CN101269060B - Use of compound HSR01-4-9 in preparing multi-drug resistant aureus restrainer - Google Patents
Use of compound HSR01-4-9 in preparing multi-drug resistant aureus restrainer Download PDFInfo
- Publication number
- CN101269060B CN101269060B CN2007100382773A CN200710038277A CN101269060B CN 101269060 B CN101269060 B CN 101269060B CN 2007100382773 A CN2007100382773 A CN 2007100382773A CN 200710038277 A CN200710038277 A CN 200710038277A CN 101269060 B CN101269060 B CN 101269060B
- Authority
- CN
- China
- Prior art keywords
- compound
- hsr01
- drug
- resistant
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicine and relates to the use of HSR01-4-9 in Compound Formula I in inhibiting the activity of drug-resistant bacteria, in particular relates to the use of Compound HSR01-4-9 in the preparation of drugs of resisting connaught fluoride quinoline resistant ketones and methicillin-resistant staphylococcus aureus (MRSA). Antibacterial tests prove that Compound HSR01-4-9 of the invention has a minimum inhibitory concentration (MIC) of 2mcg/ml (4.3 MuM), that is, the antibacterial activity of Compound HSR01-4-9 is stronger than the comparison drug norfloxacinwhen the comparison drug norfloxacin has a minimum inhibitory concentration (MIC) of 32mcg/ml (100 MuM) as for drug-resistant strain SA-1199B.Compound HSR01-4-9 can be further prepared into drugs of inhibiting drug-resistant bacteria.
Description
Technical field
The invention belongs to pharmaceutical field, the active purposes of the inhibition drug-resistant bacteria of the compound H SR01-4-9 that relates to is specifically related to the purposes of compound H SR01-4-9 in anti-anti-fluorine promise quinoline ketone methicillin-resistant staphylococcus aureus (MRSA) medicine of preparation.
Background technology
(Methicillin-Resistant Staphylococcus aureus MRSA) has become a kind of common serious disease carrying germ in the hospital in recent years to the methicillin-resistant staphylococcus aureus.Except the shallow skin infection, it also exists the degree of depth of inside of human body to infect, and severe patient can cause death.Child's influenza sense of 10-12 month U.S. outburst in 2003 has 3 examples to infect relevant (CDC, 2004) with MRSA in 42 deaths.All lactam antibioticses such as penicillin medicine series had chemical sproof MRSA, to macrolide, fluorine quinoline ketone, antibiotic such as tetracycline have also all produced drug resistance, this makes its infection become to be difficult to and treatment causes clinical hospital to become the serious source of infection.The antibiotic that can be used for treating MRSA at present has only vancomycin (vancomycin).Yet unfortunately, fully (CDC, 2002) appear in the MRSA bacterial strain 2002 of anti-vancocin in the U.S..And current up-to-date anti-MRSA azoles quinoline ketone medicine Linezoid (Zyvox
TM) and streptogramine class medicine quinupristin/dalfostin mixture be just to put on market calendar year 2001.But Linezoid drug-resistant type MRSA (Tsiodras, 2001 have appearred; Potoski, 2002).China uses widely owing to antibiotic nearly one or two years, even abuse, and particularly more and more after many hospitals became conventional antibiotics medication, this situation was equally more and more urgent for vancomycin.Except taking measures by the restriction abuse of antibiotics to slow down the speed that drug resistance MRSA increases, must research and develop new anti-multidrug resistance MRSA medicine simultaneously, it is new chemical constitution type, the anti-multidrug resistance staphylococcus aureus medicine of new model of action in support, in case after existing antibacterials can't work, the large-scale outbreak of antibacterial.
Bacterial resistance has number of mechanisms, and wherein, reducing medicine, to take in cell be a kind of in several important resistance mechanisms of antibacterial.Reduce medicine absorption cell and have several modes again: the change of membrane structure; The variation of epicyte protein; Medicine is initiatively effluxed (outer pump efflux) from cell.Present generally accepted cell is an active outer pump mechanism (Langton, et al, 2005) to the mechanism that medicine reduces permeability.Transfection in the outer pumping system of antibiotic and other toxin is from the antibacterial to the mammalian organs, all finds existence.According to World Health Organization's report, the infection with the outer chlG mechanism of multidrug resistance has accounted for 60% (World Health Organization, 2000) of hospital infection.
The methicillin-resistant staphylococcus aureus has multiple resistance mechanism, except having the drug resistant gene that chromosome is 40kb (mecA) by coding methicillin adaptor protein (Penicilin Bindin Protein, PBP) produce outside the beta-lactam generation drug resistance, also to macrolide (macrolide), fluorine quinoline ketone (fluoroqiunolones), tetracycline and quaternary ammonium salts are respectively by MsrA (Ross, 1990), NorA (Ng, 1994), TekA (Guay, 1993) and the outer chlG of QacA (Marshall, 1997) form outer pump resistance mechanism.The great majority that bacterial cell will generally use in the pump mechanism outside these type antibiotic medicine molecule " pumps ", makes medicine reduce and can't play antibacterial action in intracellular concentration.
NorA gene (42385Da) is present on the chromosomal SmaI D of the staphylococcus aureus S.aureus segment, it at first be as fluorine quinoline ketone drug resistant gene, showed drug resistance to multiple Antibiotique composition (Yu, 2002) afterwards.NorA gene overexpression product NorA albumen in S.aureus is positioned on the cytoplasma membrane as main transhipment (transporter), to comprise fluorine the multiple medicine of quinoline ketone as substrate, or transport sub-synergism with other, drug molecule is pumped the extracellular, diseaseful drug resistance (Ng, 1994).
Therefore, the MRSA bacterial strain that will contain the NorA gene screens the important channel that target is the searching medicines for inhibiting drug-resistant bacteria as one.
Summary of the invention
The active purposes of inhibition drug-resistant bacteria that the purpose of this invention is to provide compound H SR01-4-9 is specifically related to the purposes of compound H SR01-4-9 in anti-anti-fluorine promise quinoline ketone methicillin-resistant staphylococcus aureus (MRSA) medicine of preparation.
Chemical compound 1 of the present invention, 2-dihydro-3,6,8-trihydroxy-1,1-bis (3-methylbut-2-enyl)-5-(1,1-dimethylprop-2-enyl)-xanthen-2,9-dione (is called for short: HSR01-4-9)
Described chemical compound 1,2-dihydro-3,6,8-trihydroxy-1, and 1-bis (3-methylbut-2-enyl)-5-(1,1-dimethylprop-2-enyl)-xanthen-2, (be called for short: chemical constitution HSR01-4-9) is the mouth diphenylene ketone oxide chemical compound that replaces to 9-dione.Wherein the 2-position is oxidized to carbonyl; 3,6, the 8-position is that hydroxyl replaces; The 1-position is by R
1And R
2Replace; The 5-position is by R
3Replace.R
1=R
2=isoprenyl (isopentyl), R
3=1,1-dimethylprop-2-enyl (1,1-dimethyl propylene thiazolinyl).
The Wave Spectrum nature and characteristic of compound H SR01-1
The carbon of compound H SR01-1, hydrogen nuclear magnetic resonance spectroscopy data see Table 1.Compound H SR01-1 is a yellow oil, and its molecular formula is C
28H
32O
6The fragment peak m/z465.4 of its ESIMS provides molecular weight 464.
Nuclear magnetic resoance spectrum data (the CDCl of table 1, chemical compound 1
3, δ ppm, JHz)
The following method of passing through of described compound H SR01-4-9 prepares:
The root of Hypericum (Hypericum) plant Herba Hyperici Sampsonii (H.sampsonii) is pulverized, and is soaking extraction below 45 degrees centigrade with 95% ethanol, and merge extractive liquid, is evaporated to the whole volatilizations of ethanol and finishes, and adds water to the extractum suspendible, uses ethyl acetate extraction.Obtaining HSR01-1 with silica gel and the positive reversed phase column chromatography separating for several times of RP-18 after the organic facies evaporated under reduced pressure is the yellow oily chemical compound.
The compounds of this invention HSR01-4-9 is through bacteriostatic test, the result shows, for Resistant strain SA-1199B, when control drug norfloxacin minimum inhibitory concentration is MIC32 mcg/ml (100 μ M), the minimum inhibitory concentration of compound H SR01-4-9 is 2 mcg/ml (4.3 μ M), and promptly the bacteriostatic activity of compound H SR01-4-9 is better than the control drug norfloxacin.Can further prepare the medicine that suppresses drug-resistant bacteria
The specific embodiment
Embodiment 1
1.2 kilograms of the roots of Hypericum (Hypericum) plant Herba Hyperici Sampsonii (H.sampsonii), pulverize, soaking extraction five times below 45 degrees centigrade with 1 liter of 95% ethanol, merge extractive liquid, is evaporated to the whole volatilizations of ethanol and finishes, add 800 milliliters in water to the extractum suspendible, use ethyl acetate extraction.Chromatography after the organic facies evaporated under reduced pressure.The sample silica gel column chromatography, 200-300 order silica gel (Chinese Haiyang Chemical Plant, Qingdao) 800 gram, petroleum ether-ethyl acetate (gradient elution of 8:2～2:8), every flow point is 75 milliliters, silica gel thin-layer chromatography detects.Merge 83 to 112 flow point and evaporates to dryness, go up silica gel column chromatography again, 200-300 order silica gel 200 grams place 4 * 40 centimetres chromatographic column, and petroleum ether-acetone (7:3) is eluant, obtains slightly brown solid chemical compound.Reuse reverse phase silica gel RP-18 column chromatography (2 * 15 centimetres), methanol-water (8:2) eluting.Obtaining 25 milligrams of white solid chemical compounds, take off thin layer chromatography and anti-phase RP-18 efficient liquid phase chromatographic analysis through silicon, is a pure compound, is accredited as HSR01-4-9.
The Wave Spectrum nature and characteristic of described compound H SR01-4-9:
Compound H SR01-4-9 is a yellow oil, and its molecular formula is C
28H
32O
6The fragment peak m/z465.4 of its ESIMS provides molecular weight 464.Table 1 is carbon, the hydrogen nuclear magnetic resonance spectroscopy data (CDCl of compound H SR01-4-9
3, δ ppm, JHz).
Table 1
Embodiment 2 bacteriostatic tests
Determine the minimum inhibitory concentration method,
Norfloxacin (Norfloxacin) is purchased in Sigma company (Sigma Chemical Co.) Muller-Hendon's meat soup (Mueller-Hinton broth, MHB; Oxoid) transfer to every liter and contain 20 milligrams of calcium ions and magnesium ion.By comparing the McFarland standard, bacterial cultures is mixed with 5 * 10
5The inoculum of cfu/ml density.Norfloxacin and compound H SR01-4-9 are dissolved in dimethyl sulfoxide solvent and dilute among the MHB initial concentration to 512 mcg/ml.With Nunc type 96 microwell plates, 125 microlitre MHB add the 1-11 hole; 125 microlitre chemical compounds or norfloxacin (control drug) are added No. 1 hole and serial dilution, stay that No. 11 holes do not add chemical compound or medicine contrasts as bacterial growth.Last volume adds No. 12 holes, does not contain meat soup in this hole as aseptic contrast.At last, bacterial inoculum (125 microlitre) adds the 1-11 hole respectively, and should coil under 37oC and to cultivate 18 hours.Minimum inhibitory concentration (MIC) is a least concentration that cannot see bacterial growth, twice of all minimum inhibitory concentration replication.Concentration is the 3-[4 of 5 mg/ml, 5-dimethylthiazole base-2]-2,5-diphenyl tetrazolium blue bromide (MTT; Lancaster) by color xanthochromia indigo plant, be used for the growth of bacterial detection.
The staphylococcus aureus of the outer chlG of experiment antibacterial SA-1199B overexpression NorA multidrug resistance, it is MIC32 microlitre/milliliter to the drug resistance of norfloxacin.NorA albumen is main medicine efflux pump (efflux the pump) (Kaatz﹠amp of golden Portugal bacterium; Seo, 1997).
The result shows: for Resistant strain SA-1199B, when control drug norfloxacin minimum inhibitory concentration is MIC32 mcg/ml (100 μ M), the minimum inhibitory concentration of compound H SR01-4-9 is 2 mcg/ml (4.3 μ M), and promptly the bacteriostatic activity of compound H SR01-4-9 is better than the control drug norfloxacin.
Claims (3)
1. compound H SR01-4-9 is in the purposes of preparation in the anti-multi-medicine medicine-resistant staphylococcus aureus inhibitor, and described chemical compound has following structure:
2. the described purposes of claim 1 is characterized in that described golden Portugal bacterium is anti-fluorine promise quinoline ketone staphylococcus aureus.
3. the described purposes of claim 2 is characterized in that described anti-fluorine promise quinoline ketone staphylococcus aureus has the drug resistance to fluorine promise quinoline ketone antibiotic medicine simultaneously.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100382773A CN101269060B (en) | 2007-03-21 | 2007-03-21 | Use of compound HSR01-4-9 in preparing multi-drug resistant aureus restrainer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100382773A CN101269060B (en) | 2007-03-21 | 2007-03-21 | Use of compound HSR01-4-9 in preparing multi-drug resistant aureus restrainer |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101269060A CN101269060A (en) | 2008-09-24 |
| CN101269060B true CN101269060B (en) | 2011-01-05 |
Family
ID=40003452
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2007100382773A Expired - Fee Related CN101269060B (en) | 2007-03-21 | 2007-03-21 | Use of compound HSR01-4-9 in preparing multi-drug resistant aureus restrainer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101269060B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101597230B (en) * | 2009-07-03 | 2013-05-29 | 复旦大学 | Beta,beta-dimethyl-acry-lalkannin and application in preparing medicines for inhibiting drug-resistant bacteria |
| CN113072564A (en) * | 2021-03-23 | 2021-07-06 | 南京奥利墨斯医药科技有限公司 | Heteroaromatic ring compound and application thereof |
-
2007
- 2007-03-21 CN CN2007100382773A patent/CN101269060B/en not_active Expired - Fee Related
Non-Patent Citations (5)
| Title |
|---|
| An, Tian Ying et al.A new xanthone derivative from Hypericum erectum.Chinese Chemical LettersVol. 13 No. 7.2002,Vol. 13(No. 7),623-624. |
| An, Tian Ying et al.A new xanthone derivative from Hypericum erectum.Chinese Chemical LettersVol. 13 No. 7.2002,Vol. 13(No. 7),623-624. * |
| Xiao, Zhi Yong et al.A Naturally Occurring Inhibitory Agent from Hypericumsampsonii with Activity Against Multidrug-ResistantStaphylococcus aureus.Pharmaceutical Biologyvol. 46 no. 4.2008,vol. 46(no. 4),250-253. |
| Xiao, Zhi Yong et al.A Naturally Occurring Inhibitory Agent from Hypericumsampsonii with Activity Against Multidrug-ResistantStaphylococcus aureus.Pharmaceutical Biologyvol. 46 no. 4.2008,vol. 46(no. 4),250-253. * |
| 曾祎含.元宝草果实部位抗多药耐药金葡菌活性成分的研究.中国优秀硕士学位论文全文数据库.2009,全文. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101269060A (en) | 2008-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Sathiamoorthy et al. | New antifungal flavonoid glycoside from Vitex negundo | |
| Ponnusamy et al. | Indirubin potentiates ciprofloxacin activity in the NorA efflux pump of Staphylococcus aureus | |
| Zhang et al. | Enhanced chemical and biological activities of a newly biosynthesized eugenol glycoconjugate, eugenol α-D-glucopyranoside | |
| Sun et al. | Synergism of sophoraflavanone G with norfloxacin against effluxing antibiotic-resistant Staphylococcus aureus | |
| Wang et al. | Four New Cuparene‐Type Sesquiterpenes from Flammulina velutipes | |
| AU2006304868B2 (en) | Method of treating clostridium difficile-associated diarrhea | |
| CN106834160A (en) | One class square ring element compound and its application in antitumor or antibacterials are prepared | |
| CN101269060B (en) | Use of compound HSR01-4-9 in preparing multi-drug resistant aureus restrainer | |
| Yang et al. | Two novel amphomycin analogues from Streptomyces canus strain FIM-0916 | |
| US11028113B2 (en) | Cyphomycin, compositions and uses thereof | |
| CN101845081B (en) | Cyclic hexapeptide antibacterial compound | |
| Huang et al. | Three new hydroxyphenylacetic acid derivatives and a new alkaloid from endophytic fungus Mortierella sp. in Epimedium acuminatum Franch. and their antibacterial activity | |
| Li et al. | Synergistic antibacterial activity between penicillenols and antibiotics against methicillin-resistant Staphylococcus aureus | |
| CN108003000B (en) | Diphenyl ether compound and preparation method and application thereof | |
| CN101293821B (en) | Compounds for inhibiting multi-medicine medicine-resistant staphylococcus aureus activity | |
| CN111494364B (en) | Application of isopentenyl substituted phenol compound in resisting staphylococcus aureus and methicillin-resistant staphylococcus aureus | |
| CN114621092A (en) | Phenolic compound in mangrove plant-derived fungi and preparation method thereof | |
| CN107951878B (en) | Application of spiroketal polyacetylene compound in preparing drug-resistant staphylococcus aureus sensitization drug for external pump | |
| Qin et al. | A new isochroman derivative from the endophytic Microsphaeropsis arundinis | |
| CN103387555B (en) | Acetophenone-substituted straight-chain sesqui derivative and application thereof in inhibiting basterium drug resistance | |
| CN109593074B (en) | Separation preparation and application of compound with antibacterial activity in fungus secondary metabolite | |
| CN102464578A (en) | Aspidinol compound and application thereof in preparing medicines for resisting drug-resistant bacteria | |
| CN115708824B (en) | Application of 7, 8-dihydroxyflavone as iron steady state perturbation agent in preparation of polymyxin synergist | |
| CN113582863B (en) | Aminoethyl biphenyl compound and preparation method and application thereof | |
| CN101597230B (en) | Beta,beta-dimethyl-acry-lalkannin and application in preparing medicines for inhibiting drug-resistant bacteria |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110105 Termination date: 20130321 |