounds containing imine or azomethine groups and are essential organic ligands for the synthesis of novel drug molecules. Acylhydrazones, a special type of Schiff base, possess high stability due to hydrogen bonds formed between the O and N atoms within their molecules. They can hydrogen-bond with certain substances in the body, inhibiting various physiological and chemical processes and exhibiting promising antibacterial, anticancer, antiviral, anti-inflammatory, and anti-tuberculosis activities. However, currently synthesized Schiff base drugs lack a defined structure, exhibit insufficient antitumor activity, or exhibit significant toxic side effects. Summary of the Invention

[0007] In response to the deficiencies in the above-mentioned prior art, the present invention provides an imidazolyl Schiff base acylhydrazone ligand, a preparation method thereof, an imidazolyl Schiff base acylhydrazone metal drug, and applications thereof. The present invention first uses 5-bromo-2-hydroxybenzaldehyde and 4-(1H-imidazol-1-yl)benzoylhydrazine to undergo a nucleophilic addition-elimination reaction to obtain a new imidazolyl Schiff base acylhydrazone ligand, then coordinates the imidazolyl Schiff base acylhydrazone ligand with zinc nitrate or europium nitrate to obtain an imidazolyl Schiff base acylhydrazone metal drug. The new ligand is obtained by the method of the present invention, and then the ligand is used to prepare a new drug with a clear structure, low toxicity and high anticancer activity, thereby overcoming the technical defects of the metal drugs and Schiff base drugs in the prior art.

[0008] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0009] The present invention first designs and synthesizes an imidazolyl Schiff base acylhydrazone ligand, that is, an imidazole group is introduced at one end of the Schiff base acylhydrazone, so that it can easily form a complex with a one-dimensional chain structure with a metal ion. The one-dimensional chain molecules can spontaneously self-assemble to form nano-scale 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, thereby providing new strategies and methods for drug delivery and treatment.

[0010] The first purpose of the present invention is to protect an imidazolyl Schiff base acylhydrazone ligand, which is N'-(5-bromo-2-hydroxybenzylidene)-4-(1-imidazole)benzoylhydrazine, and has the chemical formula:

[0011]

[0012] The second object of the present invention is to provide a method for preparing an imidazolyl Schiff base acylhydrazone ligand, comprising the following steps:

[0013] 4-(1H-imidazol-1-yl)benzaldehyde was dissolved in anhydrous ethanol, and then 80% hydrazine hydrate was added dropwise. The mixture was stirred and refluxed at 60° C. to 80° C. for 4 h to 12 h to obtain 4-(1H-imidazol-1-yl)benzohydrazide.

[0014] 4-(1H-imidazol-1-yl)benzoylhydrazide and 5-bromo-2-hydroxybenzaldehyde are dissolved in anhydrous ethanol, and undergo a nucleophilic addition-elimination reaction to obtain an imidazolyl Schiff base acylhydrazone ligand.

[0015] Preferably, the conditions for the nucleophilic addition-elimination reaction are: stirring the reaction at 60° C. to 80° C. for 4 h to 12 h.

[0016] Preferably, the molar ratio of 4-(1H-imidazol-1-yl)benzohydrazide to 5-bromo-2-hydroxybenzaldehyde is 1:0.5-2.

[0017] The third object of the present invention is to provide an imidazolyl Schiff base acylhydrazone metal drug, which is an imidazolyl Schiff base acylhydrazone zinc complex. The introduction of zinc nitrate further reduces the toxicity of the imidazolyl Schiff base acylhydrazone zinc complex. The imidazolyl Schiff base acylhydrazone metal drug is prepared by a coordination reaction between an imidazolyl Schiff base acylhydrazone ligand and zinc nitrate. The structural formula is:

[0018] Preferably, the unit cell parameters of the imidazolyl Schiff base acylhydrazone zinc complex are β=95.001(2)°, the unit cell volume is Z=4,D c =1.818g / cm 3 .

[0019] A fourth object of the present invention is to provide an imidazolyl Schiff base acylhydrazone metal drug, which is an imidazolyl Schiff base acylhydrazone europium complex. The europium nitrate complex has a high fluorescence intensity. The introduction of methanogen ions makes it possible to visualize the distribution of the imidazolyl Schiff base acylhydrazone europium complex in tissues. The imidazolyl Schiff base acylhydrazone metal drug is prepared by a coordination reaction between an imidazolyl Schiff base acylhydrazone ligand and europium nitrate. The structural formula is:

[0020]

[0021] Preferably, the unit cell parameters of the imidazolyl Schiff base acylhydrazone europium complex are β=111.855(2)°, the unit cell volume is Z=4,D c =1.993g / cm 3 .

[0022] Preferably, the molar ratio of the imidazolyl Schiff base acylhydrazone ligand to zinc nitrate is 1:1-2, and the molar ratio of the imidazolyl Schiff base acylhydrazone ligand to europium nitrate is 1:1-2.

[0023] Preferably, the conditions for the coordination reaction of the imidazolyl Schiff base acylhydrazone ligand and europium nitrate are: heating at 60° C. to 80° C. for 48 h to 72 h.

[0024] Preferably, the conditions for the coordination reaction of the imidazolyl Schiff base acylhydrazone ligand and europium nitrate are: heating at 60° C. to 80° C. for 48 h to 72 h.

[0025] The fifth purpose of the present invention is to protect the use of imidazolyl Schiff base acylhydrazone metal drugs in the preparation of anti-tumor drugs.

[0026] Preferably, the imidazolyl Schiff base acylhydrazone metal complex shows quite 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, and also has certain toxicity against human breast cancer cell line MDA-MB-231 and human colon cancer cell line HCT116, and its toxicity to human normal ovarian epithelial cell line IOSE80 is lower than that of cisplatin.

[0027] Compared with the prior art, the present invention has the following beneficial effects:

[0028] 1. The present invention first provides an imidazolyl Schiff base acylhydrazone ligand. By introducing an imidazole group at one end of the Schiff base acylhydrazone, the coordinating active group of the imidazolyl Schiff base acylhydrazone ligand is increased, making it easy to coordinate with zinc nitrate or europium nitrate to form a complex with a one-dimensional chain structure, including an imidazolyl Schiff base acylhydrazone zinc complex and an imidazolyl Schiff base acylhydrazone europium complex. The complex uses the imidazolyl Schiff base acylhydrazone ligand as the ligand unit. The imidazolyl Schiff base acylhydrazone ligand is reacted with zinc nitrate or europium nitrate via a solvothermal one-pot method to synthesize the imidazolyl Schiff base acylhydrazone zinc complex or the imidazolyl Schiff base acylhydrazone europium complex for the first time. The present invention explores the anticancer activity of imidazolyl Schiff base acylhydrazone zinc complexes and imidazolyl Schiff base acylhydrazone europium complexes, studies the relationship between their structure and antitumor activity, develops new antitumor drugs with high activity and low toxicity, and provides a theoretical and experimental basis for the research of new bioinorganic chemical drugs.

[0029] 2. Anti-tumor activity experiments showed that the imidazolyl Schiff base acylhydrazone zinc complex and the imidazolyl Schiff base acylhydrazone europium complex exhibited significant anti-cancer activity against the human non-small cell lung cancer cell line A549, which was more active than the positive control drug cisplatin. The CCK-8 assay was used to detect the inhibition rate of the two complexes on tumor cells. Both complexes showed significant cytotoxicity against A549 cells, with IC 50 The IC value of IOSE80 in normal cells was significantly lower than that of the positive control drug cisplatin. 50 The value is higher than that of cisplatin, indicating that the toxicity to normal cell IOSE80 is relatively low. The imidazolyl Schiff base acylhydrazone metal drug of the present invention is an ideal new anticancer drug.

[0030] 3. The imidazolyl Schiff base acylhydrazone zinc complex and the imidazolyl Schiff base acylhydrazone europium complex of the present invention have molecular structures that are completely different from existing anti-tumor drugs. The imidazolyl Schiff base acylhydrazone metal drugs show anti-tumor activity that is superior to the positive control drug cisplatin against human lung cancer cells A549, human breast cancer cells SKBR3 and human nasopharyngeal carcinoma cells CNE-2Z, providing new ideas for the development of anti-tumor drugs.

[0031] 4. The methods for preparing the imidazolyl Schiff base acylhydrazone zinc complex and the imidazolyl Schiff base acylhydrazone europium complex of the present invention both produce high-purity and high-yield imidazolyl Schiff base acylhydrazone metallodrugs at low temperatures using anhydrous ethanol as a solvent. These methods are simple, produce pure products in high yield, and facilitate post-processing. Furthermore, the methods for preparing the imidazolyl Schiff base acylhydrazone zinc complex and the imidazolyl Schiff base acylhydrazone europium complex utilize a one-pot synthesis process, employ a green synthesis solvent, do not require a catalyst, and produce products with well-defined structures. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 The diagram is a synthetic route of the imidazolyl Schiff base acylhydrazone ligand of the present invention.

[0033] Figure 2 Schematic diagram of the structure of the imidazolyl Schiff base acylhydrazone zinc complex of Example 1 of the present invention.

[0034] Figure 3 Schematic diagram of the structure of the imidazolyl Schiff base acylhydrazone europium complex of Example 2 of the present invention.

[0035] Figure 4 This is a one-dimensional chain structure diagram of the imidazolyl Schiff base acylhydrazone zinc complex of Example 1 of the present invention.

[0036] Figure 5 This is a one-dimensional chain structure diagram of the imidazolyl Schiff base acylhydrazone europium complex of Example 2 of the present invention.

[0037] Figure 6 This is the mass spectrum of the imidazolyl Schiff base acylhydrazone ligand of Example 1 of the present invention.

[0038] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of the imidazolyl Schiff base acylhydrazone ligand of Example 1 of the present invention.

[0039] Figure 8 This is the infrared spectrum of the imidazolyl Schiff base acylhydrazone ligand of Example 1 of the present invention. DETAILED DESCRIPTION

[0040] 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 by the specific embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention. The experimental methods described in the embodiments of the present invention are all conventional methods unless otherwise specified.

[0041] Nitrogen-containing heterocyclic imidazole derivatives are an important class of bioactive substances. Imidazole drugs, particularly metronidazole, are highly favored in clinical practice due to their widespread application. Imidazole and its derivatives are widely used in agriculture and medicine due to their broad range of activities, such as antibacterial, antitumor, and antiparasitic properties. The present invention introduces imidazole into the ligand structure, providing rich structural diversity for the selection of bioactive agents. This further deepens the research on the structure-activity relationship of imidazole drugs and promotes the development of new imidazole drugs.

[0042] Considering the technical shortcomings of existing Schiff base drugs, such as their lack of a defined structure, insufficient anti-tumor activity, and high toxic side effects, the present invention introduces an imidazole group at one end of the Schiff base acylhydrazone to facilitate the formation of a complex with a one-dimensional chain structure, thereby increasing its retention time in tumor cells. This overcomes the problem of traditional small molecules being easily pumped out and causing multidrug resistance. Furthermore, the present invention has the following advantages:

[0043] Clear chemical structure: 1. By optimizing the synthesis method, the imidazolyl Schiff base acylhydrazone metal complex prepared by the present invention has a clear molecular structure, which overcomes the problem that the structure of Schiff base drugs in the prior art is difficult to determine, and improves the reliability of drug research and development. 2. Low toxicity: The present invention gives priority to the biocompatibility of the complex during the design and synthesis process, significantly reduces the toxic side effects of the drug, solves the problem that the current Schiff base complex may have high toxicity, and improves the safety of clinical application. 3. Excellent anti-tumor activity: By coordinating with zinc and europium metal ions, the imidazolyl Schiff base acylhydrazone metal complex of the present invention exhibits good anti-tumor activity, effectively overcoming the problem of insufficient anti-tumor activity of existing synthetic Schiff base drugs, and demonstrating its potential as a new type of anti-cancer drug.

[0044] 5-Bromo-2-hydroxybenzaldehyde, commonly known as 5-bromo-salicylaldehyde, contains a phenolic hydroxyl group and a bromine atom in its molecular structure, which imparts acidic and nucleophilic properties, allowing it to readily form a Schiff base with amino groups, thus making it valuable for pharmaceutical applications. 5-Bromo-2-hydroxybenzaldehyde reacts with 4-(1H-imidazol-1-yl)benzohydrazide to form a Schiff base acylhydrazone structure containing an imidazolyl group, significantly enhancing its activity. This design has not been reported previously.

[0045] The following examples are used to study the technical solution of the present invention. The synthetic route of the imidazolyl Schiff base acylhydrazone ligand (HL) in the present invention is as follows: Figure 1 The specific research methods and results are shown as follows:

[0046] Example 1

[0047] The preparation method of the imidazolyl Schiff base acylhydrazone zinc complex comprises the following steps:

[0048] S1. Dissolve 4-(1H-imidazol-1-yl)benzaldehyde in anhydrous ethanol, then add 80vt% 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 8h to obtain 4-(1H-imidazol-1-yl)benzohydrazide.

[0049] S2. 4-(1H-imidazol-1-yl)benzohydrazide and 5-bromo-2-hydroxybenzaldehyde were dissolved in ethanol at a molar ratio of 1:1.5. The mixture was refluxed at 78°C for 4 h and recrystallized to obtain a light yellow solid with a yield of 92%, i.e., the imidazolyl Schiff base acylhydrazone ligand N'-(5-bromo-2-hydroxybenzylidene)-4-(1-imidazole)benzohydrazide, denoted as HL. NMR (such as Figure 7 shown): 1 H NMR ( Figure 6 ,400MHz,d 6 -DMSO)δ:11.41(s,1H),10.44(s,1H),7.80(s,1H),7.59(s,1H),7.25(d,J=5.9Hz,2H),7.07-9.67(m,4H),6.60(d,J=8.8Hz,1H),6.32(s,1H),6.08(d,J=8.8Hz,1H).ESI-MS high resolution mass spectrum (such as Figure 6 shown)[MH] - :385.0289. Fourier transform infrared spectrum (such as 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).

[0050] S3. The imidazolyl Schiff base acylhydrazone ligand and zinc nitrate were mixed in a molar ratio of 1:2, then dissolved in a mixed solvent consisting of 1 mL of acetonitrile and 3 mL of methanol. The entire mixed system was placed in a polytetrafluoroethylene-lined stainless steel reactor and reacted at 70°C for 72 hours. The mixture was then slowly cooled to room temperature to obtain colorless block crystals. After filtration and drying at room temperature, the imidazolyl Schiff base acylhydrazone zinc complex ZnL was obtained as orange-yellow flaky crystals with a yield of 57.62%. The molecular formula of ZnL is [ZnLCH3OH]·NO3. Fourier transform infrared spectrum (KBr, cm -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).

[0051] Example 2

[0052] The preparation method of the imidazolyl Schiff base acylhydrazone europium complex comprises the following steps:

[0053] S1. Dissolve 4-(1H-imidazol-1-yl)benzaldehyde in anhydrous ethanol, then add 80vt% 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 8h to obtain 4-(1H-imidazol-1-yl)benzohydrazide.

[0054] S2. Dissolve 4-(1H-imidazol-1-yl)benzohydrazide 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, i.e., the imidazolyl Schiff base acylhydrazone ligand N'-(5-bromo-2-hydroxybenzylidene)-4-(1-imidazole)benzohydrazide.

[0055] S3. The imidazolyl Schiff base acylhydrazone ligand and europium nitrate were mixed in a molar ratio of 1:2, and then dissolved in a mixed solvent consisting of 1 mL of DMF and 3 mL of anhydrous ethanol. The entire mixed system was placed in a stainless steel reactor lined with polytetrafluoroethylene, reacted at 70°C for 72 hours, and then slowly cooled to room temperature to obtain colorless block crystals. After filtration and drying at room temperature, the imidazolyl Schiff base acylhydrazone europium complex EuL was obtained as orange-yellow flaky crystals with a yield of 59.2%. The molecular formula of EuL is [EuL(NO3)2DMF]. Fourier infrared (KBr, cm -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).

[0056] Example 3

[0057] The preparation method of the imidazolyl Schiff base acylhydrazone zinc complex comprises the following steps:

[0058] S1. Dissolve 4-(1H-imidazol-1-yl)benzaldehyde in anhydrous ethanol, then add 80vt% 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 12h to obtain 4-(1H-imidazol-1-yl)benzohydrazide.

[0059] S2. Dissolve 4-(1H-imidazol-1-yl)benzohydrazide 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, i.e., the imidazolyl Schiff base acylhydrazone ligand N'-(5-bromo-2-hydroxybenzylidene)-4-(1-imidazole)benzohydrazide.

[0060] S3. Mix the imidazolyl Schiff base acylhydrazone ligand and zinc nitrate in a molar ratio of 1:1.5, and then dissolve them in a mixed solvent consisting of 1 mL of acetonitrile and 3 mL of methanol. Place the entire mixed system in a polytetrafluoroethylene-lined stainless steel reactor, react at 60°C for 72 hours, and then slowly cool to room temperature to obtain colorless block crystals. After suction filtration and drying at room temperature, an imidazolyl Schiff base acylhydrazone zinc complex is obtained.

[0061] Example 4

[0062] The preparation method of the imidazolyl Schiff base acylhydrazone europium complex comprises the following steps:

[0063] S1. Dissolve 4-(1H-imidazol-1-yl)benzaldehyde in anhydrous ethanol, then add 80vt% 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 4h to obtain 4-(1H-imidazol-1-yl)benzohydrazide.

[0064] S2. Dissolve 4-(1H-imidazol-1-yl)benzohydrazide 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, i.e., the imidazolyl Schiff base acylhydrazone ligand N'-(5-bromo-2-hydroxybenzylidene)-4-(1-imidazole)benzohydrazide.

[0065] S3. Mix the imidazolyl Schiff base acylhydrazone ligand and europium nitrate in a molar ratio of 1:1, and then dissolve them in a mixed solvent consisting of 1 mL of DMF and 3 mL of anhydrous ethanol. Place the entire mixed system in a polytetrafluoroethylene-lined stainless steel reactor, react at 80°C for 48 hours, and then slowly cool to room temperature to obtain colorless block crystals. After suction filtration and drying at room temperature, an imidazolyl Schiff base acylhydrazone europium complex is obtained.

[0066] Examples 1 to 4 of the present invention all produced imidazolyl Schiff base acylhydrazone metal drugs with excellent anti-tumor properties. The following studies were conducted using ZnL of Example 1 and EuL of Example 2 as examples. The specific research methods and results are shown below:

[0067] Select single crystals with good crystal form, perform single crystal test on X-ray single crystal diffraction instrument, and use Olex2 software to analyze the crystal structure. The results are as follows Figure 2 and Figure 3 As shown, the chemical formula of the imidazolyl Schiff base acylhydrazone zinc complex is [ZnLCH3OH]·NO3, and the chemical formula of the imidazolyl Schiff base acylhydrazone europium complex is [EuL(NO3)2DMF], where L is the imidazolyl Schiff base acylhydrazone ligand anion. Both belong to the monoclinic crystal system with a space group of P2121. The unit cell parameters of the imidazolyl Schiff base acylhydrazone zinc complex are β=95.001(2)°, the unit cell volume is Z=4,D c =1.818g / cm 3 , molecular formula is C 18 H 16BrN5O6Zn, molecular weight is 543.64. The unit cell parameters of the imidazolyl Schiff base acylhydrazone europium complex are β=111.855(2)°, the unit cell volume is Z=4,D c =1.993g / cm 3 , molecular formula is C 20 H 19 BrEuN7O9, molecular weight is 733.29.

[0068] Bond lengths of imidazolyl Schiff base acylhydrazone zinc complexes and imidazolyl Schiff base acylhydrazone europium complexes The bond angles are shown in Table 1. The minimum asymmetric unit of the imidazolyl Schiff base acylhydrazone zinc complex consists of a zinc ion, a ligand anion, a coordinated methanol molecule, and a nitrate anion. The zinc ion is penta-coordinated and forms bonds 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. In addition, it forms a bond with the imidazole nitrogen atom of another ligand, forming a one-dimensional chain structure, such as Figure 4 As shown. The minimum asymmetric unit of the imidazolyl Schiff base acylhydrazone europium complex contains a europium ion, a ligand anion, two coordinated nitrate anions and a coordinated DMF molecule. The europium ion is nine-coordinated and bonds with seven oxygen atoms, the Schiff base nitrogen atom and the imidazole nitrogen atom of another ligand, forming a one-dimensional chain structure, as shown in Figure 5 shown.

[0069] Table 1 Bond lengths of imidazolyl Schiff base acylhydrazone zinc complexes and europium complexes and bond angle (°) table

[0070]

[0071] Cytotoxicity studies:

[0072] 5×10 4 cells mL -1The cells were seeded in 96-well plates (100 μL / well), and different cells were cultured with corresponding culture media. A549 used DMEM / F12 medium, MDA-MB-231 used 1640 medium, HCT116 used 1640 special medium, and IOSE80 used 1640 medium. Each culture medium was supplemented with 10 wt% fetal bovine serum. Cultured in a 37 ° C, 5% CO2 atmosphere for 24 hours to allow the cells to adhere, then the old culture medium was removed and replaced with fresh culture medium containing the test complex (previously dissolved in DMSO) with increasing concentrations (0 μmol / L, 2 μmol / L, 4 μmol / L, 8 μmol / L, 16 μmol / L, 32 μmol / L), and cultured at 37 ° C for 48 hours. Each treatment was performed in three independent experiments in triplicate. After 48 hours of administration, 10 μL / well of CCK-8 reagent was added and incubated at 37°C for 1 to 4 hours. The UV-visible absorbance was measured at 450 nm using a microplate reader. The cell survival rate under the action of different concentrations of complexes and the IC value of each complex sample on different cells were calculated. 50 value, and the complex is selected from imidazolyl Schiff base acylhydrazone zinc complex (ZnL), imidazolyl Schiff base acylhydrazone europium complex (EuL), imidazolyl Schiff base acylhydrazone ligand (HL) or cisplatin.

[0073] The cytotoxicity of ligands HL, cisplatin, ZnL, and EuL against five tumor cell lines (A549, MDA-MB-231, SKBR3, HCT116, CNE-2Z) and human normal cell line IOSE80 was determined by CCK-8 assay. The experimental results are shown in Table 2. The experimental results showed that ZnL and EuL had the strongest activity against lung cancer A549 cells, with IC 50 The IC values ​​of ZnL and EuL on SKBR3 cells and CNE-2Z cells were only 4.60±0.3μmol / L and 3.86±0.4μmol / L, respectively, and were more effective than the positive control drug cisplatin and ligand HL. 50 The values ​​were lower than the IC of the control drug cisplatin 50 The toxicity of the imidazolyl Schiff base acylhydrazone zinc complex and the imidazolyl Schiff base acylhydrazone europium complex to human normal ovarian epithelial cells IOSE80 is lower than that of the control drug cisplatin.

[0074] Table 2 IC values ​​of HL, cisplatin, ZnL and EuL against IOSE80 in different tumor cell lines and normal cells 50 value

[0075]

[0076] Obviously, those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. The above-described embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of protection thereof is not limited thereto. Equivalent substitutions or modifications made by those skilled in the art based on the present invention are all within the scope of protection of the present invention, and the scope of protection of the present invention shall be subject to the claims.

Claims

1. An imidazolyl Schiff base acylhydrazone ligand, characterized in that The imidazolyl Schiff base acylhydrazone ligand is N'-(5-bromo-2-hydroxybenzylidene)-4-(1-imidazole)benzoylhydrazide, and its chemical structure is:

2. A method for preparing an imidazolyl Schiff base acylhydrazone ligand, characterized in that: The steps include: 4-(1H-imidazol-1-yl)benzohydrazide was prepared from 4-(1H-imidazol-1-yl)benzaldehyde and hydrazine hydrate. 4-(1H-imidazol-1-yl)benzoylhydrazide and 5-bromo-2-hydroxybenzaldehyde are dissolved in anhydrous ethanol, and undergo a nucleophilic addition-elimination reaction to obtain an imidazolyl Schiff base acylhydrazone ligand.

3. The method for preparing the imidazolyl Schiff base acylhydrazone ligand according to claim 2, wherein White solid. The conditions for the nucleophilic addition-elimination reaction are: stirring and reflux at 60℃~80℃ for 4h~12h.

4. The method for preparing the imidazolyl Schiff base acylhydrazone ligand according to claim 2, wherein White powder, the molar ratio of 4-(1H-imidazol-1-yl)benzohydrazide to 5-bromo-2-hydroxybenzaldehyde is 1:0.5-2.

5. An imidazolyl Schiff base acylhydrazone metallodrug, characterized in that: The imidazolyl Schiff base acylhydrazone metal drug is an imidazolyl Schiff base acylhydrazone zinc complex, which is prepared by a coordination reaction between the imidazolyl Schiff base acylhydrazone ligand described in claim 1 and zinc nitrate, and has the structural formula:

6. The imidazolyl Schiff base acylhydrazone metallodrug according to claim 5, characterized in that The unit cell parameters of the imidazolyl Schiff base acylhydrazone zinc complex are β=95.001(2)°, the unit cell volume is Z=4,D c =1.818g / cm 3 .

7. An imidazolyl Schiff base acylhydrazone metallodrug, characterized in that: The imidazolyl Schiff base acylhydrazone metal drug is an imidazolyl Schiff base acylhydrazone europium complex, which is prepared by a coordination reaction between the imidazolyl Schiff base acylhydrazone ligand described in claim 1 and europium nitrate, and has the structural formula:

8. The imidazolyl Schiff base acylhydrazone metallodrug according to claim 7, characterized in that The unit cell parameters of the imidazolyl Schiff base acylhydrazone europium complex are β=111.855(2)°, the unit cell volume is Z=4,D c =1.993g / cm 3 .

9. The imidazolyl Schiff base acylhydrazone metallodrug according to claim 5 or claim 7, characterized in that The conditions for the coordination reaction are: heating at 60-80°C for 48-72 hours.

10. Use of the imidazolyl Schiff base acylhydrazone metal drug according to claim 5 or claim 7 in the preparation of anti-tumor drugs.

Images