CN104887677A - Natural naphthoquinone dimer and uses of natural naphthoquinone dimer in preparation of antibacterial drugs - Google Patents
Natural naphthoquinone dimer and uses of natural naphthoquinone dimer in preparation of antibacterial drugs Download PDFInfo
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- CN104887677A CN104887677A CN201410078971.8A CN201410078971A CN104887677A CN 104887677 A CN104887677 A CN 104887677A CN 201410078971 A CN201410078971 A CN 201410078971A CN 104887677 A CN104887677 A CN 104887677A
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Abstract
The present invention belongs to the pharmaceutical field, and relates to a natural naphthoquinone dimer and uses of the natural naphthoquinone dimer in preparation of antibacterial drugs. According to the present invention, the compound of the present invention does not have the bacteria growth inhibition effect, and when the compound and antibiotic norfloxacin are subjected to co-administration, the significant synergetic drug-resistant bacteria resistance effect is provided, such that the minimum bacterial inhibition concentration of the antibiotic is reduced by at least 4 times; preferably the bacterial inhibition concentration of the antibiotic is reduced to the 1/64 of the single use of the drug; and the compound provides a reverse effect for the experimental norfloxacin-resistant Staphylococcus aureus, and can be adopted as the drug synergist in a monomer or mixture form, such that the drug resistant bacterial resistance drugs can be prepared from the compound and the fluoroquinolone antibiotic. The structure formulas of the compound are defined in the instruction.
Description
Technical field
The invention belongs to pharmaceutical field, relate to and be separated the natural naphthoquinone dimer that obtains and the purposes preparation antibacterials thereof from Chinese crude drug, the purposes especially in overriding resistance S. aureus L-forms medicine.
Background technology
Research report, methicillin-resistant staphylococcus aureus (Methicillin-ResistantStaphylococcusaureus, MRSA) be one of disease carrying germ modal in hospital, except shallow table skin infection, it can also cause human depth to infect.Have research display, to all lactam antibioticses as the medicines such as penicillin have the MRSA of drug resistance, to macrolide, fluoroquinolone, the antibiotic such as tetracycline also all create drug resistance, and this makes its infection become more to be difficult to treatment.At present, the antibiotic that can be used for treating MRSA only has vancomycin, and Unfortunately, complete anti-vancocin MRSA bacterial strain occurs in the U.S. for 2002.China uses widely due to antibiotic in recent years, even abuses, and particularly vancomycin is after Duo Jia hospital becomes the medication of Conventional antibiotic class, and this situation becomes further severe.Relevant department and personnel think, the speed increased to slow down drug resistance MRSA by restriction abuse of antibiotics except taking measures, must research and develop new overriding resistance MRSA medicine simultaneously, in case when existing antibacterials cannot work, and the large-scale outbreak of bacteriological infection.
Norfloxacin is a kind of fluoroquinolone antibiotics, within 1986, starts to be used to clinical.Because it is to gram positive bacteria and gram negative bacteria, especially staphylococcus aureus, there is stronger inhibitory action and be widely used in the anti-infective therapy of urethra, respiratory tract etc.Also just because of norfloxacin is in extensive use that is clinical and animal husbandry, cause antibacterial to which creating serious drug resistance, thus limit the application of norfloxacin.Research display, the mechanism that antibacterial produces drug resistance is various, and one of them is antibacterial efflux pump.Therefore, the MRSA bacterial strain selecting to have the outer pump gene of NorA is considered to find a kind of important channel with outer pump inhibiting overriding resistance S. aureus L-forms antibiotic sensitizer as the Screening target of outer pump inhibitor.
Chinese medicine Radix Arnebiae (Arnebiaeuchroma (Royle) Johnst.) is Boraginaceae (Boraginaceae) herbaceos perennial.As the main source of redroot, Radix Arnebiae (Radix Lithospermi) begins to be loaded in Shennong's Herbal, is classified as middle product.Bitter in the mouth, cold in nature.There is removing heat from blood, invigorate blood circulation, detoxify and the function of rash, cure mainly that heat in blood poison is contained, macule purple is black, measles without adequate eruption, skin infection, eczema, burn due to hot liquid or fire etc.
Characteristic in Radix Arnebiae (Radix Lithospermi) and main chemical compositions are naphthoquinone compounds, and up to the present, from Radix Arnebiae (Radix Lithospermi), be separated the naphthoquinone compound mother nucleus structure obtained is 5,8-dihydroxy-2-dissident alkene-1,4-naphthoquinone.Difference is the position of hydroxyl and the acid of hydroxy esterification in optical activity, side chain.A few class main compound found in puccoon at present all have existence in multiple Radix Arnebiae (Radix Lithospermi), and have corresponding pharmacologically active.As the naphthoquinone compound of the main component of Radix Arnebiae (Radix Lithospermi), there is antiinflammatory, antibacterial, many-sided activity such as antitumor and anticoagulation.
Applicant of the present invention intends providing different from the dimeric structure reported the at present dimeric structure compound formed for Radix Arnebiae (Radix Lithospermi) naphthoquinone, further this naphthoquinone dimer natural component and norfloxacin are prepared composition of medicine, to reducing the minimum inhibitory concentration of norfloxacin, norfloxacin is produced to the potentiation of overriding resistance S. aureus L-forms.
The prior art of being correlated with in the present invention has:
[1]BeardenDT,DanzigerLH.Mechanismofactionofandresistancetoquinolones.Pharmacotherapy2001,21:40-61.
[2]Holmes,B,etal.Norfloxacin.Drugs.1985,30(6):482-513.
[3]MarkhamPN,NeyfakhAA.InhibitionofthemultidrugtransporterNorAInStaphylococcus aureuspreventsemergenceofnorfloxacinresistance.AntimicrobialAgentsChemotheropy.1996,40(11):2673-2674.
[4]HooperDC.Emergingmechanismsoffluoroquinoloneresistance.EmergingInfectiousDiseases.2001,7:337–341.
[5]WangW.J.,BaiJ.Y.,LiuD.P.,XueL.M.,ZhuX.Y.Theantiinflammatoryactivityof shikoninanditsinhibitoryeffectonleukotrieneB4biosynthesis.ActaPharmaceuticaSinica,1994,29:161-165.
[6]ShenC.C.,SyuW.J.,LiS.Y.,LinC.H.,LeeG.H.,SunC.M.AntimicrobialActivitiesof NaphthazarinsfromArnebiaeuchroma.JournalofNaturalProducts,2002,65:1857-1862.
[7]LiuH,JinYS,SongY,YangXN,YangXW,GengDSandChenHS.Threenewcompounds fromArnebiaeuchroma.JournalofAsianNaturalProductsResearch,2010,12(4):286–292.。
Summary of the invention
The object of this invention is to provide new natural naphthoquinone dimer and the purposes in preparation antibacterials thereof, the purposes especially in overriding resistance S. aureus L-forms medicine.
Natural naphthoquinone dimer of the present invention is the natural materials that can be used as overriding resistance synergist, its architectural feature is, forming the unit of compound is that a deoxyshikonin and one have alkannin derivatives shikonin (Alkanin and Shikonin) and derivant thereof, by the dimeric structure in conjunction with formation between naphthalene nucleus.
The invention provides different from the dimeric structure reported the at present dimeric structure compound formed for Radix Arnebiae (Radix Lithospermi) naphthoquinone, further this naphthoquinone dimer natural component and norfloxacin are prepared composition of medicine, to reducing the minimum inhibitory concentration of norfloxacin, norfloxacin is produced to the potentiation of overriding resistance S. aureus L-forms.
The present invention is separated and obtains naphthoquinone dimer compound from Radix Arnebiae (also known as lithospermum euchromum Royle), our experiments show that, these compounds itself do not have antibacterial activity, but with norfloxacin co-administered, Measure MICs of antibiotic can be made to reduce by 4 – 64 times respectively, show stronger collaborative antimicrobial agent effect.
Compound of the present invention is prepared by following method:
Adopt the root of Boraginaceae (Boraginaceae) Lithospermum (Arnebia) plant soft Radix Arnebiae (Radix Lithospermi) (also known as lithospermum euchromum Royle (Arnebia euchroma)), pulverize, 95% ethanol less than 45 degrees Celsius soak extraction, merge extractive liquid, is evaporated to ethanol and all volatilizees complete, add water to extractum suspendible, be extracted with ethyl acetate; Violet solid compound is obtained by silica gel and the positive reversed phase column chromatography separating for several times of RP-18 after organic facies evaporated under reduced pressure.
Its medical material of naphthoquinone dimer compound 1 – 11 (compound1-11) involved in the present invention obtains by commercial channel.Its physicochemical data of the compound that the present invention obtains is as follows:
By following experiment, the present invention shows that described compound has antibacterial and potentiation:
C. antibacterial culturing and detection
Antibacterial culturing operates in cell culture chamber super-clean bench, in 96 orifice plates, carry out antibacterial culturing, and Miller-Hendon's meat soup (Mueller-HintonBrooth, MHB) is culture medium.Get compound sample and antibiotic norfloxacin is in right amount each, dissolve with DMSO and be configured to certain density two kinds of mother solutions, with broth dilution.Do not add medicine as negative control.Inoculated bacteria 96 orifice plate cultivates 18-24 hour in the incubator of 37 DEG C, add MTT, observed result, when not growing completely with antibacterial, the least concentration of required medicine is for medicine is to the MIC value of this strain, with the blue bromide (Sigma) of MTT solution 3-[4,5-dimethylthiazole base-2]-2,5-diphenyltetrazoliumbromide, for the growth of bacterial detection, MTT becomes blueness by yellow and has then indicated bacterial growth;
The bacterial strain adopted is EMRSA-16, is the resistance to norfloxacin staphylococcus aureus of one.
2. synergism test shows the potentiation of the raw element of described Compounds Against,
The variable concentrations that the present invention is formed with doubling dilution on 96 orifice plates carries out compound and antibiotic synergism antibacterial tests:
Get appropriate norfloxacin to be dissolved in DMSO and to be made into antibiotic mother solution, get appropriate norfloxacin mother solution to be dissolved in meat soup and to be made into norfloxacin stock solution, get compound sample to be dissolved in DMSO in right amount and to be made into mother solution, with broth dilution, compound and antibiotic origination inhibition concentrations are respectively 128 and 256 μ g/mL, carry out orthogonal experiment with this, the concentration recording the norfloxacin corresponding to micropore that often row antibacterial does not grow is the MIC value with norfloxacin during compound sample coupling.
In experiment, compound 1 – 5 is when the highest initial concentration 128 μ g/mL, and MTT becomes blue by yellow and produces microgranular precipitation, and instruction has bacterial growth, does not namely have antibacterial activity; But with norfloxacin co-administered, compound and antibiotic exist jointly makes the micropore number of not long antibacterial increase, observe antibiotic working concentration in corresponding micropore, the existence of display compound makes Measure MICs of antibiotic reduce by 4 – 64 times respectively, shows stronger collaborative antimicrobial agent effect (as shown in table 1).
Table 1, naphthoquinone dimer are to the potentiation of the overriding resistance S. aureus L-forms EMRSA-16 of norfloxacin
Result shows, and the compounds of this invention can prepare composition of medicine with norfloxacin, produces the minimum inhibitory concentration of reduction norfloxacin and has potentiation to norfloxacin generation overriding resistance S. aureus L-forms, can be made into antiseptic injection further, external medicine preparation.
Detailed description of the invention
In the present invention's experiment, the instrument of employing and experiment material are:
Infrared spectrometer: Avatar
tM360E.S.P.
tM, ThermoNicoletCorporation;
Nuclear magnetic resonance analyser: VarianMercuryPlus400MHz NMR spectrometer with superconducting magnet, CDCl
3, DMSO, Acetone;
Mass spectrum: EI-MS:Agilent5973NMSD type mass spectrograph;
Optically-active: PolarimeterP-1020, JASCOCorporation;
Chromatographic silica gel: Yantai City's Zhifu Huang business silica gel development experiments factory; Subsidiary factory of Haiyang Chemical Plant, Qingdao;
Silica gel H (60 type): 10 ~ 40 μm, subsidiary factory of Haiyang Chemical Plant, Qingdao;
TCL plate, Yantai City's Zhifu Huang business silica gel development experiments factory;
Reverse phase silica gel: C-18, Fluka company;
Norfloxacin and MTT are purchased from Sigma (SigmaChemicalCo.Ltd.);
Miller-Hendon meat soup (Mueller-HintonBrooth, MHB) is purchased from Oxoid company.
Embodiment 1
Get the root 1 kilogram of lithospermum euchromum Royle (Arnebiaeuchroma) (being purchased from medical material company), pulverize, 95% ethanol less than 45 degrees Celsius soak extraction, merge extractive liquid, is evaporated to ethanol and all volatilizees complete, add water to extractum suspendible, be extracted with ethyl acetate, after organic facies evaporated under reduced pressure, obtain violet solid compound by silica gel and the positive reversed phase column chromatography separating for several times of RP-18, wherein, the nuclear magnetic resonance, NMR modal data of compound 2 and 3 is as shown in table 2.
The nuclear magnetic resonance, NMR modal data of table 2, compound 2 and 3
Embodiment 2, Synergistic antimicrobial potentiation to the raw element of staphylococcus aureus EMRSA-16 Compounds Against
The variable concentrations that 96 orifice plates are formed with doubling dilution carries out compound and antibiotic synergism antibacterial tests.
Get appropriate norfloxacin to be dissolved in DMSO and to be made into antibiotic mother solution, get appropriate norfloxacin mother solution to be dissolved in meat soup and to be made into norfloxacin stock solution, get compound sample to be dissolved in DMSO in right amount and to be made into mother solution, with broth dilution, compound and antibiotic origination inhibition concentrations are respectively 128 and 256 μ g/mL, carry out orthogonal experiment with this, the concentration recording the norfloxacin corresponding to micropore that often capable lucky antibacterial does not grow is the MIC value with norfloxacin during compound sample coupling.Experimental result is as shown in table 1.
Embodiment 3, compound are to the direct antibacterial action of staphylococcus aureus
Label taking accurate S. aureus L-forms strain ATCC25922, Resistant strain SA1199B, RN4220, EMRSA-15 and Xu212 carry out micropore bacteriostatic experiment.The variable concentrations that 96 orifice plates are formed with doubling dilution carries out compound and antibiotic synergism antibacterial tests.Get appropriate norfloxacin to be dissolved in DMSO and to be made into antibiotic mother solution, get appropriate norfloxacin mother solution and be dissolved in meat soup and be made into norfloxacin stock solution.Get compound sample to be dissolved in DMSO in right amount and to be made into mother solution.With broth dilution, norfloxacin is control drug, and compound is all greater than 128 μ g/mL to the minimum inhibitory concentration of tested bacterial strain.Bacteria growing inhibiting activity is not all demonstrated during the independent medication of compound.
Claims (6)
1. naphthoquinone dimer compound, it is characterized in that, forming the unit of compound is that a deoxyshikonin has alkannin derivatives shikonin (Alkanin and Shikonin) and derivant thereof with one, by combining formation dimeric structure between naphthalene nucleus;
2. the purposes of naphthoquinone dimer compound in preparation antibacterials of claim 1; Described compound is used for the preparation of antibacterials with monomer or form of mixtures.
3. the purposes of naphthoquinone dimer compound in preparation antibacterials synergist of claim 1; During described compound antibiotic norfloxacin co-administered, Measure MICs of antibiotic is made at least to reduce by 4 times.
4. the purposes of naphthoquinone dimer compound in preparation antibacterials synergist of claim 1; During described compound antibiotic norfloxacin co-administered, antibiotic Mlc is made to be reduced to 1/64th of independent medication.
5. by claim, the purposes of 2 or 3 or 4, is characterized in that, described compound itself does not have bacteria growing inhibiting effect, does not have contention effect to the growth of antibacterial and existence; Described compound not bacteria growing inhibiting in normal assays concentration range 128 μ g/mL (200 μMs).
6., by claim, the purposes of 2 or 3 or 4, is characterized in that, described compound reversal experiments drug-resistant staphylococcus aureus is to the drug resistance of norfloxacin, and wherein, when norfloxacin is individually dosed, minimum inhibitory concentration is 256 μ g/mL.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303182A (en) * | 2020-04-13 | 2020-06-19 | 中国医学科学院药用植物研究所海南分所 | Two novel naphthoquinone dimers in Li medicine red onion and preparation method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN85100335A (en) * | 1985-04-01 | 1986-08-13 | 化学工业部沈阳化工研究院 | Naphthalene liquid-phase oxidation system 1, the method for 4-naphthoquinones |
| CN85101036A (en) * | 1984-10-17 | 1986-10-08 | 日本合成橡胶株式会社 | Produce conjugated diene copolymer and contain the method for the photosensitive composition of this multipolymer |
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2014
- 2014-03-05 CN CN201410078971.8A patent/CN104887677B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN85101036A (en) * | 1984-10-17 | 1986-10-08 | 日本合成橡胶株式会社 | Produce conjugated diene copolymer and contain the method for the photosensitive composition of this multipolymer |
| CN85100335A (en) * | 1985-04-01 | 1986-08-13 | 化学工业部沈阳化工研究院 | Naphthalene liquid-phase oxidation system 1, the method for 4-naphthoquinones |
Non-Patent Citations (1)
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| 叶佳: "紫草化学成分及其抗耐药菌活性的研究", 《中国优秀硕士学位论文全文数据库》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111303182A (en) * | 2020-04-13 | 2020-06-19 | 中国医学科学院药用植物研究所海南分所 | Two novel naphthoquinone dimers in Li medicine red onion and preparation method and application thereof |
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