CN104887677B - Natural naphthoquinones dimer and its purposes in preparing antibacterials - Google Patents
Natural naphthoquinones dimer and its purposes in preparing antibacterials Download PDFInfo
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- CN104887677B CN104887677B CN201410078971.8A CN201410078971A CN104887677B CN 104887677 B CN104887677 B CN 104887677B CN 201410078971 A CN201410078971 A CN 201410078971A CN 104887677 B CN104887677 B CN 104887677B
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- norfloxacin
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- naphthoquinones
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Abstract
The invention belongs to pharmaceutical fields, are related to natural naphthoquinones dimer and its purposes in preparing antibacterials.The naphthoquinones dimer class compound itself does not inhibit bacterial growth to act on, but when with antibiotic Norfloxacin co-administered, has significant collaboration antimicrobial agent effect so that Measure MICs of antibiotic at least reduces by 4 times；It is preferred that the Mlc of antibiotic is made to be reduced to 1/the 64 of independent medication；The compound shows reverse effect for experiment drug-resistant staphylococcus aureus to the drug resistance of Norfloxacin, may prepare overriding resistance bacterial drug with fluoroquinolone antibiotics using monomer or form of mixtures as medicament synergistic agent.
Description
Technical field
The invention belongs to pharmaceutical field, it is related to from the isolated natural naphthoquinones dimer of Chinese medicine and its is preparing antibacterial
Purposes in drug, the especially purposes in overriding resistance S. aureus L-forms drug.
Background technology
Research report, methicillin-resistant Staphylococcus aureus (Methicillin-ResistantStaphylococcusaure
Us, MRSA) it is one of most common disease carrying germ in hospital, in addition to superficial skin infection, it can also cause human depth to feel
Dye.There is studies have shown that there is the MRSA of drug resistance to drugs such as all lactam antibiotics such as penicillin, to macrolide,
Fluoquinolone, the antibiotic such as tetracycline also all produce drug resistance, this makes its infection become more difficult to treat.Currently,
The antibiotic that can be used for treating MRSA only has vancomycin, Unfortunately, complete anti-vancocin MRSA bacterial strains 2002
Occur in the U.S..China is widely used due to antibiotic in recent years, or even abuse, and especially vancomycin is cured at more
After institute becomes Conventional antibiotic class medication, this situation becomes further severe.Relevant department and personnel think, are arranged in addition to taking
It applies by limiting abuse of antibiotics to slow down the speed that drug resistance MRSA increases, while new overriding resistance MRSA drugs must be researched and developed,
When can not work to prevent existing antibacterials, the large-scale outbreak of bacterium infection.
Norfloxacin is a kind of fluoroquinolone antibiotics, and 1986 start to be used for clinic.Because it is to Gram-positive
Bacterium and Gram-negative bacteria, especially staphylococcus aureus have stronger inhibiting effect and are widely used in urethra, respiratory tract
Deng anti-infective therapy.Also just because of Norfloxacin causes bacterium to which create tight in clinical and animal husbandry extensive use
Weight drug resistance, to limit the application of Norfloxacin.The mechanism that studies have shown that bacterium generates drug resistance is various, one of them
It is bacterium efflux pump.Therefore, Screening target quilt of the MRSA bacterial strains with pump gene outside NorA as outer pump inhibitor is selected
It is considered to find a kind of important channel of the overriding resistance S. aureus L-forms antibiotic sensitizer with outer pump inhibiting effect.
Chinese medicine radix macrotomiae (Arnebiaeuchroma (Royle) Johnst.), be Boraginaceae (Boraginaceae) for many years
Raw herbaceous plant.As the main source of redroot, Asian puccoon first recorded in《Sheng Nong's herbal classic》, it is classified as middle product.Bitter, it is cold in nature.
The function of having cool blood, promoting blood circulation, removing toxic substances and promoting eruption cures mainly blood-heat and toxin exuberance, atropurpureus macula, measles without adequate eruption, sore, eczema, extreme misery and scalds
Wound etc..
Characteristic and main chemical compositions in Asian puccoon are naphthoquinone compounds, up to the present, are detached from Asian puccoon
The naphthoquinone compound mother nucleus structure arrived is 5,8- dihydroxy -2- dissident's alkene -1,4- naphthoquinones.Except that optical activity, side chain
The position of middle hydroxyl and the acid of hydroxy esterification.A few class main compounds found in puccoon at present are in a variety of Asian puccoons
There is presence, and there is corresponding pharmacological activity.The naphthoquinone compound of main component as Asian puccoon, have anti-inflammatory, antibacterial,
Various activity such as antitumor and anticoagulation.
Applicant of the present invention is quasi- to provide the dimerization formed for Asian puccoon naphthoquinones different from the dimeric structure reported at present
The naphthoquinones dimer natural component and Norfloxacin are further prepared composition of medicine, to reduce promise fluorine by body structural compounds
The minimum inhibitory concentration of Sha Xing generates Norfloxacin the synergistic effect of overriding resistance S. aureus L-forms.
Have in the relevant prior art of the present invention：
[1]BeardenDT,DanzigerLH.Mechanismofactionofandresistancetoquinolones.Ph
armacotherapy2001,21:40-61.
[2]Holmes,B,etal.Norfloxacin.Drugs.1985,30(6):482-513.
[3]MarkhamPN,NeyfakhAA.InhibitionofthemultidrugtransporterNorAInStaph
ylococcus aureuspreventsemergenceofnorfloxacinresistance.AntimicrobialAgentsC
hemotheropy.1996,40(11):2673-2674.
[4]HooperDC.Emergingmechanismsoffluoroquinoloneresistance.EmergingInf
ectiousDiseases.2001,7:337–341.
[5]WangW.J.,BaiJ.Y.,LiuD.P.,XueL.M.,ZhuX.Y.Theantiinflammatoryactivit
yof shikoninanditsinhibitoryeffectonleukotrieneB4biosynthesis.ActaPharmaceuti
caSinica,1994,29:161-165.
[6]ShenC.C.,SyuW.J.,LiS.Y.,LinC.H.,LeeG.H.,SunC.M.AntimicrobialActivi
tiesof NaphthazarinsfromArnebiaeuchroma.JournalofNaturalProducts,2002,65:
1857-1862.
[7]LiuH,JinYS,SongY,YangXN,YangXW,GengDSandChenHS.Threenewcompounds
fromArnebiaeuchroma.JournalofAsianNaturalProductsResearch,2010,12(4):286–
292.。
Invention content
The object of the present invention is to provide new natural naphthoquinones dimer and its purposes in preparing antibacterials, especially
Purposes in overriding resistance S. aureus L-forms drug.
The natural naphthoquinones dimer of the present invention is the natural materials that can be used as overriding resistance synergist, and structure feature is,
Constitute compound unit be a deoxyshikonin with one with alkannin derivatives alkannin (Alkanin and
Shikonin) and its derivative, by combining the dimeric structure formed between naphthalene nucleus.
The present invention provides the dimeric structures formed for Asian puccoon naphthoquinones different from the dimeric structure reported at present
Object is closed, the naphthoquinones dimer natural component and Norfloxacin are further prepared into composition of medicine, to reduce Norfloxacin most
Low Mlc generates Norfloxacin the synergistic effect of overriding resistance S. aureus L-forms.
The present invention is from radix macrotomiae（Also known as lithospermum euchromum Royle）In isolated naphthoquinones dimer compound, our experiments show that, this
A little compounds itself do not have an antibacterial activity, but with Norfloxacin co-administered, Measure MICs of antibiotic can be made to drop respectively
Low 4-64 times, show stronger collaboration antimicrobial agent effect.
The compound of the present invention is prepared by following methods:
Using Boraginaceae (Boraginaceae) Lithospermum (Arnebia) plant radix macrotomiae（Also known as lithospermum euchromum Royle
(Arnebia euchroma)）Root, crush, 95% 45 degrees Celsius of ethyl alcohol or less soak extraction, merge extracting solution be concentrated under reduced pressure into
All volatilization finishes ethyl alcohol, adds water to medicinal extract suspension, is extracted with ethyl acetate；Silica gel and RP-18 are used after organic phase evaporated under reduced pressure
Positive reversed phase column chromatography separating for several times obtains violet solid compound.
Its medicinal material of naphthoquinones dimer compound 1-11 (compound1-11) involved in the present invention can be obtained by channel purchased in market
It arrives.Its physicochemical data of compound produced by the present invention is as follows：
The present invention shows that the compound has antibacterial and synergistic effect by following experiments：
C. Bacteria Culture and detection
Bacteria Culture operates in cell culture chamber super-clean bench, and Bacteria Culture, Miller-Hendon's meat soup are carried out in 96 orifice plates
(Mueller-HintonBrooth, MHB) is culture medium.Take compound sample and antibiotic Norfloxacin each appropriate, with DMSO
Dissolving is configured to certain density two kinds of mother liquors, with broth dilution.Drug is not added with as negative control.96 orifice plate of inoculated bacteria in
Cultivated 18-24 hours in 37 DEG C of incubator, be added MTT, observation as a result, when not grown completely with bacterium required drug it is minimum
A concentration of drug is to the MIC value of this strain, with MTT solution 3-[4,5- dimethylthiazole bases -2]- 2,5- diphenyltetrazoliumbromide indigo plant bromines
Compound (Sigma), is used for the growth of detection bacterium, and MTT becomes au bleu by yellow and then indicates there is bacterial growth；
Used bacterial strain is EMRSA-16, is a kind of resistance to Norfloxacin Staphylococcus aureus.
2. synergistic effect experiments have shown that the Compounds Against life element synergistic effect,
The present invention carries out compound and antibiotic synergism on 96 orifice plates with the various concentration that doubling dilution is formed
Antibacterial tests：
It takes appropriate Norfloxacin to be dissolved in DMSO and is made into antibiotic mother liquor, take appropriate Norfloxacin mother liquor to be dissolved in meat soup and be made into
Norfloxacin stoste takes compound sample to be dissolved in DMSO in right amount and is made into mother liquor, with broth dilution, compound and antibiotic starting suppression
Concentration processed is respectively 128 and 256 μ g/mL, carries out orthogonal experiment with this, records the promise corresponding to the often non-growing micropore of row bacterium
The concentration of Flucloxacillin is the MIC value of Norfloxacin when being combined with compound sample.
In experiment, in 128 μ g/mL of highest initial concentration, MTT becomes au bleu by yellow and generates particle compound 1-5
Shape precipitates, and instruction has bacterial growth, that is, does not have antibacterial activity；But with Norfloxacin co-administered, compound is total to antibiotic
So that the micropore number of not long bacterium is increased with existing, observes the use concentration of antibiotic in corresponding micropore, show compound
4-64 times are reduced in the presence of Measure MICs of antibiotic is made respectively, shows stronger collaboration antimicrobial agent effect（Such as 1 institute of table
Show）.
The synergistic effect of table 1, naphthoquinones dimer to the overriding resistance S. aureus L-forms EMRSA-16 of norfloxacin
The results show that the compounds of this invention can prepare composition of medicine with Norfloxacin, generating reduces the minimum of Norfloxacin
Mlc and to Norfloxacin generate overriding resistance S. aureus L-forms have synergistic effect, further can be made into antiseptic injection, outside
Use pharmaceutical preparation.
Specific implementation mode
In present invention experiment, the instrument that uses and experiment material for：
Infrared spectrometer:AvatarTM360E.S.P.TM,ThermoNicoletCorporation；
Nuclear Magnetic Resonance:VarianMercuryPlus400MHz NMR spectrometer with superconducting magnet, CDCl3,DMSO,
Acetone；
Mass spectrum:EI-MS:Agilent5973NMSD type mass spectrographs；
Optically-active:PolarimeterP-1020,JASCOCorporation；
Chromatographic silica gel:Zhifu Huang business silica gel development experiments factory of Yantai City;Subsidiary factory of Haiyang Chemical Plant, Qingdao；
Silica gel H (60 type):10~40 μm, subsidiary factory of Haiyang Chemical Plant, Qingdao；
TCL plates, 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 Corporation (SigmaChemicalCo.Ltd.)；
Miller-Hendon's meat soup (Mueller-HintonBrooth, MHB) is purchased from Oxoid companies.
Embodiment 1
Take lithospermum euchromum Royle (Arnebiaeuchroma)（It is purchased from medicinal material company）1 kilogram of root, crush, 95% ethyl alcohol 45 is Celsius
Soak extraction below spending, merging extracting solution is concentrated under reduced pressure into ethyl alcohol, and all volatilization finishes, and adds water to medicinal extract suspension, uses ethyl acetate
It extracts, violet solid compound is obtained with silica gel and the positive reversed phase column chromatography separating for several times of RP-18 after organic phase evaporated under reduced pressure,
In, the nuclear magnetic resonance modal data of compound 2 and 3 is as shown in table 2.
The nuclear magnetic resonance modal data of table 2, compound 2 and 3
Embodiment 2, the Synergistic antimicrobial synergistic effect to Staphylococcus aureus EMRSA-16 Compounds Againsts life element
Compound is carried out on 96 orifice plates with the various concentration that doubling dilution is formed to try with antibiotic synergism antibacterial
It tests.
It takes appropriate Norfloxacin to be dissolved in DMSO and is made into antibiotic mother liquor, take appropriate Norfloxacin mother liquor to be dissolved in meat soup and be made into
Norfloxacin stoste takes compound sample to be dissolved in DMSO in right amount and is made into mother liquor, with broth dilution, compound and antibiotic starting suppression
Concentration processed is respectively 128 and 256 μ g/mL, carries out orthogonal experiment with this, record is often gone corresponding to the lucky non-growing micropore of bacterium
Norfloxacin concentration be Norfloxacin when being combined with compound sample MIC value.Experimental result is as shown in table 1.
Embodiment 3, compound are to the direct antibacterial action of Staphylococcus aureus
Standard gold Portugal strains A TCC25922, antibody-resistant bacterium SA1199B, RN4220, EMRSA-15 and Xu212 is taken to carry out micro-
Hole bacteriostatic experiment.Compound and antibiotic synergism antibacterial are carried out with the various concentration that doubling dilution is formed on 96 orifice plates
Experiment.It takes appropriate Norfloxacin to be dissolved in DMSO and is made into antibiotic mother liquor, take appropriate Norfloxacin mother liquor to be dissolved in meat soup and be made into promise
Flucloxacillin stoste.It takes compound sample to be dissolved in DMSO in right amount and is made into mother liquor.With broth dilution, Norfloxacin is control drug, is changed
It closes object and 128 μ g/mL is all higher than to the minimum inhibitory concentration of tried bacterial strain.It is not shown when compound independent medication and inhibits bacterium
Growth activity.
Claims (2)
1. purposes of the naphthoquinones dimer compound in preparing antibacterials synergist；
The naphthoquinones dimer compound has alkannin derivatives alkannin by a deoxyshikonin and one
(Alkanin and Shikonin) and its derivative form dimeric structure by being combined between naphthalene nucleus；
The compound is used for the preparation of antibacterials synergist, the compound and antibiotic with monomer or form of mixtures
When Norfloxacin co-administered, makes Measure MICs of antibiotic at least and reduce by 4 times or be reduced to 1/the 64 of independent medication.
2. the purposes according to claim 1, which is characterized in that the compound reversal experiments drug-resistant staphylococcus aureus is to the resistance to of Norfloxacin
Medicine, wherein when Norfloxacin is administered alone, minimum inhibitory concentration is 256 μ g/mL.
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| CN104887677B true CN104887677B (en) | 2018-10-26 |
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| CN111303182B (en) * | 2020-04-13 | 2021-01-05 | 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 |
|---|---|---|---|---|
| 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 |
-
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)
| Title |
|---|
| 紫草化学成分及其抗耐药菌活性的研究;叶佳;《中国优秀硕士学位论文全文数据库》;20091231;第5页图1中的化合物2-5，第28页最后一段第29页第1段 * |
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Granted publication date: 20181026 Termination date: 20210305 |