A method for preparing and applying a quinolinylbenzimidazole ligand and its copper complex.

Abstract

This invention discloses a method for preparing quinolinylbenzimidazole ligands and their copper complexes, as well as their applications. It belongs to the fields of organic chemistry and medicinal chemistry. Based on quinolinylbenzimidazole ligands (i.e., 2-(1H-benzimidazole-2-yl)quinoline), this invention introduces endogenous biological copper to prepare metal-centered complexes (i.e., quinolinylbenzimidazole ligand copper complexes). By utilizing the planar stereostructure of its organic ligands and the copper metal center, the antibacterial activity and selectivity are significantly improved.

Description

Technical Field

[0001] This invention belongs to the fields of organic chemistry and medicinal chemistry, and particularly relates to a method for preparing and applying a quinolinylbenzimidazole ligand and its copper complex. Background Technology

[0002] Current antimicrobial drugs face challenges such as increasing drug resistance and insufficient activity. Quinoline compounds (especially quinolones) and benzimidazole compounds are two core pharmacophores that have been extensively studied in the field of antimicrobial therapy. The antimicrobial activity of quinoline compounds (such as classic quinolone drugs) mainly stems from the specific inhibition of bacterial type II topoisomerases (including DNA gyrase and topoisomerase IV). These compounds can stably bind to DNA-enzyme complexes, hindering key processes such as DNA supercoiling and uncoiling, ultimately leading to bacterial death due to DNA replication failure. In contrast, the antimicrobial mechanisms of benzimidazole compounds are more diverse, mainly including interfering with pathogen microtubule polymerization to affect cell division, and inhibiting the activity of energy metabolism-related enzymes (such as fumarate reductase). Both classes of compounds provide important structural templates for the design of antimicrobial agents based on specific molecular targets.

[0003] However, both types of compounds suffer from narrow antibacterial spectrum and insufficient antibacterial efficacy when used as antibacterial agents. For example, quinoline compounds exhibit strong activity against Gram-negative bacteria, but their inhibitory effect on most Gram-positive bacteria and anaerobic bacteria is limited; while benzimidazoles have an even more limited antibacterial spectrum, with their activity mainly concentrated in some fungi and parasites, and their inhibitory effect on bacteria is weak. This deficiency stems from the differences in the distribution and structure of their target sites among various pathogens. Furthermore, both types of compounds face the increasingly serious problem of bacterial resistance. For quinolines, resistance mainly arises through multiple pathways, including mutations in bacterial target proteins (such as GyrA and ParC), overexpression of drug efflux pumps, and decreased cell membrane permeability. For benzimidazoles, in addition to similar resistance mechanisms, their structural similarity to mammalian tubulin leads to poor selectivity. To achieve effective antibacterial concentrations, it is often necessary to risk inducing host toxicity, thus limiting their clinical application dosage and resulting in insufficient efficacy. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention proposes a method for preparing quinolinylbenzimidazole ligands and their copper complexes, as well as their applications.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] This invention provides the application of a quinolinylbenzimidazole ligand in the preparation of antibacterial drugs, wherein the quinolinylbenzimidazole ligand is 2-(1H-benzimidazole-2-yl)quinoline.

[0007] The antibacterial mechanism of 2-(1H-benzimidazol-2-yl)quinoline: 2-(1H-benzimidazol-2-yl)quinoline is a planar molecule with large conjugated π bonds. This structure allows it to intercalate into the phospholipid bilayer of the bacterial cell membrane or between DNA base pairs in a "molecular" manner. It has the ability to form stable complexes with bacterial DNA, thereby interfering with the normal physiological functions of bacterial DNA (such as replication or transcription) and ultimately inducing bacterial death.

[0008] Furthermore, the preparation method of the 2-(1H-benzimidazol-2-yl)quinoline includes the following steps: using quinaldinic acid and o-phenylenediamine as raw materials, a condensation and ring-closing reaction is carried out under the action of an acid catalyst to obtain the 2-(1H-benzimidazol-2-yl)quinoline.

[0009] Furthermore, the molar ratio of the quinaldinic acid to the o-phenylenediamine is 1:(1~2);

[0010] The temperature of the condensation and ring-closure reaction is 110~180℃, and the time of the condensation and ring-closure reaction is 4~8h;

[0011] The acid catalyst is polyphosphoric acid.

[0012] Furthermore, in the preparation of 2-(1H-benzimidazol-2-yl)quinoline, after the condensation and ring-closing reaction is completed, a purification step is also included.

[0013] The present invention also provides a quinolinylbenzimidazole ligand copper complex, wherein the quinolinylbenzimidazole ligand is the aforementioned quinolinylbenzimidazole ligand (i.e., the ligand in the quinolinylbenzimidazole ligand copper complex is 2-(1H-benzimidazole-2-yl)quinoline), and the structural formula of the quinolinylbenzimidazole ligand copper complex is as follows:

[0014] (C) 16 H 11 Br2CuN3) or (C) 34 H 26 BrCuN3P).

[0015] The N-coordination site in the 2-(1H-benzimidazole-2-yl)quinoline molecule possesses a strong metal-chelating ability, enabling the formation of quinolinylbenzimidazole ligand metal-center complexes. Upon entering bacteria, these quinolinylbenzimidazole ligand metal-center complexes form stable complexes that bind to bacterial DNA, disrupting the bacterial metal ion homeostasis and thus inhibiting growth. This invention, based on the quinolinylbenzimidazole ligand (i.e., 2-(1H-benzimidazole-2-yl)quinoline), introduces endogenous copper to prepare metal-center complexes (i.e., quinolinylbenzimidazole ligand copper complexes). Utilizing the planar stereostructure of the organic ligand and the copper metal center, the antibacterial activity and selectivity are significantly enhanced. The quinolinylbenzimidazole ligand copper complexes prepared in this invention exhibit concentration-dependent antibacterial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella, and Pseudomonas aeruginosa. Among them, quinolinylbenzimidazole ligand complex 1 (C... 16 H 11 At a concentration of 400 μM, Br2CuN3 showed an inhibition zone diameter of 21.16 mm against Salmonella, demonstrating extremely sensitive efficacy and providing a new approach for the development of copper complex antibacterial drugs.

[0016] The present invention also provides a method for preparing the above-mentioned quinolinylbenzimidazole ligand copper complex, comprising the following steps: dissolving quinolinylbenzimidazole ligand, soluble copper salt and / or triphenylphosphine in an organic solvent, and carrying out a coordination reaction to obtain the quinolinylbenzimidazole ligand copper complex.

[0017] Furthermore, the molar ratio of the quinolinylbenzimidazole ligand, the soluble copper salt, and the triphenylphosphine is 1:(1~2):(0~1).

[0018] Furthermore, the temperature of the coordination reaction is 25~75℃, and the time of the coordination reaction is 24~72h;

[0019] The organic solvent is methanol.

[0020] For example, the soluble copper salt is copper bromide.

[0021] The present invention also provides an antibacterial drug, the active ingredient of which is quinolinylbenzimidazole ligand (i.e., 2-(1H-benzimidazole-2-yl)quinoline) or the above-mentioned quinolinylbenzimidazole ligand copper complex.

[0022] The present invention also provides the application of the above-mentioned quinolinylbenzimidazole ligand copper complex in the preparation of antibacterial drugs.

[0023] Compared with the prior art, the present invention has the following advantages and technical effects:

[0024] This invention is based on quinolinylbenzimidazole ligands (i.e., 2-(1H-benzimidazole-2-yl)quinoline) and introduces endogenous copper to prepare metal-centered complexes (i.e., quinolinylbenzimidazole ligand copper complexes). Utilizing the planar stereostructure of the organic ligand and the copper metal center, the antibacterial activity and selectivity are significantly enhanced. Experimental data show that quinolinylbenzimidazole ligand copper complex 1 exhibits superior antibacterial activity against Salmonella compared to the ligand monomer 2-(1H-benzimidazole-2-yl)quinoline, solving the problem of high activity concentration and poor sensitivity of quinoline or benzimidazole compounds in existing technologies, and providing a new approach for developing highly effective antibacterial drugs. Attached Figure Description

[0025] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an undue limitation of the invention. In the drawings:

[0026] Figure 1 The Fourier transform infrared spectrum of 2-(1H-benzimidazol-2-yl)quinoline prepared in Example 1 is shown below.

[0027] Figure 2 The 2-(1H-benzimidazol-2-yl)quinoline prepared in Example 1 1 H NMR spectrum;

[0028] Figure 3 Curves showing the variation of inhibition zone diameter for 2-(1H-benzimidazol-2-yl)quinoline prepared in Example 1 at different concentrations;

[0029] Figure 4 The single-crystal structure diagram of quinolinylbenzimidazole ligand copper complex 1 prepared in Example 2 is shown.

[0030] Figure 5 This is a structural packing diagram of the quinolinylbenzimidazole ligand copper complex 1 prepared in Example 2;

[0031] Figure 6 Curves showing the variation of inhibition zone diameter for quinolinylbenzimidazole ligand copper complex 1 prepared in Example 2 at different concentrations;

[0032] Figure 7 The single-crystal structure diagram of the quinolinylbenzimidazole ligand copper complex 2 prepared in Example 3 is shown.

[0033] Figure 8 This is a structural packing diagram of the quinolinylbenzimidazole ligand copper complex 2 prepared in Example 3;

[0034] Figure 9 The curves showing the change in the diameter of the inhibition zone of quinolinylbenzimidazole ligand copper complex 2 prepared in Example 3 at different concentrations. Detailed Implementation

[0035] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0036] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0037] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0038] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0039] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0040] An embodiment of the present invention provides the application of a quinolinylbenzimidazole ligand in the preparation of antibacterial drugs. The quinolinylbenzimidazole ligand is 2-(1H-benzimidazole-2-yl)quinoline, with the structural formula [insert structural formula here]. .

[0041] In a preferred embodiment of the present invention, the method for preparing 2-(1H-benzimidazol-2-yl)quinoline includes the following steps: using quinaldinic acid ( ) and o-phenylenediamine ( Using 1H-benzimidazol-2-yl)quinoline as a raw material, a condensation and ring-closing reaction is carried out under the action of an acid catalyst to obtain 2-(1H-benzimidazol-2-yl)quinoline.

[0042] In a preferred embodiment of the present invention, the molar ratio of quinaldinic acid to o-phenylenediamine is 1:(1~2); the temperature of the condensation ring-closing reaction is 110~180°C, and the time of the condensation ring-closing reaction is 4~8h; the acid catalyst is polyphosphoric acid.

[0043] In a preferred embodiment of the present invention, in the preparation of 2-(1H-benzimidazol-2-yl)quinoline, after the condensation and ring-closing reaction is completed, a purification step is also included. The specific steps are as follows: the reaction solution is added to water, the pH is adjusted to 8.0~10.0, the precipitate is obtained by filtration, recrystallized with methanol and then dried.

[0044] Embodiments of the present invention also provide a quinolinylbenzimidazole ligand copper complex, wherein the quinolinylbenzimidazole ligand is the aforementioned quinolinylbenzimidazole ligand (i.e., the ligand in the quinolinylbenzimidazole ligand copper complex is 2-(1H-benzimidazole-2-yl)quinoline), and the structural formula of the quinolinylbenzimidazole ligand copper complex is as follows:

[0045] (C) 16 H 11 Br2CuN3) or (C) 34 H 26 BrCuN3P).

[0046] This invention provides two quinolinylbenzimidazole ligand copper complexes, namely quinolinylbenzimidazole ligand copper complex 1 (C 16 H 11 Br2CuN3) and quinolinylbenzimidazole ligand copper complex 2 (C 34 H 26 BrCuN3P). The crystal space group of quinolinylbenzimidazole ligand copper complex 1 is P-1, and the unit cell volume is 774.59(7) Å. 3 Z = 2, Mr = 468.64 Da, ρ calc =2.009g / cm 3 Its intramolecular quinolinylbenzimidazole ligands exhibit a planar three-dimensional structure, which is further stacked into a three-dimensional structure through Π-Π stacking. The crystal space group of the quinolinylbenzimidazole ligand copper complex 2 is P21 / n, and the unit cell volume is 2876.36(9) Å. 3 Z = 4, Mr = 651.00 Da, ρ calc =1.503 g / cm 3 Its intramolecular quinolinylbenzimidazole ligand has a planar three-dimensional structure, and is stacked into a three-dimensional structure through Π-Π stacking.

[0047] 2-(1H-benzimidazol-2-yl)quinoline is itself a planar molecule with large conjugated π bonds. This structure allows it to intercalate into the phospholipid bilayer of bacterial cell membranes or between DNA base pairs in a "molecular-weight intercalation" manner. When 2-(1H-benzimidazol-2-yl)quinoline coordinates with copper ions, it forms complexes (especially those without triphenylphosphine C450). 16 H 11 (Br2CuN3) typically maintains or enhances this planar rigidity, a structure that greatly facilitates the complex's penetration of the bacterial outer cell membrane and enhances hydrophobic interactions with intracellular lipids and membrane proteins, leading to membrane structural disorder. For triphenylphosphine-containing complexes C... 34 H 26 BrCuN3P, triphenylphosphine, is a highly lipophilic group that can efficiently carry the entire complex molecule across the hydrophobic cell membrane of bacteria. This strategy is known as the "Trojan horse" strategy, which utilizes the bacteria's preference for uptake of specific structures to deliver a lethal metal center (copper) into the bacterial cell. After the quinolinylbenzimidazole ligand copper complex interacts with the cell membrane, it will lead to: (1) membrane potential depolarization: interfering with the proton gradient of the cell membrane and affecting energy metabolism. (2) increased membrane permeability: leading to the leakage of cell contents (such as potassium ions, ATP, nucleic acids, etc.). (3) loss of membrane function: affecting the function of respiratory chain enzymes and transport proteins embedded in the membrane. The final result is the destruction of cell membrane integrity, which is one of the main reasons for the rapid death of bacteria. Copper ions (Cu 2+ / Cu + It possesses a unique variable valence state and can undergo a Fenton-like reaction within cells, catalyzing the conversion of endogenous hydrogen peroxide (H2O2) and other substances into highly toxic reactive oxygen species (Cu) such as hydroxyl radicals (·OH). + + H2O2→ Cu 2+ + ·OH + OH - Excessive production of intracellular reactive oxygen species (ROS) far exceeds the scavenging capacity of bacterial antioxidant systems (such as superoxide dismutase (SOD) and catalase (CAT), leading to severe oxidative stress in bacteria. Highly active ROS attack almost all intracellular biomolecules, including: lipid peroxidation (further damaging cell and organelle membranes); protein oxidation (causing enzyme inactivation and structural protein denaturation); and DNA damage (causing DNA strand breaks and base oxidation, interfering with replication and transcription). Quinolinylbenzimidazole copper complexes can coordinate with essential groups (such as thiol-SH and imidazole groups) in the active sites of key enzymes in bacterial life activities, or competitively replace other metal ions (such as Zn) in the enzyme active sites. 2+ Mg 2+This leads to enzyme inactivation. Potentially affected enzymes include respiratory chain-related enzymes and DNA repair enzymes. In summary, the superior antibacterial properties of quinolinylbenzimidazole copper complexes stem from their multiple, synergistic attack mechanisms: (1) Physical disruption: Utilizing a planar structure to disrupt cell membrane structure. (2) Chemical attack: Utilizing the redox activity of copper ions to induce intracellular ROS bursts, causing widespread oxidative damage. (3) Genetic interference: Inhibiting DNA function through insertion. (4) Functional inhibition: Interfering with normal metabolic processes through interaction with key enzymes.

[0048] The embodiments of the present invention also provide a method for preparing the above-mentioned quinolinylbenzimidazole ligand copper complex, comprising the following steps: dissolving quinolinylbenzimidazole ligand, soluble copper salt and / or triphenylphosphine in an organic solvent, and carrying out a coordination reaction to obtain the quinolinylbenzimidazole ligand copper complex.

[0049] In a preferred embodiment of the present invention, the molar ratio of quinolinylbenzimidazole ligand, soluble copper salt and triphenylphosphine is 1:(1~2):(0~1).

[0050] In a preferred embodiment of the present invention, the temperature of the coordination reaction is 25~75°C, the time of the coordination reaction is 24~72h, and the organic solvent is methanol.

[0051] For example, a soluble copper salt is copper bromide.

[0052] In a preferred embodiment of the present invention, the preparation of quinolinylbenzimidazole ligand copper complex 1 is carried out by the following steps: 2-(1H-benzimidazole-2-yl)quinoline and copper bromide are dissolved in methanol at a molar ratio of 1:(1~2), and a coordination reaction is carried out at 25~75°C for 24~72 h to obtain quinolinylbenzimidazole ligand copper complex 1. The molar volume ratio of quinolinylbenzimidazole ligand to methanol is 1 mmol:8 mL, and the molar volume ratio of copper bromide to methanol is 1 mmol:8 mL.

[0053] In a preferred embodiment of the present invention, the preparation of quinolinylbenzimidazole ligand copper complex 2 is carried out by the following steps: 2-(1H-benzimidazole-2-yl)quinoline, copper bromide and triphenylphosphine are dissolved in methanol at a molar ratio of 1:(1~2):1, and a coordination reaction is carried out at 25~70℃ for 24~72 h to obtain quinolinylbenzimidazole ligand copper complex 2. The molar volume ratio of quinolinylbenzimidazole ligand to methanol is 1 mmol:8 mL, and the molar volume ratio of copper bromide to methanol is 1 mmol:8 mL.

[0054] Embodiments of the present invention also provide an antibacterial drug, the active ingredient of which is quinolinylbenzimidazole ligand (i.e., 2-(1H-benzimidazole-2-yl)quinoline) or the above-mentioned quinolinylbenzimidazole ligand copper complex.

[0055] Embodiments of the present invention also provide the application of the above-mentioned quinolinylbenzimidazole ligand copper complex in the preparation of antibacterial drugs.

[0056] In a preferred embodiment of the present invention, the antibacterial drug is an antibacterial drug, and the bacteria include at least one of Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella and Pseudomonas aeruginosa.

[0057] This invention focuses on enhancing the bioactivity of compounds through molecular structure modification (such as fusion of quinoline ring and benzimidazole ring) and metal coordination (such as copper ions), providing novel antibacterial agents against Gram-positive bacteria (such as Staphylococcus aureus) and Gram-negative bacteria (such as Escherichia coli).

[0058] All raw materials used in the embodiments of the present invention were obtained through commercial purchase.

[0059] It should be noted that any aspects not described in detail in this invention are conventional practices in the field and are not the focus of this invention.

[0060] The technical solution of the present invention will be further illustrated by the following embodiments.

[0061] Example 1: Preparation of 2-(1H-benzimidazol-2-yl)quinoline

[0062] 0.01 mol quinaldinic acid and 0.01 mol o-phenylenediamine were mixed, and 0.02 mol polyphosphoric acid was added. The mixture underwent a condensation and ring-closure reaction at 130 °C for 5 h under the action of polyphosphoric acid. After the condensation and ring-closure reaction was completed, the reaction solution was added to water to adjust the pH to 9.0. The precipitate was obtained by filtration, recrystallized from methanol and dried to obtain 2-(1H-benzimidazol-2-yl)quinoline with a yield of 82%.

[0063] The Fourier transform infrared spectrum of 2-(1H-benzimidazol-2-yl)quinoline prepared in this embodiment is shown below. Figure 1 As shown, 2-(1H-benzimidazol-2-yl)quinoline is formed by the fusion of a quinoline ring and a benzimidazol ring. The pyrrole-type N (containing free H) of benzimidazol undergoes NH stretching vibration, typically at 3300~3500 cm⁻¹. -1 Within this range, this peak represents the characteristic signal of the functional group; on the quinoline ring and the aromatic ring of benzimidazole, the stretching vibration of the CH bond appears in the 3000–3100 cm⁻¹ range. -1 This is a typical characteristic of aromatic compounds; 2800~3000 cm-1 The region represents the saturated CH stretching vibration region, and the absence of a strong peak in this region indicates that the ligand does not contain saturated alkyl substitutions. Both the quinoline ring and benzimidazole contain aromatic rings, and the C=C skeletal vibrations of the aromatic ring occur between 1600 and 1500 cm⁻¹. -1 Strong absorption and multiple peaks are produced due to the superposition of the coordinated vibrations of the two aromatic rings; 1500~1300 cm⁻¹ -1 The moderately strong peaks in the region belong to the stretching vibrations of aromatic CN molecules (1220~1020 cm⁻¹). -1 (Mainly) and pyrrole-type NH bending vibration (1500~1300 cm) -1 (Nearby); 1000~700 cm -1 Multiple fine peaks in the region are attributed to out-of-plane bending vibrations of the aromatic ring CH; less than 1300 cm⁻¹ -1 The region has a complex peak shape, which includes bending vibrations of CC and CN bonds and secondary vibrations of the aromatic ring skeleton.

[0064] The 2-(1H-benzimidazol-2-yl)quinoline prepared in this embodiment 1 H NMR spectrum as shown Figure 2 As shown, 2-(1H-benzimidazol-2-yl)quinoline is composed of a quinoline ring and a benzimidazol ring linked by a single bond. 1 In the 1H NMR spectra, the aromatic protons of the quinoline and benzimidazole rings exhibit chemical shifts concentrated between 7 and 9 ppm due to ring fusion and the electronic effect of nitrogen. These protons exhibit complex coupling, splitting into multiplets, reflecting the adjacency of hydrogen atoms within the ring. The singlet around 5 ppm likely represents aromatic protons in quinoline and benzimidazole, whose chemical shift decreases to around 5 ppm due to the deshielding effect of the aromatic ring. The multiplet at 3.30 ppm indicates the presence of nitrogen atoms in the aromatic hydrocarbon; influenced by the electron-withdrawing effect of nitrogen, the chemical shift shifts to 3–4 ppm, and splits into multiplets. The 0–3 ppm range represents alkyl protons with lower chemical shifts, such as CH in the aromatic hydrocarbon structure.

[0065] The antibacterial effect of 2-(1H-benzimidazol-2-yl)quinoline prepared in this embodiment was tested. The specific procedure was as follows: 2-(1H-benzimidazol-2-yl)quinoline was dissolved in DMSO (dimethyl sulfoxide) to prepare a 20 mM stock solution. In the inhibition zone experiment, the stock solution was serially diluted with 0.1 M PBS to obtain solutions with concentrations of 0, 100, 200, 400, and 800 μM, respectively. Sterilized filter paper was soaked in the diluted solution for 15 minutes. 100 μL of the diluted bacterial solution was pipetted onto a plate and then spread evenly with a glass spreader to avoid single colony formation. The plate was labeled with the time, strain name, drug used, and number. Three parallel controls were set up for each group. Next, the drug-soaked filter paper was picked up with tweezers, drained, and placed in the marked position on the plate. Invert the plate with the filter paper attached and incubate it in a 37℃ incubator for 12 hours. After incubation, remove the plate and observe the appearance of inhibition zones. Record the diameter of the inhibition zones using calipers with a cross-hatching method; take three measurements and average the result as the final diameter. The formula for calculating the inhibition rate (%) is as follows:

[0066] Antibacterial rate = (Diameter of inhibition zone in treatment group - Diameter of inhibition zone in blank group) / Diameter of inhibition zone in treatment group × 100%

[0067] The diameter of the inhibition zone is measured in millimeters.

[0068] The antibacterial results of 2-(1H-benzimidazol-2-yl)quinoline against five bacteria are shown in Table 1 and Figure 3 As shown.

[0069] Table 1. Antibacterial effects of quinolinylbenzimidazole ligands against five types of bacteria.

[0070]

[0071] Note: "-" indicates insensitivity, "+" indicates low sensitivity, "++" indicates medium sensitivity, and "+++" indicates high sensitivity; the error is based on the results of three parallel experiments.

[0072] From Table 1 and Figure 3It can be seen that 2-(1H-benzimidazol-2-yl)quinoline showed different degrees of antibacterial effect on the tested strains at all four concentrations. It showed inhibitory effects against both *Escherichia coli* and *Salmonella*, but the effects were poor, with low drug sensitivity in both bacteria. The sensitivity of these two bacteria increased with increasing concentration of 2-(1H-benzimidazole-2-yl)quinoline, with the strongest antibacterial activity and largest inhibition zone at a concentration of 800 μM. However, the inhibitory effect of 2-(1H-benzimidazole-2-yl)quinoline against *E. coli* was better than that against *Salmonella* at all concentrations. 200, 400, and 800 μM of 2-(1H-benzimidazole-2-yl)quinoline showed inhibitory effects against *Pseudomonas aeruginosa*, with low drug sensitivity in all cases. The inhibitory effect was better at 800 μM, with the largest inhibition zone diameter. A concentration of 100 μM had no inhibitory effect, and *Pseudomonas aeruginosa* was completely insensitive to it. Concentrations of 400 and 800 μM showed... 2-(1H-benzimidazol-2-yl)quinoline at μM showed inhibitory effects against Staphylococcus aureus and Bacillus subtilis, but the effects were poor, with low drug sensitivity in both strains. 100 and 200 μM 2-(1H-benzimidazol-2-yl)quinoline showed no inhibitory effect on either bacterium, exhibiting complete insensitivity. However, 2-(1H-benzimidazol-2-yl)quinoline showed better inhibitory effects against Staphylococcus aureus than against Bacillus subtilis. For the five tested strains, higher drug concentrations resulted in stronger antibacterial effects, demonstrating a concentration-dependent relationship.

[0073] The above comparison shows that the antibacterial activity of 2-(1H-benzimidazole-2-yl)quinoline against each strain is as follows: Escherichia coli > Salmonella > Pseudomonas aeruginosa > Staphylococcus aureus > Bacillus subtilis.

[0074] Example 2 Preparation of quinolinylbenzimidazole ligand copper complex 1

[0075] 2-(1H-benzimidazole-2-yl)quinoline (prepared in Example 1) and copper bromide were dissolved in methanol at a molar ratio of 1:1 and subjected to a coordination reaction at 50°C for 48 h. The molar volume ratio of quinolinylbenzimidazole ligand to methanol was 1 mmol:8 mL, and the molar volume ratio of copper bromide to methanol was 1 mmol:8 mL. The product after the reaction was quinolinylbenzimidazole ligand copper complex 1, with a yield of 78%. The molecular formula of quinolinylbenzimidazole ligand copper complex 1 is C1. 16 H 11 Br2CuN3, crystal space group P-1, unit cell volume 774.59(7) Å 3 Z = 2, Mr = 468.64 Da, ρ calc =2.009 g / cm 3The intramolecular quinolinylbenzimidazole ligand exhibits a planar three-dimensional structure, which is further stacked into a three-dimensional structure through π-π connections. The crystal structure parameters of the quinolinylbenzimidazole ligand copper complex 1 are shown in Table 2, and some bond lengths and bond angles are shown in Table 3. The single crystal structure diagram is shown below. Figure 4 As shown, the structure stacking diagram is as follows: Figure 5 As shown.

[0076] Table 2. Crystal structure parameters of quinolinylbenzimidazole ligand copper complexes 1 and 2

[0077]

[0078] Table 3. Partial bond lengths and bond angles of quinolinylbenzimidazole ligand copper complexes 1 and 2

[0079]

[0080] The antibacterial effect of the quinolinylbenzimidazole ligand copper complex 1 prepared in Example 2 was tested. The specific process was as follows: Quinolinylbenzimidazole ligand copper complex 1 was dissolved in DMSO solvent to prepare a 20 mM stock solution. In the inhibition zone experiment, the stock solution was serially diluted with 0.1 M PBS to obtain solutions with concentrations of 50, 100, 200, and 400 μM. Sterilized filter paper was soaked in the diluted solution, shaken well, and soaked for 15 minutes. 100 μL of the diluted Staphylococcus aureus solution was pipetted onto a plate and then spread evenly with a glass spreader to avoid single colony formation. The plate was labeled with the time, strain name, drug used, and number. Three parallel controls were set up for each group. Then, the drug-soaked filter paper was picked up with tweezers, drained, and placed in the marked position on the plate. Invert the plate with the filter paper attached and incubate it in a 37℃ incubator for 12 hours. After incubation, remove the plate and observe the appearance of inhibition zones. Record the diameter of the inhibition zones using calipers with a cross-hatching method; take the average of two measurements as the final diameter. The formula for calculating the inhibition rate (%) is as follows:

[0081] Antibacterial rate = (Diameter of inhibition zone in treatment group - Diameter of inhibition zone in blank group) / Diameter of inhibition zone in treatment group × 100%

[0082] The diameter of the inhibition zone is measured in millimeters.

[0083] The inhibitory effects of quinolinylbenzimidazole ligand copper complex 1 on five bacteria are shown in Table 4. Figure 6 As shown.

[0084] Table 4. Antibacterial effects of quinolinylbenzimidazole ligand copper complex 1 against five bacteria.

[0085]

[0086] Note: "-" indicates insensitivity, "+" indicates low sensitivity, "++" indicates medium sensitivity, and "+++" indicates high sensitivity; the error is based on the results of three parallel experiments.

[0087] From Table 4 and Figure 6 It was found that quinolinylbenzimidazole ligand copper complex 1 exhibited antibacterial effects against various pathogenic bacteria, and the inhibitory effect gradually increased with increasing concentration of quinolinylbenzimidazole ligand copper complex 1, demonstrating a strong concentration-dependent effect. Among them, quinolinylbenzimidazole ligand copper complex 1 showed the worst effect against Pseudomonas aeruginosa; even when the concentration was increased to 400 μM, its drug sensitivity to Pseudomonas aeruginosa remained low. When the concentration of quinolinylbenzimidazole copper complex 1 was 50 μM, it showed no sensitivity. Quinolinylbenzimidazole copper complex 1 showed the best effect against Salmonella, exhibiting moderate sensitivity at 50 μM and extreme sensitivity at 400 μM. The sensitivity to Staphylococcus aureus changed particularly noticeably, showing a progressively increasing trend, reaching extreme sensitivity at 400 μM. Bacillus subtilis showed moderate sensitivity at 200 μM. The antibacterial effect of quinolinylbenzimidazole copper complex 1 was: Pseudomonas aeruginosa < Bacillus subtilis < Escherichia coli < Staphylococcus aureus < Salmonella.

[0088] Example 3 Preparation of quinolinylbenzimidazole ligand copper complex 2

[0089] 2-(1H-benzimidazole-2-yl)quinoline (prepared in Example 1), copper bromide, and triphenylphosphine were dissolved in methanol at a molar ratio of 1:1.5:1 and a coordination reaction was carried out at 50°C for 48 h. The molar volume ratio of quinolinylbenzimidazole ligand to methanol was 1 mmol:8 mL, and the molar volume ratio of copper bromide to methanol was 1 mmol:8 mL. The product obtained after the reaction was quinolinylbenzimidazole ligand copper complex 2, with a yield of 79%. The crystal space group of quinolinylbenzimidazole ligand copper complex 2 was P21 / n, and the unit cell volume was 2876.36(9) Å. 3 Z = 4, Mr = 651.00 Da, ρ calc =1.503g / cm 3 The intramolecular quinolinylbenzimidazole ligand exhibits a planar three-dimensional structure, which is further stacked into a three-dimensional structure through π-π connections. The crystal structure parameters of the quinolinylbenzimidazole ligand copper complex 2 are shown in Table 2, and some bond lengths and bond angles are shown in Table 3. The single crystal structure diagram is shown below. Figure 7 As shown, the structure stacking diagram is as follows: Figure 8 As shown.

[0090] The antibacterial effect of the quinolinylbenzimidazole ligand copper complex 2 prepared in Example 3 was tested. The specific process was as follows: Quinolinylbenzimidazole ligand copper complex 2 was dissolved in DMSO solvent to prepare a 20 mM stock solution. In the inhibition zone experiment, the stock solution was serially diluted with 0.1 M PBS to obtain solutions with concentrations of 50, 100, 200, and 400 μM, respectively. Sterilized filter paper was soaked in the diluted solution, shaken well, and soaked for 15 minutes. 100 μL of the diluted Staphylococcus aureus solution was pipetted onto a plate and then spread evenly with a glass spreader to avoid single colony formation. The plate was labeled with the time, strain name, drug used, and number. Three parallel controls were set up for each group. Then, the drug-soaked filter paper was picked up with tweezers, drained, and placed in the marked position on the plate. Invert the plate with the filter paper attached and incubate it in a 37℃ incubator for 12 hours. After incubation, remove the plate and observe the appearance of inhibition zones. Record the diameter of the inhibition zones using calipers with a cross-hatching method; take the average of two measurements as the final diameter. The formula for calculating the inhibition rate (%) is as follows:

[0091] Antibacterial rate = (Diameter of inhibition zone in treatment group - Diameter of inhibition zone in blank group) / Diameter of inhibition zone in treatment group × 100%

[0092] The diameter of the inhibition zone is measured in millimeters.

[0093] The inhibitory effects of quinolinylbenzimidazole ligand copper complex 2 on five bacteria are shown in Table 5. Figure 9 As shown.

[0094] Table 5. Antibacterial effects of quinolinylbenzimidazole ligand complex 2 against five bacterial strains.

[0095]

[0096] Note: "-" indicates insensitivity, "+" indicates low sensitivity, "++" indicates medium sensitivity, and "+++" indicates high sensitivity; the error is based on the results of three parallel experiments.

[0097] From Table 5 and Figure 9It is known that quinolinylbenzimidazole ligand complex 2 has antibacterial effects against various pathogenic bacteria, but the effects are generally weak. At a concentration of 400 μM, quinolinylbenzimidazole ligand complex 2 shows intermediate sensitivity against Staphylococcus aureus, but low sensitivity against Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. At a concentration of 50 μM, it shows no sensitivity against Bacillus subtilis and Pseudomonas aeruginosa. For Salmonella, it only shows intermediate sensitivity at a concentration of 400 μM. The antibacterial effect of quinolinylbenzimidazole ligand complex 2 is: Pseudomonas aeruginosa < Bacillus subtilis < Escherichia coli < Staphylococcus aureus < Salmonella.

[0098] The above are merely preferred embodiments of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.

Claims

1. A copper complex of a quinolinyl benzimidazole ligand characterized in that, The structural formula of the quinolinylbenzimidazole ligand copper complex is as follows: 。 2. A process for the preparation of the copper complex of the quinolinyl benzimidazole ligand according to claim 1, characterized in that, Includes the following steps: Quinolinylbenzimidazole ligand, copper bromide, and triphenylphosphine were dissolved in an organic solvent and subjected to a coordination reaction to obtain the quinolinylbenzimidazole ligand copper complex. The molar ratio of the quinolinylbenzimidazole ligand, the copper bromide, and the triphenylphosphine is 1:(1~2):

1.

3. The process for the preparation of quinolinyl benzimidazole ligand copper complex according to claim 2, characterized in that, The coordination reaction is carried out at a temperature of 25~75℃ for 24~72h. And / or, the organic solvent is methanol.

4. An antibacterial agent, characterized by, The active ingredient is the quinolinylbenzimidazole ligand copper complex as described in claim 1, and the bacteria are Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella and Pseudomonas aeruginosa.

5. The use of the quinolinylbenzimidazole ligand copper complex as described in claim 1 in the preparation of antibacterial drugs, characterized in that, The bacteria mentioned are Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Salmonella, and Pseudomonas aeruginosa.

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