CN115772173B - 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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- CN115772173B CN115772173B CN202211640011.7A CN202211640011A CN115772173B CN 115772173 B CN115772173 B CN 115772173B CN 202211640011 A CN202211640011 A CN 202211640011A CN 115772173 B CN115772173 B CN 115772173B
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- -1 Benzofuran compound Chemical class 0.000 title claims abstract description 24
- IANQTJSKSUMEQM-UHFFFAOYSA-N benzofuran Natural products C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 26
- 241000131458 Elsholtzia Species 0.000 claims description 23
- 238000000605 extraction Methods 0.000 claims description 21
- 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
- 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
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000004599 antimicrobial 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
- 238000010828 elution Methods 0.000 claims 1
- 150000001907 coumarones Chemical class 0.000 abstract description 12
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 7
- 229930014626 natural product Natural products 0.000 abstract description 2
- 229940125782 compound 2 Drugs 0.000 description 20
- 238000001228 spectrum Methods 0.000 description 20
- 229940125904 compound 1 Drugs 0.000 description 19
- 229940126214 compound 3 Drugs 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 238000004364 calculation method Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 238000005100 correlation spectroscopy Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000000022 bacteriostatic agent Substances 0.000 description 4
- 238000002072 distortionless enhancement with polarization transfer spectrum Methods 0.000 description 4
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 239000000341 volatile oil Substances 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000001142 circular dichroism spectrum Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 125000005704 oxymethylene group Chemical group [H]C([H])([*:2])O[*:1] 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000002211 ultraviolet spectrum Methods 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 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
- 206010019345 Heat stroke Diseases 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 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
- 241000046198 Triteleia hyacinthina Species 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000003385 bacteriostatic 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
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 241000411851 herbal medicine Species 0.000 description 2
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 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
- 238000012986 modification Methods 0.000 description 2
- 201000009240 nasopharyngitis Diseases 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 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
- 239000013641 positive control Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 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
- YKFLAYDHMOASIY-UHFFFAOYSA-N γ-terpinene Chemical compound CC(C)C1=CCC(C)=CC1 YKFLAYDHMOASIY-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010063659 Aversion Diseases 0.000 description 1
- 241001649247 Boehmeria Species 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 238000003775 Density Functional Theory Methods 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 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
- 208000003251 Pruritus 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
- 206010047700 Vomiting Diseases 0.000 description 1
- 208000012873 acute gastroenteritis Diseases 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000004774 atomic orbital Methods 0.000 description 1
- 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
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000032770 biofilm formation Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000004422 calculation algorithm Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002212 electronic circular dichroism spectrum Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229940124600 folk medicine Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 238000005325 percolation Methods 0.000 description 1
- 238000013139 quantization Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 208000026425 severe pneumonia Diseases 0.000 description 1
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- 206010040872 skin infection Diseases 0.000 description 1
- 239000012747 synergistic agent Substances 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 229940126680 traditional chinese medicines Drugs 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention relates to the technical field of natural compounds, in particular to benzofuran compounds, a preparation method and application thereof, and an antibacterial agent. The benzofuran compound is at least one compound selected from the compounds shown in the following formulas 1 to 3:a formula 1,2, and the method comprisesFormula 3. The non-volatile part is prepared, has good antibacterial effect, further enriches the types of compounds extracted from the herba elsholtziae, and further expands the selection types of antibacterial agents.
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 genus Boehmeria of family Labiatae. And standing the herb. The stem is 9-40 cm high, slender, multi-branched from the base, or short and small without branching, and is white and soft. She Xianzhuang from oblong to linear. Distributed in north Vietnam and China; in China, the regions of Shandong, jiangsu, zhejiang, anhui, jiangxi, hunan, hubei, guizhou, sichuan, guangxi, guangdong, fujian and Taiwan. Growing on a grass slope or under a forest at an elevation of up to 1400 meters.
The stem and leaf are picked in sunny days in summer and autumn and the fruit is ripe, the stem and leaf are taken as part of the land to be eaten, and the stem and leaf are decocted together with white hyacinth bean or white hyacinth bean flower to be eaten together in China for avoiding heatstroke. Herba Moslae is also used for tea brewing and drinking in summer to prevent common cold. Herba Moslae also has certain medicinal effects, and Chinese country Wei Jianwei defines herba Moslae as a medicinal and edible substance (i.e. food and Chinese medicinal material substance) since 2012. Chinese folk medicine is used as medicine for treating heatstroke, common cold, aversion to cold, stomach ache, emesis, acute gastroenteritis, dysentery, traumatic blood stasis and pain, edema of lower limbs, edema of face, dyspepsia, skin eczema, pruritus and multiple furuncle, and is also an essential medicine for treating venomous snake bite.
Modern pharmacological studies show that the herba elsholtziae has biological activities such as antibiosis, antivirus and the like, the main pharmacological active component of the herba elsholtziae is generally considered to be volatile component-essential oil, and the research on the chemical component and the pharmacological activity of the herba elsholtziae is based on the research at present. The essential oil of herba Moslae contains carvacrol, p-cymene, muscophenol acetate, thymol and gamma-terpinene as main components. The herba Moslae essential oil can strongly inhibit biofilm formation of Staphylococcus aureus. In addition, petroselinic alcohol is a potential alternative therapy for the treatment of excessive immune responses induced by influenza a virus infection, and the cold-resistant effect of elsholtzia may depend on the antiviral effect of carvacrol. The herba Moslae essential oil can also play a therapeutic role in IVA infected mice, inhibit IVA replication and inflammatory mediators, and promote antioxidant capacity.
It can be seen that the research on the herba Moslae is basically focused on its volatile components, while the experimental research on the non-volatile part of herba Moslae is very little.
In view of this, the present invention has been made.
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 the non-volatile part of the elsholtzia, has good antibacterial effect, further enriches the types of compounds extracted from the elsholtzia, and further amplifies the selection types of antibacterial agents.
The invention is realized in the following way:
in a first aspect, the present invention provides a benzofuran compound selected from at least one of compounds represented by the following formulas 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: separating the non-volatile extract of herba Moslae to form the benzofuran compound.
In an alternative embodiment, the step of separating comprises: gradient eluting the herba Moslae non-volatile extract with ether solvent-ester solvent;
preferably, the step of separating comprises: gradient eluting the herba Moslae non-volatile extract with petroleum ether-ethyl acetate;
preferably, the volume ratio of petroleum ether to ethyl acetate in petroleum ether-ethyl acetate is 100:0-0: 100.
in an alternative embodiment, the preparation method of the elsholtzia non-volatile extract comprises the following steps: extracting herba Moslae extract.
In an alternative embodiment, the step of extracting comprises: mixing the herba Moslae extract, ether solvent and alcohol-water solvent, and separating and collecting alcohol-water part;
preferably, the step of extracting comprises: mixing and dispersing the elsholtzia extract and petroleum ether, then mixing and standing with a methanol water solution, and then recovering a methanol water part;
preferably, the concentration of the aqueous methanol solution is 8-12%.
In an alternative embodiment, the preparation method of the elsholtzia extract comprises the following steps: and (3) performing supercritical extraction on the elsholtzia.
In an alternative embodiment, the conditions of supercritical extraction include: the pressure of the extraction kettle is kept between 12 and 15.0MPa, the temperature is between 45 and 50 ℃ and the CO content is between 20 and 30kg/h 2 Circulating extraction at a flow rate; 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 circularly extracting for 2-3 hours.
In a third aspect, the present invention provides an application of the benzofuran compounds according to the previous embodiments in preparation of antibacterial agents.
In a fourth aspect, the present invention provides an antimicrobial agent comprising the benzofuran compounds of the previous embodiments.
In an alternative embodiment, the bacteria inhibited by the antimicrobial agent comprise gram positive cocci, 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, in particular to a benzofuran compound with an obvious antibacterial effect on staphylococcus aureus. The compound is separated from the non-volatile component of the elsholtzia, so that the type of the compound for the non-volatile component of the elsholtzia is further amplified, and the selection type of the antibacterial agent is also further amplified.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the embodiments will be briefly described below, it being understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a two-dimensional nuclear magnetic spectrum of compounds 1-3 provided in an example of the present invention;
FIG. 2 is a graph of the ECD calculation results for compounds 1-3 provided in the examples of the present invention (compounds 1-3, respectively, from left to right);
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the compound 1 provided in the embodiment of the present invention;
FIG. 4 is a nuclear magnetic resonance spectrum of the compound 1 according to the embodiment of the present invention;
FIG. 5 is a DEPT spectrum of compound 1 provided in the examples of the present invention;
FIG. 6 is a DEPT90 spectrum of compound 1 provided in the examples of the present invention;
FIG. 7 is a DEPT135 spectrum of compound 1 provided in the examples of the present invention;
FIG. 8 is a HSQC spectrum of Compound 1 provided in the examples of the present invention;
fig. 9 is an HMBC spectrum of compound 1 provided in the example of the present invention;
FIG. 10 is a COSY spectrum of Compound 1 provided in the examples of the present invention;
FIG. 11 is a NOESY spectrum of Compound 1 provided in the examples of the present invention;
FIG. 12 is a HRESIMS pattern of Compound 1 provided in the examples of the present invention;
FIG. 13 is a CD spectrum of Compound 1 provided in the examples of the present invention;
FIG. 14 is a UV spectrum of Compound 1 provided in the examples of the present invention;
FIG. 15 is a nuclear magnetic resonance hydrogen spectrum of compound 2 according to the example of the present invention;
FIG. 16 is a nuclear magnetic resonance spectrum of compound 2 according to the embodiment of the present invention;
FIG. 17 is a DEPT spectrum of Compound 2 provided in the examples 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 by an example of the present invention;
FIG. 20 is a HSQC spectrum of Compound 2 provided in the example of the present invention;
FIG. 21 is a HMBC spectrum of Compound 2 provided in the examples of the present invention;
FIG. 22 is a COSY spectrum of Compound 2 provided in the examples of the present invention;
FIG. 23 is a NOESY spectrum of Compound 2 provided in the example of the present invention;
FIG. 24 is a HRESIMS pattern of Compound 2 provided in the examples of the present invention;
FIG. 25 is a CD spectrum of Compound 2 provided in the examples of the present invention;
FIG. 26 is a UV spectrum of Compound 2 provided in the examples of the present invention;
FIG. 27 is a nuclear magnetic resonance hydrogen spectrum of compound 3 according to the example of the present invention;
FIG. 28 is a nuclear magnetic resonance spectrum of compound 3 according to the embodiment of the present invention;
FIG. 29 is a DEPT spectrum of Compound 3 provided in the 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 the present example;
FIG. 32 is a HSQC spectrum of Compound 3 provided in the example of the present invention;
FIG. 33 is a HMBC spectrum of Compound 3 provided in the examples of the present invention;
FIG. 34 is a COSY spectrum of Compound 3 provided in the example of the present invention;
FIG. 35 is a NOESY spectrum of Compound 3 provided in the example of the present invention;
FIG. 36 is a HRESIMS pattern of Compound 3 provided in the examples of the present invention;
FIG. 37 is a CD spectrum of Compound 3 provided in the example of the present invention;
fig. 38 is a UV spectrum of compound 3 provided in the example of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The embodiment of the invention provides a benzofuran compound, which is at least one compound selected from the following compounds shown in formulas 1 to 3:
and
The compound has excellent antibacterial effect, particularly has remarkable inhibitory effect on staphylococcus aureus, and can be used for preparing antibacterial agents.
It should be noted that the benzofuran compounds provided in the embodiments of the present invention are extracted from herba elsholtziae, especially separated from non-volatile components of herba elsholtziae, which is merely exemplary, and it is understood that the benzofuran compounds extracted from other natural materials containing the benzofuran compounds are also within the scope of the embodiments of the present invention.
The embodiment of the invention provides a preparation method of the benzofuran, which comprises the following steps:
first, preparing herba Moslae extract;
extracting herba Moslae, specifically, performing supercritical extraction on herba Moslae, specifically, preparing herba Moslae extract by supercritical extraction, wherein the supercritical extraction comprises the following steps: weighing proper amount of herba Moslae, pulverizing, placing in supercritical extraction kettle, starting heating device of extraction kettle and separation kettle, and opening compression pump after reaching set temperature; maintaining the pressure of the extraction kettle at 12-15.0MPa (for example, any value between 12-15MPa such as 12MPa, 13MPa, 14MPa, 15MPa, etc.), and circularly extracting at a C02 flow rate of 20-30kg/h (for example, any value between 20-30kg/h such as 20kg/h, 25kg/h, 30kg/h, etc.) at a temperature of 45-50deg.C (for example, any value between 45 deg.C, 47 deg.C, 50 deg.C, etc.); the pressure and temperature of the separation kettle I are respectively 9-10.0MPa (for example, any value between 9-10MPa such as 9MPa, 9.5MPa, 10MPa and the like) and 35-40 ℃ (for example, any value between 35-40 ℃ such as 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃ and 40 ℃); the pressure and temperature of the separation kettle II are respectively 6-8.0 (for example, any value between 6-8MPa such as 6MPa, 7MPa, 8MPa and the like) MPa and 25-30 ℃ (for example, any value between 25 ℃ C., 26 ℃ C., 27 ℃ C., 28 ℃ C., 29 ℃ C., 30 ℃ C., and the like) 25-30 ℃; the extraction is cycled for 2-3 hours (e.g., anywhere between 2-3 hours such as 2 hours, 2.5 hours, and 3 hours).
The supercritical CO is adopted 2 The extraction is only one extraction method provided by the embodiment of the invention, and it can be understood that other extraction methods can be adopted to extract the elsholtzia extract containing the benzofuran compounds, and other extraction methods can be decoction extraction, percolation extraction, immersion extraction and the like. It will be appreciated that the elsholtzia extract may also be purchased directly.
Secondly, preparing a non-volatile extract of the elsholtzia;
extracting the elsholtzia extract, specifically, mixing and dispersing the elsholtzia extract and petroleum ether to form a suspension, then pouring the suspension into a separating funnel, adding an alcohol-water solvent such as a methanol water solution (the concentration of the methanol water solution is 8-12%, for example, any value between 8-12% such as 8%, 9%, 10%, 11%, 12% and the like), uniformly mixing, standing for extraction, extracting for 5 times, and recovering a methanol water part to obtain the elsholtzia non-volatile extract.
Thirdly, preparing a benzofuran compound;
separating the above herba Moslae non-volatile extract with 200-300 mesh normal phase silica gel column, gradient eluting with ether solvent-ester solvent, and specifically gradient eluting with petroleum ether-ethyl acetate; wherein the volume ratio of petroleum ether to ethyl acetate in 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 are separated into compounds represented by formulas 1-3 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 herbal medicine have remarkable antibacterial activity and have been widely used as alternative drugs for treating infectious diseases. The herbs can produce a variety of secondary metabolites to resist invasion by microorganisms in the environment. At present, many small molecule compounds extracted from Chinese herbal medicine have been demonstrated to be effective in inhibiting bacteria. Therefore, finding monomeric compounds from traditional Chinese medicines is a viable source of antimicrobial compounds. Therefore, the embodiment of the invention also provides application of the benzofuran compound, and the benzofuran compound can inhibit bacteria, especially gram-positive bacteria such as staphylococcus aureus, so that the benzofuran compound can be used for preparing a bacteriostatic agent.
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 effect, or synergistic agents capable of improving the bacteriostatic effect of the compounds shown in the formulas 1 to 3, or other auxiliary materials such as lubricants, thickeners, disintegrating agents and the like.
The features and capabilities of the present invention are described in further detail below in connection with the examples.
Example 1
The embodiment of the invention provides 3 benzofuran compounds, the structural formulas of which are respectively shown as follows:
formula 1 (hereinafter referred to as compound 1), -, and->Formula 2 (hereinafter referred to as Compound 2) and +.>Formula 3 (hereinafter referred to as compound 3).
The embodiment also provides a preparation method of the benzofuran compound, which comprises the following steps:
first, preparing herba Moslae extract
Weighing proper amount of herba Moslae, pulverizing, placing in supercritical extraction kettle, starting heating device of extraction kettle and separation kettle, and opening compression pump after reaching set temperature; the pressure of the extraction kettle is kept at 12MPa, the temperature is 45 ℃, and the CO is 20kg/h 2 Circulating extraction at a flow rate; 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 cycled for 2 hours.
Second step, preparing the non-volatile extract of herba Moslae
3Kg of the elsholtzia extract is taken, 1.5L of petroleum ether is added for dispersion, then the suspension is poured into a 5L separating funnel, 1.5L of 10% methanol aqueous solution is added, a plug of the separating funnel is plugged, the mixture is carefully mixed uniformly, the mixture is subjected to standing extraction for five times, and 10% methanol-water part is recovered, so that 18.19g of elsholtzia non-volatile extract is obtained.
Third step, separation
18g of the non-volatile extract of the elsholtzia chinensis is taken, separated by a normal phase silica gel column with 200 meshes to 300 meshes, and eluted by a petroleum ether-ethyl acetate gradient, wherein the petroleum ether is 100 percent compared with the ethyl acetate: 0,90: 10, 80:20, 70:30, 60:40,50:50,40:60,30:70,20:80,10:90 and 0:100, 5 column volumes were washed per ratio, fractions were collected every 100mL of eluent, tested on TLC plates, identical fractions were combined, identical components were combined to give four components: sxr1-1 to sxr1-4 are separated into compound 1, compound 2 and compound 3 by HPLC.
The benzofuran compounds obtained above were characterized as follows:
and carrying out nuclear magnetism detection and mass spectrum detection on the 3 benzofuran compounds.
Conformational analysis
Conformational analysis was performed in a Yan Fuyun platform (https:// closed. Yinfotek. Com /) using the systematic algorithm of Confab in the MMFF94 force field, with an RMSD threshold of 0.2℃and an energy window of 50kcal/mol.
Nuclear magnetic resonance calculations, theoretical calculations were performed using gaussian 0914. First, all conformations were optimized at PM 6. The room temperature equilibrium population was calculated according to Boltzmann's law of distribution, on the basis of which the main conformation of the population was maintained to be more than 1%. The selected conformations were further optimized using HF/6-31G (d) and B3LYP/6-31G (d). Vibration frequency analysis confirmed structural stability. IEFPCM model simulation calculations were performed in the corresponding solvents, calculated using a quantization (GIAO) method including atomic orbitals at mPW PW91/6-311+g (2 d, p) level. The TMS corrected NMR chemical shift values were averaged over Boltzmann distributions and fitted to the experimental values by linear regression. To confirm the conclusion of the NMR calculation, a dp4+ analysis was also performed.
ECD calculation: this structure was derived from previous NMR calculations and ECD calculations were performed using the time dependent Density functional theory (TD-DFT) using the IEFPCM model at the B3LYP/6-311G (d, p) level in the corresponding solvent.
The results of the above characterization are shown in FIGS. 1-38 and tables 1-2.
Table 1 compounds 1 and 2 1 H NMR 13 C NMR data (500 MHz)
TABLE 2 Compound 3 1 H NMR 13 C NMR data (500 MHz) solvent: deuterated chloroform
From the above characterization results, compound 1 was pale yellowA coloured oil. Its molecular formula is C 16 H 20 O 6 From HR-ESI-MS data, m/z:331.1149[ M+Na ]] + (calcd 331.1113) indicating seven unsaturations. The structure contains a pentasubstituted benzene ring and three methyl (including a methoxy) signals [ delta C70.62 (d), 104, 34 (d), 65.29 (d)]. According to it 13 C-NMR (125 MHz, methyl-d 4) and Dept spectra, the structure containing three oxymethylene signals, two methylene signals [ δC71.45 (t), 32.06 (t)]And three methyl signals [ δC25.11 (q), 25.21 (q), 56.72 (q)]The structure of 2 is shown to contain an oxyheptane ring. Comparing the nuclear magnetic resonance data of compound 1 and compound 2, it can be deduced that both compound 1 and compound 2 have an oxygenated cycloheptane attached to a benzene ring, which is mainly different from the furan ring attached to the benzene ring. According to HMBC spectra, H-2 is associated with C-15 and C-16, indicating that the isopropanol structure is attached to the furan ring. HMBC shows a strong correlation between C-8 and H-10, H-8 and C-10, indicating that dehydration between C-8 and C-10 forms an oxygen bridge. These data can infer the structure shown in fig. 1. Based on the chemical shift and the specific oxygen bridge structure of compound 1, the possible structures were calculated by NMR and ECD. Finally, by comparing the ECD with the results, it is suggested to determine the structure of Compound 1 as (2S, 8S,10R, 11R).
Compound 2 was a pale yellow oil. According to HR-ESI-MS data, its molecular formula is C 13 H 14 O 5 ，m/z：251.0915[M+H] + (calcd 251.0919) indicating seven unsaturations. According to 1 H-NMR (500 MHz, chloroform-d) spectrum, compound 2 comprising a pentasubstituted benzene ring structure [ delta H6.89 (1H, s)]An olefin signal [ delta H6.69 (1H, d, J=2.5 Hz), 7.57 (1H, d, J=2.5 Hz)]And a methoxy signal [3.86 (3H, s)]. According to 13 C-NMR (125 MHz, chloroform-d) spectrum and Dept spectrum, the structure of the compound contained two oxymethylenes [ δC100.05 (d), 69.85 (d)]Two methylene groups and one methoxy group. These data can be inferred to the structure shown in fig. 2. The nuclear magnetic resonance data of 2- (8R, 10R) and 2- (8R, 10S) were calculated by TDDFT. The results show that 2- (8R, 10R) is suitable for compound 2. To determine the absolute of Compound 2The calculated ECD spectra of the corresponding isomers 2 (8R, 10R) and ent (8S, 10S) were compared with the experimental spectra for the configuration. The calculated (8R, 10R) ECD was very consistent with the experimental curve. Therefore, it is suggested that the absolute configuration of compound 2 should be (8 r,10 r).
Compound 3 was a yellow oil. Its molecular formula is C 13 H 12 O 4 According to HR-ESI-MS data, the molecular formula is determined as m/z:233.0814[ M+H ]] + (calcd 233.0808) indicated 8 unsaturations. It is provided with 1 The H NMR spectrum comprises an unsubstituted phenyl group (δh 6.93,1H, s), two CIS-coupled olefinic protons (δh 6.69,1H, d, j=2.0 Hz;7.55,1H, d, j=2.0 Hz;6.12,1H, d, j=6.0 Hz;6.50,1H, d, j=6.0 Hz), and a methoxy group (δh 3.85,1H, s). 13 C nuclear magnetic resonance spectra show signals of 13 carbon atoms which are classified as five quaternary carbon atoms on the phenyl group (δC145.29, s;116.57, s;126.78, s;150.14, s;111.40, s), four carbons on the double bond (δC145.43, d;107.23, d;142.11, d;101.75, d), one methylene group (δ0C72.24, d), one oxymethylene group (δ1C62.99, t), and one methoxy group (δ2C56.14, q). According to these data, the structure contains a benzodifuran ring. HMBC showed that δ3h6.93 was related to δ4c107.23, δ5c116.57, δ6c145.26, δ7h6.69 was related to δ8c145.26. This also confirms the presence of the benzodifuran ring. The correlation between δ9h3.79, δh3.871 and δc74.24 suggests that methoxy and methylene are attached to the same carbon. COSY shows that δh7.55 and δh6.69 on the double bond are related. COSY shows that δh5.73 and δh4.18 on the double bond are related, and δh5.73 and δh4.18 are also related. Based on the above data, the structure of compound 3 was determined to be represented by formula 3. The absolute configuration was calculated using ECD. The absolute configuration of proposal 3 should be (11S).
In vitro bacteriostasis test: a96-well plate microdilution method is adopted. First, a sterile 96-well plate (100. Mu.L/well) was added at a concentration of 1X 10 6 Bacterial suspension of CFU staphylococcus aureus 100 μl of drug (compounds 1-3) dissolved in NB medium was added to the first well, mixed well, then 100 μl was added to the second well, diluted sequentially to the ninth well, 100 μl was aspirated from the ninth well, and 100 μl of reject was collected. First, theTen wells served as positive controls for the drug-free bacterial solution and the eleventh served only as negative controls for NB medium. The treatment method of the positive control drug is the same. After mixing, the mixture was cultured in a biochemical incubator at 37℃for 24 hours. OD600 values were measured.
The results are shown in the following table, wherein +represents an inhibition of 50% or more and-represents less than 50%.
From the above table, it is found that compounds 1 to 3 show good antibacterial effect at a concentration of 125. Mu.g/mL to 500. Mu.g/mL, and inhibit the growth of Staphylococcus aureus, wherein compound 3 can still inhibit the growth of Staphylococcus aureus at a low concentration.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. 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 selected from any one of compounds represented by the following formulas 1 to 3:
1, & gt>2 +.>Formula 3.
2. A process for the preparation of the benzofuran compound as claimed in claim 1, comprising: separating the non-volatile extract of herba Moslae to form the benzofuran compound;
the separating step comprises: gradient eluting the herba Moslae non-volatile extract with ether solvent-ester solvent;
the preparation method of the elsholtzia non-volatile extract comprises the following steps: extracting herba Moslae extract;
the extraction steps include: mixing the herba Moslae extract, ether solvent and alcohol-water solvent, and separating and collecting alcohol-water part;
the preparation method of the elsholtzia extract comprises the following steps: carrying out supercritical extraction on the elsholtzia;
the conditions of supercritical extraction include: the pressure of the extraction kettle is kept between 12 and 15.0MPa, the temperature is between 45 and 50 ℃ and the CO content is between 20 and 30kg/h 2 Circulating extraction at a flow rate; 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 circularly extracting for 2-3 hours.
3. The method of preparing as claimed in claim 2, wherein the step of separating comprises: and (3) carrying out gradient elution on the elsholtzia non-volatile extract by using petroleum ether-ethyl acetate.
4. The preparation method of claim 3, wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate is 100:0-0: 100.
5. the method of claim 2, wherein the step of extracting comprises: mixing and dispersing the elsholtzia extract and petroleum ether, then mixing and standing with a methanol water solution, and then recovering a methanol water part.
6. The process according to claim 5, wherein the concentration of the aqueous methanol solution is 8 to 12%.
7. Use of a benzofuran compound as claimed in claim 1 for the preparation of an antibacterial agent.
8. An antibacterial agent comprising the benzofuran compound according to claim 1.
9. The antimicrobial agent of claim 8, wherein the bacteria inhibited by the antimicrobial agent comprises gram-positive cocci.
10. The antimicrobial agent of claim 8, wherein the bacteria inhibited by the antimicrobial agent is staphylococcus aureus.
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| WO2016131098A1 (en) * | 2015-02-16 | 2016-08-25 | The University Of Queensland | Sulfonylureas and related compounds and use of same |
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| CN110003153A (en) * | 2019-03-07 | 2019-07-12 | 宁波大学 | A kind of benzofuran compounds and its preparation method and application |
| CN111303094A (en) * | 2020-04-08 | 2020-06-19 | 山东中医药大学 | Phenobarbital derivatives of Phellinus ribirus, and preparation method and application thereof |
| CN113173928A (en) * | 2021-04-25 | 2021-07-27 | 武汉国粹医药科技有限公司 | Terpenoid, preparation method and application thereof, and antibacterial agent |
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| WO2016131098A1 (en) * | 2015-02-16 | 2016-08-25 | The University Of Queensland | Sulfonylureas and related compounds and use of same |
| CN106117171A (en) * | 2016-06-29 | 2016-11-16 | 云南中烟工业有限责任公司 | A kind of supercritical fluid chromatography prepares the benzisoxa furfuran compound methods and applications in Nicotiana tabacum L. with antibacterial activity |
| CN110003153A (en) * | 2019-03-07 | 2019-07-12 | 宁波大学 | A kind of benzofuran compounds and its preparation method and application |
| CN111303094A (en) * | 2020-04-08 | 2020-06-19 | 山东中医药大学 | Phenobarbital derivatives of Phellinus ribirus, and preparation method and application thereof |
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