CN115197183B - Sulfur-containing dibenzofuran type compound and preparation method and application thereof - Google Patents
Sulfur-containing dibenzofuran type compound and preparation method and application thereof Download PDFInfo
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- CN115197183B CN115197183B CN202110393266.7A CN202110393266A CN115197183B CN 115197183 B CN115197183 B CN 115197183B CN 202110393266 A CN202110393266 A CN 202110393266A CN 115197183 B CN115197183 B CN 115197183B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title abstract description 5
- 239000011593 sulfur Substances 0.000 title abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 title abstract description 5
- 150000004826 dibenzofurans Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 41
- 239000003814 drug Substances 0.000 claims abstract description 36
- 229940079593 drug Drugs 0.000 claims abstract description 16
- 241000194031 Enterococcus faecium Species 0.000 claims abstract description 15
- 241000412366 Alternaria mali Species 0.000 claims abstract description 11
- 241000223600 Alternaria Species 0.000 claims abstract description 8
- 241000323752 Alternaria longipes Species 0.000 claims abstract description 7
- 241001329956 Nothopassalora personata Species 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 241001655175 Sorbus pohuashanensis Species 0.000 claims description 28
- 235000012072 hua qui shu Nutrition 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 27
- 239000012046 mixed solvent Substances 0.000 claims description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 239000007788 liquid Substances 0.000 claims description 16
- 238000010828 elution Methods 0.000 claims description 12
- 238000002347 injection Methods 0.000 claims description 12
- 239000007924 injection Substances 0.000 claims description 12
- 239000000284 extract Substances 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 9
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 claims description 7
- 238000002791 soaking Methods 0.000 claims description 7
- 230000002538 fungal effect Effects 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 5
- 208000035143 Bacterial infection Diseases 0.000 claims description 5
- 206010017533 Fungal infection Diseases 0.000 claims description 5
- 208000031888 Mycoses Diseases 0.000 claims description 5
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 241000233866 Fungi Species 0.000 claims description 4
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims description 4
- 239000006187 pill Substances 0.000 claims description 4
- 239000006188 syrup Substances 0.000 claims description 4
- 235000020357 syrup Nutrition 0.000 claims description 4
- 238000011282 treatment Methods 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- 238000013375 chromatographic separation Methods 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- -1 dibenzofuran compound Chemical class 0.000 abstract description 5
- 230000005764 inhibitory process Effects 0.000 abstract description 4
- TXCDCPKCNAJMEE-UHFFFAOYSA-N Dibenzofuran Natural products C1=CC=C2C3=CC=CC=C3OC2=C1 TXCDCPKCNAJMEE-UHFFFAOYSA-N 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 206010037549 Purpura Diseases 0.000 abstract 1
- 241001672981 Purpura Species 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 10
- 241000196324 Embryophyta Species 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000001580 bacterial effect Effects 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- 241000588626 Acinetobacter baumannii Species 0.000 description 4
- 240000005662 Aronia melanocarpa Species 0.000 description 4
- 235000007425 Aronia melanocarpa Nutrition 0.000 description 4
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 4
- 241000191967 Staphylococcus aureus Species 0.000 description 4
- 241000191963 Staphylococcus epidermidis Species 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 4
- 229940041011 carbapenems Drugs 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 229930000044 secondary metabolite Natural products 0.000 description 3
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 2
- 240000007124 Brassica oleracea Species 0.000 description 2
- 235000003899 Brassica oleracea var acephala Nutrition 0.000 description 2
- 235000011301 Brassica oleracea var capitata Nutrition 0.000 description 2
- 235000001169 Brassica oleracea var oleracea Nutrition 0.000 description 2
- 241000223218 Fusarium Species 0.000 description 2
- 206010027146 Melanoderma Diseases 0.000 description 2
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 2
- IHPVFYLOGNNZLA-UHFFFAOYSA-N Phytoalexin Natural products COC1=CC=CC=C1C1OC(C=C2C(OCO2)=C2OC)=C2C(=O)C1 IHPVFYLOGNNZLA-UHFFFAOYSA-N 0.000 description 2
- 244000061456 Solanum tuberosum Species 0.000 description 2
- 235000002595 Solanum tuberosum Nutrition 0.000 description 2
- 241001092391 Sorbus Species 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000008260 defense mechanism Effects 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000003113 dilution method Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229960004125 ketoconazole Drugs 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000000280 phytoalexin Substances 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 241001149961 Alternaria brassicae Species 0.000 description 1
- 235000010149 Brassica rapa subsp chinensis Nutrition 0.000 description 1
- 235000000536 Brassica rapa subsp pekinensis Nutrition 0.000 description 1
- 241000499436 Brassica rapa subsp. pekinensis Species 0.000 description 1
- 241000588698 Erwinia Species 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- 241001676783 Preussia isomera Species 0.000 description 1
- 235000014459 Sorbus Nutrition 0.000 description 1
- 241000209140 Triticum Species 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 241000082085 Verticillium <Phyllachorales> Species 0.000 description 1
- 241001123668 Verticillium dahliae Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001775 anti-pathogenic effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000006353 environmental stress Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 244000053095 fungal pathogen Species 0.000 description 1
- 244000000004 fungal plant pathogen Species 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000008345 mountainash Nutrition 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- OZQGLZFAWYKKLQ-UHFFFAOYSA-N oxazinane Chemical group C1CCONC1 OZQGLZFAWYKKLQ-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000012137 tryptone Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
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
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
-
- 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
-
- 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
- A61P31/10—Antimycotics
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Communicable Diseases (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 discloses a sulfur-containing dibenzofuran compound, and a preparation method and application thereof, and belongs to the technical field of medicine preparation. The structural formula of the compound provided by the invention is
Description
Technical Field
The invention relates to the technical field of medicine preparation, in particular to a sulfur-containing dibenzofuran compound, and a preparation method and application thereof.
Background
Plants often suffer from adverse factors such as physical, chemical, biological and the like in the environment during the growth process, and the influence of environmental stress can cause the change of secondary metabolites of the plants and start in-vivo defense mechanisms, so that the damage to the plants is reduced or avoided, the plants show a certain stress resistance, and the accumulation of active secondary metabolites in the plants is increased. Such as Aronia melanocarpa (Sorbus aucu pa) infection with epidemic disease, biphenyl phytoalexins can be produced around the focus to inhibit further proliferation of erwinia fire. Recently, we have also found that, after stimulating the Suspension cells of Sorbus Pohuashanensis (SPSC) for a certain period of time, the de novo synthesis of biphenyl phytoalexins is induced by using yeast extract as a bioenductor. Therefore, the plant suspension cells are cultured by using a biotechnology means, and a plant cell defense mechanism is started by adding fungus extracts, so that the secondary metabolite with specific biological activity is induced to be synthesized, more antibacterial compounds with structure specificity and obvious activity can be found, and the method has important significance for the deep development of plant resources.
Disclosure of Invention
The invention provides a sulfur-containing dibenzofuran compound and a preparation method and application thereof, and the compound has obvious inhibition activity on Alternaria mali (Alternaria mali), alternaria longifolia (Alternaria longipes), chinese cabbage black spot (Cercospora personata) and multi-drug-resistant enterococcus faecium (multitug-resistant Enterococcus faecium).
The invention firstly provides a compound shown in a formula I or pharmaceutically acceptable salt thereof;
the second object of the present invention is to provide a process for preparing the above compound of formula I, comprising the steps of:
s1: soaking and extracting dry suspension cells of Sorbus pohuashanensis with methanol or ethanol, and concentrating the extractive solution to obtain extract;
s2: performing silica gel column chromatography gradient elution on the extract obtained in the step S1 by using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent to obtain 9 components, and collecting the 4 th component;
s3: performing silica gel column chromatography gradient elution on the component collected in the step S2 by using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent, and collecting the 2 nd component;
s4: and (3) carrying out Sephadex LH-20 column chromatography on the 2 nd component obtained in the step (S3) by using a dichloromethane/methanol mixed solvent to obtain the compound shown in the formula I.
In the preparation method, in S2, the silica gel column chromatography gradient elution is performed by sequentially using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent with volume ratio of 200:0, 99.5:0.5, 99:1, 98:2, 90:10, 80:20, 70:30, 60:40, 50:50;
s3, performing silica gel column chromatography gradient elution by sequentially using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent with volume ratios of 100:1, 99:1 and 98:2;
in S4, the volume ratio of the dichloromethane/methanol mixed solvent is 1:1.
In the preparation method, in S1, the soaking and extracting temperature is room temperature; the times of soaking and extracting are 1-3 times;
s3, performing gradient elution on the silica gel column for 1 time;
in S4, the number of chromatographic separations of the Sephadex LH-20 column is 1; the Sephadex LH-20 column chromatography separation further comprises a step of concentrating chromatographic liquid.
The room temperature is well known to those skilled in the art and is typically 15 to 40 ℃.
In the preparation method, the concentration is reduced pressure concentration at 40 ℃.
The application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preparing the medicines for preventing and/or treating fungal or bacterial infection also belongs to the protection scope of the invention.
The use of the compounds of formula I or pharmaceutically acceptable salts thereof for the prophylaxis and/or treatment of fungal or bacterial infections is also within the scope of the invention.
Specifically, the fungus is Alternaria mali, alternaria longifolia Alternaria Longipes or Alternaria longifolia Cercospora personata;
the bacteria are multi-drug resistant enterococcus faecium multitug-resistant Enterococcus faecium.
The invention also provides a medicine for preventing and/or treating fungal or bacterial infection, which comprises the compound shown in the formula I or pharmaceutically acceptable salt thereof.
The medicine is oral preparation or injection preparation.
The oral preparation is powder, tablet, sugar-coated agent, capsule, solution, syrup or dripping pill; the injection is powder injection or solution injection.
In the medicine, the content of the compound shown in the formula I or the pharmaceutically acceptable salt thereof is 0.1-99 wt%; specifically, the content of the catalyst may be 0.5 to 90wt%.
When the compound of the present invention is used as a medicament, it may be used directly or in the form of a pharmaceutical composition. When the medicine composition is used, the medicine composition contains 0.1-99wt% of the Sorbus pohuashanensis B (the compound shown in the formula I), the content of the Sorbus pohuashanensis B (the compound shown in the formula I) is preferably 0.5-90wt% for ensuring the optimal treatment effect, and the balance is a pharmaceutically acceptable carrier and/or excipient which is nontoxic and inert to human and animals.
The pharmaceutically acceptable carrier or excipient in the pharmaceutical composition is one or more selected from solid, semi-solid and liquid diluents, fillers and pharmaceutical adjuvants such as lactose, starch, magnesium stearate, sodium chloride solution, etc. The pharmaceutical composition is administered in the form of a unit weight dose. The medicine of the invention can be administrated by oral administration and injection (intravenous injection and intramuscular injection), wherein the oral administration can be used for solid or liquid preparations, such as powder, tablets, sugar-coated agents, capsules, solutions, syrups, dripping pills and the like; the injection can be used in solid or liquid preparation, such as powder injection, solution injection, etc.
The beneficial effects of the invention are as follows:
(1) The compound has novel structure and obvious inhibition activity on Alternaria mali (Alternaria mali), alternaria longifolia (Alternaria longipes), alternaria brassicae (Cercospora personata) and enterococcus faecium with multiple drug resistance (multi drug-resistance E.fa);
(2) The method of the invention uses the yeast-induced plant suspension cell culture technology to produce and extract the active ingredients, has the characteristics of high production speed, easily controlled growth conditions, stable yield and quality, and is beneficial to industrial operation. And, the yield can be continuously improved by optimizing the cell culture conditions.
Detailed Description
The following detailed description of the invention is provided in connection with the accompanying drawings that are presented to illustrate the invention and not to limit the scope thereof.
The experimental methods in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The preparation method of the dried Sorbus pohuashanensis suspension cells used in the following examples is the same as the preparation method of the dried Sorbus pohuashanensis suspension cells in the following documents except that Sorbus pohuashanensis is replaced with Sorbus pohuashanensis (Li Jiaxing, li Huiliang, zhou Liangyun, etc.. Yeast induces chemical components and antibacterial activity of Sorbus pohuashanensis suspension cells [ J ]. Natural product research and development, 2019,031 (012): 2071-2076.).
The filler of the silica gel column is 200-300 meshes.
Methicillin-resistant staphylococcus aureus (metacinllin-resistant Staphylococcus aureus), carbapenem-resistant pseudomonas aeruginosa (Carbapenems-resistant Pseudomonas aeruginosa), carbapenem acinetobacter baumannii (Carbapenems-resistant Acinetobacter baumannii), multi-drug resistant enterococcus faecium (multitug-resistant Enterococcus faecium) and multi-drug resistant staphylococcus epidermidis (multitug-resistant Staphylococcus epidermidis) are described in the literature ((±) -prenomide: A new alkaloid featuring a rare naturally occurring tetrahydro-2H-1,2-oxazin skeleton from an endophytic fungus Preussia isomera by using OSMAC strategy, hai-Li Chen etc., fitotepia, 141 (2020) 104475), and are available to the public from the university of army of medicine, or from the institute of chinese traditional chinese medicine, the applicant) via the university of army of medicine, and these biological materials are used only for the relevant experiments of the duplicate invention and cannot be used for other purposes.
EXAMPLE 1 preparation of Sorbus pohuashanensis B
1. Preparation method
S1: soaking and extracting dried suspension cells of Sorbus pohuashanensis with methanol at room temperature for 3 times, mixing extractive solutions, and concentrating under reduced pressure at 40deg.C to obtain extract 6kg;
s2: sequentially performing silica gel column chromatography gradient elution on the extractum obtained in the step S1 by using dichloromethane/methanol mixed solvents with volume ratios of 200:0, 99.5:0.5, 99:1, 98:2, 90:10, 80:20, 70:30, 60:40 and 50:50 to obtain 9 components, and collecting the 4 th component;
s3: sequentially performing silica gel column chromatography gradient elution on the components collected by S2 by using dichloromethane/methanol mixed solvents with volume ratios of 100:1, 99:1 and 98:2, and collecting the 2 nd component in the components for 1 time;
s4: separating the 2 nd component obtained by S3 treatment by Sephadex LH-20 column chromatography with dichloromethane/methanol mixed solvent at volume ratio of 1:1 for 1 time, and concentrating the chromatographic liquid at 40deg.C under reduced pressure to obtain 5mg of Sorbus pohuashanensis B.
2. Analysis of results
And carrying out mass spectrum, ultraviolet and infrared analysis on the obtained white powder finished product of the arone B, wherein the analysis results are as follows:
sorbus pohuashanensis B molecular formula C 14 H 12 O 4 S；ESIMS(neg.)：m/z 275[M-1] - ；HRESIMS(neg.)：m/z 275.0385(275.0384calcd for C 14 H 11 O 4 S)；UV(MeOH)λ max ：262，303，320(sh)nm；IR(KBr)ν max ：3235，2956，2922，2852，1735，1623，1587，1494，1454，1385，1313，1251，1212，1029，969，939cm -1 .
Nuclear magnetic resonance analysis was performed on Sorbus pohuashanensis, and the results are shown in Table 1.
TABLE 1 Nuclear magnetic resonance Spectroscopy data for Sorbus pohuashanensis B (δin ppm, J in Hz)
By combining the mass spectrum, ultraviolet, infrared and nuclear magnetic resonance analysis results, the prepared Sorbus pohuashanensis B has the following structure:
example 2
1. In order to examine the anti-pathogenic fungus effect of the prepared compound, five pathogenic fungi including potato verticillium wilt (Verticillium dahliae) ATCC 42216, alternaria mali ATCC 6663, gibberella wheat (Gibberella saubinetii) ATCC 20193, alternaria longifolia (Alternaria longipes) ATCC 26293 and black spot cabbage (Cercospora personata) ATCC 18592 are selected, and the antibacterial activity of the Sorbus pohuashanensis B is determined by a double dilution method.
Compound solution preparation: dissolving the compound prepared in example 1, namely the Sorbus pohuashanensis B and the positive control ketoconazole in DMSO to prepare a solution of 10 mg/mL;
preparing PDB culture solution: 25g of PDB (the ingredients are 5.0g/L of potato extract powder, 20.0g/L of glucose and 0.1g/L of chloramphenicol, shanghai Bo microorganism science and technology Co., ltd.) is taken, 1000mL of distilled water is added, heated, boiled and dissolved, and sterilized at 121 ℃ for 20 minutes for standby;
preparing a test bacterial liquid: inoculating plant pathogenic fungi stored in a 4 ℃ inclined plane into PDB culture solution, and culturing for 3-4d at 28 ℃ and 160 r/min;
the experimental method comprises the following steps: the test bacterial liquid is diluted 100 times by PDB culture liquid. In a 96-well plate, 198. Mu.L of the test bacterial liquid after dilution is added to each well of the first row. Adding 100 mu L of diluted test bacterial liquid into each row of holes; adding 2 mu L of compound solution in the first row, sucking 100 mu L of mixed solution to the second row after the mixed solution is uniformly sucked and mixed by a pipette, sucking 100 mu L of mixed solution to the third row after the mixed solution is uniformly mixed, and discarding the sucked mixed solution in the last row after the last rows are operated as above; the concentration of each row of compounds is 0.1mg/mL,0.05mg/mL,0.025mg/mL and 0.0125mg/mL, which are gradually decreased. One positive control and negative control per plate (2 μl ketoconazole solution and 2 μl DMSO solution, respectively).
And (3) judging results: culturing at 28 deg.C for 72 hr, and observing. The minimum concentration of compound without fungal growth was the Minimum Inhibitory Concentration (MIC) and the experimental results are shown in table 2.
TABLE 2 antifungal Activity of Sorbus pohuashanensis B (MIC, μg/mL)
As can be seen from Table 2, the Sorbus pohuashanensis B has obvious inhibition activity on Alternaria mali (Alternaria mali), alternaria longifolia (Alternaria longipes) and George cabbages (Cercospora personata).
2. In order to examine the effect of the prepared compound on drug-resistant pathogenic bacteria, 5 drug-resistant bacteria (provided by army medical university) of methicillin-resistant staphylococcus aureus (Methicin-resistant Staphylococcus aureus), carbapenem pseudomonas aeruginosa (Carbapenems-resistant Pseudomonas aeruginosa), carbapenem acinetobacter baumannii (Carbapenems-resistant Acinetobacter baumannii), multi-drug-resistant enterococcus faecium (multi drug-resistant Enterococcus faecium) and multi-drug-resistant staphylococcus epidermidis (multi drug-resistant Staphylococcus epidermidis) are selected, and the antibacterial activity of the compound of the mountain ash B is measured by adopting a double dilution method.
Compound solution preparation: the compound of Sorbus pohuashanensis B prepared in example 1 and positive control ciprofloxacin were dissolved in DMSO to prepare a 10mg/mL solution;
preparing LB culture solution: taking LB 25g (with the components of 10.0g/L tryptone, 5.0g/L yeast powder and 10.0g/L sodium chloride, shanghai Bo microorganism science and technology Co., ltd.), adding 1000mL of distilled water, heating, boiling and dissolving, and sterilizing at 121 ℃ for 15 minutes for later use;
preparing a test bacterial liquid: the drug-resistant bacteria are inoculated into LB culture solution from a freezing tube, and the culture solution is cultivated for 10 hours at a constant temperature of 37 ℃ and 160r/min until the culture solution becomes turbid.
The experimental method comprises the following steps: diluting the test bacterial liquid by 1000 times with LB culture liquid; in a 96-well plate, 198. Mu.L of the test bacterial liquid after dilution is added to each well of the first row. Adding 100 mu L of diluted test bacterial liquid into each row of holes; adding 2 mu L of compound solution in the first row, sucking 100 mu L of mixed solution to the second row after the mixed solution is uniformly sucked and mixed by a pipette, sucking 100 mu L of mixed solution to the third row after the mixed solution is uniformly mixed, and discarding the sucked mixed solution in the last row after the last rows are operated as above; the concentration of each row of compounds is 0.1mg/mL,0.05mg/mL,0.025mg/mL and 0.0125mg/mL, which are gradually decreased. One positive control and negative control per plate (2 μl ciprofloxacin solution and 2 μl DMSO solution, respectively).
And (3) judging results: culturing at 37 deg.C for 12 hr, and observing. The minimum compound concentration at which no bacteria grow is found to be the Minimum Inhibitory Concentration (MIC), and the experimental results are shown in table 3.
TABLE 3 antibacterial Activity of Sorbus pohuashanensis B (MIC, μg/mL)
As can be seen from Table 3, the Sorbus pohuashanensis B has obvious inhibitory activity against multi-drug resistant enterococcus faecium (Multidrug-resistant Enterococcus faecium).
Example 3
The invention also prepares the prepared compound into a medicament which can be used, and the compound of the Sorbus pohuashanensis B can be prepared into powder, tablets, sugar-coated agents, capsules, solutions, syrups or drop pills according to different medication habits. Wherein,
1. the tablet comprises: 10mg of the compound Sorbus pohuashanensis, 180mg of lactose, 55mg of starch and 5mg of magnesium stearate;
the preparation method comprises the following steps: mixing the compound Aronia melanocarpa extract, lactose and starch, wetting with water, sieving, drying, sieving, adding magnesium stearate, and tabletting, wherein the content of Aronia melanocarpa extract is 10mg.
2. The capsule comprises: 100mg of compound Sorbus pohuashanensis, 100mg of starch and a proper amount of magnesium stearate;
the preparation method comprises the following steps: the compound is mixed with the auxiliary, sieved, mixed well in a suitable container and the resulting mixture is filled into hard gelatin capsules.
3. The ampoule agent comprises: 2mg of the compound Sorbus pohuashanensis B and 10mg of sodium chloride;
the preparation method comprises the following steps: dissolving Aronia melanocarpa extract and sodium chloride in appropriate amount of injectable water, filtering, and packaging into ampoule under aseptic condition.
Claims (9)
1. A compound of formula i or a pharmaceutically acceptable salt thereof;
2. a process for the preparation of a compound of formula i according to claim 1, comprising the steps of:
s1: soaking dried yeast-induced Sorbus pohuashanensis suspension cells in methanol or ethanol, and concentrating the extractive solution to obtain extract;
s2: performing silica gel column chromatography gradient elution on the extract obtained in the step S1 by using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent to obtain 9 components, and collecting the 4 th component;
s3: performing silica gel column chromatography gradient elution on the component collected in the step S2 by using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent, and collecting the 2 nd component;
s4: and (3) carrying out Sephadex LH-20 column chromatography on the 2 nd component obtained in the step (S3) by using a dichloromethane/methanol mixed solvent to obtain the compound shown in the formula I.
3. The preparation method according to claim 2, characterized in that: s2, performing silica gel column chromatography gradient elution by sequentially using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent with volume ratios of 200:0, 99.5:0.5, 99:1, 98:2, 90:10, 80:20, 70:30, 60:40 and 50:50;
s3, performing silica gel column chromatography gradient elution by sequentially using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent with volume ratios of 100:1, 99:1 and 98:2;
in S4, the volume ratio of the dichloromethane/methanol mixed solvent is 1:1.
4. A method of preparation according to claim 2 or 3, characterized in that: s1, soaking and extracting at room temperature; the times of soaking and extracting are 1-3 times;
s3, performing gradient elution on the silica gel column for 1 time;
in S4, the number of chromatographic separations of the Sephadex LH-20 column is 1; the Sephadex LH-20 column chromatography separation further comprises a step of concentrating chromatographic liquid.
5. Use of a compound of formula i according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prophylaxis and/or treatment of fungal or bacterial infections;
the fungus is Alternaria mali, alternaria longifolia Alternaria Longipes or George longifolia Cercospora personata;
the bacteria are multi-drug resistant enterococcus faecium multitug-resistant Enterococcus faecium.
6. A medicament for the prevention and/or treatment of fungal or bacterial infections, characterized in that: comprising a compound of formula i as defined in claim 1 or a pharmaceutically acceptable salt thereof.
7. A medicament according to claim 6, characterized in that: the medicine is an oral preparation or an injection preparation.
8. A medicament according to claim 7, characterized in that: the oral preparation is powder, tablet, sugar-coated agent, capsule, solution, syrup or dripping pill; the injection is powder injection or solution injection.
9. A medicament according to any of claims 6-7, characterized in that: the content of the compound shown in the formula I or pharmaceutically acceptable salt thereof in the medicament is 0.1-99 wt%.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1180146A (en) * | 1997-09-01 | 1999-03-26 | Kyorin Pharmaceut Co Ltd | New dibenzofuran derivative |
| WO2007039609A1 (en) * | 2005-10-03 | 2007-04-12 | Institut Pasteur | Pyranodibenzofuran derivatives with antifungal and antibacterial activity |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH1180146A (en) * | 1997-09-01 | 1999-03-26 | Kyorin Pharmaceut Co Ltd | New dibenzofuran derivative |
| WO2007039609A1 (en) * | 2005-10-03 | 2007-04-12 | Institut Pasteur | Pyranodibenzofuran derivatives with antifungal and antibacterial activity |
Non-Patent Citations (3)
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| Kokubun，Tetsuo等.Phytoalexin induction in the sapwood of plants of the maloideae (rosaceae): biphenyls or dibenzofurans.Phytochemistry.1995,第40卷(第6期),第1649-1654页. * |
| 李佳兴等.酵母诱导欧洲花楸悬浮细胞的化学成分及抑菌活性.天然产物研究与开发.2019,第31卷(第12期),第2071-2072页. * |
| 莫歌等.不同类型诱导子对欧洲花楸悬浮细胞次生代谢的影响.中药材.2014,第37卷(第6期),第927-931页. * |
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