CN111909059B - Cu-metformin complex with antibacterial effect, crystal structure thereof, preparation method and application - Google Patents
Cu-metformin complex with antibacterial effect, crystal structure thereof, preparation method and application Download PDFInfo
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- CN111909059B CN111909059B CN202010884679.0A CN202010884679A CN111909059B CN 111909059 B CN111909059 B CN 111909059B CN 202010884679 A CN202010884679 A CN 202010884679A CN 111909059 B CN111909059 B CN 111909059B
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- 229960003105 metformin Drugs 0.000 title claims abstract description 57
- 239000013078 crystal Substances 0.000 title claims abstract description 34
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229960004329 metformin hydrochloride Drugs 0.000 claims abstract description 39
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims abstract description 38
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims abstract description 37
- 230000003385 bacteriostatic effect Effects 0.000 claims abstract description 28
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims abstract description 12
- 229910000366 copper(II) sulfate Inorganic materials 0.000 claims abstract description 11
- 239000000243 solution Substances 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000000022 bacteriostatic agent Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 2
- 241000894006 Bacteria Species 0.000 abstract description 7
- 241000588724 Escherichia coli Species 0.000 abstract description 4
- 241000191967 Staphylococcus aureus Species 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 4
- 241000192125 Firmicutes Species 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 3
- 206010059866 Drug resistance Diseases 0.000 abstract description 2
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 229940088710 antibiotic agent Drugs 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 230000009466 transformation Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 10
- 239000003446 ligand Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 4
- 229910052927 chalcanthite Inorganic materials 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910021645 metal ion Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 241000607528 Aeromonas hydrophila Species 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 2
- 235000014469 Bacillus subtilis Nutrition 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 2
- 241000193985 Streptococcus agalactiae Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229910002480 Cu-O Inorganic materials 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 235000013622 meat product Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/02—Guanidine; Salts, complexes or addition compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/34—Copper; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a Cu-metformin complex with an antibacterial effect, a crystal structure thereof, a preparation method and application, wherein the Cu-metformin complex has a structure shown in a formula I. The invention uses metformin hydrochloride and CuSO4·5H2The coordination effect of O precise positioning constructs a novel three-dimensional Cu-metformin complex. The invention evaluates the bacteriostatic activity of metformin hydrochloride and Cu-metformin complex on gram-positive bacteria and gram-negative bacteria (such as staphylococcus aureus, escherichia coli and the like). Research shows that metformin hydrochloride has no bacteriostatic activity and is mixed with CuSO4·5H2The Cu-metformin complex formed after O coordination obtains good bacteriostatic activity. The invention realizes the transformation of the bacteriostatic activity of the compound from nothing to nothing. The Cu-metformin complex provided by the application can obviously improve the drug resistance problem of the existing antibiotics and has higher safety.
Description
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a Cu-metformin complex with a bacteriostatic effect, a crystal structure thereof, a preparation method and application.
Background
The development of metal-drug complex synthesis has attracted a great deal of attention over the past few decades. The metal-drug complex shows high diversity of structure due to its dynamic property, and the coordination of metal ions and bioactive ligands is widely applied in many fields, stimulating great interest in its structure and medicinal activity.
At present, the research of metal-drug complexes mainly focuses on the aspects of anticancer and antiviral activities, biological and pharmacological characteristics of free drugs and the like, but reports on bacteriostatic activity are less, and if a proper drug is selected as a ligand, the introduction of metal ions to generate bacteriostatic activity is an extremely advantageous solution.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a Cu-metformin complex with antibacterial effect, its crystal structure, preparation method and application, and the prepared Cu-metformin complex has good antibacterial activity.
Metformin hydrochloride has been used as a first-line medicament for treating independent diabetes mellitus for decades and has the characteristic of high safety, and the metformin hydrochloride is used as a ligand to introduce metal ions, so that the precise positioning synthesis of a cyclic metal-medicament complex is realized, a three-dimensional structure is formed between molecules through hydrogen bond action, and the antibacterial activity is realized, and the research on the aspect is not reported yet.
Specifically, the invention provides a Cu-metformin complex with an antibacterial effect, which has a structure shown in a formula I:
the invention provides a Cu-metformin complex crystal with an antibacterial effect, wherein unit cell parameters of the crystal are as follows:
α＝90°；β＝98.1510(10)°；γ＝90°。
the Cu-metformin complex crystal with the antibacterial effect is monoclinic, and the central space group is P21/n.
The crystal structure of the Cu-metformin complex crystal is shown in figure 1, and metformin hydrochloride and CuSO4·5H2O forms a cyclic metal-drug complex through coordination.
The Cu-metformin complex forms a zigzag 1D chain structure through the hydrogen bonding of Cu-O … O-S, as shown in figure 2.
The 1D chain structure forms a 3D structure under the hydrogen bonding of N … O … N, as shown in fig. 3.
The invention provides a preparation method of the Cu-metformin complex crystal with the antibacterial effect, which comprises the following steps:
A) providing an alcoholic solution of metformin hydrochloride;
B) adjusting the pH value of the metformin hydrochloride alcohol solution to 5-7 by using triethylamine;
C) mixing CuSO4·5H2And dropwise adding the O aqueous solution into the metformin hydrochloride alcohol solution after the pH is adjusted, filtering and standing to obtain the Cu-metformin complex crystal.
In the invention, the alcohol solution of metformin hydrochloride can be a methanol solution or an ethanol solution of metformin hydrochloride.
Preferably, in the alcoholic solution of metformin hydrochloride, the mass concentration of metformin hydrochloride is 8.28-49.68 mg/mL; more preferably 13.25 to 33.12 mg/mL.
Preferably, the CuSO is4·5H2In aqueous O solution, CuSO4·5H2The mass concentration of O is 12.5 to 150mg/mL, and more preferably 25 to 100 mg/mL.
According to the invention, preferably, triethylamine is adopted to adjust the pH value of the metformin hydrochloride alcohol solution to 6.
In a preferred embodiment of the invention, the metformin hydrochloride and the CuSO4·5H2The molar ratio of O is 2: 1-1: 4; more preferably 1:1 to 1: 2.
Preferably, the temperature of the standing is room temperature.
The Cu-metformin complex crystal prepared by the invention is a blue blocky crystal.
The invention provides the Cu-metformin complex with the bacteriostatic effect, or the Cu-metformin complex crystal prepared by the preparation method, and the application of the Cu-metformin complex crystal in the bacteriostatic field.
Preferably, the bacteriostatic field is inhibition of one or more of gram-negative bacteria and gram-positive bacteria.
In some embodiments of the present invention, the Cu-metformin complex having antibacterial effect, or the above Cu-metformin complex crystal having antibacterial effect, or the Cu-metformin complex crystal prepared by the above preparation method, may be used for inhibiting one or more of staphylococcus aureus, bacillus subtilis, streptococcus agalactiae, escherichia coli, pseudomonas aeruginosa, salmonella typhimurium, and aeromonas hydrophila.
The invention provides a bacteriostatic agent which comprises the Cu-metformin complex with bacteriostatic effect, or the Cu-metformin complex crystal prepared by the preparation method.
The invention uses metformin hydrochloride and CuSO4·5H2The coordination function of O precise positioning constructs a novel three-dimensional Cu-metformin complex. The invention evaluates the bacteriostatic activity of metformin hydrochloride and the Cu-metformin complex on gram-positive bacteria and gram-negative bacteria (such as staphylococcus aureus, escherichia coli and the like). The research shows that the metformin hydrochloride has no bacteriostatic activity and is mixed with CuSO4·5H2The Cu-metformin complex formed after O coordination obtains good bacteriostatic activity. The invention realizes the transformation of the bacteriostatic activity of the compound from nothing to nothing.
The wide use of antibiotic drugs is an important cause for the generation of drug-resistant bacteria, and simultaneously causes the problem of antibiotic residues in meat products and the environment. Different from the bacteriostatic mechanism that most of bacteriostatic drugs generate bacteriostatic action by destroying cell membranes, cell walls and other modes of bacteria, in the Cu-metformin complex provided by the application, the Cu metal element generates bacteriostatic action by redox action, so that the problem of drug resistance of the existing antibiotics can be obviously improved. Meanwhile, Cu is a biologically-relevant substance and is a basic element of life activities; metformin is a safe drug in many years of clinical practice. Therefore, the Cu-metformin complex provided by the application has higher safety when acting on organisms.
Drawings
FIG. 1 is a schematic diagram of a crystal structure of a Cu-metformin complex crystal provided by the invention;
FIG. 2 is a schematic diagram of a 1D chain structure of the Cu-metformin complex provided by the invention;
FIG. 3 is a schematic diagram of a 3D structure of the Cu-metformin complex provided by the invention.
Detailed Description
In order to further illustrate the present invention, the following will describe in detail the Cu-metformin complex with bacteriostatic effect, its crystal structure, preparation method and application with reference to the examples.
In the examples described below, unless otherwise indicated, the test procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer.
Example 1
Metformin hydrochloride ligand (165.63mg, 10mmol) was dissolved in 10mL of methanol solution, pH was adjusted to 6 with triethylamine, CuSO4·5H2O (500mg,20mmol) was dissolved in 10mL of an aqueous solution and CuSO was added under magnetic stirring4·5H2And slowly dripping the O aqueous solution into the metformin hydrochloride solution, continuously stirring for 30min, filtering, and standing at room temperature for 2 weeks to precipitate blue blocky crystals.
The unit cell parameters of the obtained Cu-metformin complex are as follows:
α＝90°；β＝98.1510(10)°；γ＝90°。
example 2
Metformin hydrochloride ligand (248.40mg, 15mmol) was dissolved in 10mL of methanol solution, pH was adjusted to 6 with triethylamine, CuSO4·5H2O (750mg,30mmol) was dissolved in 10mL of an aqueous solution and stirred magneticallyUnder the condition, adding CuSO4·5H2Slowly dripping the O aqueous solution into the metformin hydrochloride solution, continuously stirring for 30min, filtering, and standing at room temperature for 2 weeks to separate out blue blocky crystals which are Cu-metformin complex.
The unit cell parameters of the obtained Cu-metformin complex are as follows:
α＝90°；β＝98.1510(10)°；γ＝90°。
example 3
Metformin hydrochloride ligand (496.80mg, 30mmol) was dissolved in 10mL of methanol solution, pH was adjusted to 6 with triethylamine, CuSO4·5H2O (500mg,20mmol) was dissolved in 10mL of an aqueous solution and CuSO was added under magnetic stirring4·5H2And slowly dripping the O aqueous solution into the metformin hydrochloride solution, continuously stirring for 30min, filtering, and standing at room temperature for 2 weeks to separate out blue blocky crystals, wherein the crystals are Cu-metformin complex.
The unit cell parameters of the obtained Cu-metformin complex are as follows:
α＝90°；β＝98.1510(10)°；γ＝90°。
example 4
And (3) determining the Minimum Inhibitory Concentration (MIC) of the Cu-metformin complex to seven kinds of bacteria, inspecting the inhibitory effect of the Cu-metformin complex and comparing the Cu-metformin complex with a metformin hydrochloride ligand. The seven kinds of bacteria are: staphylococcus aureus, bacillus subtilis, streptococcus agalactiae, escherichia coli, pseudomonas aeruginosa, salmonella typhimurium and aeromonas hydrophila.
Inoculating the activated strain in culture medium, culturing for 24 hr, and adjusting the concentration of the strain to 108CFU/mL-1. Preparation ofThe concentration was 2048. mu.g/mL-1The Cu-metformin hydrochloride complex solution is ready for use. The complex solution was diluted by 2-fold dilution to final concentrations of 1024, 512, 256, 128, 64.0, 48.0, 32.0, 16.0, 8.0, 4.0ug mL-1Adding the mixture into a 96-well plate respectively, comparing with metformin hydrochloride with the same concentration, culturing at constant temperature of 37 ℃ for 14h, and repeating for 3 times, wherein the bacteria-free growing hole has the minimum inhibitory concentration.
The inhibitory concentrations and MICs are shown in table 1.
TABLE 1 bacteriostatic concentration and MIC value of Cu-metformin hydrochloride complex
As can be seen from the above examples, metformin hydrochloride itself has no bacteriostatic activity, and CuSO is used in the present application4·5H2And the Cu-metformin complex prepared by coordinating O and metformin hydrochloride has antibacterial activity.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A Cu-metformin complex with antibacterial effect has a structure shown in formula I:
2. the Cu-metformin complex crystal with the bacteriostatic effect is characterized in that unit cell parameters of the crystal are as follows:
α＝90°；β＝98.1510(10)°；γ＝90°；
the Cu-metformin complex has a structure shown in a formula I:
3. a method for preparing the bacteriostatic Cu-metformin complex crystal according to claim 2, comprising the steps of:
A) providing an alcoholic solution of metformin hydrochloride;
B) adjusting the pH value of the metformin hydrochloride alcohol solution to 5-7 by using triethylamine;
C) mixing CuSO4·5H2And dropwise adding the O aqueous solution into the metformin hydrochloride alcohol solution after the pH is adjusted, filtering and standing to obtain the Cu-metformin complex crystal.
4. The preparation method according to claim 3, wherein the mass concentration of metformin hydrochloride in the metformin hydrochloride alcohol solution is 8.28-49.68 mg/mL; the CuSO4·5H2In aqueous O solution, CuSO4·5H2The mass concentration of O is 12.5-150 mg/mL.
5. The method of claim 3, wherein the metformin hydrochloride and CuSO are used in combination4·5H2The molar ratio of O is 2: 1-1: 4.
6. The method according to claim 3, wherein the alcoholic solution of metformin hydrochloride is a methanol solution of metformin hydrochloride or an ethanol solution of metformin hydrochloride.
7. The method according to claim 3, wherein the temperature at which the solution is allowed to stand is room temperature.
8. The use of the bacteriostatic Cu-metformin complex according to claim 1, or the bacteriostatic Cu-metformin complex crystal according to claim 2, or the Cu-metformin complex crystal prepared by the preparation method according to any one of claims 3 to 6 in preparing a bacteriostatic agent.
9. The use of claim 8, wherein the bacteriostatic agent is one or more of a gram negative bacteriostatic agent, a gram positive bacteriostatic agent.
10. A bacteriostatic agent, comprising the Cu-metformin complex with bacteriostatic effect according to claim 1, or the Cu-metformin complex crystal with bacteriostatic effect according to claim 2, or the Cu-metformin complex crystal prepared by the preparation method according to any one of claims 3 to 7.
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| Zn~(2+),Cu~(2+)及Ni~(2+)对二甲双胍的配合作用及降血糖活性研究;朱苗力等;《化学学报》;20040815(第08期);第783-788页 * |
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