CN109305939B - Norfloxacin metal complex and preparation method and application thereof - Google Patents
Norfloxacin metal complex and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a norfloxacin metal complex, which takes norfloxacin as a ligand to be coordinated with a subgroup metal element, and the preparation method comprises the following steps: norfloxacin is mixed with a compound containing an accessory group metal element, the pH value is adjusted, and the norfloxacin metal complex is obtained after the temperature rise reaction and the post-treatment. The complex is applied to surface bacteriostasis of various daily utensils, surface antibiosis of medical instruments, bacteriostasis by adopting various medicament formulations and the like. The preparation method provided by the invention is simple and feasible, wide in raw material source, high in yield and easy to purify.
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to a norfloxacin metal complex, and a preparation method and application thereof.
Background
The quinolone is a broad-spectrum antibacterial agent which is clinically and widely applied in recent years, and has the remarkable advantages of high efficiency, broad spectrum and the like. The third-generation quinolone drug is represented by Norfloxacin (Norfloxacin ). It is a derivative with a modified 4-quinolone structure, and is also called fluoroquinolones (fluoroquinolones) because a fluorine (F) is added on the 6 th position, and the structure increases lipid solubility and enhances the penetrating power to tissue cells, so that the absorption is good, the tissue concentration is high, the half-life period is long, and the antibacterial spectrum and the bactericidal effect are greatly increased.
Bacteria have a very low frequency of congenital resistance to quinolones, but acquired resistance develops very quickly. With the increasing use of quinolone drugs, a large number of drug-resistant bacteria are generated in the process, and the drug-resistant trend is continuously increased, and clinically common drug-resistant bacteria include pseudomonas, enterococcus, staphylococcus aureus and the like. On one hand, norfloxacin has quick antibacterial effect and wide antibacterial spectrum, and on the other hand, the norfloxacin is relatively comprehensive in product development, low in price and relatively suitable for mass consumption. Therefore, the drug resistance of bacteria to norfloxacin drugs is effectively reduced, which is a problem to be solved at present.
According to the reports of relevant documents, after a drug molecule with biological activity forms a complex with metal ions, the biological activity of the drug can be obviously improved, and the drug resistance of bacteria to the drug can be further reduced. Therefore, the preparation of the novel norfloxacin metal complex, particularly the screening of the norfloxacin metal complex with the antibacterial performance obviously superior to that of norfloxacin, and the loading of the norfloxacin metal complex on various high polymer materials have important significance in improving the durability of the medicine and avoiding the problem of over-quick medicine release.
Disclosure of Invention
In order to solve the above problems, the present inventors have conducted intensive studies and, as a result, have found that: mixing norfloxacin with a compound containing an accessory group metal element, adding a pH regulator, heating for reaction, and carrying out post-treatment to obtain the norfloxacin metal complex. The complex has excellent biological activity, and the present invention has been completed.
The object of the present invention is to provide the following:
in a first aspect, the present invention provides a norfloxacin metal complex, which has the following structure: [ M (NF)m(H2O)n](OH)3Wherein M represents a subgroup metal element.
In the invention, M is preferably a VB group metal element, more preferably one of a vanadium element, a niobium element and a tantalum element, M is 1-6, preferably 2-4, and n is 0-5, preferably 1-3.
In a second aspect, the present invention provides a process for the preparation of a norfloxacin metal complex, the process comprising the steps of:
(1) mixing Norfloxacin (NF) and a compound containing an accessory group metal element, optionally stirring;
(2) adjusting the pH of the mixture or solution thereof in step (1) to acidic, optionally with stirring;
(3) heating to react;
(4) and after the reaction is finished, cooling and drying to obtain the target product.
In a third aspect, the norfloxacin metal complex according to the first aspect is used, especially for antibiosis, preferably daily ware surface bacteriostasis, medical device surface bacteriostasis and bacteriostasis by adopting a pharmaceutical dosage form.
The norfloxacin metal complex is compounded with the polyenol to form a membrane structure, and the structure is preferably as follows: [ M (NF)m(H2O)n](OH)3P, P represents a polyalkenol, preferably polyvinyl alcohol (PVA).
The norfloxacin metal complex and the polyene alcohol complex are prepared by the following method:
(1) preparing a polyalkene alcohol solution;
(2) preparing norfloxacin metal complexes according to the second aspect, and solutions thereof;
(3) preparing the norfloxacin metal complex and the polyene alcohol complex.
The norfloxacin metal complex provided by the invention has the following beneficial effects:
(1) the norfloxacin metal complex is successfully prepared by the method provided by the invention, the preparation method is simple and easy to implement, the operation is simple, the raw material source is wide, and the industrial popularization is facilitated.
(2) The norfloxacin metal complex provided by the invention obviously improves the biological activity of the drug and effectively solves the problem of drug resistance of bacteria.
(3) The norfloxacin metal complex is not only limited in the field of biology, but also can be applied to surface bacteriostasis of various daily utensils, surface antibiosis of medical appliances, bacteriostasis by adopting various medicament formulations and the like, and has wide application range.
(4) The norfloxacin metal complex is loaded on a high molecular material, particularly a polyene alcohol material, and has good antibacterial slow-release effect and improved drug availability as a high molecular composite antibacterial material.
Drawings
FIG. 1 shows the infrared spectra of the starting material norfloxacin and example 1;
FIG. 2a shows a schematic representation of the bacteriostatic diameter of the starting material norfloxacin (I) and example 1(II) for E.coli;
FIG. 2b shows a schematic representation of the bacteriostatic diameters of the starting material norfloxacin (I) and example 1(II) against Staphylococcus aureus.
Detailed Description
The features and advantages of the present invention will become more apparent and appreciated from the following detailed description of the invention.
The word "exemplary" is used exclusively herein to mean "serving as an example, embodiment, or illustration. Any embodiment described herein as "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments. While the various aspects of the embodiments are presented in drawings, the drawings are not necessarily drawn to scale unless specifically indicated.
According to a first aspect of the present invention, there is provided a norfloxacin metal complex,
the norfloxacin metalThe complex has the following structure: [ M (NF)m(H2O)n](OH)3Wherein M represents a subgroup metal element;
in the present invention, m is 1 to 6, preferably 2 to 4, such as 2;
n is 0 to 5, preferably 1 to 3, such as 2.
In the invention, the norfloxacin metal complex uses norfloxacin as an organic ligand, and preferably carboxyl and ketocarbonyl of norfloxacin molecules coordinate with a subgroup metal element.
In a preferred embodiment, the metal atom of the subgroup takes a hexacoordinate mode, and the norfloxacin molecule coordinates to the metal element of the subgroup by means of chelate coordination, wherein the carboxyl group coordinates to the metal atom in a monodentate manner.
In a preferred embodiment, M is a group VB metal element, preferably one of vanadium, niobium, and tantalum, and more preferably vanadium.
In a preferred embodiment, M is vanadium, which has anti-inflammatory, bactericidal and other biological activities, the physiological effect and toxicity of vanadium compounds are related to the total amount, chemical property and form of vanadium, and the vanadium compounds have the function of promoting the physiological functions of animals in a reasonable dosage range, such as maintaining the growth of organisms, promoting the absorption of glucose, exhibiting insulin-like effect and the like, and also have better biological activities after forming complexes with drug molecules, and can be used for diagnosing and treating certain diseases. Vanadium plays an important role in regulating blood sugar metabolism, urinary metabolism, cardiovascular metabolism, tumor resistance and the like.
In a preferred embodiment, the norfloxacin metal complex has a metal atom as the vertex, and two norfloxacin molecules are arranged at two sides and have a V-shaped structure.
According to a second aspect of the present invention, there is provided a process for preparing the norfloxacin metal complex described above, which comprises the steps of:
mixing Norfloxacin (NF) and a compound containing an accessory group metal element, and optionally stirring;
in a preferred embodiment, the compound containing a group VB metal element is a compound containing a group VB metal element, preferably one of compounds containing a vanadium element, a niobium element, or a tantalum element, and more preferably a compound containing a vanadium element;
the compound containing a group metal element is selected from oxides, oxoacid salts, and the like containing a group metal element, preferably an oxoacid salt containing a group metal element, more preferably an oxoacid salt containing a group VB metal element, particularly preferably one of oxoacid salts containing a vanadium element, a niobium element, or a tantalum element, and further preferably an oxoacid salt containing a vanadium element, such as ammonium metavanadate.
Preferably, the molar ratio of the compound containing the metal element of the subgroup to norfloxacin is 1: 1.5-2.5, such as 1: 2.
In a preferred embodiment, a solvent is added in step (1), preferably water, an organic solvent or a combination of both, more preferably a combination of water and an organic solvent, wherein,
the organic solvent is preferably one or more of methanol, ethanol, isopropanol, acetone, etc., and is preferably ethanol.
In the present invention, when the solvent is a combination of an organic solvent and water, the volume ratio of the organic solvent to the water is preferably 1:1 to 4, more preferably 1:1.5 to 3, such as 1: 2.
In the invention, the weight volume ratio of norfloxacin to added solvent is (0.10-0.20) parts by weight: (10-30) parts by volume, more preferably (0.12-0.15) parts by weight: (12 to 20) parts by volume, for example, 0.13 part by weight: 15 parts by volume, wherein 1 part by weight based on 1g and 1 part by volume based on 1 mL.
In a preferred embodiment, a salt strong electrolyte solution, preferably a KCl solution or a NaCl solution, etc., more preferably a KCl solution, is also added in step (1).
Preferably, the concentration of the salt strong electrolyte is 1-4 mol.L-1More preferably 1.5 to 3 mol.L-1Such as 3 mol. L-1。
Preferably, the weight volume ratio of the added norfloxacin to the salt strong electrolyte solution is (0.10-0.20) parts by weight: (1-4), more preferably (0.12-0.15) parts by volume: (1.5 to 3) parts by volume, for example, 0.13 part by weight: 2 parts by volume, wherein 1 part by weight based on 1g and 1 part by volume based on 1 mL.
In the invention, salt strong electrolyte is added to balance various electrolytes in the solution and keep relatively stable, which is beneficial to the generation of norfloxacin metal complex.
In a preferred embodiment, the mixture or the solution thereof in step (1) is stirred at 15-35 ℃ for reaction, preferably, the temperature is controlled to be 20-30 ℃, and more preferably, 25 ℃.
In a preferred embodiment, the stirring time is 0.5 to 2.5 hours, preferably 0.5 to 2.5 hours, and more preferably 1 hour.
Step (2), adjusting the pH of the mixture or the solution thereof in the step (1) to acidity, and optionally stirring;
in the present invention, the pH is adjusted using a weak acid, which is formic acid, acetic acid, benzoic acid, oxalic acid, etc., preferably acetic acid.
Preferably, the concentration of the weak acid is 1-4 mol.L-1Preferably 1.5 to 3 mol.L-1Such as 2 mol. L-1。
In a preferred embodiment, the pH of the mixture or the solution thereof is adjusted to 3.5 to 5.5, preferably to 4, and the inventors found that both the piperazinyl and the carboxyl groups of norfloxacin are protonated at pH < 3, that both the piperazinyl and the carboxyl groups are deprotonated at pH > 10, that the N atom of the piperazinyl group can participate in coordination of the metal in neutral and weakly alkaline conditions, but the N atom of the piperazinyl group cannot participate in coordination of the metal in weakly acidic conditions, and thus the pH is preferably adjusted to 3.5 to 5.5 according to the present invention.
In a preferred embodiment, the solution in step (2) is stirred at 15-30 ℃ for 10-60 min, preferably, the temperature is controlled at 20-25 ℃ for 1-1.5 h, and further, at 25 ℃ for 30 min.
Step (3), heating for reaction;
in a preferred embodiment, the solution obtained in step (2) is transferred to a reaction vessel, preferably a polytetrafluoroethylene low-pressure reaction kettle, and the reaction is carried out under the condition of constant temperature and heating temperature, wherein the heating temperature is 100-200 ℃, preferably 120-160 ℃, and more preferably 130 ℃.
In a preferred embodiment, the reaction time is 4 to 6 days, preferably 5 days, so that the reaction is sufficient.
And (4) after the reaction is finished, cooling and drying to obtain a target product.
In a preferred embodiment, the temperature reduction after the reaction is finished can be performed by natural temperature reduction or programmed temperature reduction, preferably programmed temperature reduction, and further, the temperature reduction is performed to 10 ℃ to 50 ℃, preferably 15 ℃ to 40 ℃, more preferably 20 ℃ to 35 ℃, such as 25 ℃.
In the step (4) of the present invention, it is preferable that the concentration is 5 to 20 Kh-1The temperature reduction rate is more preferably 8 to 15 Kh-1Particularly preferably 10 Kh-1And is beneficial to obtaining good crystal form.
In a preferred embodiment, the product obtained after the temperature reduction is washed to remove soluble impurities that may be attached to the surface, and the washing liquid used for washing the solid is preferably distilled water.
In a preferred embodiment, after the product after temperature reduction is washed, it is dried, preferably by vacuum drying, atmospheric heating, natural drying, etc., more preferably by vacuum drying, to obtain the object product of the present invention, i.e., the norfloxacin metal complex, whose structure can be represented as follows: [ M (NF)m(H2O)n](OH)3Wherein, in the step (A),
m represents a metal element of the subgroup, preferably a metal element of the VB group, more preferably one of vanadium, niobium and tantalum, especially vanadium,
m is 1 to 6, preferably 2 to 4, such as 2; n is 0 to 5, preferably 1 to 3, such as 2.
Infrared spectrum analysis shows that the absorption peaks of the complex and the ligand norfloxacin are different, and NF is in1730cm-1The characteristic stretching vibration absorption peak (v) of carboxyl group appearsC＝O) After the complex is formed, the absorption peak disappears at 1579cm-1、1385cm-1Absorption peaks corresponding to asymmetric stretching vibration and symmetric stretching vibration of carboxyl group appeared, indicating that carboxyl group on carbostyril ring in NF coordinates with vanadium in monodentate manner, NF was in 1622cm-1The absorption peak (C ═ O) appears in the position, and after the complex is formed, the absorption peak is red-shifted to 1637cm-1Here, it is shown that the carbonyl group also participates in the coordination. In addition, the complex is also at 3440cm-1Nearby shows H2Strong stretching vibration absorption peak of O.
Therefore, the norfloxacin metal complex of the invention is 1579cm-1、1385cm-1、1637cm-1、3440cm-1There is an absorption peak.
In the invention, the norfloxacin and the metal ions have a synergistic effect, so that the antibacterial activity of the complex is stronger than that of norfloxacin, thereby remarkably improving the biological activity of the drug and further reducing the drug resistance of bacteria to the drug.
According to a third aspect of the present invention there is provided the use of a norfloxacin metal complex as described above, especially for antibacterial applications.
The antibacterial agent is preferably in vitro antibacterial, and is more preferably used for surface bacteriostasis of various daily utensils, surface antibiosis of medical instruments, bacteriostasis by adopting various medicament formulations and the like.
In application, the norfloxacin metal complex can also be compounded with polyenol to form a membrane structure.
The structure is preferably as follows: [ M (NF)m(H2O)n](OH)3-P, wherein P represents a polyalkenol, preferably polyvinyl alcohol (PVA);
the above complex can be prepared according to the following method:
(1) preparation of Polyethanolic solution
Dissolving the polyenol in a solvent, heating and stirring, wherein the solvent is preferably distilled water.
In a preferred embodiment, the solution is heated and stirred until all the polyenol is melted, preferably at a temperature of 70 to 120 ℃, more preferably 80 to 100 ℃, for example 90 ℃, and the solution is in a gelatinous transparent state.
In a preferred embodiment, the polyalkenol solution is treated with mechanical agitation or ultrasonic agitation after the polyalkenol is completely dissolved, preferably ultrasonic agitation, to remove air bubbles from the solution.
In a preferred embodiment, the weight/volume ratio of the above-mentioned polyenol to the solvent is (1 to 5 parts by weight), (10 to 50) parts by volume, more preferably (1.5 to 3) parts by weight, (15 to 30) parts by volume, such as 2 parts by weight: 20 parts by volume, wherein 1 part by weight is based on 1g and 1 part by volume is based on 1 mL.
In a preferred embodiment, the polyvinyl alcohol is preferably polyvinyl alcohol, which is a safe biodegradable high molecular organic substance, has no toxicity or side effect on human body, has good biocompatibility, good adhesive strength, easy film formation, and excellent mechanical properties of the film, and the tensile strength is enhanced along with the increase of polymerization degree and alcoholysis degree.
(2) Preparing a norfloxacin metal complex according to the second aspect described above, and a solution thereof;
in a preferred embodiment, the obtained norfloxacin metal complex is dissolved in a solvent and uniformly mixed, preferably, the solution is sufficiently and uniformly mixed by adopting a mechanical stirring mode or an ultrasonic oscillation mode, and more preferably, the ultrasonic oscillation mode is adopted.
Preferably, the mixing time is 1-5 h, more preferably 2-4 h, such as 3h, so that the norfloxacin metal complex is uniformly dispersed in the solvent, wherein the solvent is preferably distilled water.
In a preferred embodiment, the weight/volume ratio of the norfloxacin metal complex to the solvent is (0.0050-0.015): (2-6)% by volume, more preferably (0.006-0.0012): (2-4)% by volume, such as 0.0080: 3% by volume, wherein 1 part by weight based on 1g is 1 part by volume based on 1 mL.
(3) Preparation of composite membranes [ M (NF)m(H2O)n](OH)3-P
Mixing the solution prepared from the norfloxacin metal complex with a polyene alcohol solution;
in a preferred embodiment, the polyalkene alcohol solution prepared in the step (1) is added into the norfloxacin metal complex solution prepared in the step (2), and stirred, preferably vigorously stirred for 1-4 h, more preferably 1.5-3 h, such as 3h, so as to uniformly mix the two;
in a preferred embodiment, the volume ratio of the norfloxacin metal complex solution to the polyvinyl alcohol solution measured in the step (3) is 1 (0.5-2), and more preferably 1: (0.8-1.5), such as 1: 1;
in a preferred embodiment, the mixed solution of the norfloxacin metal complex solution and the polyvinyl alcohol solution is treated by a mechanical stirring method or an ultrasonic oscillation method, preferably an ultrasonic oscillation method, to remove air bubbles in the mixed solution.
Forming a film on the mixed solution;
in a preferred embodiment, the mixed solution obtained above is dried to form a film, preferably, the mixed solution is poured into a film forming container and then dried to form a film, further, the film is dried by using a vacuum drying method, a normal pressure heating method, a natural drying method, or the like, and more preferably, the vacuum drying method is used.
In the present invention, the film forming container is preferably a glass container, a plastic container or the like, more preferably a plastic container such as a 96-well circular plate cap.
In a preferred embodiment, the drying is performed at 40 ℃ to 80 ℃, more preferably at 45 ℃ to 60 ℃, such as 50 ℃, and further, the drying time is preferably 1 to 4 hours, more preferably 1.5 to 3 hours, such as 2 hours.
In a preferred embodiment, the dry formed composite film, which may be designated as [ M (NF) ], is peeled off and collected for usem(H2O)n](OH)3-P, in particular as described above.
The composite membrane has a slow release effect, and can reduce the release rate of the norfloxacin metal complex, so that the drug release speed is stable, the drug effect is improved, and the drug administration times are reduced.
In the present invention, the inventors believe that the factor is [ M (NF) ]m(H2O)n](OH)3The nitrogen on the piperazinyl of the norfloxacin can form hydrogen bonds with hydroxyl on the surface of PVA, so that the content of [ M (NF) ]m(H2O)n](OH)3The release rate from the polyenol is increased, thereby achieving the slow release effect.
Examples
Example 1
0.20mmol of ammonium metavanadate and 0.40mmol of Norfloxacin (NF) were mixed, and 2mL of KCl (3 mol. L) was added-1) Adding 10mLH2O and 5mL of ethanol, and stirred at room temperature for 1 h.
With 2 mol. L-1The pH of the HAc solution was adjusted to 4.0 and stirring was continued at room temperature for 0.5 h.
Transferring the uniformly stirred turbid solution into a 25mL polytetrafluoroethylene low-pressure reaction kettle, and reacting for 5 days at the constant temperature of 130 ℃.
At 10 K.h-1The temperature is reduced to room temperature in a programmed way. Green needle crystals were obtained. Washing with distilled water, drying in vacuum drying oven to obtain product V (NF)2(H2O)2](OH)3The complex was obtained in 40% yield (in V) by X-ray single crystal diffraction as described in Experimental example 1 and by infrared spectroscopy as described in Experimental example 2.
Example 2
2.0g of polyvinyl alcohol (PVA) was added to 20.0mL of distilled water, and the mixture was heated and stirred at 90 ℃ until the solid PVA was completely dissolved and the solution was in a colloidal transparent state, and then all the air bubbles were removed by ultrasonic oscillation to form a polyvinyl alcohol solution, at which time the concentration of the PVA solution obtained was 10%.
Take 9.82X 10-3mmol of [ V (NF) prepared in example 12(H2O)2](OH)3And 3mL of distilled water is added, ultrasonic oscillation is carried out for 3h, and the norfloxacin metal complex solution is formed after uniform dispersion.
Adding 3mL of the prepared polyvinyl alcohol solution into the norfloxacin metal complex solution, stirring vigorously for 2h, and then performing ultrasonic oscillation to remove all bubbles in the mixed solution.
Taking a circular groove of a 96-hole plate cover as a template, taking 30 mu L of mixed solution, injecting the mixed solution into the groove, carrying out vacuum drying at 50 ℃ for 2h, and taking out the mixed solution to obtain a composite membrane (V (NF) ([ V (NF))2(H2O)2](OH)3PVA) which is then peeled from the well plate and collected for use.
Comparative example
Comparative example 1
2.0g of polyvinyl alcohol (PVA) is weighed, 20.0mL of distilled water is added, the mixture is heated and stirred at 90 ℃ until the solid PVA is completely dissolved, the solution is in a colloidal transparent state, and then all bubbles are removed by adopting an ultrasonic oscillation method, so that the polyvinyl alcohol solution is formed. The polyvinyl alcohol solution thus obtained had a concentration of 10%.
Weighing 0.0064g of norfloxacin, adding 3mL of distilled water, and carrying out ultrasonic oscillation for 3h to uniformly disperse norfloxacin in an aqueous solution to form a norfloxacin solution;
3mL of the polyvinyl alcohol solution prepared above was added to the norfloxacin solution prepared above, and stirred vigorously for 2 hours to ensure that the norfloxacin aqueous solution and PVA could be mixed uniformly, followed by ultrasonic oscillation to remove all air bubbles from the mixed solution.
And taking a circular groove of a 96-hole plate cover as a template, injecting 30 mu L of mixed solution into the groove, carrying out vacuum drying at 50 ℃ for 2h, taking out, stripping the dried and formed composite membrane (NF-PVA) from the hole plate, and collecting for later use.
Examples of the experiments
X-ray single crystal diffraction of sample of Experimental example 1
The sample used in this example was the sample prepared in example 1.
The X-ray single crystal diffraction data of the sample is obtained by using Mo K α ray on Agilent Super Nova type CCD X-ray single crystal diffractometer with multiple layers of films
Diffraction data were collected as incident radiation at a temperature of 293K.
Collected data are corrected by LP factor and empirical absorption, the structure is analyzed by using a SHELXTL software package by adopting a direct method, the optimization is carried out by a full matrix least square method, and all non-hydrogen atom coordinates are corrected by adopting anisotropic thermal parameters. The hydrogen atom coordinates on the organic group are obtained by a geometric hydrogenation method, wherein,
the crystallographic data of the samples are shown in table 1:
TABLE 1
aR1＝Σ||Fo|-|Fc||/Σ|Fo|,bwR2＝[Σ[w(Fo 2-Fc 2)2]/Σw(Fo 2)2]
Bond length of sample
And key angle (°) are as shown in table 2:
TABLE 2
As can be seen from the analysis of tables 1 and 2,
example 1 the sample prepared was composed of 1 vanadium atom (V), 2 norfloxacin molecules (NF) and 3 hydroxide ions (OH)-) Is formed in a V-shaped structure, wherein,
V5+adopting a six-coordination mode, and presenting a distorted octahedral configuration;
four oxygen atoms participating in coordination on the vanadium atom are respectively from 3-carboxyl and 4-ketocarbonyl of two norfloxacin, a covalent bond forms a stable structure of a six-membered ring, and the V-O bond is long
To (c) to (d);
the length of the V-O bond of the ketone-carbonyl coordination is slightly longer than that of the V-O bond of the carboxyl coordination, and the maximum difference between the two is
Without being bound by any theory, the inventor believes that the nitrogen atom at the tail end of the piperazinyl forms a hydrogen bond with an oxygen atom on a V-O bond respectively to connect each unit structure to form a one-dimensional chain-shaped stacking structure, and the hydrogen bonds play an important role in the stability of the crystal in the crystal structure;
meanwhile, the organic ligand norfloxacin between each chain has weak pi.pi.pi stacking effect, and the distance between the centers of two aromatic rings is
A 2D molecular network structure is formed in space.
Experimental example 2 Infrared Spectrometry of sample
The samples used in this example were norfloxacin starting material and the sample obtained in example 1.
Taking a small amount of the samples, respectively pressing the samples into slices by a KBr tabletting method, and performing infrared spectrum test by using a VERTEX 70 Fourier transform infrared spectrometer, wherein the measuring range is 4000-500 cm-1The results are shown in fig. 1, in which,
curve a shows the infrared spectrum of a sample prepared from the raw material norfloxacin;
curve b shows the infrared spectrum of the sample obtained in example 1.
As can be seen from fig. 1:
NF at 1730cm-1Characteristic stretching vibration of carboxyl groupDynamic absorption Peak (v)C＝O) Disappeared in example 1.
Example 1 at 1579cm-1、1385cm-1The absorption peak corresponds to the asymmetric stretching vibration and the symmetric stretching vibration of the carboxyl, and the difference between the absorption peak and the symmetric stretching vibration is 194cm-1Because the difference is less than 200cm-1It is demonstrated that the carboxyl group on the quinolone ring coordinates to vanadium in a monodentate manner in NF.
NF at 1622cm-1The 3-position carbonyl stretching vibration absorption peak (C ═ O) appeared in (A), and was red-shifted to 1637cm in example 1-1Here, it is shown that the carbonyl group also participates in the coordination.
In addition, example 1 was also conducted at 3440cm-1Nearby shows H2Strong stretching vibration absorption peak of O.
Therefore, the existence and the variation trend of the characteristic absorption peak of the infrared spectrum indicate that the metal complex with NF exists in the structure, and the result is consistent with the crystal structure analysis result.
Experimental example 4 measurement of antibacterial Properties of sample
The samples used in this example were norfloxacin starting material and the sample obtained in example 1.
The antibacterial performance test of the sample adopts a paper sheet method, the test method refers to a national standard test method, wherein,
FIG. 2a shows the bacteriostatic diameters of the starting material norfloxacin (I) and example 1(II) against E.coli;
FIG. 2b shows the bacteriostatic diameters of norfloxacin (I) and example 1(II) on Staphylococcus aureus.
As can be seen from FIG. 2a, the inhibition effect of example 1 on Escherichia coli is slightly higher than that of norfloxacin serving as a raw material, and the inhibition diameter of example 1 is 29mm and the inhibition diameter of norfloxacin serving as a raw material on Escherichia coli is 27mm (III is a blank sample and has no inhibition effect) obtained by taking an average value through three measurements.
As can be seen from FIG. 2b, the inhibitory diameters of example 1 and the raw material norfloxacin on Staphylococcus aureus were 30mm and 27mm, respectively.
The result shows that compared with norfloxacin serving as a ligand, the norfloxacin compound in example 1 has a stronger bacteriostatic effect under the condition of the same molar concentration, and has a better inhibitory effect on staphylococcus aureus.
Experimental example 5 in vitro measurement of sustained Release behavior of sample
The samples used in this example were composite membranes obtained in example 2 and comparative example 1.
The sustained release effect of the composite membrane was monitored by measuring the cumulative amount of the compound released during each time period.
The operation method comprises the following steps: 10 samples prepared in example 2 and comparative example 1 are respectively placed in a 20mL beaker, 10mL of distilled water is added, the membrane is taken out after being soaked for 3h at 37 ℃, the sample is placed in a new 20mL beaker again, 10mL of distilled water is added, the membrane is taken out after being soaked for 3h at 37 ℃, the operation is carried out once every 3h in the first 12h, and the sampling is repeated every 12h within 12 h-48 h. The sampled solution was collected at 275nm excitation wavelength for ultraviolet absorbance test, which revealed,
the cumulative release of comparative example 1 reached 91% within 0h to 9h, and after 9h, the release of NF in aqueous solution was almost unchanged, indicating that there was a burst release process of NF within the first 9h, during which the cumulative release of NF reached the maximum, and after 9h, the release of NF was close to zero;
example 2([ V (NF))2(H2O)2](OH)3PVA composite film) within 0-12 h, the cumulative release amount reaches about 86%. A slow release process exists between 12h and 48h, the release accumulation amount is kept between 3% and 5%, the cumulative release amount after 48h reaches about 91%, and example 2 shows a slow release process in aqueous solution.
In summary, the sustained release phenomenon in the aqueous solution of example 2, without being bound by any theory, is believed to be due to [ V (NF) ]2(H2O)2](OH)3The nitrogen on the piperazinyl in the structure of the mesoorganic ligand can form rich hydrogen bonds with hydroxyl on the surface of PVA, so that the content of [ V (NF) ]is reduced2(H2O)2](OH)3The release rate from PVA, thereby achieving the slow release effect.
The invention has been described in detail with reference to specific embodiments and illustrative examples, but the description is not intended to be construed in a limiting sense. Those skilled in the art will appreciate that various equivalent substitutions, modifications or improvements may be made to the technical solution of the present invention and its embodiments without departing from the spirit and scope of the present invention, which fall within the scope of the present invention. The scope of the invention is defined by the appended claims.
Claims (3)
1. A complex formed by norfloxacin metal complex and polyenol has the following structure: [ V (NF)m(H2O)n](OH)3-P, wherein m is 2, n is 2, V represents vanadium, P represents a polyalkenol.
2. The use of the compound of claim 1 for surface bacteriostasis of everyday objects and surface antibiosis of medical instruments.
3. Use of a complex according to claim 1 for the preparation of a bacteriostatic pharmaceutical dosage form.
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| 金属与喹诺酮类药物构筑的配合物的研究进展;康新平等;《化学研究与应用》;20120630;第24卷(第6期);455-458 * |
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