CN104788413B - Lignin type compound and its application in preparation of synergistic drug resistant staphylococcus aureus resistance drugs - Google Patents
Lignin type compound and its application in preparation of synergistic drug resistant staphylococcus aureus resistance drugs Download PDFInfo
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- CN104788413B CN104788413B CN201410025318.5A CN201410025318A CN104788413B CN 104788413 B CN104788413 B CN 104788413B CN 201410025318 A CN201410025318 A CN 201410025318A CN 104788413 B CN104788413 B CN 104788413B
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- compound
- norfloxacin
- staphylococcus aureus
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/83—Oxygen atoms
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Abstract
The invention belongs to the field of pharmacy, and relates to a new lignin type compound and its application in the preparation of synergistic drug resistant staphylococcus aureus resistance drugs, and concretely relates to a compound 7R,8S,5'S-8-methyl-5'-methoxy-1'-propenyl-7-(3,4-dimethoxyphenyl)-2',5'-dihydro-2'-benzofuranone ((-)-denudatin B) and its use in the preparation of synergistic fluoroquinolones and methicillin resistant staphylococcus aureus resistance drugs. The compound and an antibiotic norfloxacin can be used in a combined manner to reduce the lowest bacteriostasis concentration of norfloxacin by 4 times. The compound (-)-denudatin B can improve the inhibition effect of the antibiotic norfloxacin on drug resistant staphylococcus aureus SA1199B, or reduces the use amount of the antibiotic norfloxacin to 1/4 of the original single use amount. The compound can be used for preparing antibiotic synergistic drugs.
Description
Technical field
The invention belongs to pharmaceutical field, is related to a kind of neolignan type compound and its is preparing collaboration overriding resistance gold Portugal
Purposes in bacterium medicine, and in particular to compound 7R, 8S, 5'S-8- methyl -5'- methoxyl group -1'- acrylic -7- (3,4- diformazans
Phenyl) -2', 5'- dihydro -2'- benzofuranones ((-)-denudatin B) and its prepare collaboration resist resistance to fluoroquinolone
Purposes in class methicillin-resistant staphylococcus aureus medicine.
Background technology
Prior art discloses methicillin-resistant staphylococcus aureus (Methicillin-Resistant
Staphylococcus aureus, MRSA) it is one of modal disease carrying germ in hospital, except superficial skin infection, it is also
Human depth can be caused to infect.Nowadays, there is the MRSA of drug resistance to medicines such as all lactam antibioticses such as penicillins,
Drug resistance is also all generated to antibiotic such as macrolide, fluoroquinolone, tetracyclines, this causes its infection to become more to be difficult to
Treatment.It is reported that, at present, the antibiotic that can be used to treat MRSA only has vancomycin, Unfortunately, resists completely mould through the ages
Plain MRSA bacterial strains have occurred for 2002 in the U.S..China is widely used in recent years due to antibiotic, or even abuse, particularly
After multiple hospitals become Conventional antibiotic class medication, this situation becomes further severe to vancomycin.Know together in the industry, except
Take measures by limiting abuse of antibiotics to slow down the speed that drug resistance MRSA increases, while new overriding resistance MRSA must be researched and developed
Medicine, during in case existing antibacterials cannot work, the large-scale outbreak of antibacterial.
Research shows that antibacterial can produce drug resistance (Drug Resistance) by number of ways, and wherein antibacterial is to medicine
The outer row of generation acts on and caused outer pump (efflux) drug resistance is important mechanism of drug resistance.According to the report of World Health Organization (WHO)
Accuse, the bacterial infection with multidrug resistance efflux pump has accounted for the 60% of nosocomial infection.
Methicillin-resistant staphylococcus aureus have various resistance mechanisms, except with the drug resistant gene that chromosome is 40kb
(mecA) produced to beta-lactam by coding methicillin adaptor protein (Penicilin Binding Protein, PBP)
Outside the drug resistance of antibiotic, also drug resistance is produced to polytype antibiotic.To fluoroquinolones
(fluoroquinolones) overexpression NorA is passed through[1]Outer chlG produces drug resistance.Bacterial cell will be general by efflux pump
Pump out all over most antibiotic for using extracellular, intracellular antibiotic concentration is reduced and antibacterial action cannot be played.
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 aureuses, urethra, respiratory tract are widely used in stronger inhibitory action
Deng anti-infective therapy.Also just because of norfloxacin is in clinic and the extensive application of animal husbandry, antibacterial is serious resistance to which creating
The property of medicine, so as to limit the application of norfloxacin.It is known in the art that the mechanism for producing drug resistance is various, one of them is thin
Bacterium efflux pump.Therefore, the MRSA bacterial strains with the outer pump genes of NorA are selected to be to find as the Screening target of outer pump inhibitor
A kind of important channel of the overriding resistance S. aureus L-forms antibiotic sensitizer with outer pump inhibitory action.
Present inventor, is intended providing and is matched somebody with somebody with norfloxacin respectively by using natural component (-)-denudatin B
5 one-tenth composition of medicine, reduce the minimum inhibitory concentration of norfloxacin, and to norfloxacin the potentiation of overriding resistance S. aureus L-forms is produced
The purpose of effect.
Have in related prior art of the invention：
[1]Guay,GG,et al.The Tet(K)Gene of plasmid PT181 of Staphylococcus
aureus encodes an efflux protein that contains 14 transmenbrane
helices.Plasmid.1993,30(2):163-166.
[2]Bearden DT,Danziger LH.Mechanism of action of and resistance to
quinolones.Pharmacotherapy2001,21:40-61.
[3]Holmes,B,et al.Norfloxacin.Drugs.1985,30(6):482-513.
[4]Markham PN,Neyfakh AA.Inhibition of the multidrug transporter NorA
In Staphylococcus aureus prevents emergence of norfloxacin
resistance.Antimicrobial Agents Chemotheropy.1996,40(11):2673-2674.
[5]Hooper DC.Emerging mechanisms of fluoroquinolone
resistance.Emerging Infectious Diseases.2001,7:337–341.
The content of the invention
The purpose of the present invention is the defect for overcoming prior art, there is provided a kind of neolignan type compound and its prepare
Purposes in collaboration overriding resistance S. aureus L-forms medicine, and in particular to compound 7R, 8S, 5'S-8- methyl -5'- methoxyl group -1'- propylene
Base -7- (3,4- Dimethoxyphenyls) -2', 5'- dihydro -2'- benzofuranones ((-)-denudatinB) and its prepare association
With the purposes in the anti-methicillin-resistant staphylococcus aureus of resistance to fluoroquinolones medicine.
Invention further provides suppressing the antibacterial group of resistant Staphylococcus aureus (drug-resistant MRSA)
Compound.
The neolignan type compound of the present invention has following structure：Its molecular formula is C21H24O5, molecular weight 356；
The present invention is combined for preparing anti-fluorine-resistant quinoline promise using compound (-)-denudatin B and antibiotic norfloxacin
The medicine of ketone methicillin-resistant staphylococcus aureus, wherein, in combination medicine, the amount of every kind of active constituent is for so that simultaneously
Medication thing produces the amount of the anti-methicillin-resistant staphylococcus aureus of the resistance to fluoroquinolones active function of collaboration.
In the present invention, it is anti-to fluoroquinolones that drug-resistant staphylococcus aureus refer to that methicillin-resistant staphylococcus aureus have simultaneously
The drug resistance of raw element medicine.
In the present invention, by described native compound (-)-denudatin B and antibiotic norfloxacin in variable concentrations
Under carry out bacteriostatic experiment independent to the S. aureus L-forms of resistance to fluoroquinolone SA1199 bacterial strains, and both form compositionss of different ratio and carry out
Bacteriostatic test, as a result shows, the compound produces antibacterial potentiation, effect and sun to norfloxacin in synergism mode
Property medicine Reserpine quite, synergistic function is obvious.
In the present invention, described compound itself is for the resistance to methoxy of resistance to fluoroquinolones containing the outer pump gene of NorA drug resistances
The growth of XiLin staphylococcus aureuses (MRSA) strain SA1199B does not have inhibitory action, but it and antibiotic norfloxacin compatibility
When can make norfloxacin minimum inhibitory concentration value reduce by 4 times.The present invention relates to compound (-)-denudatin B can improve anti-
Inhibitory action of the raw element norfloxacin to drug-resistant staphylococcus aureus SA1199B；Or it is reduced to the dosage of antibiotic norfloxacin
The a quarter of the independent consumption of its original.
Native compound in the present invention can be isolated from plant.
Compound (-)-denudatin B according to the present invention can be further used for preparing antibiotic synergism medicine；It is more excellent
Choosing, the compound is made with the effect of overriding resistance staphylococcus aureuses with norfloxacin or other fluoroquinolone antibiotics
Pharmaceutical composition, described pharmaceutical composition can be overriding resistance S. aureus L-forms external medicine preparation or other forms medicine.
Specific embodiment
Embodiment 1. separates potentiating compounds (-)-denudatin B from plant betel leaf.
The chloroform extraction position extractum of 95% ethanol extraction of Fructus Piperiss platymiscium betel leaf (Piper betle), uses 200-
The silica gel mixed sample of 300 mesh carries out column chromatography, is a flow point per 20mL.First post is rushed with chloroform, collect flow point 9, be designated as Fr02-9；
With chloroform-acetone（9:1）Eluting, collects flow point 32-36, is designated as Fr02-32.Weigh after evaporated under reduced pressure, Fr02-9 is 260mg.
Fr02-9 is separated, with chloroform-acetone（9:1）Eluting, collects flow point 4-6, is designated as Fr02-9-4, weighs after evaporated under reduced pressure
For 106mg.Fr02-9-4 is separated, with petroleum ether-acetone（8:2）Eluting, collects flow point 2-4, is designated as Fr02-9-4-2,
44mg is weighed as after evaporated under reduced pressure.Continue to Fr02-9-4-2 purification, it is final to obtain faint yellow solid 15mg, Jing thin layer chromatographys and liquid
A sterling is mutually detected as, (-)-denudatinB is obtained.
Compound identification：Separating obtained compound 5mg is taken, adds deuterochloroform dissolving to carry out nuclear magnetic resonance, NMR and mass spectroscopy structural
Test.Mass spectrometry experiments show that the molecular weight of this compound is respectively 356,1H-NMR and13C-NMR data are as shown in table 1 respectively, knot
Structure is as shown in Equation 1.
The compound of table 1.1H-NMR and13C-NMR data
The structural formula of the chemicals of formula 1.
Embodiment 2. separates potentiating compounds (-)-denudatin B from plant Caulis Piperis Kadsurae.
Fructus Piperiss platymiscium Caulis Piperis Kadsurae（Piper kadsura(Choisy)Ohwi）Aerial partss coarse powder, uses dichloromethane room
Temperature is extracted four times, and extracting solution concentrating under reduced pressure obtains blackish green extractum.Take extractum 40g Jing silica gel H column chromatographies, cyclohexane-acetone gradient
Merging is known in eluting, TLC inspections, and concentrating under reduced pressure obtains 17 parts（Fr1-17）.Fr3（3.4g）Jing silica gel column chromatographies（Hexamethylene-the third
Ketone）With preparation TLC（Dichloromethane-ethyl acetate）Obtain compound (-)-denudatin B, common 170mg.
Compound identification methods and qualification result are with embodiment 1.
Synergistic function result when embodiment 3. determines that compound (-)-denudatin B are combined with norfloxacin
Compound (-)-denudatin B and norfloxacin carry out compound association by following synergism test methods respectively
With antibiotic synergy test, result of the test is as shown in table 2.
1）The potentiation of synergism method test Compounds Against life element
Norfloxacin and MTT are purchased from Sigma (Sigma Chemical Co.Ltd.), Miller-Hendon's meat soup
(Mueller-Hinton Brooth, MHB) is purchased from Oxoid companies；Take appropriate norfloxacin to be dissolved in DMSO to be made into antibiotic female
Liquid, takes appropriate norfloxacin mother solution and is dissolved in meat soup and be made into norfloxacin stock solution., take compound sample and be dissolved in DMSO in right amount and be made into
Mother solution, takes a certain amount of compound stock solutions and adds in the test tube 1 for filling meat soup, mixes, and it is 128ug/mL solution to be made into concentration, so
After follow equimultiple dilution method and operate successively, until test tube 7, bacteria suspension is configured to 106CFU/mL, adds appropriate toward 96 orifice plates per hole
Meat soup, then a certain amount of norfloxacin stock solution is added per hole toward first row, make first hole concentration be 256ug/mL, then according to equimultiple
Dilution method is operated successively, until the 10th arranges, the solution suctioned out during the 10th is arranged adds to the 12nd row, every hole addition of past eighth row etc.
Amount meat soup, remaining each row adds the solution in the corresponding numbering test tube of equivalent, and toward the every hole in addition to the 12nd row equivalent is added
Bacteria suspension, 18-24 hours are cultivated by this 96 orifice plate in 37 DEG C of incubator, add MTT, observe result, record often row antibacterial
The concentration of the norfloxacin corresponding to hole not grown, wherein MIC when 96 orifice plate H rows are shown that norfloxacin is alone, its
He manages it the MIC value of norfloxacin when being shown to be combined with compound sample；
Had based on report medicine Reserpine (reserpine) and suppress efflux pump effect, it can suppress drug-resistant bacteria pair
The outer row effect of medicine, increases the fungistatic effect of antibiotic, Reserpine（It is purchased from Aladdin chemical reagents corporation, Aladdin
Chemistry Co.Ltd）As the positive control medicine in the present embodiment, sharp blood is tested using this synergism experimental technique
The flat inhibitory action with norfloxacin combination to SA1199B, as a result shows, can be husky by promise fluorine when Reserpine concentration is 4 μ g/mL
Star reduces by 4 times to the minimum inhibitory concentration of SA1199B, and by 64 μ g/mL 16 μ g/mL are down to；
2. antibacterial experiment method
Take the compound sample and antibiotic norfloxacin is each appropriate, with DMSO dissolvings certain density two kinds are configured to
Mother solution, take this mother solution in right amount plus respectively into appropriate meat soup with compound sample and norfloxacin stock solution so that 96
Orifice plate head holes concentration is 128ug/mL, and appropriate meat soup is added per hole toward 96 orifice plates, then adds equivalent promise fluorine toward the A-D holes of first row
Husky star stock solution, E-H holes add equivalent compound sample stock solution, then according to equimultiple dilution method takes equivalent to the 2nd from the 1st row
Row, until the 10th row, 0 solution of sucking-off adds to the 12nd row during the 10th is arranged, and toward the every hole in addition to the 12nd row equivalent is added
Bacteria suspension, 18-24 hours are cultivated by this 96 orifice plate in 37 DEG C of incubator, add MTT, observe result, with antibacterial completely not
The least concentration of required medicine is MIC value of the medicine to this strain during growth；
Concentration is 3- [4,5- dimethylthiazoles base-the 2] -2,5- diphenyltetrazoliumbromides indigo plant bromide (MTT of 5mg/mL；
Sigma 20 μ L) are added to be used for the growth of detection bacterium per hole, MTT becomes au bleu and then indicated bacterial growth by yellow；
As a result show, for Resistant strain SA1199B, the MIC value of norfloxacin is 64 μ g/mL, compound (-)-
Denudatin B are more than 128 μ g/mL to the MIC of this bacterial strain, but during with norfloxacin compatibility, can make norfloxacin to bacterial strain
The MIC value of SA1199B is down to 16 μ g/mL, and than MIC during alone norfloxacin 4 times are reduced, and as a result shows, (-)-denudatin
B synergistic functions are identical with document report Reserpine, with obvious Synergistic antimicrobial activity.
Experimental bacteria SA1199B in the present embodiment is the Staphylococcus aureus of the outer chlG of overexpression NorA multidrug resistances
Bacterium, norfloxacin is 64 μ g/mL to its MIC value, and described NorA albumen is the main efflux pump of S. aureus L-forms（efflux
pump）.
The minimum inhibitory concentration (MIC) of the compound of table 2. and norfloxacin (Norfloxacin) to drug resistance strain SA1199B
With Mlc index (FICI)
Wherein：
（1）FICI≤0.5 is synergism；0.5<FICI≤1 summation action；1<FICI≤2 are without dependent interaction;；2<
FICI≤4 are antagonism；
（2）Compound is to SA1199B strains all without direct effect (MIC>128 μ g/mL), but energy when being combined with norfloxacin
MIC4 times of antibiotic is reduced, synergism is obvious.
Claims (6)
1. compound (-)-Denudatin B and norfloxacin or other fluoroquinolone antibiotics of the structure of formula 1 combines and is used for
Prepare the purposes in the medicine of the anti-methicillin-resistant staphylococcus aureus of resistance to fluoroquinolones；
2. the purposes as described in claim 1, it is characterised in that the compound of the described structure of formula 1
(-)-Denudatin B do not have direct growth inhibitory action to antibacterial, medication combined with fluoroquinolone antibiotics to make
Used time, with overriding resistance staphylococcus aureuses synergism.
3. the purposes as described in claim 1, it is characterised in that the compound of the structure of formula 1 shares raising promise fluorine with norfloxacin
Inhibitions of the Sha Xing to resistant Staphylococcus aureus SA1199B, when being used in combination, norfloxacin is to resistant S Fructus Vitis viniferae
The minimum inhibitory concentration of coccus SA1199B is a quarter when being used alone；Reduce the using dosage of norfloxacin antibiotic
Fungistatic effect is not changed.
4. purposes of the compound of the structure of formula 1 described in claim 1 in overriding resistance antibacterial Trimethoprim is prepared.
5. the purposes as described in claim 1, it is characterised in that described medicine for the structure of formula 1 compound and norfloxacin
Or pharmaceutical composition made by other fluoroquinolone antibiotics.
6. the purposes of claim 5 is pressed, and pharmaceutical composition therein makes external medicine preparation or other forms pharmaceutical preparation.
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| CN101401850A (en) * | 2008-11-11 | 2009-04-08 | 江西本草天工科技有限责任公司 | Piper hancei total alkaloid extract and uses thereof |
| CN101450107A (en) * | 2008-10-06 | 2009-06-10 | 浙江天台山乌药生物工程有限公司 | Total-flavone extract of lindera root leaves and preparation method and use thereof |
| CN101534816A (en) * | 2006-11-17 | 2009-09-16 | 株式会社太平洋 | External composition for skin containing manassantin B as active ingredient and the use thereof for skin whitening |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101534816A (en) * | 2006-11-17 | 2009-09-16 | 株式会社太平洋 | External composition for skin containing manassantin B as active ingredient and the use thereof for skin whitening |
| CN101450107A (en) * | 2008-10-06 | 2009-06-10 | 浙江天台山乌药生物工程有限公司 | Total-flavone extract of lindera root leaves and preparation method and use thereof |
| CN101401850A (en) * | 2008-11-11 | 2009-04-08 | 江西本草天工科技有限责任公司 | Piper hancei total alkaloid extract and uses thereof |
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| Yin-Ye Wang等.Characterization of Platelet Activating Factor(PAF) Binding Sites in Rabbit Platelet Membranes.《Journal of Chinese Pharmaceutical Sciences》.1993,第2卷(第1期),第89页右栏第2段. * |
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