CN110870874A - Medicine with antibacterial effect and application thereof - Google Patents
Medicine with antibacterial effect and application thereof Download PDFInfo
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- CN110870874A CN110870874A CN201810913538.XA CN201810913538A CN110870874A CN 110870874 A CN110870874 A CN 110870874A CN 201810913538 A CN201810913538 A CN 201810913538A CN 110870874 A CN110870874 A CN 110870874A
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- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- 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
- A61K33/245—Bismuth; Compounds thereof
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- 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
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- 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 medicament with antibacterial effect and application thereof, wherein the active ingredient of the medicament comprises hinokitiol and bismuth salt, or the active ingredient of the medicament comprises a bismuth compound prepared from hinokitiol and bismuth salt; the structural formula of the bismuth compound is shown as the following formula I:
formula I. According to the medicine, hinokitiol and bismuth salt are used in a combined manner, or a bismuth compound prepared from hinokitiol and bismuth salt is used as an active ingredient, so that hinokitiol can generate a synergistic effect on bismuth ions, and the antibacterial effect of the bismuth ions is remarkably enhanced.
Description
Technical Field
The invention relates to the field of medicines, in particular to a medicine with an antibacterial effect and application thereof.
Background
Bacterial infections are still one of the leading causes of morbidity and mortality in humans in today's society. However, the wide and large-scale use of antibiotics causes pathogenic bacteria to generate drug resistance to most antibiotics, and becomes a serious public health problem. Current clinical treatments for bacterial infections are primarily those using long-term, high-dose, broad-spectrum antibiotics or mixed antibiotics, which are effective in controlling disease progression, but may also produce more resistant bacteria. Therefore, the search for a novel antibacterial strategy with high antibacterial activity is an urgent research topic of scientific research and medical workers.
Metal drugs play an important role in new antibacterial strategies due to their unique mode of action with multi-target binding (nat. rev. microbiol.,2013,11, 371-. The metal medicament is used alone or combined with antibiotics to show great potential of resisting multiple drug-resistant bacteria, and can obviously improve the cure rate of drug-resistant bacteria infection. The metal antibacterial agent exerts its medicinal effect by binding with various proteins/enzymes in bacteria, and exerts its antibacterial effect by means of oxidative stress, protein/enzyme dysfunction, cell membrane damage, etc. caused by increase of active oxygen species in bacteria. Compared with the traditional antibiotics, the metal compound has the advantages of multiple target points, capability of delaying the generation of drug resistance of bacteria and the like.
Bismuth compounds have been used as drugs for over 200 years, have low toxicity compared with the same family of arsenic and antimony, and are considered as heavy metals that are almost non-toxic to the human body. In recent years, with the sequential use of Bismuth-containing drugs such as Colloidal Bismuth Citrate (CBS), Ranitidine Bismuth Citrate (RBC), Bismuth Subsalicylate (BBS) and Colloidal Bismuth Pectin (CBP) in the treatment of digestive system diseases such as gastric ulcer, ulcerative colitis and dyspepsia, studies on the potential applications of Bismuth compounds in the medical field have been focused. Recent research results indicate that bismuth agents used in clinical treatment of bacterial infections, in combination with antibiotics, can synergistically inhibit superbacteria carrying NDM-1 resistance factors (nat. commun.,2018,9, 439).
Small molecules with metal chelation and transport capacity have wide application in the treatment of diseases associated with metal imbalance. The hinokitiol is a monoterpene natural compound with tropolone skeleton extracted from trunk of Chamaecyparis obtusa, and has induced differentiation, good antibacterial property, antiinflammatory and antioxidant effects. The latest research result published in the journal of Science shows that hinokitiol can utilize iron concentration gradient to regulate the transport of iron inside and outside cells, and can effectively relieve physiological imbalance caused by the functional deficiency of iron transport protein (Science,2017,356, 608-616).
Although bismuth-containing drugs have been successfully applied to clinical treatment of helicobacter pylori infection, bismuth-containing drugs have the disadvantage of low antibacterial effect in the aspect of broad-spectrum antibacterial. Therefore, the development of a bismuth-containing drug which can effectively resist bacteria is urgently needed.
Disclosure of Invention
Based on this, the object of the present invention is to provide a drug having an antibacterial effect, which is highly effective against bacteria.
The purpose of the invention is realized by the following technical scheme:
a medicine with antibacterial effect comprises hinokitiol and bismuth salt as active ingredients, or comprises bismuth compound prepared from hinokitiol and bismuth salt; the structural formula of the bismuth compound is shown as the following formula I:
in some embodiments, the active ingredient of the medicament comprises hinokitiol and a bismuth salt.
In some embodiments, the drug comprises (1-25) by mole: 1 hinokitiol and bismuth salt.
In some embodiments, the medicine comprises hinokitiol and bismuth salt in a molar ratio of (1-6): 1.
In some embodiments, the medicine comprises hinokitiol and bismuth salt in a molar ratio of (1-3): 1.
In some of these embodiments, the bismuth salt is bismuth nitrate.
The invention also aims to provide application of the medicament in preparing a medicament for preventing and treating bacterial infection.
In some of these embodiments, the bacteria are staphylococcus aureus, pseudomonas aeruginosa, escherichia coli, burkholderia cepacia.
In some of these embodiments, the bacterium is staphylococcus aureus.
The invention also aims to provide a medicament for preventing and treating bacterial infection, wherein the active ingredient of the medicament comprises hinokitiol and bismuth salt, or the active ingredient of the medicament comprises a bismuth compound prepared from the hinokitiol and the bismuth salt; the structural formula of the bismuth compound is shown as the following formula I:
compared with the prior art, the invention has the following beneficial effects:
according to the medicine, hinokitiol and bismuth salt are used in a combined manner, or a bismuth compound prepared from hinokitiol and bismuth salt is used as an active ingredient, so that hinokitiol can generate a synergistic effect on bismuth ions, and the antibacterial effect of the bismuth ions is remarkably enhanced.
Drawings
FIG. 1 is a graph showing the concentration settings of the biofilm bactericides and the results of the bacterial survival tests in example 2;
FIG. 2 is a diagram of the morphology of bacteria observed by the scanning electron microscope technique in example 3;
FIG. 3 is a graph of the sample of example 4 showing the enhanced absorption of bismuth ions by hinokitiol;
FIG. 4 is a graph showing the antibacterial effect of different concentrations of hinokitiol and bismuth nitrate in example 5.
Detailed Description
In order that the invention may be more fully understood, reference will now be made to the following description. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
Five small molecular ligands with iron chelation capacity, namely Hinokitiol (Hinokitiol), Maltol (Maltol), Deferiprone (Deferiprone), Deferasirox (DFX) and Deferoxamine (Deferoxamine, DFO), are selected and tested for influences on the antibacterial effect of the bismuth agent.
And, three bismuth compounds, bismuth junenol (Bi (Hino))3) Bismuth maltol (Bi (Ma))3) And bismuth deferiprone (Bi (Defe)3). The three bismuth compounds were synthesized analogously: respectively mixing hinokitiol, maltol and deferiprone with bismuth nitrate, dissolving in acetone-water mixed solvent, heating in 65 deg.C water bath for 3 hr, cooling to room temperature, vacuum filtering, washing with acetone twice, and drying overnight to obtain corresponding bismuth compound.
The structural formula of the small molecular ligand and the bismuth compound synthesized by the small molecular ligand is as follows:
example 1
This example tests the Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) of these antibacterial agents to be tested by adding bismuth nitrate alone, three bismuth compounds (represented by Bi-Hino, Bi-Deferiprone and Bi-Maltol respectively), and bismuth nitrate in combination with five ligands (represented by Bi + Hino, Bi + Deferiprone, Bi + Maltol, Bi + DFO and Bi + DFX respectively).
Wherein, the test bacteria are laboratory standard bacteria, including: staphylococcus aureus (Staphylococcus aureus Newman), Pseudomonas aeruginosa (Pseudomonas aeruginosa PAO1), Escherichia coli (Escherichia coli K12), and Burkholderia cepacia J2315.
MIC and MBC values were tested by medium microdilution (ref. nat. protocols,2008,3, 163-:
50 μ L of the antibacterial agent to be tested was added to the 96-well plate in advance. Setting the concentration of 10 bismuth agents by adopting a sesquidilution method to ensure that the final concentration of bismuth ions is 256 mu M-0.5 mu M; the final concentration of ligand added was 50. mu.M.
The test bacteria were cultured in LB or TSB (for Staphylococcus aureus) basal medium, and the bacteria grew to a late log phase (OD)6000.6-0.8), and diluting with fresh culture medium until the density of bacteria is 10 by converting the corresponding relation between OD value and bacteria amount (CFU/mL) according to growth curve6CFU/mL, 50. mu.L of the bacterial suspension was added to a 96-well plate.
Standing a 96-well plate in an incubator at 37 ℃ for culturing for 16-20 hours, and reading OD (optical density) of each well by using an enzyme-labeling instrument600And (4) light absorption value. And judging according to the OD value, wherein the minimum concentration at which the bacteria do not grow is the MIC value of the medicament. Meanwhile, 10. mu.L of bacterial liquid is taken from each well with the concentration higher than the MIC (including the MIC concentration), evenly coated on an LB agar plate, and placed in an incubator at 37 ℃ for overnight culture, so that the minimum concentration at which bacteria can not grow on the LB plate is the MBC value of the medicine. The MIC and MBC values were measured as shown in Table 1 below.
TABLE 1
TABLE 2 MIC (μ M) of each small molecule ligand
According to the test results of the above tables 1 and 2, hinokitiol can significantly enhance the antibacterial effect of bismuth ions among all the ligands tested, and bismuth-hinokitiol compound, bismuth and hinokitiol can significantly reduce the MBC value of the bismuth agent compared with the single use of bismuth nitrate. The ratio of MBC to MIC is less than or equal to 4, which can be regarded as the drug has bactericidal effect. According to this standard, the combination of bismuth-hinokitiol compound, bismuth and hinokitiol can be regarded as having bactericidal effect against tested bacteria including Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli.
According to the results of the embodiment, the natural compound hinokitiol can more easily and obviously enhance the antibacterial effect of bismuth ions, particularly has no inhibition effect (MIC >256 mu M) on staphylococcus aureus when used alone, and after the hinokitiol is added (the concentration of the added hinokitiol is 50 mu M, and the independent addition has no influence on bacterial growth), the minimum inhibitory concentration of bismuth ions can be reduced to 2 mu M, the minimum bactericidal concentration is reduced to 8 mu M, the antibacterial effect is obviously improved, and the hinokitiol can be regarded as having a bactericidal effect.
Example 2
This example tests the inhibitory effect of hinokitiol in combination with bismuth nitrate on Staphylococcus aureus growing in biofilm mode. Firstly, a staphylococcus aureus biofilm growth model is established.
PE20 catheter treatment and sterilization: cutting the catheter into small segments of about 1cm, soaking in alcohol for 1 hr, and sterilizing under UV overnight. Experiments were performed using TSB + 1% (m/v) Glucose (Glucose) medium.
After the bacterial monoclone was spotted on 5mL of the culture medium and cultured overnight, the bacterial monoclone was diluted to 50mL of the culture medium at a ratio of 1:1000, and the treated PE20 catheter was placed into the culture medium together.
After incubation for 48 hours at 37 ℃, the vials were removed, rinsed three times in PBS and placed in 24-well plates. Drugs were added to 24-well plates at different concentrations diluted in medium (TSB + 1% Glucose), 1mL per well. The drug in the well is 50 μ M hinokitiol and bismuth nitrate (sesquidiluted) with concentration gradient of 512 μ M to 0.5 μ M. After incubation at 37 ℃ for 24 hours, the tubes were rinsed three times with PBS, and then placed into 1.5mL centrifuge tubes containing 500. mu.L PBS, respectively, and sonicated for 5 minutes. Dilution plating was then performed and colonies were counted.
In this example, experimental drug concentration settings and bacterial growth in 24-well plates after 24 hours of culture are shown in FIG. 1A. The change in the survival rate of Staphylococcus aureus grown in the biofilm mode after adding Staphylococcus aureus to these antibacterial agents to be tested set in a 24-well plate with 50. mu.M Hino alone, 512. mu.M Bi alone, 8. mu.M Bi in combination with 50. mu.M Hino, 16. mu.M Bi in combination with 50. mu.M Hino, and 32. mu.M Bi in combination with 50. mu.M Hino is shown in B in FIG. 1. From the concentration of 8 μ M bismuth nitrate, it can be detected that the combination of hinokitiol and bismuth significantly reduces the survival rate of Staphylococcus aureus growing in a biofilm mode. The high-concentration bismuth and hinokitiol are mixed to generate precipitation, but the improvement of the antibacterial effect of the bismuth agent is still detected along with the increase of the bismuth concentration; the precipitation does not affect the antibacterial activity of the bismuth agent.
Example 3
In the embodiment, the antibacterial effect of the medicament is judged by observing the bacterial form by a scanning electron microscope technology.
Referring to the procedure of example 1, cultured Staphylococcus aureus was added to an antibacterial agent to be tested, which contained 50. mu.M bismuth nitrate (Bi), 50. mu.M hinokitiol, and 50. mu.M bismuth nitrate in combination (Bi + Hino), alone, while no antibacterial agent was added as a Control (CK), and the cells were subjected to electron microscope scanning 8 hours after the addition of Staphylococcus aureus.
The same test was performed for pseudomonas aeruginosa.
The results are shown in FIG. 2. As can be seen from FIG. 2, the bacteria were in a severely damaged form after the bacteria were treated with hinokitiol in combination with bismuth ions for 8 hours.
Example 4
The embodiment researches the mechanism of antibacterial synergistic effect of hinokitiol on bismuth nitrate.
Referring to the procedure of example 1, cultured Staphylococcus aureus was added to the tested antibacterial agents separately in combination with 20. mu.M bismuth nitrate ("20 Bi" in FIG. 3), 20. mu.M bismuth nitrate and 5. mu.M hinokitiol ("20 Bi +5 Hino" in FIG. 3), 20. mu.M bismuth nitrate and 20. mu.M hinokitiol ("20 Bi +20 Hino" in FIG. 3), and 20. mu.M bismuth nitrate and 50. mu.M hinokitiol ("20 Bi +50 Hino" in FIG. 3); meanwhile, the cultured pseudomonas aeruginosa is respectively added into the to-be-tested antibacterial drugs of 20 mu M bismuth nitrate (20 Bi in figure 3), 20 mu M bismuth nitrate and 5 mu M hinokitiol (20 Bi +5Hino in figure 3) which are singly used in combination, and 20 mu M bismuth nitrate and 20 mu M hinokitiol (20 Bi +20Hino in figure 3) which are used in combination; then, each treatment was incubated at 37 ℃ for 16 to 20 hours.
According to the conventional operation, the bismuth intake in the bacteria is detected by using inductively coupled plasma mass spectrometry, and the active oxygen free radical level in the bacteria after the drug treatment is detected by using a CM-H2DCFDA probe. The results are shown in FIG. 3.
As can be seen from fig. 3, the bismuth ion absorption by staphylococcus aureus was significantly increased after hinokitiol was added, and the bismuth ion absorption by staphylococcus aureus was continuously increased as the hinokitiol concentration was increased. In addition, by testing the level of active oxygen free radicals in staphylococcus aureus, the combination of hinokitiol and bismuth nitrate can be observed, so that the level of the active oxygen free radicals in bacteria is greatly increased. Thus, hinokitiol can explain to some extent the mechanism of the enhancement of the antibacterial effect of bismuth ions by promoting the absorption of bismuth ions by bacteria and causing an increase in the level of active oxygen radicals in the bacteria.
Example 5
The embodiment is mainly used for further exploring the better combined dosage of the hinokitiol and the bismuth nitrate on the basis of determining that the combined use of the hinokitiol and the bismuth nitrate has obvious antibacterial effect.
In the embodiment, firstly, a chessboard microdilution method is adopted to test the antibacterial effect of the combination of hinokitiol (2-128 mu M) and bismuth nitrate (0.5-128 mu M). Initial concentration of bacteria was 5X 105CFU/mL, respectively adding hinokitiol (2-128 μ M) and bismuth nitrate (0.5-128 μ M) at different concentrations, standing at 37 deg.C for 16-20 hr, and reading OD600And (4) light absorption value. The results of the experiment are shown in FIG. 4.
In addition, hinokitiol and bismuth nitrate were used in combination at different molar ratios (total molar concentration of both 25. mu.M), respectively added to a concentration of 5X 105CFU/mL pseudomonas aeruginosa,After the staphylococcus aureus is subjected to static culture at 37 ℃ for 24 hours, the viable bacteria are counted by diluting and plating, and the survival rate of the bacteria is determined. Meanwhile, hinokitiol alone and bismuth nitrate alone were used as controls. The results of the experiments are shown in Table 3.
TABLE 3
As can be seen from the results of FIG. 4, the MIC value for bismuth nitrate against Pseudomonas aeruginosa was reduced to 4. mu.M and that for Staphylococcus aureus was reduced to 0.5. mu.M in the presence of hinokitiol. The partial inhibitory concentration indexes FICI (the sum of quotient of the minimum inhibitory concentration MIC value of each drug divided by the MIC value of each drug when the drugs are used singly) of the cypress alcohol and the bismuth nitrate for inhibiting the pseudomonas aeruginosa and the staphylococcus aureus is 0.094 and 0.035 respectively, which shows that the combination of the cypress alcohol and the bismuth nitrate has synergistic effect (the FICI is less than or equal to 0.5). As can be seen from Table 3, when the two drugs are used in combination at the same final concentration (25. mu.M) and the molar ratio of sabinol to bismuth nitrate is 1:1 and 25:1, the antibacterial effect is good, which indicates that the combination effect of the two drugs is significant. Further, when the molar ratio of the two is 3:1 and 1:1, respectively, the antibacterial effect is more remarkable, which indicates that the preferred matching amount exists when the two drugs are used in combination.
In conclusion, the medicine provided by the invention combines hinokitiol and bismuth salt for use, or takes a bismuth compound prepared from hinokitiol and bismuth salt as an active ingredient, so that hinokitiol and bismuth ion have synergistic effect, and the antibacterial effect of bismuth ion is obviously enhanced.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. The medicine with antibacterial effect is characterized in that the active ingredient of the medicine comprises a combination of hinokitiol and bismuth salt, or the active ingredient of the medicine comprises a bismuth compound prepared from hinokitiol and bismuth salt; the bismuth compound is shown as the following formula I:
2. the drug having antibacterial effect according to claim 1, wherein the active ingredient of the drug comprises a combination of hinokitiol and bismuth salt.
3. The drug having an antibacterial effect according to claim 1 or 2, which comprises hinokitiol and a bismuth salt in a molar ratio of (1-25): 1.
4. The drug having antibacterial effect according to claim 3, characterized in that the drug comprises hinokitiol and bismuth salt in a molar ratio of (1-6): 1.
5. The drug having antibacterial effect according to claim 4, characterized in that the drug comprises hinokitiol and bismuth salt in a molar ratio of (1-3): 1.
6. The drug having an antibacterial effect according to claim 1 or 2, characterized in that the bismuth salt is bismuth nitrate.
7. Use of a medicament according to claims 1 to 6 for the manufacture of a medicament for the prevention and treatment of bacterial infections.
8. The use according to claim 7, wherein the bacteria are Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Burkholderia cepacia.
9. The use of claim 8, wherein said bacterium is staphylococcus aureus.
10. A medicine for preventing and treating bacterial infection is characterized in that the active ingredient of the medicine comprises the combination of hinokitiol and bismuth salt, or the active ingredient of the medicine comprises a bismuth compound prepared from hinokitiol and bismuth salt; the structural formula of the bismuth compound is shown as the following formula I:
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114569620A (en) * | 2022-04-13 | 2022-06-03 | 南京大学 | Application of reagent based on tropolone compounds in preparation of tumor treatment drugs |
| CN116211879A (en) * | 2023-02-07 | 2023-06-06 | 湖北省农业科学院畜牧兽医研究所 | Sabina alcohol and clindamycin composition and application thereof in bacteria inhibition |
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| CN103079557A (en) * | 2010-02-03 | 2013-05-01 | 微生物公司 | Bismuth-thiols as antiseptics for biomedical uses, including treatment of bacterial biofilms and other uses |
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| DE19510229A1 (en) * | 1995-03-23 | 1996-09-26 | Keppler Bernhard K Priv Doz Dr | Bismuth complexes with tropolone, thiosemicarbazone or di:thiocarbazonic acid ester cpds. |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114569620A (en) * | 2022-04-13 | 2022-06-03 | 南京大学 | Application of reagent based on tropolone compounds in preparation of tumor treatment drugs |
| CN116211879A (en) * | 2023-02-07 | 2023-06-06 | 湖北省农业科学院畜牧兽医研究所 | Sabina alcohol and clindamycin composition and application thereof in bacteria inhibition |
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Application publication date: 20200310 |
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| WD01 | Invention patent application deemed withdrawn after publication |