CN105147652A - Novel application of embelin or embelin compound in bacterium inhibition - Google Patents
Novel application of embelin or embelin compound in bacterium inhibition Download PDFInfo
- Publication number
- CN105147652A CN105147652A CN201510577998.6A CN201510577998A CN105147652A CN 105147652 A CN105147652 A CN 105147652A CN 201510577998 A CN201510577998 A CN 201510577998A CN 105147652 A CN105147652 A CN 105147652A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound shown
- compound
- beta
- anthracene shellfish
- 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.)
- Granted
Links
- 0 *C1C=CC=CC1 Chemical compound *C1C=CC=CC1 0.000 description 2
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
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a novel application of an embelin or embelin compound in bacterium inhibition. According to the novel application, the embelin or embelin compound has an effect of inhibiting enzyme activity of beta-lactamase, especially a prominent effect of inhibiting the wide anti-biological hydrolytic activity of New Delhi metallo-beta-lactamase-1, can be used for remarkably improving the sensitivity of drug-resistance bacteria on antibiotics, remarkably reducing the minimal inhibitory concentration of multiple antibiotics on superbug, reversing the drug resistance of drug-resistance bacteria and reducing clinical hazard of serious drug-resistance bacteria, and has certain bacteriostatic activity. A high-concentration embelin or embelin compound has remarkable bacteriostatic activity on staphylococcus aureus, pseudomonas aeruginosa, salmonella typhimurium, shigella sonnei, shigella flexneri, klebsiella pneumoniae, escherichia coli and other pathogenic bacteria, and even can be used for completely inhibiting bacterium growth.
Description
Technical field
The present invention relates to anthracene shellfish element or the novelty teabag of anthracene shellfish chlorins compound in anti-bacteria.
Background technology
From penicillin in 1940 be applied to clinical since, antibiotic plays an important role in control with disease therapy.The beta-lactam class antibiotic comprising penicillin is that current clinical practice is comparatively wide, a class antibacterium microbial medicine of large usage quantity.Along with it widely uses, cause many antibacterials of human diseases to create drug resistance, occur the fastbacteria resisting Multiple Classes of Antibiotics in recent years repeatedly.China's bacterial resistance examining report published for 2010 shows, the drug resistance of antibacterial to the beta-lactam antibiotic such as penicillin, cephalosporin is obvious, wherein Drug Resistance of E. coli is more than 50%, and main resistance mechanism is the beta-lactamase producing super wide spectrum, and zymogenic rate is up to 68%.2010, a kind of fastbacteria of product New Delhi metallo-β-lactamase-1 (NDM-1, NewDelhiMetallo-β-lactamase-1), in India, Britain and Pakistani propagation, caused extensive concern and the report of Chinese scholars and media.Producing the antibacterial of NDM-1, because its extensive drug resistance causes treatment of infection very difficult, is " superbacteria (superbug) " by media report.At present, the antibacterial of product NDM-1 is separated in more than 30 countries and regions such as the U.S., Canada, Germany, Japan, China Hong Kong and Taiwan and report, and constantly has new infeetioa case to occur.On 1O 26th, 2010, CDC and Military Medical Science Institute announce to have found " superbacteria " that produce NDM-1 respectively in Ningxia of China's Mainland and Fujian simultaneously, and constantly have new clinical separation strain to be found at home.
Current clinical the most frequently used antibiotic mostly containing beta-lactam ring structure, comprises penicillins, cephalosporins, carbapenems etc.Wherein carbapenem antibiotic antimicrobial spectrum is the widest, and resistant rate is minimum, is called as " trump card " in antibiotic, is generally used for the treatment of severe infection patient.The beta-lactamase (β-lactamase) of Production by Bacteria unboiled water solution beta-lactam antibiotic is the main mechanism of antibacterial to beta-lactam antibiotic resistance.Along with widely using of beta-lactam antibiotic, the kind of beta-lactamase is also in continuous increase.According to the molecular structure of beta-lactamase, A, B, C, D tetra-class can be divided into.TEM type beta-lactamase, belongs to category-A beta-lactamase, is to find the earliest and one of beta-lactamase of most species, and at least existing 183 kinds of TEM enzymes are found, with TEM-1, TEM-2 for representative at present.SHV type beta-lactamase, belongs to category-A beta-lactamase, is one of beta lactamase that distribution is the widest, has found 134 kinds of SHV enzymes at present.Compared with A, C, D class beta lactamase, category-B beta-lactamase has unique molecular structure, and the performance of its enzymatic activity needs the participation of metal ion, is generally Zn
2+, therefore also referred to as metallo-β-lactamase.IMP type and VIM type beta lactamase are its important representatives.Because they can be hydrolyzed the carbapenems such as imipenum, meropenem antibacterials, be also referred to as carbapenem enzyme.NDM-1 is a kind of newfound carbapenem enzyme, belongs to category-B beta-lactamase.NDM-1 enzyme hydrolysis substrate comprises penicillins, cephalosporins and carbapenems etc., shows as and produces enzyme antibacterial to the extensive drug resistance of these medicines.Report display, the bacteremic case fatality rate that the Klebsiella Pneumoniae carrying NDM-1 drug resistant gene causes is up to 50%.
The method comparatively successfully resisting bacterial resistance at present clinically by beta-lactam antibiotic and beta-lactamase inhibitor drug combination.Sulbactam, clavulanic acid and Tazobactam Sodium are clinical widely used beta-lactamase inhibitors for a long time, and they reach the object of protection beta-lactam antibiotic by suppressing beta-lactam enzymatic activity.The clinical conventional compound preparation be made up of ampicillin/sulbactam, amoxicillin/sulbactam, Sulbactam/Cefoperazone, amoxicillin/clavulanate potassium etc.But current experiment in vitro shows these three kinds of beta-lactamase inhibitors existing to NDM-1 without any inhibit activities.
Summary of the invention
The object of this invention is to provide anthracene shellfish element or the novelty teabag of anthracene shellfish chlorins compound in anti-bacteria.
The first novelty teabag that the invention provides anthracene shellfish element or anthracene shellfish chlorins compound is anthracene shellfish element or the application of anthracene shellfish chlorins compound in the product preparing anti-bacteria.
Based on the first novelty teabag above-mentioned, the present invention also protects a kind of product of anti-bacteria, and its active component is anthracene shellfish element or anthracene shellfish chlorins compound.
Described antibacterial specifically can be gram-positive bacterium or gram negative bacteria, also can for carrying the drug-resistant bacteria of the encoding gene of beta-lactamase.Described beta-lactamase specifically can be NDM-1 albumen, TEM-1 albumen, VIM-1 albumen, SHV-18 albumen or IMP-1 albumen.Described beta-lactamase specifically can be the IMP-1 albumen shown in sequence 9 of the NDM-1 albumen shown in sequence 1 of sequence table, the TEM-1 albumen shown in sequence 3 of sequence table, the VIM-1 albumen shown in sequence 5 of sequence table, the SHV-18 albumen shown in sequence 7 of sequence table or sequence table.Described antibacterial can be staphylococcus aureus (Staphylococcusaureus), Pseudomonas aeruginosa (Pseudomonasaeruginosa), Salmonella typhimurium (Salmonellatyphimurium), Song Shi shigella dysenteriae (Shigellasonnei), Shigella flexneri (Shigellaflexneri), Klebsiella Pneumoniae (Klebsiellapneumoniae) or escherichia coli (Escherichiacoli).
The present invention also protects the application in the product preparing anti-bacteria of inhibitor and antibiotic; Described inhibitor is anthracene shellfish element or anthracene shellfish chlorins compound.
The present invention also protects a kind of product of anti-bacteria, and its active component is inhibitor and antibiotic; Described inhibitor is anthracene shellfish element or anthracene shellfish chlorins compound.
Described antibiotic is beta-lactam antibiotic.Described beta-lactam antibiotic is carbapenem antibiotic, Penicillin antibiotics or cephalosporins.Described carbapenem antibiotic specifically can be biapenem or meropenem.Described Penicillin antibiotics specifically can be ampicillin or benzylpenicillin.Described cephalosporins specifically can be cefepime, ceftazidime or cefradine.Described antibacterial specifically can be gram-positive bacterium or gram negative bacteria, also can for carrying the drug-resistant bacteria of the encoding gene of beta-lactamase.Described beta-lactamase specifically can be NDM-1 albumen, TEM-1 albumen, VIM-1 albumen, SHV-18 albumen or IMP-1 albumen.Described beta-lactamase specifically can be the IMP-1 albumen shown in sequence 9 of the NDM-1 albumen shown in sequence 1 of sequence table, the TEM-1 albumen shown in sequence 3 of sequence table, the VIM-1 albumen shown in sequence 5 of sequence table, the SHV-18 albumen shown in sequence 7 of sequence table or sequence table.Described antibacterial can be staphylococcus aureus (Staphylococcusaureus), Pseudomonas aeruginosa (Pseudomonasaeruginosa), Salmonella typhimurium (Salmonellatyphimurium), Song Shi shigella dysenteriae (Shigellasonnei), Shigella flexneri (Shigellaflexneri), Klebsiella Pneumoniae (Klebsiellapneumoniae) or escherichia coli (Escherichiacoli).
The second novelty teabag that the invention provides anthracene shellfish element or anthracene shellfish chlorins compound is that anthracene shellfish element or anthracene shellfish chlorins compound are preparing the application in beta-lactamase inhibitor.
Based on above-mentioned the second novelty teabag, the present invention also protects a kind of beta-lactamase inhibitor, and its active component is anthracene shellfish element or anthracene shellfish chlorins compound.
Described beta-lactamase specifically can be NDM-1 albumen, TEM-1 albumen, VIM-1 albumen, SHV-18 albumen or IMP-1 albumen.Described beta-lactamase specifically can be the IMP-1 albumen shown in sequence 9 of the NDM-1 albumen shown in sequence 1 of sequence table, the TEM-1 albumen shown in sequence 3 of sequence table, the VIM-1 albumen shown in sequence 5 of sequence table, the SHV-18 albumen shown in sequence 7 of sequence table or sequence table.
The present invention also protects anthracene shellfish element or anthracene shellfish chlorins compound to suppress the application in the product of beta-lactam enzyme hydrolysis beta-lactam antibiotic in preparation.
The present invention also protects a kind of product suppressing beta-lactam enzyme hydrolysis beta-lactam antibiotic, and its active component is anthracene shellfish element or anthracene shellfish chlorins compound.
Described beta-lactamase specifically can be NDM-1 albumen, TEM-1 albumen, VIM-1 albumen, SHV-18 albumen or IMP-1 albumen.Described beta-lactamase specifically can be the IMP-1 albumen shown in sequence 9 of the NDM-1 albumen shown in sequence 1 of sequence table, the TEM-1 albumen shown in sequence 3 of sequence table, the VIM-1 albumen shown in sequence 5 of sequence table, the SHV-18 albumen shown in sequence 7 of sequence table or sequence table.Described beta-lactam antibiotic is carbapenem antibiotic, Penicillin antibiotics or cephalosporins.Described carbapenem antibiotic specifically can be biapenem or meropenem.Described Penicillin antibiotics specifically can be ampicillin or benzylpenicillin.Described cephalosporins specifically can be cefepime, ceftazidime or cefradine.
Arbitrary described anthracene shellfish element is compound shown in formula 4 (compound 4) above;
Arbitrary described anthracene shellfish chlorins compound is compound shown in formula 1 above, the corresponding salt of compound shown in formula 1, the solvate of compound shown in formula 1, compound shown in formula 2, the corresponding salt of compound shown in formula 2, the solvate of compound shown in formula 2, compound shown in formula 3, the corresponding salt of compound shown in formula 3, the solvate of compound shown in formula 3, compound shown in formula 5, the corresponding salt of compound shown in formula 5, the solvate of compound shown in formula 5, the corresponding salt of compound shown in formula 4, the solvate of compound shown in formula 4, the complex of compound shown in formula 4, the high polymer of compound shown in the polymer of compound shown in formula 4 or formula 4,
In formula 1, R is-H (forming compound 1-1) ,-CH
2cH
2cH
2cH
2cH
2cH
3(forming compound 1-2),
(forming compound 1-3),
(forming compound 1-4),
(forming compound 1-5),
(formed compound 1-6) or
(forming compound 1-7).
In formula 2, R
1for-OCOCH
3or
r
2for-OCH
3or
In formula II, R
1and R
2for combining (1) or (2) as follows:
(1) R
1=OCOCH
3, R
2=OCH
3(forming compound 2-1); (2)
(forming compound 2-2).
In formula 3, R
3for-CH
2-CH
2-(CH
3)
2(formed compound 3-1) or
(forming compound 3-2).
In formula 5, R
4for-OCH
3(forming compound 5-1) ,-OCH
2cH
3(forming compound 5-2),
(forming compound 5-3),
(forming compound 5-4),
(forming compound 5-5),
(forming compound 5-6),
(forming compound 5-7),
(forming compound 5-8),
(forming compound 5-9),
(forming compound 5-10),
(formed compound 5-11) or
(forming compound 5-12).
The ammonium salt that the alkyl that described " the corresponding salt of compound shown in formula 4 " can be the C1-C6 of compound shown in the ammonium salt of compound shown in the bivalent metal ion salt of compound shown in the monovalent metallic ion salt of compound shown in formula 4, formula 4, formula 4 or formula 4 replaces.
Described " the monovalent metallic ion salt of compound shown in formula 4 " is compound (compound 7) shown in compound shown in formula 6 (compound 6) or formula 7.
Described " the bivalent metal ion salt of compound shown in formula 4 " is compound (compound 10) shown in compound (compound 9) shown in compound shown in compound shown in formula 8 (compound 8), formula 8-1 (compound 8-1, compound 8-1 are the salt of compound 8), formula 9 or formula 10.
In formula 8, M
1for Co
2+, Ni
2+, Cu
2+or Zn
2+; The octahedral chelate structure of represented by dotted arrows; S is solvent (specifically can be water).
In formula 8-1, M
2for Co
2+, Ni
2+, Cu
2+or Zn
2+; The octahedral chelate structure of represented by dotted arrows; S is solvent (specifically can be water).
In formula 9, M
3for Co
2+, Ni
2+, Cu
2+or Zn
2+; The octahedral chelate structure of represented by dotted arrows; S is solvent (specifically can be water).
In formula 10, M
4for Co
2+, Ni
2+, Cu
2+or Zn
2+; The octahedral chelate structure of represented by dotted arrows; S is solvent (specifically can be water).
Described " ammonium salt of compound shown in formula 4 " is compound shown in formula 11 (compound 11).
Described " ammonium salt of the alkyl replacement of the C1-C6 of compound shown in formula 4 " is compound shown in formula 12 (compound 12).
Described " complex of compound shown in formula 4 " is compound (compound 16) shown in compound (compound 15) shown in anthracene shellfish element-polyethylene glycol complex (compound 14) shown in the element-1,2,3-indantrione monohydrate complex of anthracene shellfish shown in formula 13 (compound 13), anthracene shellfish element-phosphatide complexes, formula 14, formula 15 or formula 16.
Described " polymer of compound shown in formula 4 " is dimer, and described dimer is compound shown in formula 17 (compound 17).
Described " high polymer of compound shown in formula 4 " is compound shown in formula 18 (compound 18).
In described formula 18, n >=2 (n specifically can be 2-8).
The corresponding salt of compound shown in formula 1 specifically can be compound pharmaceutically acceptable salt shown in formula 1.The corresponding salt of compound shown in formula 2 specifically can be compound pharmaceutically acceptable salt shown in formula 2.The corresponding salt of compound shown in formula 3 specifically can be compound pharmaceutically acceptable salt shown in formula 3.The corresponding salt of compound shown in formula 5 specifically can be compound pharmaceutically acceptable salt shown in formula 5.The corresponding salt of compound shown in formula 4 specifically can be compound pharmaceutically acceptable salt shown in formula 4.
" solvent " in described " solvate of compound shown in formula 1 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution." solvent " in described " solvate of compound shown in formula 2 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution." solvent " in described " solvate of compound shown in formula 3 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution." solvent " in described " solvate of compound shown in formula 5 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution." solvent " in described " solvate of compound shown in formula 4 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution.In arbitrary described dimethyl sulphoxide aqueous solution, the volume fraction of dimethyl sulfoxide is preferably 0.1-20% above.In arbitrary described sorbitan monooleate polyoxyethylene ether aqueous solution, the volume fraction of sorbitan monooleate polyoxyethylene ether is preferably 0.04-4% above.The purposes of anthracene shellfish element or anthracene shellfish chlorins compound can be promoted by the mode adding solvent.Liquid-solid compression (liquisolidcompacts) technology also can be adopted to promote the purposes of anthracene shellfish element or anthracene shellfish chlorins compound.
Arbitrary described product specifically can be medicine above.In medicine provided by the invention, except described effective ingredient, diluent, excipient, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant, synergist and the additive etc. that pharmaceutically allow can be added.The administration form of medicine provided by the invention, can be the oral formulations such as tablet, capsule, soft capsule, powder, granule, granula subtilis, liquor, pill, Emulsion or suspension, also can be the non-oral formulations such as injection (as powder, water preparation, oil preparation) suppository, ointment, plaster, patch, spray, tincture or eye drop.Described preparation all can adopt those skilled in the art know conventional preparation method and obtain.Its route of administration can be oral, percutaneous, vein or intramuscular injection.
The invention provides anthracene shellfish element or the following novelty teabag of anthracene shellfish chlorins compound: (1) lives inhibited to the enzyme of beta-lactamase (NDM-1 albumen, TEM-1 albumen, SHV-18 albumen, VIM-1 albumen or IMP-1 albumen etc.), particularly to New Delhi metal beta lactamase-1 (NDM-1 albumen) widely antibiont hydrolysing activity there is outstanding inhibitory action; (2) fastbacteria can significantly be increased to antibiotic sensitivity, obvious reduction Multiple Classes of Antibiotics (meropenem, biapenem, cefepime, cefradine, the cefradine etc.) minimum inhibitory concentration to super fastbacteria, the drug resistance of reversing drug resistance bacterium, reduces the clinical harm of serious fastbacteria; (3) there is bacteriostatic activity to a certain degree, the anthracene shellfish element of high concentration or anthracene shellfish chlorins compound have obvious bacteriostatic activity to pathogen such as staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhimurium, Song Shi shigella dysenteriae, Shigella flexneri, Klebsiella Pneumoniae, escherichia coli, even can bacteria growing inhibiting completely.
The present invention has major application for field of medicaments and health field and is worth.
Accompanying drawing explanation
Fig. 1 is reacting flow chart.
Fig. 2 is the agarose gel electrophoresis figure of pcr amplification product.
Fig. 3 is the polyacrylamide gel electrophoresis figure of NDM-1 protein solution.
Fig. 4 is that the relative enzyme of NDM-1 albumen in each system is lived.
Detailed description of the invention
Following embodiment is convenient to understand the present invention better, but does not limit the present invention.Experimental technique in following embodiment, if no special instructions, is conventional method.Test material used in following embodiment, if no special instructions, is and purchases available from routine biochemistry reagent shop.Quantitative test in following examples, all arranges and repeats experiment for three times, results averaged.
Bacillus coli DH 5 alpha: Transgen company.E. coli bl21 (DE3): Transgen company.Plasmid pET-22b (+): Novagen company.Klebsiella Pneumoniae (Klebsiellapneumoniae): ATCC is numbered BAA-2146, this bacterial strain is the Klebsiella Pneumoniae carrying NDM-1 drug resistant gene, is called for short Klebsiella Pneumoniae BAA-2146.Klebsiella Pneumoniae (Klebsiellapneumoniae): ATCC is numbered 700603, this bacterial strain is the Klebsiella Pneumoniae carrying SHV-18 drug resistant gene, is called for short Klebsiella Pneumoniae 700603.Escherichia coli (Escherichiacoli): ATCC is numbered 35218, this bacterial strain is the escherichia coli of carrying TEM-1 drug resistant gene, is called for short escherichia coli 35218.
Biapenem (carbapenem antibiotic), meropenem (carbapenem antibiotic), benzylpenicillin (Penicillin antibiotics), ampicillin (Penicillin antibiotics), cefepime (cephalosporins, forth generation cephalosporin), ceftazidime (cephalosporins, third generation cephalosporin), cefradine (cephalosporins, second generation cephalosporin), sulbactam, Tazobactam Sodium and clavulanic acid, all purchased from Nat'l Pharmaceutical & Biological Products Control Institute.
Compound: Embelin (2 shown in formula 4 used in following embodiment, 5-dihydroxy-3-undecyl-1,4-benzoquinone), English name is 2,5-Dihydroxy-3-undecyl-1,4-benzoquinone or 2,5-dihydroxy-3-undecylcyclohexa-2,5-diene-1,4-dione; Sigma company (purity >98%); No. CAS is 550-24-3, and No. EINECS is 208-979-8, and molecular formula is C
17h
26o
4, molecular weight is 294.3859; InChI=1/C17H26O4/c1-2-3-4-5-6-7-8-9-10-11-13-16 (20) 14 (18) 12-15 (19) 17 (13) 21/h12,18,21H, 2-11H2,1H3; Common form: orange plate crystal; Density: 1.131g/cm
3; Boiling point: the boiling point under 760mmHg is 431.9 DEG C; Flash-point: 229.1 DEG C; Vapour pressure: be 2.85E-09mmHg at 25 DEG C.
Shown in formula 2-1 in following embodiment, compound shown in compound and formula 5-2 shown in compound, formula 5-1 is all by document XuM, DengZ, LiJ, FuH, ProkschP, etal.Chemicalconstituentsfromthemangroveplant, Aegicerascorniculatum.JNatProd2004:67:762-6. prepare.
Compound shown in formula 5-3 in following embodiment, compound shown in formula 5-4, compound shown in formula 5-5, compound shown in formula 5-6, compound shown in formula 5-7, compound shown in formula 5-8, compound shown in formula 5-9, compound shown in formula 5-10, compound shown in formula 5-11, compound shown in compound and formula 3-2 shown in formula 5-12 is all by document SekarMahendran, ShrishailappaBadami, etal.SynthesisandEvaluationofAnalgesicandAnti-inflammato ryActivitiesofMostActiveFreeRadicalScavengingDerivatives ofEmbelin-AStructure – ActivityRelationship.Chem.Pharm.Bull.59 (8) 913-919 (2011). prepare.
Shown in formula 1-1 in following embodiment, compound shown in compound and formula 1-7 shown in compound, formula 1-6 shown in compound, formula 1-5 shown in compound, formula 1-4 shown in compound, formula 1-3 shown in compound, formula 1-2 is all by document JianyongChen, ZanetaNikolovska-Coleska, etal.Design, synthesis, andcharacterizationofnewembelinderivativesaspotentinhibi torsofX-linkedinhibitorofapoptosisprotein.2006.ElsevierL td.16:5805 – 5808. prepares.As shown in Figure 1, the condition in Fig. 1 is corresponding reacting flow chart: (a) n-BuLi, THF, 0 DEG C and 10min; (b) H
2, 10%Pd-C, EtOAc and RT; (c) CAN, CH3CN-H2O, 0 DEG C and 1h; (d) HClO4, HCl, dioxane, RT and 48h.
Shown in formula 3-1 in following embodiment, compound shown in compound and formula 12 is all by document GuptaOP, AliMM, RayGhatakBJ, etal.Somepharmacologicalinvestigationsofembelinanditssem isyntheticderivatives.IndianJPhysiolPharmacol.1977Jan-Ma r; 21 (1): 31-9. prepare.
Shown in formula 6 in following embodiment, compound shown in compound and formula 7 is all by document ZutshiU, SharmaSC, KaulJL, AtalCK.Kineticfateofpotassiumembelate, anon-narcoticcentrallyactinganalgesicafteroralandintrave nousadministration.Pharmacology.40:179-184. prepares.
Shown in formula 11 in following embodiment, compound presses document YaredDebebe., MesfinTefera., etal.2015.EvaluationofanthelminticpotentialoftheEthiopia nmedicinalplantEmbeliaschimperiVatkeinvivoandinvitroagai nstsomeintestinalparasites.BMCComplementaryandAlternativ eMedicine.15:187. prepares.
Shown in formula 8 in following embodiment, compound shown in compound and formula 10 shown in compound, formula 9 is all by document VaddadiUshaRani., GhantaJyothi., etal.2010.ChemicalSpeciationofBinaryComplexesofEmbelinWi thSomeBiologicallyImportantMetalIons.ActaChim.Slov.57:91 6 – 921. prepares.
Shown in formula 13 in following embodiment, compound presses document S.Mahendran, S.Badami, etal.2011Antioxidant, analgesicandanti-inflammatorypropertiesofnewninhydrinadd uctofembelin.PharmaceuticalChemistryJournal.Volume45, Issue9, pp547-551. prepare.
Compound anthracene shellfish element-phosphatide complexes in following embodiment presses document RahilaAhmadPathan., and UmaBhandari.2011.Preparation & characterizationofembelin – phospholipidcomplexaseffectivedrugdeliverytool.JInclPhen omMacrocyclChem.69:139-14 prepares.
Shown in formula 14 in following embodiment, compound presses document YixianHuang, JianqinLu, etal.PEG-DerivatizedEmbelinasaDualFunctionalCarrierforth eDeliveryofPaclitaxel.BioconjugChem.2012July18; 23 (7): 1443 – 1451 prepare.
Shown in formula 15 in following embodiment, compound shown in compound and formula 16 is all by document RosalynPena, SandraJimenez-Alonso, etal.Multicomponentsynthesisofantibacterialdihydropyridi nanddihydropyranembelinderivatives.J.Org.Chem.2013,78,7977-7985 prepares.
Shown in formula 17 in following embodiment, compound presses document C.Balachandran., V.Duraipandiyan., etal.2013.Synthesisandmedicinalpropertiesofplant-derived vilangin.EnvironChemLett.11:303-308 prepares.
Shown in formula 18 in following embodiment, compound presses document R.Renuka., S.Rajasekaran., etal.2001.ElectrochemicallySynthesizedPolymerofthePlantS ubstanceEmbelin (2,5-Dihydroxy-3-Undecyl-1,4-Benzoquinone) .AppliedBiochemistryandBiotechnology prepares.
The preparation of embodiment 1, albumen
One, the preparation of NDM-1 albumen
1, with the genomic DNA of Klebsiella Pneumoniae BAA-2146 for template, pcr amplification is carried out with the primer pair of P1 and P2 composition, obtain pcr amplification product (there is the sequence 2 of sequence table from the NDM-1 gene shown in 5 ' end the 1 to 810 nucleotide in pcr amplification product, the NDM-1 albumen shown in sequence 1 of polynucleotide).
P1：5’-
catatggaattgcccaatattatg-3’；
P2：5’-
ctcgaggcgcagcttgtcggccat-3’。
PCR condition: 95 DEG C of 3min; 94 DEG C of 30s, 60 DEG C of 30s, 72 DEG C of 1min, 30 circulations; 72 DEG C of 5min.
PCR reaction system (50 μ l): template 2 μ l, each 2 μ l, the dNTP4 μ l of upstream and downstream primer, EasyTaqpolymerase0.5 μ l, 10 × buffer5 μ l, adds H
2o to 50 μ l.
The agarose gel electrophoresis figure of pcr amplification product is shown in Fig. 2, and M is Marker (2000bp), and 1 is pcr amplification product.Amplified fragments is about 819bp, in the same size with expection
2, use the pcr amplification product of restricted enzyme NdeI and XhoI double digestion step 1, reclaim digestion products.
3, with restricted enzyme NdeI and XhoI double digestion plasmid pET-22b (+), the carrier framework of about 5400bp is reclaimed.
4, the digestion products of step 2 is connected with the carrier framework of step 3, obtains recombiant plasmid pET-22b (+)-ndm1.According to sequencing result, carry out structure to recombiant plasmid pET-22b (+)-ndm1 to be described below: between NdeI and the XhoI restriction enzyme site of plasmid pET-22b (+), insert the sequence 2 of sequence table from the double chain DNA molecule shown in 5 ' end the 4 to 810 nucleotide, the encoding gene of the His label on this double chain DNA molecule and carrier framework merges, and expresses the NDM-1 albumen that N-terminal has His label.
5, recombiant plasmid pET-22b (+)-ndm1 is imported e. coli bl21 (DE3), obtain recombinant bacterium.
6, the recombinant bacterium that step 5 obtains is seeded to LB culture medium, works as OD
600nmadding IPTG when reaching exponential phase to final concentration is that 0.1mmol/L carries out abduction delivering, and abduction delivering is after 4 hours, collected by centrifugation thalline.
7, thalline step 6 obtained carries out ultrasonication (400W; Work 5s, interval 3s, circulate 99 times), the then centrifugal 20min of 5000g, collects supernatant.
8, the supernatant that step 7 obtains is splined on nickel post and carries out affinity chromatograph, the imidazole concentration of balance liquid is 40mmol/L, the imidazole concentration of eluent is 400mmol/L, collected the eluent after post (NDM-1 protein liquid), be contained in bag filter the Hepes buffer being placed in 10mM to dialyse, then get the solution in bag filter, be NDM-1 protein solution.
The polyacrylamide gel electrophoresis figure of NDM-1 protein solution is shown in Fig. 3, and M is the protein Marker of 12-80kd, and 1 and 2 is NDM-1 protein solution.Can find out, there is the protein fragments of 28KD in swimming lane 1 and swimming lane 2, with expection in the same size.
Two, the preparation of TEM-1 albumen
1, with the genomic DNA of escherichia coli 35218 for template, pcr amplification is carried out with the primer pair of P3 and P4 composition, obtain pcr amplification product (there is the sequence 4 of sequence table from the TEM-1 gene shown in 5 ' end the 1 to 858 nucleotide in pcr amplification product, the TEM-1 albumen shown in sequence 3 of polynucleotide).
P3：5’-
catatgagtattcaacatttccgtgt-3’；
P4：5'-
ctcgagccaatgcttaatcagtgag-3'。
2, use the pcr amplification product of restricted enzyme NdeI and XhoI double digestion step 1, reclaim digestion products.
3, with restricted enzyme NdeI and XhoI double digestion plasmid pET-22b (+), the carrier framework of about 5400bp is reclaimed.
4, the digestion products of step 2 is connected with the carrier framework of step 3, obtains recombiant plasmid pET-22b (+)-tem1.
5, recombiant plasmid pET-22b (+)-tem1 is imported e. coli bl21 (DE3), obtain recombinant bacterium.
6, with 6 of step one.
7, with 7 of step one.
8, with 8 of step one.Obtain TEM-1 protein solution.
Three, the preparation of VIM-2 albumen
1, by the sequence 6 of artificial synthesized sequence table between XhoI and the NdeI restriction enzyme site of double chain DNA molecule insertion vector pET-22b (+) shown in 5 ' end the 1 to 798 nucleotide, obtain recombiant plasmid pET-22b (+)-vim2.The VIM-2 albumen shown in sequence 5 of the double chain DNA molecule polynucleotide shown in sequence 6 of sequence table.
2, recombiant plasmid pET-22b (+)-vim2 is imported e. coli bl21 (DE3), obtain recombinant bacterium.
3, with 6 of step one.
4, with 7 of step one.
5, with 8 of step one.Obtain VIM-2 protein solution.
Four, the preparation of SHV-18 albumen
1, with the genomic DNA of Klebsiella Pneumoniae 700603 for template, pcr amplification is carried out with the primer pair of P5 and P6 composition, obtain pcr amplification product (there is the sequence 8 of sequence table from the SHV-18 gene shown in 5 ' end the 1 to 858 nucleotide in pcr amplification product, the SHV-18 albumen shown in sequence 7 of polynucleotide).
P5：5’-
catatgcgttattttcgcctgtgtat-3’；
P6：5’-
ctcgaggcgttgccagtgctcgatc-3’。
2, use the pcr amplification product of restricted enzyme NdeI and XhoI double digestion step 1, reclaim digestion products.
3, with restricted enzyme NdeI and XhoI double digestion plasmid pET-22b (+), the carrier framework of about 5400bp is reclaimed.
4, the digestion products of step 2 is connected with the carrier framework of step 3, obtains recombiant plasmid pET-22b (+)-shv18.
5, recombiant plasmid pET-22b (+)-shv18 is imported e. coli bl21 (DE3), obtain recombinant bacterium.
6, with 6 of step one.
7, with 7 of step one.
8, with 8 of step one.Obtain SHV-18 protein solution.
Five, the preparation of IMP-1 albumen
1, by the sequence 10 of artificial synthesized sequence table between XhoI and the NdeI restriction enzyme site of double chain DNA molecule insertion vector pET-22b (+) shown in 5 ' end the 1 to 798 nucleotide, obtain recombiant plasmid pET-22b (+)-imp1.The IMP-1 albumen shown in sequence 9 of the double chain DNA molecule polynucleotide shown in sequence 10 of sequence table.
2, recombiant plasmid pET-22b (+)-imp1 is imported e. coli bl21 (DE3), obtain recombinant bacterium.
3, with 6 of step one.
4, with 7 of step one.
5, with 8 of step one.Obtain IMP-1 protein solution.
Embodiment 2, the inhibit activities of anthracene shellfish element to various beta-lactamase
Anthracene shellfish element (Embelin) is i.e. compound shown in formula 4.
One, the inhibit activities of anthracene shellfish element to NDM-1 albumen
1, the NDM-1 protein solution prepared by embodiment 1, biapenem and containing 50 μMs of ZnCl
210mMHEPES buffer (pH7.5) mixing, make that the concentration of NDM-1 albumen is 0.5 μ g/ml, the concentration of biapenem is 0.5mM.
2, the system of step 1 is divided into some groups, adds not commensurability anthracene shellfish element respectively, 30 DEG C of reaction 10min, detect 235nm (antibiotic specificabsorption peak) absorption value (A
235nmvalue).
The relative enzyme of NDM-1 albumen in system live=(the A when reaction of this system starts when anthracene shellfish element adopts variable concentrations
235nmthe A of-finish time
235nmvalue)/(A when reaction of this system starts when anthracene shellfish element concentration is 0
235nmthe A of-finish time
235nmvalue) × 100%.
The half-inhibition concentration IC that anthracene shellfish element is lived to NDM-1 enzyme
50compounds I concentration (μM) corresponding when the relative enzyme work of=NDM-1 albumen in system is 50%.
Carry out repeating experiment for three times, results averaged.
In each system, the relative enzyme of NDM-1 albumen is lived and is seen Fig. 4.Result shows, anthracene shellfish element to NDM-1 albumen as beta-lactamase enzyme live (the enzyme work of NDM-1 albumen as beta-lactamase and the activity of NDM-1 Proteolytic enzyme biapenem) there is obvious inhibitory action, to the half-inhibition concentration IC of the NDM-1 albumen of 0.5 μ g/ml
50it is 2.11 ± 0.17 μMs.
Anthracene shellfish element is replaced to carry out above-mentioned experiment with sulbactam, Tazobactam Sodium or clavulanic acid.Result shows, when concentration reaches 1mM, sulbactam, Tazobactam Sodium, the clavulanic acid activity to NDM-1 Proteolytic enzyme biapenem does not have inhibitory action.
Two, the inhibit activities of anthracene shellfish element to TEM-1 albumen
With the NDM-1 albumen that the TEM-1 albumen replacement initial concentration that initial concentration is 1.95 μ g/ml is 0.5 μ g/ml, replace initial concentration to be the biapenem of 0.5mM with the benzylpenicillin that initial concentration is 2mM, other is with step one.
Result shows, anthracene shellfish element to TEM-1 albumen as beta-lactamase enzyme live (the enzyme work of TEM-1 albumen as beta-lactamase and the activity of TEM-1 Proteolytic enzyme benzylpenicillin) there is obvious inhibitory action, to the half-inhibition concentration IC of the TEM-1 albumen of 1.95 μ g/ml
50it is 1.8 ± 0.4 μMs.
Anthracene shellfish element is replaced to carry out above-mentioned experiment with sulbactam, Tazobactam Sodium or clavulanic acid.Result shows, when concentration reaches 1mM, sulbactam, Tazobactam Sodium, the clavulanic acid activity to TEM-1 Proteolytic enzyme benzylpenicillin does not have inhibitory action.
Three, the inhibit activities of anthracene shellfish element to VIM-2 albumen
With the NDM-1 albumen that the VIM-2 albumen replacement initial concentration that initial concentration is 44 μ g/ml is 0.5 μ g/ml, replace initial concentration to be the biapenem of 0.5mM with the meropenem that initial concentration is 0.25mM, other is with step one.
Result shows, anthracene shellfish element to VIM-2 albumen as beta-lactamase enzyme live (the enzyme work of VIM-2 albumen as beta-lactamase and the activity of VIM-2 Proteolytic enzyme meropenem) there is obvious inhibitory action, to the half-inhibition concentration IC of the VIM-2 albumen of 44 μ g/ml
50it is 225 ± 28 μMs.
Anthracene shellfish element is replaced to carry out above-mentioned experiment with sulbactam, Tazobactam Sodium or clavulanic acid.Result shows, when concentration reaches 1mM, sulbactam, Tazobactam Sodium, the clavulanic acid activity to VIM-2 Proteolytic enzyme meropenem does not have inhibitory action.
Four, the inhibit activities of anthracene shellfish element to SHV-18 albumen
With the NDM-1 albumen that the SHV-18 albumen replacement initial concentration that initial concentration is 72 μ g/ml is 0.5 μ g/ml, replace initial concentration to be the biapenem of 0.5mM with the cefepime that initial concentration is 0.5mM, other is with step one.
Result shows, anthracene shellfish element to SHV-18 albumen as beta-lactamase enzyme live (the enzyme work of SHV-18 albumen as beta-lactamase and the activity of SHV-18 Proteolytic enzyme cefepime) there is obvious inhibitory action, to the half-inhibition concentration IC of the SHV-18 albumen of 72 μ g/ml
50it is 18.5 ± 3.9 μMs.
Replace anthracene shellfish element to carry out above-mentioned experiment with sulbactam, Tazobactam Sodium or clavulanic acid, result shows, when concentration reaches 1mM, sulbactam, Tazobactam Sodium, the clavulanic acid activity to SHV-18 Proteolytic enzyme cefepime does not have inhibitory action.
Five, the inhibit activities of anthracene shellfish element to IMP-1 albumen
With the NDM-1 albumen that the IMP-1 albumen replacement initial concentration that initial concentration is 7.44 μ g/ml is 0.5 μ g/ml, other is with step one.
Result shows, anthracene shellfish element to IMP-1 albumen as beta-lactamase enzyme live (the enzyme work of IMP-1 albumen as beta-lactamase and the activity of IMP-1 Proteolytic enzyme biapenem) there is obvious inhibitory action, to the half-inhibition concentration IC of the IMP-1 albumen of 7.44 μ g/ml
50it is 102 ± 17 μMs.
Replace anthracene shellfish element to carry out above-mentioned experiment with sulbactam, Tazobactam Sodium or clavulanic acid, result shows, when concentration reaches 1mM, sulbactam, Tazobactam Sodium, the clavulanic acid activity to IMP-1 Proteolytic enzyme biapenem does not have inhibitory action.
Embodiment 3, compound are to the reverse of the drug resistance of fastbacteria
Antibiotic refers to ampicillin, cefradine, ceftazidime, cefepime, meropenem or biapenem.
Inhibitor refers to the compound (compound shown in formula 1-1 provided in the present invention, compound shown in formula 1-2, compound shown in formula 1-3, compound shown in formula 1-4, compound shown in formula 1-5, compound shown in compound and formula 1-7 shown in formula 1-6, compound shown in formula 2-1, compound shown in formula 3-1, compound shown in formula 3-2, compound shown in formula 4, compound shown in formula 5-1, compound shown in formula 5-2, compound shown in formula 5-3, compound shown in formula 5-4, compound shown in formula 5-5, compound shown in formula 5-6, compound shown in formula 5-7, compound shown in formula 5-8, compound shown in formula 5-9, compound shown in formula 5-10, compound shown in formula 5-11, compound shown in formula 5-12, compound shown in formula 6, compound shown in formula 7, compound shown in formula 8, compound shown in formula 9, compound shown in formula 10, compound shown in formula 11, compound shown in formula 12, compound shown in formula 13, compound shown in formula 14, compound shown in formula 15, compound shown in formula 16, compound shown in compound shown in formula 17 or formula 18), sulbactam, Tazobactam Sodium or clavulanic acid.
1, MH broth bouillon (beef powder 2.0g/L, soluble starch 1.5g/L, acid hydrolyzed casein 17.5g/L is adopted; PH7.4) cultivating Klebsiella Pneumoniae BAA-2146 is 1.5 × 10 to bacterial concentration
8cFU/ml, dilutes 1000 times with MH broth bouillon, and namely bacterial concentration is 1.5 × 10
5cFU/ml.
2, bacterium liquid step 1 obtained is divided into some groups, add not commensurability antibiotic respectively, make its concentration be 4096mg/L, 2048mg/L, 1024mg/L, 512mg/L, 256mg/L, 128mg/L, 64mg/L, 32mg/L, 16mg/L, 8mg/L, 4mg/L, 2mg/L, 1mg/L, 0.5mg/L, 0.25mg/L, 0.125mg/L or 0.0625mg/L.
3, the system of each group step 2 obtained is divided into some groups again, adds not commensurability inhibitor respectively, makes its concentration be 60mg/L, 40mg/L, 20mg/L, 10mg/L, 4mg/L, 1mg/L, 0.5mg/L, 0.25mg/L or 0mg/L.
4, each individual system step 3 obtained 37 DEG C, 180rpm/min shaken cultivation 18 hours, detect the OD of bacterium liquid
600nmvalue.
Operational approach is carried out with reference to the regulation of Laboratory Standard committee of the U.S. (Clinicalandlaboratorystandardsinstitute, CLSI), and result criteria for interpretation judges with reference to the marginal value of CLSI in 2012.
Arrange and repeat experiment for three times, results averaged.
Calculate minimum inhibitory concentration (Minimalinhibitoryconcentration, MIC), the antibiotic least concentration namely completely required for bacteria growing inhibiting (works as OD
600nmvalue is less than negative control group OD
600nmvalue 110% time, think complete bacteria growing inhibiting; Negative control group only adds inhibitor, antibiotic and culture medium).
Each compound provided in the present invention all can reduce the minimum inhibitory concentration of each Antibiotics on Klebsiella Pneumoniae.Add the different compounds of same concentrations (60mg/L), the MIC of different Antibiotics on Klebsiella Pneumoniae reduces 2-512 doubly, and Be very effective is better than existing inhibitor (clavulanic acid, sulbactam or Tazobactam Sodium).Test result shows, when compound shown in the formula 4 adding 40mg/L, the fungistatic effect of cefradine, ceftazidime, cefepime improves 4 times, 32 times and 8 times respectively, and the fungistatic effect of meropenem and biapenem improves 512 times and 128 times (MIC reduces to 0.125mg/L and 0.0625mg/L respectively) respectively.Each compound provided in the present invention can the drug resistance (MIC reduce 2-512 doubly) of reversing drug resistance bacterium in various degree, significantly improves fastbacteria to antibiotic sensitivity; Wherein, shown in compound shown in compound shown in formula 5-1, formula 5-12, formula 6, shown in compound, formula 12, the effect of compound, formula 17 shown in compound, formula 13 is better than compound shown in formula 4; Sulbactam, Tazobactam Sodium, the clinical conventional beta-lactamase inhibitor of clavulanic acid three kinds on each antibiotic MIC without any impact.Partial results is see table 1 (in table 1: the numerical value of the cell of the first row refers to the initial concentration of inhibitor; Second numerical value walking to the second Ariadne refers to antibiotic minimum inhibitory concentration, and unit is mg/L).
The complex of table 1 antibiotic and inhibitor detects the bacteriostatic activity producing NDM-1 fastbacteria
The direct antibacterial activity of embodiment 3, compound
Antibacterial refers to compound shown in formula 1-1, compound shown in formula 1-2, compound shown in formula 1-3, compound shown in formula 1-4, compound shown in formula 1-5, compound shown in compound and formula 1-7 shown in formula 1-6, compound shown in formula 2-1, compound shown in formula 3-1, compound shown in formula 3-2, compound shown in formula 4, compound shown in formula 5-1, compound shown in formula 5-2, compound shown in formula 5-3, compound shown in formula 5-4, compound shown in formula 5-5, compound shown in formula 5-6, compound shown in formula 5-7, compound shown in formula 5-8, compound shown in formula 5-9, compound shown in formula 5-10, compound shown in formula 5-11, compound shown in formula 5-12, compound shown in formula 6, compound shown in formula 7, compound shown in formula 8, compound shown in formula 9, compound shown in formula 10, compound shown in formula 11, compound shown in formula 12, compound shown in formula 13, compound shown in formula 14, compound shown in formula 15, compound shown in formula 16, compound shown in compound shown in formula 17 or formula 18.
Bacterium to be measured is respectively following bacterium: staphylococcus aureus (Staphylococcusaureus): ATCC is numbered 29213; Pseudomonas aeruginosa (Pseudomonasaeruginosa): ATCC is numbered 15442; Salmonella typhimurium (Salmonellatyphimurium): CICC is numbered 21484; Song Shi shigella dysenteriae (Shigellasonnei): CICC is numbered 21535; Shigella flexneri (Shigellaflexneri): CICC is numbered 21534; Klebsiella Pneumoniae (Klebsiellapneumoniae): ATCC is numbered 700603; Escherichia coli (Escherichiacoli): ATCC is numbered 25922.
1, adopting MH broth bouillon to cultivate bacterium to be measured to bacterial concentration is (1.5 × 10
8cFU/ml), dilute 1000 times with MH broth bouillon, namely bacterial concentration is 1.5 × 10
5cFU/ml.
2, get the bacterium liquid that step 1 obtains, add antibacterial and make its initial concentration be 128mg/L, then 37 DEG C, 180rpm/min shaken cultivation 18 hours, detect the OD of bacterium liquid
600nmvalue.
Operational approach is carried out with reference to the regulation of Laboratory Standard committee of the U.S. (Clinicalandlaboratorystandardsinstitute, CLSI), and result criteria for interpretation judges with reference to the marginal value of CLSI in 2012.Arrange and repeat experiment for three times, results averaged.
Each antibacterial all has significantly directly bacteriostatic activity to pathogen such as staphylococcus aureus, Pseudomonas aeruginosa, Salmonella typhimurium, Song Shi shigella dysenteriae, Shigella flexneri, Klebsiella Pneumoniae and escherichia coli, all can suppress the growth of above-mentioned antibacterial under the concentration of 128mg/L.
Claims (10)
1. anthracene shellfish element or the application of anthracene shellfish chlorins compound in the product preparing anti-bacteria.
2. a product for anti-bacteria, its active component is anthracene shellfish element or anthracene shellfish chlorins compound.
3. inhibitor and the antibiotic application in the product preparing anti-bacteria; Described inhibitor is anthracene shellfish element or anthracene shellfish chlorins compound.
4. a product for anti-bacteria, its active component is inhibitor and antibiotic; Described inhibitor is anthracene shellfish element or anthracene shellfish chlorins compound.
5. anthracene shellfish element or anthracene shellfish chlorins compound are preparing the application in beta-lactamase inhibitor.
6. a beta-lactamase inhibitor, its active component is anthracene shellfish element or anthracene shellfish chlorins compound.
7. anthracene shellfish element or anthracene shellfish chlorins compound suppress the application in the product of beta-lactam enzyme hydrolysis beta-lactam antibiotic in preparation.
8. suppress a product for beta-lactam enzyme hydrolysis beta-lactam antibiotic, its active component is anthracene shellfish element or anthracene shellfish chlorins compound.
9. apply as claimed in claim 1, or, product as claimed in claim 2, or, apply as claimed in claim 3, or, product as claimed in claim 4, or, apply as claimed in claim 5, or, beta-lactamase inhibitor as claimed in claim 6, or, apply as claimed in claim 7, or product as claimed in claim 8, it is characterized in that: above arbitrary described anthracene shellfish chlorins compound is compound shown in formula 1, the corresponding salt of compound shown in formula 1, the solvate of compound shown in formula 1, compound shown in formula 2, the corresponding salt of compound shown in formula 2, the solvate of compound shown in formula 2, compound shown in formula 3, the corresponding salt of compound shown in formula 3, the solvate of compound shown in formula 3, compound shown in formula 5, the corresponding salt of compound shown in formula 5, the solvate of compound shown in formula 5, the corresponding salt of compound shown in formula 4, the solvate of compound shown in formula 4, the complex of compound shown in formula 4, the high polymer of compound shown in the polymer of compound shown in formula 4 or formula 4,
In formula 1, R is-H ,-CH
2cH
2cH
2cH
2cH
2cH
3,
In formula 2, R
1for-OCOCH
3or
r
2for-OCH
3or
In formula 3, R
3for-CH
2-CH
2-(CH
3)
2or
In formula 5, R
4for-OCH
3,-OCH
2cH
3,
10. application as claimed in claim 9, beta-lactamase inhibitor or product, is characterized in that:
In formula 2, R
1and R
2for combining (1) or (2) as follows:
(1)R
1＝OCOCH
3，R
2＝OCH
3；
The ammonium salt that shown in the ammonium salt of compound shown in the bivalent metal ion salt of compound shown in the monovalent metallic ion salt that described " the corresponding salt of compound shown in formula 4 " is compound shown in formula 4, formula 4, formula 4 or formula 4, the alkyl of the C1-C6 of compound replaces;
Described " the monovalent metallic ion salt of compound shown in formula 4 " is compound shown in compound shown in formula 6 or formula 7;
Described " the bivalent metal ion salt of compound shown in formula 4 " is compound shown in compound shown in compound shown in compound shown in formula 8, formula 8-1, formula 9 or formula 10;
In formula 8, M
1for Co
2+, Ni
2+, Cu
2+or Zn
2+; The octahedral chelate structure of represented by dotted arrows; S is solvent;
In formula 8-1, M
2for Co
2+, Ni
2+, Cu
2+or Zn
2+; The octahedral chelate structure of represented by dotted arrows; S is solvent;
In formula 9, M
3for Co
2+, Ni
2+, Cu
2+or Zn
2+; The octahedral chelate structure of represented by dotted arrows; S is solvent;
In formula 10, M
4for Co
2+, Ni
2+, Cu
2+or Zn
2+; The octahedral chelate structure of represented by dotted arrows; S is solvent;
Described " ammonium salt of compound shown in formula 4 " is compound shown in formula 11;
Described " ammonium salt of the alkyl replacement of the C1-C6 of compound shown in formula 4 " is compound shown in formula 12;
Described " complex of compound shown in formula 4 " is compound shown in compound shown in anthracene shellfish element-polyethylene glycol complex shown in the element-1,2,3-indantrione monohydrate complex of anthracene shellfish shown in formula 13, anthracene shellfish element-phosphatide complexes, formula 14, formula 15 or formula 16;
Described " polymer of compound shown in formula 4 " is dimer, and described dimer is compound shown in formula 17;
Described " high polymer of compound shown in formula 4 " is compound shown in formula 18;
In described formula 18, n >=2;
Described " the corresponding salt of compound shown in formula 1 " is preferably compound pharmaceutically acceptable salt shown in formula 1; The corresponding salt of compound shown in described formula 2 is preferably " shown in formula 2 compound pharmaceutically acceptable salt "; Described " the corresponding salt of compound shown in formula 3 " is preferably compound pharmaceutically acceptable salt shown in formula 3; Described " the corresponding salt of compound shown in formula 5 " is preferably compound pharmaceutically acceptable salt shown in formula 5; Described " the corresponding salt of compound shown in formula 4 " is preferably compound pharmaceutically acceptable salt shown in formula 4;
" solvent " in described " solvate of compound shown in formula 1 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution; " solvent " in described " solvate of compound shown in formula 2 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution; " solvent " in described " solvate of compound shown in formula 3 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution; " solvent " in described " solvate of compound shown in formula 5 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution; " solvent " in described " solvate of compound shown in formula 4 " is preferably dimethyl sulphoxide aqueous solution, olive oil or sorbitan monooleate polyoxyethylene ether aqueous solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510577998.6A CN105147652B (en) | 2015-09-11 | 2015-09-11 | New application of embelin or embelin compounds in inhibiting bacteria |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510577998.6A CN105147652B (en) | 2015-09-11 | 2015-09-11 | New application of embelin or embelin compounds in inhibiting bacteria |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105147652A true CN105147652A (en) | 2015-12-16 |
| CN105147652B CN105147652B (en) | 2018-02-13 |
Family
ID=54788942
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510577998.6A Active CN105147652B (en) | 2015-09-11 | 2015-09-11 | New application of embelin or embelin compounds in inhibiting bacteria |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105147652B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107875149A (en) * | 2017-11-19 | 2018-04-06 | 郑士平 | It is a kind of treat drug-resistant bacteria caused by urinary tract infections transdermal absorption formulation |
| CN110004087A (en) * | 2019-04-12 | 2019-07-12 | 江西省科学院微生物研究所 | It is a kind of inhibit Phomopsis defence pseudomonad and its application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2409536A1 (en) * | 2011-12-22 | 2013-06-26 | Universidad De La Laguna | Syetetic heterocyclic quinonas with antimicrobial activity. (Machine-translation by Google Translate, not legally binding) |
-
2015
- 2015-09-11 CN CN201510577998.6A patent/CN105147652B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2409536A1 (en) * | 2011-12-22 | 2013-06-26 | Universidad De La Laguna | Syetetic heterocyclic quinonas with antimicrobial activity. (Machine-translation by Google Translate, not legally binding) |
Non-Patent Citations (3)
| Title |
|---|
| M. CHITRA,ET AL.: "Antibacterial activity of embelin", 《FITOTERAPIA》 * |
| M. STASIUK,ET AL.: "Embelin - a promising bioactive compound from the Myrsinaceae family", 《GLOBAL JOURNAL OF BIOCHEMISTRY》 * |
| ROSALYN PEÑA,ET AL.: "Multicomponent Synthesis of Antibacterial Dihydropyridin and Dihydropyran Embelin Derivatives", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107875149A (en) * | 2017-11-19 | 2018-04-06 | 郑士平 | It is a kind of treat drug-resistant bacteria caused by urinary tract infections transdermal absorption formulation |
| CN110004087A (en) * | 2019-04-12 | 2019-07-12 | 江西省科学院微生物研究所 | It is a kind of inhibit Phomopsis defence pseudomonad and its application |
| CN110004087B (en) * | 2019-04-12 | 2022-10-21 | 江西省科学院微生物研究所 | Defensive pseudomonas capable of inhibiting phomopsis and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105147652B (en) | 2018-02-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101738210B1 (en) | - pharmaceutical compositions comprising betalactam antibiotic sulbactam and betalactamase inhibitor | |
| CN102871996B (en) | Antibiotic composition and application thereof | |
| CN105801610A (en) | Novel broad-spectrum beta-lactamase inhibitor | |
| CN103687598A (en) | Pharmaceutical compositions comprising sulbactam and beta-lactamase inhibitor | |
| Cheng et al. | Design, synthesis and antibacterial activity studies of thiazole derivatives as potent ecKAS III inhibitors | |
| CN105452259A (en) | Tricyclic benzoxaborole compound, preparation method therefor, and use thereof | |
| CN105147652A (en) | Novel application of embelin or embelin compound in bacterium inhibition | |
| CN106798731B (en) | Preparation method of florfenicol soluble powder | |
| US8338476B2 (en) | Compositions and methods of sensitizing methicillin resistant Staphylococcus aureus to beta-lactam antibiotics | |
| KR20140035376A (en) | Compositions comprising antibacterial agent and tazobactam | |
| CN113842380B (en) | New use of vedofluradelmol as NDM-1 inhibitor or antibiotic protectant | |
| KR101953981B1 (en) | Use of β-nicotinamide adenine dinucleotide 2’-phosphate reduced (NADPH) and its derivatives as beta-lactamase inhibitors | |
| CN113209090B (en) | Application of methimazole in preparation of metallo-beta-lactamase inhibitor | |
| CN102743388B (en) | Composition used for inhibiting bacteria generating novel beta lactamase | |
| CN112999220B (en) | Application of alpha-lipoic acid as and/or preparing metallo-beta-lactamase inhibitor | |
| CN103230367B (en) | Cefpodoxime proxetil composition dry suspension and preparation method thereof | |
| CA2774772A1 (en) | Compositions and methods for treating bacterial infections using ceftaroline | |
| WO2015142952A1 (en) | Compounds for treatment of fluorquinolone-resistant bacteria | |
| KR102457866B1 (en) | New inhibitors for the metallo-beta-lactamase produced by a multi-resistant bacteria and methods of preparation thereof | |
| WO2012131690A1 (en) | Drug delivery form as a bilayer tablet | |
| ES2752040B2 (en) | Bacterial strain of Streptomyces Althioticus producing desertomycin and desertomycin produced by it | |
| Zaman et al. | In vitro and in vivo evaluation of antibiotic combinations against multidrug resistant Proteus mirabilis isolated from admitted patients of Dhaka Medical College Hospital, Dhaka | |
| JPS6189A (en) | Novel 6 beta-halopenicillanate, manufacture and use | |
| EP3404026B1 (en) | Pyrimido-isoquinolin-quinone derivative compounds, and pharmaceutically acceptable salts, isomers and tautomers thereof; pharmaceutical composition; preparation method; and use thereof in the treatment of diseases caused by bacteria and multidrug-resistant bacteria | |
| CN1452968A (en) | Novel drug-fast bacteria resisting medicine composition and its prepn and use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |