CN115772173A - Benzofuran compound, preparation method and application thereof, and antibacterial agent - Google Patents
Benzofuran compound, preparation method and application thereof, and antibacterial agent Download PDFInfo
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- CN115772173A CN115772173A CN202211640011.7A CN202211640011A CN115772173A CN 115772173 A CN115772173 A CN 115772173A CN 202211640011 A CN202211640011 A CN 202211640011A CN 115772173 A CN115772173 A CN 115772173A
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- -1 Benzofuran compound Chemical class 0.000 title claims abstract description 27
- IANQTJSKSUMEQM-UHFFFAOYSA-N benzofuran Natural products C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 241001549572 Elsholtzia splendens Species 0.000 claims abstract description 5
- 241000131458 Elsholtzia Species 0.000 claims description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 238000000605 extraction Methods 0.000 claims description 20
- 239000003208 petroleum Substances 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- 238000000926 separation method Methods 0.000 claims description 11
- 241000191967 Staphylococcus aureus Species 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 9
- 238000000194 supercritical-fluid extraction Methods 0.000 claims description 9
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 7
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 6
- 241000894006 Bacteria Species 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000004599 antimicrobial Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 7
- 229930014626 natural product Natural products 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 description 25
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- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 6
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- 239000000463 material Substances 0.000 description 5
- 239000000341 volatile oil Substances 0.000 description 5
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- 238000004057 DFT-B3LYP calculation Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
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- 235000010580 Psophocarpus tetragonolobus Nutrition 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WFMIUXMJJBBOGJ-UHFFFAOYSA-N Thymyl acetate Chemical compound CC(C)C1=CC=C(C)C=C1OC(C)=O WFMIUXMJJBBOGJ-UHFFFAOYSA-N 0.000 description 2
- 241000046198 Triteleia hyacinthina Species 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- HHTWOMMSBMNRKP-UHFFFAOYSA-N carvacrol Natural products CC(=C)C1=CC=C(C)C(O)=C1 HHTWOMMSBMNRKP-UHFFFAOYSA-N 0.000 description 2
- RECUKUPTGUEGMW-UHFFFAOYSA-N carvacrol Chemical compound CC(C)C1=CC=C(C)C(O)=C1 RECUKUPTGUEGMW-UHFFFAOYSA-N 0.000 description 2
- 235000007746 carvacrol Nutrition 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
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- 238000007906 compression Methods 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
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- WYXXLXHHWYNKJF-UHFFFAOYSA-N isocarvacrol Natural products CC(C)C1=CC=C(O)C(C)=C1 WYXXLXHHWYNKJF-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
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- 125000005704 oxymethylene group Chemical group [H]C([H])([*:2])O[*:1] 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
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- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- BAVONGHXFVOKBV-ZJUUUORDSA-N (-)-trans-carveol Natural products CC(=C)[C@@H]1CC=C(C)[C@@H](O)C1 BAVONGHXFVOKBV-ZJUUUORDSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 241001649247 Boehmeria Species 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 241001478240 Coccus Species 0.000 description 1
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- 201000004624 Dermatitis Diseases 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 206010017553 Furuncle Diseases 0.000 description 1
- 238000003937 GIAO Methods 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 241000207923 Lamiaceae Species 0.000 description 1
- 241000717677 Mosla chinensis Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000004078 Snake Bites Diseases 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 239000005844 Thymol Substances 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000012873 acute gastroenteritis Diseases 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
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- 239000003963 antioxidant agent Substances 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
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- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
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Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of natural compounds, and particularly relates to a benzofuran compound, a preparation method and application thereof and an antibacterial agent. The benzofuran compound is at least one selected from the following compounds shown in formulas 1 to 3:
the formula 1,
Formula 2 and
and (3) formula. The non-volatile part of the antibacterial agent is prepared, so that the antibacterial agent has good antibacterial effect, the types of compounds extracted from the elsholtzia splendens are further enriched, and the selection types of the antibacterial agent are further expanded.
Description
Technical Field
The invention relates to the technical field of natural compounds, in particular to benzofuran compounds, a preparation method and application thereof and an antibacterial agent.
Background
Herba Moslae (academic name: mosla chinensis Maxim.) is a plant of Boehmeria genus of Labiatae family. Standing herbaceous plants. The stem is 9-40 cm high, slender, and has multiple branches from the base, or the plant is short and not branched, and is white, fluffy and soft. Leaf-line-shaped oblong to line-shaped lanceolate. Distributed in northern vietnam and china; in China, the Chinese is distributed in Shandong, jiangsu, zhejiang, anhui, jiangxi, hunan, hubei, guizhou, sichuan, guangxi, guangdong, fujian and Taiwan. Growing in grass slope or under forest with elevation of 1400 m.
The stems and leaves are flourishing in summer and autumn, the fruits are picked in fine days in the mature period, the overground parts are taken for eating, and the overground parts are often decocted with white hyacinth beans or white hyacinth bean flowers in China to be eaten as soup, so that the heatstroke is avoided. Herba Moslae is also used as tea in summer to prevent common cold. Herba Moslae has certain medicinal efficacy, and is defined as a medicinal and edible material (which is a food and a Chinese medicinal material) from 2012 of Wei Jian Pong in China. The Chinese folk uses the whole herbs as the medicine for treating heatstroke, fever, cold, stomach pain, emesis, acute gastroenteritis, dysentery, traumatic injury, blood stasis and pain, edema of lower limbs, facial edema, dyspepsia, eczema, pruritus and multiple furuncle, and also is the essential medicine for treating venomous snake bite.
Modern pharmacological studies show that the elsholtzia chinensis has biological activities of resisting bacteria, viruses and the like, generally speaking, the main pharmacological active component of the elsholtzia chinensis is a volatile component, namely essential oil, and the current researches on the chemical components and the pharmacological activities of the elsholtzia chinensis are also based on the essential oil. The essential oil of herba Moslae comprises carvacrol, p-cymene, thymol acetate, thymol and gamma-pinene. Herba Moslae essential oil can strongly inhibit biofilm formation of Staphylococcus aureus. In addition, carveol is a potential alternative therapy for the treatment of excessive immune response induced by influenza a virus infection, and the cold-resistant effect of elsholtzia may depend on the antiviral effect of carvacrol. Elsholtzia essential oil can also play a therapeutic role in mice infected with IVA, inhibit IVA replication and inflammatory mediators, and promote antioxidant capacity.
It can be seen that the studies on the volatile components of elsholtzia are mainly focused on, while the experimental studies on the non-volatile part of elsholtzia are few.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide benzofuran compounds, a preparation method and application thereof and an antibacterial agent. The benzofuran compound provided by the embodiment of the invention is prepared from a nonvolatile part of elsholtzia, has a good antibacterial effect, further enriches the types of compounds extracted from elsholtzia, and further expands the selection types of antibacterial agents.
The invention is realized by the following steps:
in a first aspect, the present invention provides a benzofuran compound selected from at least one of the following compounds represented by formulae 1 to 3:
and
in a second aspect, the present invention provides a method for preparing a benzofuran compound according to the foregoing embodiment, including: and (3) separating the elsholtzia non-volatile matter extract to form the benzofuran compound.
In an alternative embodiment, the step of separating comprises: performing gradient elution on the elsholtzia non-volatile extract by using an ether solvent-ester solvent;
preferably, the step of separating comprises: performing gradient elution on the elsholtzia non-volatile extract by using petroleum ether-ethyl acetate;
preferably, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate is 100: 100.
in an alternative embodiment, the step of preparing the elsholtzia non-volatile extract comprises: and extracting the elsholtzia extract.
In an alternative embodiment, the step of extracting comprises: mixing the elsholtzia extract, an ether solvent and an alcohol-water solvent, and then separating and collecting an alcohol-water part substance;
preferably, the step of extracting comprises: mixing and dispersing the elsholtzia extract and petroleum ether, mixing and standing with a methanol water solution, and recovering a methanol water part;
preferably, the concentration of the aqueous methanol solution is 8-12%.
In an alternative embodiment, the preparation of the elsholtzia extract comprises the steps of: performing supercritical extraction on the elsholtzia.
In an alternative embodiment, the conditions of the supercritical extraction include: the pressure of the extraction kettle is kept between 12 and 15.0MPa, the temperature is between 45 and 50 ℃, and 20 to 30kg/h of CO 2 Performing flow rate circulation extraction; the pressure and temperature of the separation kettle I are respectively 9-10.0MPa and 35-40 ℃; the pressure and the temperature of the separation kettle II are respectively 6-8.0MPa and 25-30 ℃; the extraction is circulated for 2-3 hours.
In a third aspect, the present invention provides a use of the benzofuran compound described in the previous embodiment in the preparation of an antibacterial agent.
In a fourth aspect, the present invention provides an antibacterial agent comprising the benzofuran compound according to the previous embodiment.
In an alternative embodiment, the bacteria inhibited by the antimicrobial agent comprise a gram positive coccus, preferably staphylococcus aureus.
The invention has the following beneficial effects: the embodiment of the invention provides a benzofuran compound which has an excellent antibacterial effect, and particularly has a remarkable antibacterial effect on staphylococcus aureus. The compound is separated from the nonvolatile components of the elsholtzia, and the types of the compound for the nonvolatile components of the elsholtzia are further expanded, and the selection type of the antibacterial agent is also further expanded.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings required in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and those skilled in the art can also obtain other related drawings based on the drawings without inventive efforts.
FIG. 1 is a two-dimensional nuclear magnetic spectrum of compounds 1-3 provided in the examples of the present invention;
FIG. 2 is a graph of ECD calculations for compounds 1-3 provided by an example of the present invention (compounds 1-3 from left to right, respectively);
FIG. 3 is a nuclear magnetic hydrogen spectrum of Compound 1 provided in an example of the present invention;
FIG. 4 is a nuclear magnetic carbon spectrum of Compound 1 provided in an example of the present invention;
FIG. 5 is a DEPT spectrum of Compound 1 provided in an example of the present invention;
FIG. 6 is a DEPT90 spectrum of Compound 1 provided in an example of the present invention;
FIG. 7 is a DEPT135 spectrum of Compound 1 provided in the examples of the present invention;
FIG. 8 is an HSQC spectrum of Compound 1 provided in the examples herein;
FIG. 9 is an HMBC spectrum of compound 1 provided in an example of the present invention;
FIG. 10 is a COSY spectrum of the compound 1 provided by the embodiment of the invention;
FIG. 11 is a NOESY spectrum of Compound 1 provided in the examples herein;
FIG. 12 is a HRESIMS spectrum of Compound 1 provided by an example of the present invention;
FIG. 13 is a CD spectrum of Compound 1 provided in an example of the present invention;
FIG. 14 shows a UV spectrum of Compound 1 provided in an example of the present invention;
FIG. 15 is a nuclear magnetic hydrogen spectrum of Compound 2 provided by an example of the present invention;
FIG. 16 is a nuclear magnetic carbon spectrum of Compound 2 provided in an example of the present invention;
FIG. 17 is a DEPT spectrum of Compound 2 provided in an example of the present invention;
FIG. 18 is a DEPT90 spectrum of Compound 2 provided in an example of the present invention;
FIG. 19 is a DEPT135 spectrum of Compound 2 provided in an example of the present invention;
FIG. 20 is an HSQC spectrum of Compound 2 provided in the examples of the present invention;
FIG. 21 is an HMBC spectrum of compound 2 provided in an example of the present invention;
FIG. 22 is a COSY spectrum of Compound 2 provided in the examples herein;
FIG. 23 is a NOESY spectrum of Compound 2 provided in an example of the present invention;
FIG. 24 is an HRESIMS spectrum of Compound 2 provided in accordance with the example of the present invention;
FIG. 25 is a CD spectrum of Compound 2 provided in the examples of the present invention;
FIG. 26 shows a UV spectrum of Compound 2 provided in an example of the present invention;
FIG. 27 is a nuclear magnetic hydrogen spectrum of Compound 3 provided in an example of the present invention;
FIG. 28 is a nuclear magnetic carbon spectrum of Compound 3 provided in an example of the present invention;
FIG. 29 is a DEPT spectrum of Compound 3 provided in an example of the present invention;
FIG. 30 is a DEPT90 spectrum of Compound 3 provided in an example of the present invention;
FIG. 31 is a DEPT135 spectrum of Compound 3 provided in an example of the present invention;
FIG. 32 is a HSQC spectrum of Compound 3 provided in the examples of the present invention;
FIG. 33 is an HMBC spectrum of compound 3 provided in an example of the present invention;
FIG. 34 is a COSY spectrum of Compound 3 provided in the examples hereof;
FIG. 35 is a NOESY spectrum of Compound 3 provided in an example of the present invention;
FIG. 36 is a HRESIMS spectrum of Compound 3 provided in accordance with the example of the present invention;
FIG. 37 is a CD spectrum of Compound 3 provided in an example of the present invention;
FIG. 38 shows a UV spectrum of Compound 3 provided in the examples of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Embodiments of the present invention provide benzofuran compounds selected from at least one of the following compounds represented by formulae 1 to 3:
and
the compound has excellent bacteriostatic effect, especially has obvious inhibitory effect on staphylococcus aureus, and can be used for preparing bacteriostatic agents.
It should be noted that the benzofuran compound provided in the examples of the present invention is extracted from elsholtzia, and particularly, is separated from the nonvolatile fraction of elsholtzia, but it is understood that the benzofuran compound extracted from other natural materials containing the benzofuran compound is also within the scope of the present invention.
The embodiment of the invention provides a preparation method of benzofuran, which comprises the following steps:
firstly, preparing a herba elsholtziae extract;
the preparation method comprises the following steps of extracting herba elsholtziae, specifically, performing supercritical extraction on the herba elsholtziae, specifically, preparing herba elsholtziae extract by using the supercritical extraction, wherein the supercritical extraction comprises the following operations: weighing an appropriate amount of herba Moslae, pulverizing, placing in a supercritical extraction kettle, starting heating devices of the extraction kettle and the separation kettle, and starting a compression pump after the temperature reaches a set temperature; circularly extracting at a C02 flow rate of 20-30kg/h (e.g. at any value between 20-30kg/h such as 20kg/h, 25kg/h and 30 kg/h) at an extraction kettle pressure of 12-15.0MPa (e.g. at any value between 12-15MPa such as 12MPa, 13MPa, 14MPa and 15 MPa), a temperature of 45-50 ℃ (e.g. at any value between 45-50 ℃ such as 45 ℃, 47 ℃ and 50 ℃); the pressure and temperature of the separation vessel I are respectively 9-10.0MPa (e.g. any value between 9-10MPa such as 9MPa, 9.5MPa and 10 MPa) and 35-40 deg.C (e.g. any value between 35-40 deg.C such as 35 deg.C, 36 deg.C, 37 deg.C, 38 deg.C, 39 deg.C and 40 deg.C); the pressure and temperature of the separation vessel II are 6-8.0MPa (e.g., 6MPa, 7MPa, or any value between 6-8MPa such as 8 MPa) and 25-30 deg.C (e.g., 25 deg.C, 26 deg.C, 27 deg.C, 28 deg.C, 29 deg.C, or any value between 25-30 deg.C such as 30 deg.C), respectively; the extraction is circulated for 2 to 3 hours (e.g., any value between 2 and 3 hours such as 2 hours, 2.5 hours, and 3 hours).
Note that supercritical CO is used 2 The extraction is only one extraction method provided by the embodiment of the invention, and it is understood that other extraction methods can be adopted to extract the elsholtzia extract containing the benzofuran compound, and other extraction methods can be adoptedIs prepared through decoction, percolation, immersion and other steps. It is understood that the elsholtzia extract can also be purchased directly.
Secondly, preparing a non-volatile extract of elsholtzia;
the elsholtzia extract is extracted, specifically, the elsholtzia extract and petroleum ether are mixed and dispersed to form a suspension, then the suspension is poured into a separating funnel, an alcohol-water solvent such as a methanol water solution (the concentration of the methanol water solution is 8-12%, such as any value between 8-12% such as 8%, 9%, 10%, 11% and 12%) is added, then the uniform mixing is carried out, standing extraction is carried out, extraction is carried out for 5 times, and the methanol water part is recovered, so that the volatile-free extract of the elsholtzia is obtained.
Thirdly, preparing benzofuran compounds;
separating the elsholtzia non-volatile matter extract by using a normal phase silica gel column of 200 meshes to 300 meshes, and performing gradient elution on the elsholtzia non-volatile matter extract by using an ether solvent-ester solvent, specifically performing gradient elution on the elsholtzia non-volatile matter extract by using petroleum ether-ethyl acetate; wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate is 100:0 to 0:100. TCL plates were tested and the same components were combined to give four components: sxr1-1 to sxr1-4, and separating into compounds shown in formulas 1-to 3 by HPLC.
Staphylococcus aureus can cause a range of diseases, from superficial skin infections to severe pneumonia. Numerous studies have shown that many bioactive compounds extracted from traditional herbs have significant antibacterial activity and have been widely used as alternative drugs for treating infectious diseases. Herbs can produce a variety of secondary metabolites to combat microbial invasion into the environment. Currently, many small molecule compounds extracted from Chinese herbs have been shown to be effective in inhibiting bacteria. Therefore, searching for monomeric compounds from Chinese medicinal materials is a feasible source of antibacterial compounds. Accordingly, embodiments of the present invention also provide the use of the above benzofuran compound, which can inhibit bacteria, particularly gram positive bacteria such as staphylococcus aureus, and thus can be used for preparing bacteriostatic agents.
Further, the embodiment of the invention also provides a bacteriostatic agent which comprises any one of the compounds shown in the formulas 1 to 3. The bacteriostatic agent can also comprise other bacteriostatic agents with bacteriostatic effects, or synergists capable of improving the bacteriostatic effects of the compounds shown in the formulas 1 to 3, or other conventional auxiliary materials, such as a lubricant, a thickening agent, a disintegrating agent and the like.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
The embodiment of the invention provides 3 benzofuran compounds, the structural formulas of which are respectively shown as follows:
This example also provides a method for preparing the benzofuran compound, comprising:
the first step is to prepare the elsholtzia extract
Weighing an appropriate amount of herba Moslae, pulverizing, placing in a supercritical extraction kettle, starting heating devices of the extraction kettle and the separation kettle, and starting a compression pump after a set temperature is reached; the pressure of the extraction kettle is kept at 12MPa, the temperature is 45 ℃, and 20kg/h of CO is used 2 Flow rate circulation extraction; the pressure and the temperature of the separation kettle I are respectively 9MPa and 40 ℃; the pressure and the temperature of the separation kettle II are respectively 7MPa and 30 ℃; the extraction was circulated for 2 hours.
Step two, preparing the extract of the non-volatile substance of the elsholtzia splendens
Taking 3Kg of the elsholtzia chinensis extract, adding 1.5L of petroleum ether for dispersion, then pouring the suspension into a 5L separating funnel, adding 1.5L of 10% methanol aqueous solution, plugging a plug of the separating funnel, carefully mixing, standing for extraction, extracting for five times, and recovering 10% methanol-water part to obtain 18.19g of elsholtzia chinensis nonvolatile extract.
Third step, separation
Taking 18g of the elsholtzia splendens volatile-free extract, separating by using a normal phase silica gel column of 200 meshes to 300 meshes, and carrying out gradient elution by using petroleum ether-ethyl acetate, wherein the ratio of petroleum ether to ethyl acetate is 100:0,90: 10, 80:20, 70:30, 60:40,50:50,40:60,30:70,20, 80,10, 90 and 0,5 column volumes are washed in each ratio, fractions are collected every 100mL of eluate, tested with TLC plates, the same fractions are combined, and the same components are combined to give four components: sxr1-1 to sxr1-4, and separating into compound 1, compound 2 and compound 3 by HPLC.
The benzofuran compound obtained above was characterized as follows:
and carrying out nuclear magnetic detection and mass spectrum detection on the 3 benzofuran compounds.
Conformational analysis
Conformational analysis was performed in a Yin Yang cloud platform (https:// close. Yinfotek. Com /) using Confab's system algorithm in MMFF94 force field with RMSD threshold of 0.2 ° and energy window of 50kcal/mol.
Nuclear magnetic resonance calculations were performed using gaussian 0914 for theoretical calculations. First, all conformations were optimized at PM 6. The room temperature equilibrium population was calculated according to the Boltzmann law of distribution, on the basis of which the predominant conformation of the population was maintained over 1%. The selected conformation is further optimized using HF/6-31G (d) and B3LYP/6-31G (d). The vibration frequency analysis confirmed the structural stability. IEFPCM model simulation calculations were performed in the corresponding solvents, calculated using the quantification of atomic orbitals (GIAO) method at mPW1PW91/6-311+ G (2d, p) levels. TMS corrected NMR chemical shift values were averaged over the Boltzmann distribution and fitted to the experimental values by linear regression. To confirm the conclusion of the NMR calculation, DP4+ analysis was also performed.
ECD calculation: this structure was derived from previous NMR calculations using time dependent density functional theory (TD-DFT) and IEFPCM models, ECD calculations were performed at B3LYP/6-311G (d, p) levels in the corresponding solvents.
The above characterization results are shown in FIGS. 1 to 38 and tables 1 to 2.
TABLE 1 preparation of Compounds 1 and 2 1 H NMR and 13 c NMR data (500 MHz)
TABLE 2 preparation of Compound 3 1 H NMR and 13 c NMR data (500 MHz) solvent: deuterated chloroform
According to the above characterization results, compound 1 was a pale yellow oil. The molecular formula is C 16 H 20 O 6 M/z, determined from HR-ESI-MS data: 331.1149[ M ] +Na] + (calcd 331.1113), indicating seven unsaturations. The structure contains a penta-substituted benzene ring and three methyl (including a methoxy) signals [ δ C70.62 (d), 104, 34 (d), 65.29 (d)]. According to which 13 C-NMR (125MHz, methyl-d 4) and Dept spectra, the structure contains three signals of oxymethylene, two signals of methylene [ delta C71.45 (t), 32.06 (t)]And three methyl signals [ Delta C25.11 (q), 25.21 (q), 56.72 (q)]Indicating that the structure of 2 contains one oxiheptane ring. Comparing the nmr data of compound 1 and compound 2, it can be concluded that both compound 1 and compound 2 have an oxygen-containing cycloheptane attached to the benzene ring, which is mainly different from the furan ring attached to the benzene ring. According to the HMBC spectrum, H-2 is associated with C-15 and C-16, indicating that the isopropanol structure is linked to the furan ring. HMBC showed strong associations between C-8 and H-10, and between H-8 and C-10, indicating that dehydration between C-8 and C-10 forms an oxygen bridge. These data may infer the structure shown in fig. 1. The possible structures were calculated by NMR and ECD based on the chemical shift and the specific oxygen bridge structure of Compound 1. Finally, by comparing the ECD and the results, it is suggested to perform the conversionThe structure of Compound 1 was defined as (2S, 8S,10R, and 11R).
In vitro bacteriostasis test: a96-well plate microdilution method was used. First, a sterile 96-well plate (100. Mu.L/well) was added at a concentration of 1X 10 6 CFU of bacterial suspension of Staphylococcus aureus, 100. Mu.L of drug (compounds 1-3) dissolved in NB medium was added to the first well, mixed, 100. Mu.L was added to the second well, diluted sequentially to the ninth well, and 100. Mu.L of waste material was aspirated from the ninth well. The tenth well served as a positive control for drug-free bacterial solution, and the eleventh well served only as a negative control for NB medium. The positive control drug treatment method is the same. After mixing, the mixture was incubated in a biochemical incubator at 37 ℃ for 24 hours. OD600 values were measured.
The results are shown in the following table, in which + represents an inhibition ratio of 50% or more and-represents less than 50%.
According to the table, the compounds 1 to 3 show good antibacterial effect and can inhibit the growth of staphylococcus aureus at the concentration of 125-500 mug/mL, wherein the compound 3 can still inhibit the growth of staphylococcus aureus at low concentration.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A benzofuran compound characterized by being at least one compound selected from the group consisting of compounds represented by the following formulae 1 to 3:
2. a process for producing a benzofuran compound according to claim 1, comprising: and (3) separating the elsholtzia non-volatile matter extract to form the benzofuran compound.
3. The method of claim 2, wherein the step of separating comprises: carrying out gradient elution on the elsholtzia non-volatile matter extract by using an ether solvent-ester solvent;
preferably, the step of separating comprises: performing gradient elution on the elsholtzia splendens non-volatile matter extract by using petroleum ether-ethyl acetate;
preferably, the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate is 100: 100.
4. the method according to claim 2, wherein the step of preparing the elsholtzia non-volatile extract comprises: and (4) extracting the elsholtzia extract.
5. The method of claim 4, wherein the step of extracting comprises: mixing the elsholtzia extract, an ether solvent and an alcohol-water solvent, and then separating and collecting an alcohol-water part substance;
preferably, the step of extracting comprises: mixing and dispersing the elsholtzia extract and petroleum ether, mixing and standing with a methanol water solution, and recovering a methanol water part;
preferably, the concentration of the aqueous methanol solution is 8-12%.
6. The method according to claim 4, wherein the step of preparing the Elsholtzia splendens extract comprises: performing supercritical extraction on herba Moslae.
7. The method of claim 6, wherein the supercritical extraction conditions comprise: the pressure of the extraction kettle is kept between 12 and 15.0MPa, the temperature is between 45 and 50 ℃, and 20 to 30kg/h of CO 2 Flow rate circulation extraction; the pressure and the temperature of the separation kettle I are respectively 9-10.0MPa and 35-40 ℃; the pressure and the temperature of the separation kettle II are respectively 6-8.0MPa and 25-30 ℃; and circulating extraction for 2-3 hours.
8. Use of the benzofuran compound of claim 1 in the preparation of an antibacterial agent.
9. An antibacterial agent characterized by comprising the benzofuran compound according to claim 1.
10. The antimicrobial agent according to claim 9, wherein the bacteria inhibited by the agent comprise gram positive cocci, preferably staphylococcus aureus.
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