CN115197183A - 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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- CN115197183A CN115197183A CN202110393266.7A CN202110393266A CN115197183A CN 115197183 A CN115197183 A CN 115197183A CN 202110393266 A CN202110393266 A CN 202110393266A CN 115197183 A CN115197183 A CN 115197183A
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- mixed solvent
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- methanol mixed
- column chromatography
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000004826 dibenzofurans Chemical class 0.000 title abstract description 4
- 239000011593 sulfur Substances 0.000 title abstract description 4
- 229910052717 sulfur Inorganic materials 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 239000003814 drug Substances 0.000 claims abstract description 30
- 241000412366 Alternaria mali Species 0.000 claims abstract description 10
- 241000194031 Enterococcus faecium Species 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 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
- 239000000243 solution Substances 0.000 claims description 33
- 239000012046 mixed solvent Substances 0.000 claims description 23
- 238000010828 elution Methods 0.000 claims description 14
- 238000010898 silica gel chromatography Methods 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
- 241001655175 Sorbus pohuashanensis Species 0.000 claims description 10
- 235000012072 hua qui shu Nutrition 0.000 claims description 10
- 239000000843 powder Substances 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 239000000725 suspension Substances 0.000 claims description 9
- 229960001701 chloroform Drugs 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 7
- 230000002538 fungal effect Effects 0.000 claims description 7
- 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
- 208000035143 Bacterial infection Diseases 0.000 claims description 6
- 206010017533 Fungal infection Diseases 0.000 claims description 6
- 208000031888 Mycoses Diseases 0.000 claims description 6
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- 241000266342 Alternaria longissima Species 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 241000894006 Bacteria Species 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 241000233866 Fungi 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
- 241001157813 Cercospora Species 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 241000323752 Alternaria longipes Species 0.000 abstract description 4
- 241001329956 Nothopassalora personata Species 0.000 abstract description 4
- 241000223600 Alternaria Species 0.000 abstract description 3
- 241001149961 Alternaria brassicae Species 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 235000004489 Sorbus commixta Nutrition 0.000 description 12
- 241001115347 Sorbus commixta Species 0.000 description 12
- 235000002639 sodium chloride Nutrition 0.000 description 9
- 241000196324 Embryophyta Species 0.000 description 8
- 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
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 7
- 239000011259 mixed solution Substances 0.000 description 6
- 241000191967 Staphylococcus aureus Species 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 241000194032 Enterococcus faecalis Species 0.000 description 4
- 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 4
- 229920002472 Starch Polymers 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 230000000844 anti-bacterial effect Effects 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
- 238000012258 culturing Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229960003085 meticillin Drugs 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000013641 positive control Substances 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
- 241000588626 Acinetobacter baumannii Species 0.000 description 3
- 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
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 241001092391 Sorbus Species 0.000 description 3
- 235000014459 Sorbus Nutrition 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229940032049 enterococcus faecalis Drugs 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 238000007873 sieving Methods 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 241000223218 Fusarium Species 0.000 description 2
- 241000221960 Neurospora Species 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
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- 241001123668 Verticillium dahliae 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
- -1 biphenyl phytoalexin Chemical class 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 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
- 238000003113 dilution method Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 239000000463 material Substances 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000000203 mixture Substances 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
- 229930000044 secondary metabolite Natural products 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- PYIXHKGTJKCVBJ-UHFFFAOYSA-N Astraciceran Natural products C1OC2=CC(O)=CC=C2CC1C1=CC(OCO2)=C2C=C1OC PYIXHKGTJKCVBJ-UHFFFAOYSA-N 0.000 description 1
- 241000221377 Auricularia Species 0.000 description 1
- NDVRQFZUJRMKKP-UHFFFAOYSA-N Betavulgarin Natural products O=C1C=2C(OC)=C3OCOC3=CC=2OC=C1C1=CC=CC=C1O NDVRQFZUJRMKKP-UHFFFAOYSA-N 0.000 description 1
- 241000588694 Erwinia amylovora 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
- 241000202564 Kalopanax Species 0.000 description 1
- 241000319057 Kalopanax septemlobus Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000009790 Sorbus aucuparia Nutrition 0.000 description 1
- 244000019194 Sorbus aucuparia Species 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 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
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 239000000969 carrier 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
- 238000004587 chromatography analysis 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
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating 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
- 239000000411 inducer 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
- 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
- 238000004806 packaging method and process Methods 0.000 description 1
- 229930000223 plant secondary metabolite Natural products 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 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
- 239000008215 water for injection Substances 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
Landscapes
- 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 type compound and a preparation method and application thereof, belonging 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 type compound and a preparation method and application thereof.
Background
The plant is often influenced by adverse factors such as physics, chemistry, biology and the like in the environment in the growth process, and the environmental stress influence can cause the change of plant secondary metabolites and start an in vivo defense mechanism, thereby reducing or avoiding the damage of the plant, leading the plant to present certain stress resistance and causing the increase of the accumulation of active secondary metabolites in the plant. For example, after the European mountain ash (Sorbus auricularia) is infected with the epidemic disease, biphenyl phytoalexin can be generated around the focus to inhibit the further proliferation of the Erwinia amylovora. Recently, it has been found through research that the yeast extract is used as a biological inducer to stimulate Sorbus Pohuashanensis Suspension Cells (SPSC) for a certain period of time, and then the de novo synthesis of biphenyl phytoalexins is induced. Therefore, the plant suspension cells are cultured by a biotechnology means, a plant cell defense mechanism is started by adding the fungus extract, and a secondary metabolite with specific biological activity is induced and synthesized, so that the discovery of more antibacterial compounds with specific structures and remarkable activity is facilitated, and the method has important significance for the deep development of plant resources.
Disclosure of Invention
The compound has obvious inhibitory activity on Alternaria mali, alternaria longissima, alternaria brassicae and multi-drug resistant Enterococcus faecium.
The invention firstly provides a compound shown as a formula I or a pharmaceutically acceptable salt thereof;
the second object of the present invention is to provide a process for the preparation of the compound represented by the above formula I, which comprises the steps of:
s1: soaking and extracting the dried Sorbus pohuashanensis suspension cells with methanol or ethanol, and concentrating the extract to obtain an 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 trichloromethane/methanol mixed solvent to obtain 9 components, and collecting the 4 th component;
s3: performing silica gel column chromatography gradient elution on the collected component of S2 by using a dichloromethane/methanol mixed solvent or a trichloromethane/methanol mixed solvent, and collecting the 2 nd component;
s4: and (3) carrying out Sephadex LH-20 column chromatography separation on the 2 nd component obtained from the S3 by using a dichloromethane/methanol mixed solvent to obtain the compound shown in the formula I.
In the above preparation method, in S2, the silica gel column chromatography gradient elution is performed by sequentially performing silica gel column chromatography gradient elution with a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent at a volume ratio of 200, 99.5;
in S3, the silica gel column chromatography gradient elution is carried out by sequentially using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent with the volume ratio of 100, 99;
in S4, the volume ratio of the dichloromethane/methanol mixed solvent is 1:1.
In the preparation method, in the step S1, the temperature for soaking and extracting is room temperature; the soaking and extracting times are 1 to 3;
in S3, the number of gradient elution of the silica gel column chromatography is 1;
in S4, the times of Sephadex LH-20 column chromatography separation are 1 time; the Sephadex LH-20 column chromatography separation also comprises a step of concentrating the chromatographic solution.
The room temperature is well known to those skilled in the art and is generally from 15 to 40 ℃.
In the above preparation method, the concentration is a 40 ℃ reduced pressure concentration.
The application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preparing the medicament for preventing and/or treating fungal or bacterial infection also belongs to the protection scope of the invention.
The application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in preventing and/or treating fungal or bacterial infection also belongs to the protection scope of the invention.
Specifically, the fungus is Alternaria mali, alternaria longissima Longipes or Cercospora brassicae personata;
the bacterium is Multidrug-resistant Enterococcus faecium.
The invention also provides a medicament 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, tablets, sugar-coated preparations, capsules, solutions, syrup or dropping pills; 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, it may be 0.5 to 90wt%.
When the compound of the present invention is used as a pharmaceutical, it may be used as it is or in the form of a pharmaceutical composition. When the pharmaceutical composition is used, the pharmaceutical composition contains 0.1-99 wt% of the sorbol B (compound shown in formula I) in percentage by mass, and in order to ensure the optimal treatment effect, the content of the sorbol B (compound shown in formula I) is preferably 0.5-90 wt%, and the balance is medicinal carriers and/or excipients which are 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 and the like. The pharmaceutical composition is used in the form of an amount to be administered per unit body weight. 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, syrup, dropping pills and the like; the injection can be solid or liquid preparation, such as powder for injection, solution injection, etc.
The invention has the following beneficial effects:
(1) The compound has a novel structure, and has obvious inhibitory activity on Alternaria mali (Alternaria mali), alternaria elongata (Alternaria longipes), alternaria brassicae (Cercospora personata) and multi-drug-resistant enterococcus faecium (multidug-resistant E.faecalis);
(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 and stable yield and quality, and is beneficial to industrial operation. Moreover, the yield can be continuously improved by optimizing the cell culture conditions.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.
The experimental procedures in the following examples are conventional unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The method for producing the suspension cells of the dried Sorbus commixta used in the following examples is the same as the method for producing the suspension cells of the dried Sorbus commixta in the following documents, except that the Sorbus commixta is replaced with Sorbus commixta (Li Jiaxing, li Huiliang, zhou Liangyun, etc.. Yeast induces the chemical components and bacteriostatic activity of the suspension cells of Sorbus commixta [ J ]. Natural products research and development, 2019,031 (012): 2071-2076.).
The filler of the silica gel column is 200-300 meshes.
Methicillin-resistant Staphylococcus aureus (methicillin-resistant Staphylococcus aureus), carbapenem-resistant Pseudomonas aeruginosa (carbapenem-resistant Pseudomonas aeruginosa), carbapenem-resistant Acinetobacter baumannii (carbapenem-resistant Enterococcus faecalis), multi-drug-resistant Enterococcus faecium (multi-drug-resistant Enterococcus faecalis) and multi-drug-resistant Staphylococcus epidermidis (multi-drug-resistant Staphylococcus epidermidis) in the following examples are described in the literature (±) -preissoide: a new enteric resistant a naturaceutical curative trap saline-2H-3236 zx3236-oxcarbazn enteric coating reagent, obtained from university of military medical science 3763, or are available as materials of western medicine 3763, clinical laboratory university, or clinical laboratory university of the applicant, i.e., university of military medical university 3763, or clinical laboratory university of traditional Chinese medicine 3763, namely, university of the present invention.
EXAMPLE 1 preparation of Sorbus B
1. Preparation method
S1: soaking and extracting 20kg of dried Sorbus commixta suspension cells with methanol at room temperature for 3 times, mixing extractive solutions, and concentrating under reduced pressure at 40 deg.C to obtain 6kg of extract;
s2: performing silica gel column chromatography gradient elution on the extractum obtained in the step S1 by using a dichloromethane/methanol mixed solvent with the volume ratio of 200, 99.5, 99.1, 98;
s3: sequentially carrying out silica gel column chromatography gradient elution on the collected components of the S2 by using a dichloromethane/methanol mixed solvent with the volume ratio of 100, 99 and 98, wherein the elution is carried out for 1 time in total, and collecting the 2 nd component;
s4: subjecting the 2 nd component obtained by S3 treatment to Sephadex LH-20 column chromatography with dichloromethane/methanol mixed solvent of 1:1 for 1 time in total, and concentrating the chromatography solution under reduced pressure at 40 deg.C to obtain Sorbus commixta Hemsl 5mg.
2. Analysis of results
The obtained finished product of the kalopanax pohuashansu white powder is analyzed by mass spectrum, ultraviolet and infrared rays, and the analysis result is 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 B, and the results are shown in Table 1.
TABLE 1 nuclear magnetic resonance spectroscopy data (delta in ppm, J in Hz) for Sorbus pohuashanensis B
According to the results of the mass spectrum, ultraviolet, infrared and nuclear magnetic resonance analysis, the sorbosol prepared by the invention has the following structure:
example 2
1. In order to examine the anti-pathogenic fungus effect of the prepared compound, five pathogenic fungi of potato Verticillium dahliae (Verticillium dahliae) ATCC 42216, alternaria mali (Alternaria mali) ATCC 6663, gibberella saubenii (Gibberella saubenecii) ATCC 20193, alternaria longissima (Alternaria longipes) ATCC 26293 and Neurospora brassicae (Cercospora personata) ATCC 18592 are selected, and the anti-bacterial activity of the Sorbus pohuashanensis B is determined by a double dilution method.
Compound solution preparation: the compound Sorbus pohuashanensis B prepared in example 1 and the positive control ketoconazole are dissolved in DMSO to prepare a solution of 10 mg/mL;
preparing a PDB culture solution: adding 1000mL of distilled water into 25g of PDB (potato extract powder 5.0g/L, glucose 20.0g/L, chloramphenicol 0.1g/L, shanghai Bo microbial science and technology Co., ltd.), boiling for dissolving, and sterilizing at 121 deg.C for 20 min;
preparing test bacterial liquid: inoculating plant pathogenic fungi stored in a 4 deg.C slant into PDB culture solution, culturing at 28 deg.C and 160r/min for 3-4d;
the experimental method comprises the following steps: the test cell liquid was diluted 100 times with the PDB culture solution. In a 96-well plate, 198. Mu.L of diluted test bacterial liquid was added to each well of the first row. Adding 100 mu L of diluted test bacterial liquid into each hole of the other rows; adding 2 mu L of compound solution into the first row, sucking 100 mu L of mixed solution to the second row after the compound solution is uniformly sucked and mixed by a liquid transfer gun, sucking 100 mu L of mixed solution to the third row after the compound solution is uniformly mixed, operating the last rows in the same way, and discarding the mixed solution sucked from the last row; the concentration of the compounds in each row is 0.1mg/mL,0.05mg/mL,0.025mg/mL and 0.0125mg/mL in turn, and is decreased progressively. One positive and negative control per plate (2. Mu.L of ketoconazole solution and 2. Mu.L of DMSO solution, respectively).
And (5) judging a result: culturing at 28 deg.C, and observing after 72 hr. The minimal compound concentration at which no fungal growth was observed was the Minimal Inhibitory Concentration (MIC), and the results are shown in table 2.
TABLE 2 antifungal Activity of Sorbus pohuashanensis B (MIC, μ g/mL)
As can be seen from Table 2, sorbus pohuashanensis B.has a significant inhibitory activity against Alternaria malayi (Alternaria mali), alternaria longissima (Alternaria longipes) and Neurospora brassicae (Cercospora personata).
2. In order to examine the effect of the prepared compound on drug-resistant pathogenic bacteria, the invention selects methicillin-resistant Staphylococcus aureus (methicillin-resistant Staphylococcus aureus), carbapenem-resistant Pseudomonas aeruginosa (Carbapenems-Carbapenems aeruginosa), carbapenem-resistant Acinetobacter baumannii (carbapenem-resistant Acinetobacter baumannii), multi-drug-resistant Enterococcus faecium (Multidrug-resistant Enterococcus faecium) 5 drug-resistant bacteria (Multidrug-resistant Staphylococcus aureus) (provided by army medical university), and the antibacterial activity of the compound antheridium can be determined by a diplodization dilution method.
Compound solution preparation: the compound Sorbus commixta B prepared in example 1 and positive control ciprofloxacin were dissolved in DMSO to prepare a solution of 10 mg/mL;
preparing an LB culture solution: taking 25g of LB (the components are tryptone 10.0g/L, yeast powder 5.0g/L, sodium chloride 10.0g/L, shanghai Bo microbial science and technology Co., ltd.), adding 1000mL of distilled water, heating to boil and dissolve, and sterilizing at 121 ℃ for 15 minutes for later use);
preparing test bacterial liquid: inoculating the drug-resistant bacteria to LB culture solution from a freezing tube, and culturing at the constant temperature of 37 ℃ and 160r/min for 10h 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 diluted test bacterial liquid was added to each well of the first row. Adding 100 mu L of diluted test bacterial liquid into each hole of the other rows; adding 2 mu L of compound solution into the first row, sucking 100 mu L of mixed solution to the second row after the compound solution is uniformly sucked and mixed by a liquid transfer gun, sucking 100 mu L of mixed solution to the third row after the compound solution is uniformly mixed, operating the last row, and discarding the mixed solution sucked out; the concentration of the compounds in each row is 0.1mg/mL,0.05mg/mL,0.025mg/mL and 0.0125mg/mL in turn, and is decreased progressively. One positive and negative control per plate (2. Mu.L ciprofloxacin solution and 2. Mu.L DMSO solution, respectively).
And (5) judging a result: culturing at 37 deg.C, and observing after 12 hr. The minimal compound concentration at which no bacterial growth was observed was the Minimal Inhibitory Concentration (MIC), and the results are shown in table 3.
TABLE 3 antibacterial Activity of Sorbus commixta B (MIC, μ g/mL)
As can be seen from Table 3, sorbus B has a significant inhibitory activity against multi-drug resistant Enterococcus faecium (multidug-resistant Enterococcus faecalis).
Example 3
The invention also prepares the prepared compound into usable medicines, and the sorbosol can be prepared into powder, tablets, sugar-coated agents, capsules, solutions, syrup or dropping pills and the like according to different medication habits. Wherein the content of the first and second substances,
1. the tablet comprises: 10mg of kalopanax septemlobus extract, 180mg of lactose, 55mg of starch and 5mg of magnesium stearate;
the preparation method comprises the following steps: mixing the compound Sorbus commixta ethyl, lactose and starch, moistening with water, sieving the moistened mixture, drying, sieving, adding magnesium stearate, and tabletting to obtain tablet with weight of 250mg, wherein the content of Sorbus commixta ethyl is 10mg.
2. The capsule comprises: 100mg of the compound sorbosol, 100mg of starch and a proper amount of magnesium stearate;
the preparation method comprises the following steps: mixing the compound with adjuvants, sieving, mixing in suitable container, and encapsulating the obtained mixture into hard gelatin capsule.
3. The ampoule agent comprises: 2mg of the compound sorbosol and 10mg of sodium chloride;
the preparation method comprises the following steps: dissolving Sorbus commixta B and sodium chloride in appropriate amount of water for injection, filtering, and packaging the obtained solution in ampoule bottle 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 as claimed in claim 1, comprising the steps of:
s1: soaking and extracting the dried Sorbus pohuashanensis suspension cells with methanol or ethanol, and concentrating the extract to obtain an 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 trichloromethane/methanol mixed solvent to obtain 9 components, and collecting the 4 th component;
s3: performing silica gel column chromatography gradient elution on the collected component of S2 by using a dichloromethane/methanol mixed solvent or a trichloromethane/methanol mixed solvent, and collecting the 2 nd component;
s4: and (3) carrying out Sephadex LH-20 column chromatography separation on the 2 nd component obtained from the S3 by using a dichloromethane/methanol mixed solvent to obtain the compound shown in the formula I.
3. The production method according to claim 2, characterized in that: in S2, the silica gel column chromatography gradient elution is carried out by sequentially using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent at a volume ratio of 200, 99.5, 99.1, 98, 10, 80, 20, 70, 60, 40, 50;
in S3, the silica gel column chromatography gradient elution is carried out by sequentially using a dichloromethane/methanol mixed solvent or a chloroform/methanol mixed solvent with the volume ratio of 100, 99;
in S4, the volume ratio of the dichloromethane/methanol mixed solvent is 1:1.
4. The production method according to claim 2 or 3, characterized in that: in S1, the temperature for soaking and extracting is room temperature; the soaking and extracting times are 1 to 3;
in S3, the number of gradient elution of the silica gel column chromatography is 1;
in S4, the times of Sephadex LH-20 column chromatography separation are 1 time; the Sephadex LH-20 column chromatography separation also comprises a step of concentrating the chromatographic solution.
5. The use of a compound of formula i as claimed in claim 1 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prophylaxis and/or treatment of fungal or bacterial infections; or
The use of a compound of formula i as defined in claim 1, or a pharmaceutically acceptable salt thereof, for the prophylaxis and/or treatment of fungal or bacterial infections;
specifically, the fungus is Alternaria mali, alternaria longissima Longipes or Cercospora brassicae personata;
the bacterium is Multidrug-resistant Enterococcus faecium.
6. A medicament for the prevention and/or treatment of fungal or bacterial infections characterized by: comprising a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof.
7. The medicament of claim 6, wherein: the medicine is an oral preparation or an injection preparation.
8. The medicament of claim 7, wherein: the oral preparation is powder, tablet, sugar-coated preparation, capsule, solution, syrup or dripping pill; the injection is powder injection or solution injection.
9. The medicament according to any one of claims 6 to 7, characterized in that: in the medicament, the content of the compound shown in the formula I or the pharmaceutically acceptable salt thereof in claim 1 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)
| Title |
|---|
| KOKUBUN，TETSUO等: "Phytoalexin induction in the sapwood of plants of the maloideae (rosaceae): biphenyls or dibenzofurans", PHYTOCHEMISTRY, vol. 40, no. 6, pages 1649 - 1654 * |
| 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, vol. 31, no. 12, pages 2071 - 2072 * |
| 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, vol. 37, no. 6, pages 927 - 931 * |
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