CN102603524A - Quinones derivative as well as preparation method of quinones derivative and application of quinones derivative as antibacterial agent - Google Patents
Quinones derivative as well as preparation method of quinones derivative and application of quinones derivative as antibacterial agent Download PDFInfo
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- CN102603524A CN102603524A CN2012100098068A CN201210009806A CN102603524A CN 102603524 A CN102603524 A CN 102603524A CN 2012100098068 A CN2012100098068 A CN 2012100098068A CN 201210009806 A CN201210009806 A CN 201210009806A CN 102603524 A CN102603524 A CN 102603524A
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- quinones
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- deoxybostrycin
- bostrycin
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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
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Abstract
The invention relates to a quinones derivative as well as a preparation method of the quinones derivative and an application of the quinones derivative as an antibacterial agent. During the preparation, marine fungi Nigrospora sp.(HM565952) is subjected to strain culture in a culture medium, then, the marine fungi are subjected to fermentation culture in a fermentation culture medium, next, the obtained fermentation liquid is filtered, thalli are removed, and the fermentation liquid is extracted by ethyl acetate; after the extraction liquid is concentrated, chromatographic separation is carried out, and the obtained eluent is concentrated to obtain two red crystals which are respectively 4-Deoxybostrycin and Bostrycin; and acetyl oxide is added into solution in which the two compounds dissolve for reaction to obtain 3-Acetoxy-4-deoxybostrycin and 3-Acetoxy-bostrycin. The quinones derivative provided by the invention has the obvious antibacterial activity on Bacillus subtilis, Bacillus cereus, Micrococcus tetragenus, Micrococcus lutea, Staphylococcus aureus, Staphylococcus albus, Escherichia coli, Vibrio parahaemolyticus and Vibrio anguillarum and can be used for developing antibacterial agents, in addition, raw materials can be produced in large scales, and the resource limitation is avoided, so the application prospect is wide.
Description
Technical field
The present invention relates to a kind of naphthoquinone derivatives, particularly relate to a kind of naphthoquinone derivatives and preparation method thereof and application with anti-microbial effect.
Background technology
Bacterium can colonize in respiratory tract, skin and the umbilical region of human body; When they invade some positions of human body; Can cause infection; Comprise urinary tract infection, digestive tract infection, pulmonary infection, wound infection, biliary tract infection, peritonitis, septicemia and meningitis etc., the people is stomachache, vomiting, diarrhoea and heating in metainfective symptom, to the relatively poor old man of physique and child sometimes or even fatal.According to 1995-2007 classification of diseases investigation, Chinese infection accounts for whole diseases 49% of number of always falling ill, and wherein bacterial infection accounts for 18%～21% of whole diseases.
Yet the resistance of bacterium is fairly obvious.2006-2007 year, Ministry of Health whole nation bacterial resistance monitoring net monitoring result showed that intestinal bacteria are 71.3% to the resistant rate of CIPROFLOXACIN USP 24, was 67.2% to the resistant rate of levofloxacin.Indivedual provinces and cities are higher than 80% to the resistant rate of CIPROFLOXACIN USP 24, to the resistant rate of levofloxacin near 80%.Moxifloxacin is the kind of going on the market in recent years, and its resistance is also on the rise.There is test to show that tetrads is to the general resistance of penicillium mould family in addition.In order to reduce chemical sproof generation, be badly in need of exploitation new high sensitizing drug or drug combination, to improve the validity of clinical application.In addition, the antiseptic-germicide that uses at present mainly is the broad-spectrum antimicrobial preparation, and selectivity is relatively poor.Do not see the marine natural selective antibiotic agent that from marine microorganism, obtains to have important antibiotic value in recent years as yet.
Summary of the invention
The object of the present invention is to provide a kind of naphthoquinone derivatives that derives from thalassiomycetes and preparation method thereof and application as antiseptic-germicide, it can satisfy the demand of prior art.
A kind of naphthoquinone derivatives is characterized in that its structural formula does
R is H in the formula, or is OH
The preparation method of above-mentioned naphthoquinone derivatives; It is characterized in that in substratum, thalassiomycetes Nigrospora sp. (HM565952) being carried out spawn culture earlier; In fermention medium, fungi is carried out fermentation culture again; With the gained filtering fermentation liquor, remove thalline then, fermented liquid is used ethyl acetate extraction; Extraction liquid concentrates laggard circumstances in which people get things ready for a trip spectrum to be separated, and the gained elutriant is concentrated, and gets two kinds of red crystallizations, is respectively 4-Deoxybostrycin and Bostrycin; In being dissolved with the solution of above-claimed cpd, add acetic anhydride, obtain 3-Acetoxy-4-deoxybostrycin and 3-Acetoxy-bostrycin after the reaction.
The application of above-mentioned naphthoquinone derivatives in the preparation antiseptic-germicide.
The present invention has obtained a kind of quinones from thalassiomycetes, and this compound has been carried out chemically modified, obtains naphthoquinone derivatives; Have significant anti-microbial activity, can be used for developing antiseptic-germicide, and raw material can carry out scale operation; Do not receive resource limit, therefore have a extensive future.
Embodiment
The preparation of compound of the present invention
(1) the used substratum of spawn culture of fungi Nigrospora sp. (HM565952) contains glucose 1.0% (weight percent; Yeast extract paste 0.1%, peptone 0.2%, agar 1.0%, thick sea salt 3% down together); All the other are water; Process the test tube slant during use, fungal bacterial strain was cultivated 5 days down at 30 ℃.
Described bacterium culture medium contains glucose 0.1%-5.0% (weight percent, down together), yeast extract paste 0.01%-1%, peptone 0.01%-1%, agar 0.1%-3.0%, thick sea salt 3%, and all the other are water.(2) the used fermention medium of fermentation culture of fungi Nigrospora sp. (HM565952) contains glucose 1.0% (weight percent; Yeast extract paste 0.1%, peptone 0.2%, thick sea salt 3% down together); All the other are water, and fungal bacterial strain was cultivated 30 days in 28 ℃.
Described fermention medium contains glucose 0.1%-5.0% (weight percent, down together), yeast extract paste 0.01%-1%, peptone 0.01%-1%, thick sea salt 3%, and all the other are water.
(3) separation and Extraction of compound 4-Deoxybostrycin
With the gained filtering fermentation liquor, remove thalline; Fermented liquid is with ethyl acetate extraction 5 times, after the gained extraction liquid is concentrated, carries out chromatographic separation, elutriant concentrate two kinds of red crystallizations, be respectively 4-Deoxybostrycin and Bostrycin.
(4) preparation of anthraquinone derivative
Exsiccant 4-Deoxybostrycin or Bostrycin (0.05mol) are dissolved in the exsiccant acetone (25mL), add exsiccant pyridine (5mL), be added drop-wise to acetic anhydride (0.15mol) in the reaction soln gradually under the room temperature; After reactant stirs 12 hours at ambient temperature; With TLC detect raw material consumption fully after, in reactant, add the zero(ppm) water termination reaction, extract with chloroform; After extraction liquid concentrates; Separate with the preparation thin-layer chromatography, use ETHYLE ACETATE and sherwood oil volume ratio are 1 developping agent expansion, obtain anthraquinone derivative of the present invention.
The spectral data of gained compound
3-Acetoxy-4-deoxybostrycin：red?crystals；mp?115℃；[α]
24 D-166.9(c?0.08，MeOH)；
1H?NMR(400MHz，CDCl
3，δ，ppm，J/Hz)：13.08(1H，s，10-OH)，12.73(1H，s，9-OH)，6.16(1H，s，H-6)，5.07(1H，dd，J＝7.5，5.5Hz，H-3)，3.92(3H，s，H-12)，3.17(1H，dd，J＝19.0，5.5Hz，H-4β)，3.06(1H，d，J＝18.7Hz，H-1β)，2.94(1H，dd，J＝19.0，7.5Hz，H-4α)，2.82(1H，d，J＝18.7Hz，H-1α)，2.14(3H，s，C-3-OAc)，1.36(3H，s，H-11)；
13C?NMR(100MHz，CDCl
3，δ，ppm)：184.2(C，C-5)，177.7(C，C-8)，170.5(C，C-3-OAc)，161.3(C，C-9)，160.6(C，C-7)，159.5(C，C-10)，137.4(C，C-4a)，135.2(C，C-1a)，109.6(CH，C-6)，109.6(C，C-9a)，107.7(C，C-10a)，73.6(CH，C-3)，69.3(C，C-2)，56.7(CH
3，C-12)，35.6(CH
2，C-1)，27.1(CH
2，C-4)，25.5(CH
3，C-11)，21.1(CH
3，C-3-OAc)；EI-MS?m/z：362[M]
+；HREIMS?m/z?362.0993[M]
·+(calcd?for?C
18H
18O
8，362.0996).
3-Acetoxy-bostrycin：red，amorphous?powder；mp?198℃；[α]
24 D-169.9(c0.085，MeOH)；
1H?NMR(400MHz，CDCl
3，δ，ppm，J/Hz)：13.49(1H，s，10-OH)，12.61(1H，s，9-OH)，6.20(1H，s，H-6)，5.24(1H，d，J＝7.2Hz，H-3)，5.16(1H，d，J＝7.2Hz，H-4)，3.96(3H，s，H-12)，3.15(1H，d，J＝18.8Hz，H-1α)，2.82(1H，d，J＝18.8Hz，H-1β)，2.22(3H，s，C-3-OAc)，1.39(3H，s，H-11)；
13C?NMR(100MHz，CDCl
3，δ，ppm)：184.8(C，C-5)，178.2(C，C-8)，170.5(C，C-3-OAc)，160.9(C，C-7)，160.8(C，C-9)，159.5(C，C-10)，138.4(C，C-4a)，135.2(C，C-1a)，110.4(C，C-9a)，109.7(CH，C-6)，108.6(C，C-10a)，78.1(CH，C-3)，70.8(CH
2，C-2)，68.7(CH，C-4)，56.9(CH
3，C-12)，36.0(CH
2，C-1)，26.0(CH
3，C-11)，21.0(CH
3，C-3-OAc)；EI-MS?m/z：378[M]
·+，360[M-H
2O]
+，342[M-2H
2O]
+；HREIMS?m/z378.0945[M]
·+(calcd?for?C
18H
18O
9，378.0945).
The structural formula of compound that makes is:
R is H in the formula, or is OH
The mensuration of the anti-microbial activity of compound of the present invention
(1) compound of the present invention is according to literature method (Pierce C.G.; Uppuluri P.; Teistan A.R.; Wormley Jr.F.L.; Mowat E.; Ramage G.; Lopez-ribot J.L.Nat.Protoc.2008; 3; 1494-1500), test compounds is to the bacteriostatic activity of subtilis (Bacillus subtilis), bacillus cereus (Bacillus cereus), tetrads (Micrococcus tetragenus), Sarcina lutea (Micrococcus lutea), streptococcus aureus (Staphylococcus aureus), Staphylococcus albus (Staphylococcus albus), intestinal bacteria (Escherichia coli) and marine bacteria Vibrio parahaemolyticus (Vibrio parahaemolyticus), Vibrio anguillarum (Vibrio anguillarum).
(2) the antibiotic inhibition of compound of the present invention is active
Compound of the present invention is to subtilis (Bacillus subtilis); Bacillus cereus (Bacillus cereus); Tetrads (Micrococcus tetragenus); Sarcina lutea (Micrococcus lutea); Streptococcus aureus (Staphylococcus aureus); Staphylococcus albus (Staphylococcus albus); Intestinal bacteria (Escherichia coli) and marine bacteria Vibrio parahaemolyticus (Vibrio parahaemolyticus); It is active that Vibrio anguillarum (Vibrio anguillarum) has significant inhibition.Wherein 3-Acetoxy-4-deoxybostrycin is better than positive control drug CIPROFLOXACIN USP 24 (Ciprofloxacin) to the restraining effect of bacillus cereus (B.cereus), and its minimum inhibition concentration (MIC) is 0.0488 μ M, and is as shown in table 1.
Table 1 compound of the present invention is active to the inhibition of bacterium
Naphthoquinone derivatives of the present invention has subtilis (Bacillus subtilis), bacillus cereus (Bacillus cereus), tetrads (Micrococcus tetragenus), Sarcina lutea (Micrococcus lutea), streptococcus aureus (Staphylococcus aureus), Staphylococcus albus (Staphylococcus albus), intestinal bacteria (Escherichia coli) and marine bacteria Vibrio parahaemolyticus (Vibrio parahaemolyticus), Vibrio anguillarum (Vibrio anguillarum) selects to suppress active; Can be made into antiseptic-germicide; And raw material can carry out large scale fermentation production, has a extensive future.
Claims (3)
1. a naphthoquinone derivatives is characterized in that structural formula does
R is H in the formula, or is OH.
2. the preparation method of the described naphthoquinone derivatives of claim 1; It is characterized in that in substratum, thalassiomycetes being carried out spawn culture earlier, in fermention medium, fungi is carried out fermentation culture again, then with the gained filtering fermentation liquor; Remove thalline, fermented liquid is used ethyl acetate extraction; Extraction liquid concentrates laggard circumstances in which people get things ready for a trip spectrum to be separated, and the gained elutriant is concentrated, and gets two kinds of red crystallizations, is 4-Deoxybostrycin and Bostrycin; In being dissolved with the solution of above-claimed cpd, add acetic anhydride, obtain 3-Acetoxy-4-deoxybostrycin and 3-Acetoxy-bostrycin after the reaction; Described thalassiomycetes is thalassiomycetes Nigrospora sp. (HM565952); Described chromatographic separation is that silica gel chromatographic column separates; Described eluent is ETHYLE ACETATE-sherwood oil mixed solvent of volume ratio 10%-50%.
3. the described naphthoquinone derivatives of claim 1 is preparation subtilis (Bacillus subtilis); Bacillus cereus (Bacillus cereus); Tetrads (Micrococcus tetragenus); Sarcina lutea (Micrococcus lutea); Streptococcus aureus (Staphylococcus aureus); Staphylococcus albus (Staphylococcus albus); Intestinal bacteria (Escherichia coli) and marine bacteria Vibrio parahaemolyticus (Vibrio parahaemolyticus); Application in Vibrio anguillarum (Vibrio anguillarum) antiseptic-germicide.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102796017A (en) * | 2012-08-24 | 2012-11-28 | 中山大学 | Natural product deoxybostrycin derivatives and preparation method and application thereof |
| CN105152901A (en) * | 2015-09-28 | 2015-12-16 | 三峡大学 | Preparation method for anthraquinone compound and application of anthraquinone compound as receptor tyrosine kinase inhibitor |
| CN106620831A (en) * | 2016-12-22 | 2017-05-10 | 石佳明 | Dressing for caring skin ulcer |
| CN106860909A (en) * | 2016-12-22 | 2017-06-20 | 石佳明 | A kind of foam dressing of nursing skin ulcer |
| CN106978356A (en) * | 2017-03-24 | 2017-07-25 | 湖北省荆楚药材研究院 | One plant of production bostrycin Chinese mugwort endogenetic fungus HCH285 |
| CN109456196A (en) * | 2018-10-23 | 2019-03-12 | 中山大学 | A kind of quinones and the preparation method and application thereof in marine fungi source |
| CN112111410A (en) * | 2018-03-14 | 2020-12-22 | 扬州大学 | Preparation method of dibenzoxepin compound |
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| CN101862314A (en) * | 2010-06-18 | 2010-10-20 | 中山大学 | Application of quinine compound in preparing anti-tubercle bacillus drugs |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796017A (en) * | 2012-08-24 | 2012-11-28 | 中山大学 | Natural product deoxybostrycin derivatives and preparation method and application thereof |
| CN105152901A (en) * | 2015-09-28 | 2015-12-16 | 三峡大学 | Preparation method for anthraquinone compound and application of anthraquinone compound as receptor tyrosine kinase inhibitor |
| CN106620831A (en) * | 2016-12-22 | 2017-05-10 | 石佳明 | Dressing for caring skin ulcer |
| CN106860909A (en) * | 2016-12-22 | 2017-06-20 | 石佳明 | A kind of foam dressing of nursing skin ulcer |
| CN106978356A (en) * | 2017-03-24 | 2017-07-25 | 湖北省荆楚药材研究院 | One plant of production bostrycin Chinese mugwort endogenetic fungus HCH285 |
| CN112111410A (en) * | 2018-03-14 | 2020-12-22 | 扬州大学 | Preparation method of dibenzoxepin compound |
| CN112111410B (en) * | 2018-03-14 | 2022-06-14 | 扬州大学 | Preparation method of dibenzooxepinone compound |
| CN109456196A (en) * | 2018-10-23 | 2019-03-12 | 中山大学 | A kind of quinones and the preparation method and application thereof in marine fungi source |
| CN109456196B (en) * | 2018-10-23 | 2021-04-06 | 中山大学 | Quinone compound from marine fungi as well as preparation method and application thereof |
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| CN102603524B (en) | 2019-01-15 |
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