CN117683002A - Phloroglucinol derivative and preparation method and application thereof - Google Patents
Phloroglucinol derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN117683002A CN117683002A CN202410144437.6A CN202410144437A CN117683002A CN 117683002 A CN117683002 A CN 117683002A CN 202410144437 A CN202410144437 A CN 202410144437A CN 117683002 A CN117683002 A CN 117683002A
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- CN
- China
- Prior art keywords
- phloroglucinol
- phloroglucinol derivative
- bacteria
- derivative
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 125000002444 phloroglucinyl group Chemical class [H]OC1=C([H])C(O[H])=C(*)C(O[H])=C1[H] 0.000 title claims 9
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- 241000191967 Staphylococcus aureus Species 0.000 claims abstract description 16
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- 230000001404 mediated effect Effects 0.000 claims abstract description 6
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- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
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- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
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- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
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- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
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- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
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- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- SWGJCIMEBVHMTA-UHFFFAOYSA-K trisodium;6-oxido-4-sulfo-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 SWGJCIMEBVHMTA-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
-
- 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
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D11/00—Solvent extraction
- B01D11/02—Solvent extraction of solids
- B01D11/0288—Applications, solvents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D11/00—Solvent extraction
- B01D11/04—Solvent extraction of solutions which are liquid
- B01D11/0492—Applications, solvents used
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/10—Selective adsorption, e.g. chromatography characterised by constructional or operational features
- B01D15/18—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns
- B01D15/1864—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns using two or more columns
- B01D15/1871—Selective adsorption, e.g. chromatography characterised by constructional or operational features relating to flow patterns using two or more columns placed in series
-
- 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
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (AREA)
- Analytical Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a phloroglucinol derivative, a preparation method thereof and application thereof in preparation of antibacterial drugs. The molecular structure of the phloroglucinol derivative is shown as formula I, and the configuration is 7S,1′R,4′S,5′R,7′R,10′R. The phloroglucinol derivative is formed by heterozygosis of acyl phloroglucinol and gordonane type sesquiterpene, and is a chemical entity with a novel framework structure. The compound has low concentration resistance to Staphylococcus aureus and methicillinGram-positive bacteria such as staphylococcus aureus and vancomycin-mediated drug-resistant staphylococcus aureus have remarkable inhibition effect, low toxicity to eukaryotic cells and good safety.
Description
Technical Field
The invention belongs to the technical field of natural medicines and chemical medicines, and particularly relates to a phloroglucinol derivative, and a preparation method and application thereof.
Background
Bacterial infections are common and frequently occurring. At present, clinical drug-resistant bacteria infection is becoming serious, bacterial drug resistance is showing a trend towards multi-drug resistance, and methicillin-resistant staphylococcus aureus (MRSA), ampicillin-resistant Lin Feiyan streptococcus (PRSP), multi-drug-resistant tubercle bacillus (MDR-TB) and the like are spreading rapidly. The increased infection of drug-resistant bacteria and the gradually increased mortality rate indicate that the traditional antibacterial drugs can not meet the requirements of modern clinical treatment. Therefore, research and development of novel antibacterial drugs have important clinical application value.
Disclosure of Invention
Based on this, it is an object of the present invention to provide a novel antibacterial agent.
In order to achieve the above object, the present invention includes the following technical solutions.
In one aspect, the invention provides a phloroglucinol derivative or a pharmaceutically acceptable salt thereof, wherein the molecular structure of the phloroglucinol derivative is shown as formula I, and the configuration is 7S,1′R,4′S,5′R,7′R,10′R，
。
In a second aspect, the invention provides a method for preparing the phloroglucinol derivative, which comprises the following steps:
pulverizing aerial parts of Japanese snow plum, percolating with 85-98% ethanol water solution, concentrating the extract, extracting with petroleum ether, and separating and purifying the extract to obtain the phloroglucinol derivative.
Wherein the separation and purification comprises: concentrating the extractive solution, separating and purifying by silica gel column chromatography, sephadex LH-20 chromatographic column, octadecyl silane bonded silica gel column chromatography, and preparative HPLC.
In a third aspect, the invention provides the use of the phloroglucinol derivative or a pharmaceutically acceptable salt thereof in the manufacture of an antibacterial medicament.
In particular to application of the phloroglucinol derivative or the pharmaceutically acceptable salt thereof in preparing medicines for inhibiting bacterial growth.
The invention relates to application of phloroglucinol derivatives or pharmaceutically acceptable salts thereof in preparing medicines for treating and/or preventing bacterial infection.
In a fourth aspect, the invention provides an antibacterial drug prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the phloroglucinol derivative or pharmaceutically acceptable salt thereof.
The invention has the following beneficial effects:
(1) The invention discovers and separates and extracts phloroglucinol derivative with novel structure from the Japanese snow plum, the compound is formed by heterozygosis of acyl phloroglucinol and gordonane type sesquiterpene, the sesquiterpene part has a 6/6/5 cage structure, and the compound is a chemical entity with novel skeleton structure.
(2) The invention discovers that the phloroglucinol derivative with low concentration has obvious antibacterial activity on gram-positive bacteria such as staphylococcus aureus, methicillin-resistant staphylococcus aureus, vancomycin-mediated drug-resistant staphylococcus aureus and the like; in particular, the compound has remarkable inhibitory activity on multi-drug resistant bacteria, can be used as a new chemical entity for preparing novel antibacterial drugs and is used for treating diseases caused by drug resistant bacteria infection.
(3) The phloroglucinol derivative has low toxicity to eukaryotic cells, high safety and good drug property.
Drawings
FIG. 1 shows a phloroglucinol derivative 1 H NMR spectrum.
FIG. 2 shows a phloroglucinol derivative 13 C NMR spectrum.
FIG. 3 shows a phloroglucinol derivative 1 H- 1 H COSY profile.
FIG. 4 is a HSQC spectrum of a phloroglucinol derivative.
Fig. 5 is an HMBC spectrum of a phloroglucinol derivative.
FIG. 6 is a NOESY spectrum of a phloroglucinol derivative.
FIG. 7 is a single crystal X-ray diffraction pattern of a phloroglucinol derivative.
FIG. 8 is a graph showing measured ECD and calculated ECD fits for phloroglucinol derivatives.
Detailed Description
The present invention will be described more fully hereinafter in order to facilitate an understanding of the present invention. This invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer. The various chemicals commonly used in the examples are commercially available.
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. The term "and/or" as used herein includes any and all combinations of one or more of the associated listed items.
Furthermore, as used herein, the term "or" is an inclusive "or" symbol and is equivalent to the term "and/or" unless the context clearly dictates otherwise. The term "based on" is not exclusive and allows for being based on other factors not described, unless the context clearly dictates otherwise. Furthermore, throughout the specification, the meaning of "a", "an", and "the" include plural referents. The meaning of "in" is included "in" and "on".
In order to develop more novel antibacterial drugs to overcome the problem that the existing clinical drugs cannot meet the drug-resistant bacteria infection requirement, in one embodiment of the invention, a phloroglucinol derivative or pharmaceutically acceptable salt thereof is provided, the molecular structure of the phloroglucinol derivative is shown as formula I, and the configuration is 7S,1′R,4′S,5′R,7′R,10′R，
。
In another embodiment of the present invention, there is provided a method for preparing the phloroglucinol derivative, comprising the steps of:
pulverizing aerial parts of Japanese snow plum, percolating with 85-98% ethanol water solution, concentrating the extract, extracting with petroleum ether, and separating and purifying the extract to obtain the phloroglucinol derivative.
In some of these embodiments, the aqueous ethanol solution has a volume concentration of 90-95%.
In some embodiments, the number of times of percolation extraction is 4-6, and the ratio of ethanol water solution to Australian snow plum is 0.8-1.2L/1 kg each time.
In some of these embodiments, the separation and purification comprises: concentrating the extractive solution, separating and purifying by silica gel column chromatography, sephadex LH-20 chromatographic column, octadecyl silane bonded silica gel column chromatography, and preparative HPLC.
In another embodiment of the invention, there is provided the use of the phloroglucinol derivative or pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting bacterial growth.
In another embodiment of the invention, there is provided the use of said phloroglucinol derivative or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prophylaxis of bacterial infections.
The bacteria of the invention can be non-drug-resistant bacteria, single-drug-resistant bacteria or multi-drug-resistant bacteria.
The phloroglucinol derivative or the pharmaceutically acceptable salt thereof has better antibacterial activity on gram-positive bacteria, such as staphylococcus, enterococcus and the like; wherein the staphylococcus includes staphylococcus aureus, methicillin-resistant staphylococcus aureus, vancomycin-mediated drug-resistant staphylococcus aureus, staphylococcus epidermidis and the like; enterococcus include enterococcus faecalis, enterococcus faecium, and the like.
In another embodiment of the invention, an antibacterial agent is provided, which is prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the phloroglucinol derivative or pharmaceutically acceptable salt thereof.
Wherein the amount of active ingredient contained is within a safe and effective amount range, and the "safe and effective amount" means: the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
"pharmaceutically acceptable excipients" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity.
"compatible" as used herein means that the components of the composition or formulation are capable of being admixed with and between the active ingredients of the present invention without significantly reducing the efficacy of the active ingredients.
Examples of pharmaceutically acceptable excipients (or carriers) are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulphate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween), wetting agents (e.g. sodium lauryl sulphate), colorants, flavourings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
The mode of administration of the active ingredient or pharmaceutical composition or pharmaceutical formulation of the present invention is not particularly limited, and representative modes of administration include, but are not limited to: oral, transdermal, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and the like. That is, the dosage forms of the pharmaceutical formulation thereof include, but are not limited to: capsules, granules, tablets, pills, powder, drops, paste, patches, liniment, spray, powder, suppositories, sustained release agents, injection and the like.
Solid dosage forms for oral administration include capsules, granules, tablets, pills, powders, and the like. In these solid dosage forms, the active ingredient is admixed with at least one conventional inert excipient (or adjuvant or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients:
(a) Fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid;
(b) Binders, for example, hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia;
(c) Humectants, for example, glycerin;
(d) Disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
(e) Slow solvents, such as paraffin;
(f) Absorption accelerators, for example quaternary amine compounds;
(g) Wetting agents, for example cetyl alcohol and glycerol monostearate;
(h) Adsorbents, such as kaolin; and
(i) Lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage forms may also comprise buffering agents.
The solid dosage forms may also be prepared using coatings and shells, such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such a composition may be released in a delayed manner in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, in particular, cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of these substances and the like. In addition to these inert diluents, the compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active ingredient, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances, and the like.
Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
The present invention will be described in further detail with reference to specific examples.
EXAMPLE 1 isolation and extraction of phloroglucinol derivatives
The separation and extraction of the phloroglucinol derivative comprises the following steps:
(1) Weighing dried Japanese snow plumThryptomene saxicola) Pulverizing aerial parts 50.4. 50.4 kg into coarse powder, percolating with 95% (v/v) ethanol water solution for 5 timesEach time 50L, the percolates were combined and concentrated under reduced pressure to give a total extract of about 12 kg without alcoholic smell. Mixing the extract with water: suspending the extract with water at a ratio of 3L to 1kg, extracting with petroleum ether for 5 times, wherein the petroleum ether dosage is equal volume of water, concentrating the extract under reduced pressure to remove petroleum ether, and obtaining petroleum ether extraction part 1.9 kg.
(2) Performing silica gel column chromatography on the petroleum ether extraction part, eluting by using petroleum ether-ethyl acetate as an eluent according to elution gradients of petroleum ether and ethyl acetate with volume ratios of 100:0, 100:1, 100:3, 100:5, 100:7, 100:10, 100:30, 100:50, 100:100 and 0:100, analyzing by Thin Layer Chromatography (TLC), and combining similar fractions to obtain 10 main fractions Fr. 1-Fr.. The fraction Fr. (petroleum ether/ethyl acetate 100:7 elution part, 200 g) is concentrated and then subjected to silica gel column chromatography, and elution is carried out according to the elution gradient of petroleum ether and ethyl acetate with the volume ratio of 100:0, 100:1, 100:3, 100:5, 100:7, 100:10, 100:30, 100:50 and 100:100, so as to obtain 6 subfractions Fr. A-Fr. 7F.
(3) The subfractions Fr. C (31.1 g) are concentrated and then are loaded on a Sephadex LH-20 chromatographic column, dichloromethane-methanol (volume ratio is 1:1) is used as a mobile phase, elution is carried out at the flow rate of 0.5 mL/min, and the eluent is collected and analyzed by TLC to obtain 10 fractions Fr. C-1-Fr. 7C-10. The fraction Fr. C-5-6 (3.9 g) was concentrated and subjected to reverse phase ODS column chromatography using methanol-water (MeOH-H) 2 O) is an eluent, elution is carried out according to the elution gradient of 60:40, 70:30, 80:20, 90:10 and 100:0 of the volume ratio of methanol to water, and the elution flow with the volume ratio of methanol to water of 90:10 is collected. Concentrating the eluate, dissolving with methanol, and separating and purifying with reversed phase preparative HPLC, wherein the chromatographic column is Phenomnex C 18 The chromatographic column (4.6X1250 mm,5 μm) was eluted with methanol-water at a volume ratio of 90:10 at a flow rate of 3 mL/min, and the eluent with a retention time of 25.4 min was collected and concentrated to give the phloroglucinol derivative (10.6 mg) which was purple-red in vanillin-concentrated sulfuric acid reaction (TLC).
EXAMPLE 2 structural identification of phloroglucinol derivatives
The phloroglucinol derivative obtained by separation and extraction in example 1 was subjected to ultraviolet, infrared, mass spectrum and nuclear magnetic resonance detection by conventional methods, and the results were as follows:
UV (CHCl 3 )λ max (logε) 204 (4.04), 279 (4.03) nm。
IR (KBr)ν max 3440, 2955, 2932, 2867, 1633, 1442, 1382, 1363, 1304, 1180, 1143, 1064, 999, 966, 839 cm -1 。
HR-ESI-MSm/z487.2691 [M + H] + (calculated value C) 28 H 39 O 7 : 487.2690)。
Hydrogen spectrum @ 1 H NMR) and carbon spectrum [ ] 13 C NMR) data are shown in table 1.
1 H NMR, 13 C NMR, 1 H- 1 The H COSY, HSQC, HMBC and NOESY nuclear magnetic resonance spectra are shown in figures 1-6.
And obtaining the single crystal of the phloroglucinol derivative in the mixed solution of methanol and dichloromethane by adopting a solvent volatilization method. The crystal with good crystal face and proper size is selected for single crystal X-ray diffraction analysis, the instrument used is Rigaku single crystal diffractometer, and the light source is Cu KαTarget atλRadiation at 1.54184 a. The collected diffraction data were analyzed using the SHELXTL 6.10 package and Olex2 1.2 software, and the X-ray diffraction structure is shown in FIG. 7. The results of the measured and calculated ECD fits are shown in fig. 8.
From the above physicochemical data, NMR data, single crystal X-ray diffraction data, and measured and calculated ECD fitting results, it is understood that the phloroglucinol derivative prepared in example 1 has a structure as shown in formula I and a configuration of 7S,1′R,4′S,5′R,7′R,10′R。
；
TABLE 1 phloroglucinol derivatives 1 H (400 MHz) and 13 c (100 MHz) NMR data
；
；
Note that: the solvent is CDCl 3 ，δThe unit is expressed in ppm,Jin Hz.
EXAMPLE 3 inhibition of various bacteria by phloroglucinol derivatives
Staphylococcus aureusS. aureus ATCC29213 methicillin-resistant staphylococcus aureusS. aureus ATCC33591 (MRSA), vancomycin-mediated drug resistant Staphylococcus aureusS. aureus Mu50 (VISA), staphylococcus epidermidisS. epidermidis ATCC12228, enterococcus faecalisE. faecalis ATCC29212 enterococcus faeciumE. faecium 13-01, escherichia coliE. coliATCC25922, pseudomonas aeruginosaPs. AeruginosaAll the strains are purchased from the institute of medical biotechnology of the national academy of medical science.
The Minimum Inhibitory Concentration (MIC) of the in vitro inhibitory effect of the compound is determined by adopting a broth microdilution method, and the specific operation method is as follows:
(1) Bacterial culture: the experimental bacteria were grown in Mueller-Hinton (MH) broth medium at a growth concentration of 8-12 h to about 0.5 Mcfarland (1X 10) 8 CFU) is ready for use.
(2) The sample to be tested was dissolved in ethanol and diluted to 1000. Mu.g/mL with the culture broth. Serial dilution with culture medium was continued to bring the sample concentration from 160 μg/mL to 0.156 μg/mL. In addition, ampicillin and vancomycin at a certain concentration were formulated as positive controls.
(3) 100 mu L of the drug-containing culture solution and 100 mu L of the fungus-containing culture solution with different concentrations are added into each well of a 96-well plate, so that the final fungus solution concentration is 5 multiplied by 10 4 CFU, 96-well plates were sealed with Trypticase Soy Broth (TSB) plus broth as negative control (TSB medium, 100 μl each) and without broth (TSB broth 200 μl), and incubated in a 37 ℃ incubator for 24 h.
(4) The experiments were repeated three times in parallel, assuming that the apparent growth of bacteria in the negative control wells was a precondition, and that the minimum concentration of the drug at which no apparent growth of bacteria in the wells was observed by naked eyes after dosing was MIC (μg/mL) of the drug, and the results are shown in table 2.
TABLE 2 inhibition of various bacteria by phloroglucinol derivatives (MIC, μg/mL)
The result shows that the phloroglucinol derivative has remarkable antibacterial activity on staphylococcus aureus, methicillin-resistant staphylococcus aureus and vancomycin-mediated drug-resistant staphylococcus aureus, has MIC value of 0.156 mug/mL, is obviously superior to clinical common medicines such as positive medicines ampicillin and vancomycin, and has important significance on developing novel medicines for resisting drug-resistant bacteria; the phloroglucinol derivative has strong antibacterial activity on staphylococcus epidermidis, enterococcus faecalis and enterococcus faecium, and the MIC value is 4-8 mug/mL.
The phloroglucinol derivative provided by the invention is taken as a novel chemical entity with a molecular structure completely different from that of the existing antibacterial drug, has remarkable inhibitory activity on multi-drug resistant bacteria, and can be taken as a novel chemical entity for preparing novel antibacterial drugs.
EXAMPLE 4 Effect of phloroglucinol derivatives on Normal cells
The test method comprises the following steps: human embryonic kidney cells HEK 293 (purchased from Shanghai cell Bank of China academy of sciences) were cultured to log phase in DMEM medium containing 10% (v/v) fetal bovine serum and double antibodies (100U/mL each of penicillin and streptomycin), washed with PBS, and digested with 0.25% (w/v) trypsin. Suspending cells in fresh DMEM medium, and adjusting cell density to 1×10 6 Spreading 96-well plate with 200 μl/well, adding samples with different concentrations after cell adhesion, and heating at 37deg.C and 5% CO 2 Co-culture 24 h under conditions. After the completion of the culture, 20. Mu.L of 5mg/mL MTT solution was added to each well, and the culture was continued for 4 h. The wells were aspirated with a pipette, 100 μl DMSO was added to each well, and the wells were gently shaken at room temperature for 10 min, and the absorbance OD of each well was measured with a microplate reader at 570 nm wavelength. Pressing the buttonThe following formula calculates the cell growth inhibition rate and the experiment is repeated at least 3 times more. Cell growth inhibition rate calculation formula: inhibition (%) = (1-dosing OD)/control OD x 100%, results are shown in table 3.
TABLE 3 cytotoxicity of phloroglucinol derivatives on HEK 293
The experimental result shows that the phloroglucinol derivative has 9.61 percent of cell growth inhibition rate on human normal cell embryo kidney cell HEK 293 at a high concentration of 200 mug/mL and shows very low cytotoxicity.
The above examples illustrate only a few embodiments of the invention, which are described in detail and are not to be construed as limiting the scope of the invention. It should be noted that it will be apparent to those skilled in the art that several variations and modifications can be made without departing from the spirit of the invention, which are all within the scope of the invention. Accordingly, the scope of protection of the present invention is to be determined by the appended claims.
Claims (10)
1. A phloroglucinol derivative or a pharmaceutically acceptable salt thereof is characterized in that the molecular structure of the phloroglucinol derivative is shown as a formula I, and the configuration is 7S,1′R,4′S,5′R,7′R,10′R，
。
2. A process for the preparation of the phloroglucinol derivative of claim 1, comprising the steps of:
pulverizing aerial parts of Japanese snow plum, percolating with 85-98% ethanol water solution, concentrating the extract, extracting with petroleum ether, and separating and purifying the extract to obtain the phloroglucinol derivative.
3. The method for producing a phloroglucinol derivative according to claim 2, wherein the volume concentration of the aqueous ethanol solution is 90-95%; and/or the number of the groups of groups,
the times of percolation extraction are 4-6 times, and the ratio of the ethanol aqueous solution to the Japanese snow plum is 0.8-1.2L/1 kg each time; and/or the number of the groups of groups,
the separation and purification comprises the following steps: concentrating the extractive solution, separating and purifying by silica gel column chromatography, sephadex LH-20 chromatographic column, octadecyl silane bonded silica gel column chromatography, and preparative HPLC.
4. Use of a phloroglucinol derivative of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting bacterial growth.
5. Use of a phloroglucinol derivative or a pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for the treatment and/or prophylaxis of bacterial infections.
6. The use according to claim 4 or 5, wherein the bacteria are drug resistant bacteria.
7. The use according to claim 4 or 5, wherein the bacteria are gram-positive bacteria.
8. The use according to claim 7, wherein the bacteria are staphylococci, enterococci.
9. The use according to claim 8, wherein the bacteria are staphylococcus aureus, methicillin-resistant staphylococcus aureus, vancomycin-mediated drug-resistant staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis, enterococcus faecium.
10. An antibacterial drug, which is characterized by being prepared from an active ingredient and pharmaceutically acceptable auxiliary materials, wherein the active ingredient comprises the phloroglucinol derivative or pharmaceutically acceptable salt thereof according to claim 1.
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| AU8530782A (en) * | 1981-07-02 | 1983-01-06 | Noristan Ltd. | Phlorophenone derivatives |
| WO2013103969A1 (en) * | 2012-01-05 | 2013-07-11 | Rutgers, The State University Of New Jersey | Antibacterial agents: phloroglucinol derivatives |
| CN104761565A (en) * | 2015-04-16 | 2015-07-08 | 中国科学院华南植物园 | Myrtle ketone compound and application thereof in preparation of antibacterial medicines |
| CN106967085A (en) * | 2016-01-14 | 2017-07-21 | 暨南大学 | A kind of phloroglucinol derivatives noval chemical compound and its application in antibacterials are prepared |
| CN107417697A (en) * | 2016-05-23 | 2017-12-01 | 暨南大学 | A kind of phloroglucin derivative and its application in antibacterials are prepared |
| US20230062900A1 (en) * | 2021-08-05 | 2023-03-02 | Jonathan SORRES | New antibacterial compound isolated from psiloxylon mauritianum and its derivatives |
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| AU8530782A (en) * | 1981-07-02 | 1983-01-06 | Noristan Ltd. | Phlorophenone derivatives |
| WO2013103969A1 (en) * | 2012-01-05 | 2013-07-11 | Rutgers, The State University Of New Jersey | Antibacterial agents: phloroglucinol derivatives |
| CN104761565A (en) * | 2015-04-16 | 2015-07-08 | 中国科学院华南植物园 | Myrtle ketone compound and application thereof in preparation of antibacterial medicines |
| CN106967085A (en) * | 2016-01-14 | 2017-07-21 | 暨南大学 | A kind of phloroglucinol derivatives noval chemical compound and its application in antibacterials are prepared |
| CN107417697A (en) * | 2016-05-23 | 2017-12-01 | 暨南大学 | A kind of phloroglucin derivative and its application in antibacterials are prepared |
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