CN101293821B - Compounds for inhibiting multi-medicine medicine-resistant staphylococcus aureus activity - Google Patents
Compounds for inhibiting multi-medicine medicine-resistant staphylococcus aureus activity Download PDFInfo
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- CN101293821B CN101293821B CN2007100401755A CN200710040175A CN101293821B CN 101293821 B CN101293821 B CN 101293821B CN 2007100401755 A CN2007100401755 A CN 2007100401755A CN 200710040175 A CN200710040175 A CN 200710040175A CN 101293821 B CN101293821 B CN 101293821B
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Abstract
The invention belongs to the pharmaceutical field, and relates to compound of 1S<*>,2R<*>,7R<*>-3-benzoyl-2-hydroxy-8,8-dimethyl-1,5,7-tri(3-methyl-2-butenyl)-bbicyclo-[3.3.1]nonan-2-ene-4,9-dione. The compound has the molecular formula and the plane structure of 7-epiclusianone. The stereochemical configuration of a chiral carbon atom is the enantiomer of 7-epiclusianone, and is named as ent-7-epiclusianone. The pharmacological and bacteriostatic experimental results show that the compound has pharmacological activities for inhibiting multi-drug resistant Staphylococcus aureus; and for methi-cillin-resistant Staphylococcus aureus containing fluoroquinolone-resistant genes NorA, the minimum inhibitory concentration (MIC) of the compound is only of 4 Mu g/mL (7.3 Mu M) and the compound activity is higher than a contrast drug when the MIC of norfloxacin positive contrast drug is of 32 Mu g/mL (100 Mu M). The compound can be used for preparing antibacterial injections and external pharmaceutical preparations.
Description
Technical field
The invention belongs to pharmaceutical field; relate to compound 1S*; 2R*; 7R*-3-benzoyl-2-hydroxyl-8,8-dimethyl-1,5; 7-three (3-methyl-2-butene base)-dicyclo [3.3.1] ninth of the ten Heavenly Stems-2-alkene-4; the 9-diketone, called after ent-7-epiclusianone (to call HSRO1-1 in the following text), and the purposes in anti-anti-fluorine promise quinoline ketone methicillin-resistant staphylococcus aureus (MRSA) medicine of preparation.
Background technology
Bacterial resistance is a serious day by day problem.(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 infections, it also exists the degree of depth of inside of human body to infect, and severe patient can cause death.China uses widely owing to microbiotic 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 resistance MRSA increases, must research and develop new anti-multidrug resistance MRSA medicine simultaneously, it is new chemical structure type, the anti-multidrug resistance staphylococcus aureus medicine of the new mode of action in support, in case after existing antibacterials can't work, the large-scale outbreak of bacterium.
Bacterial resistance has number of mechanisms, and wherein, reducing medicine, to take in cell be a kind of in several important resistance mechanisms of bacterium.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 the outer pump mechanism of active to the mechanism that medicine reduces permeability.Transfection in the outer pump system of microbiotic and other toxin is from the bacterium 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% of hospital infection.
The methicillin-resistant staphylococcus aureus has multiple resistance mechanism, except having the drug resistant gene that karyomit(e) is 40kb (mecA) by coding X-1497 adaptor protein (Penicilin Bindin Protein, PBP) produce outside the beta-lactam generation resistance, also to macrolide (macrolide), fluorine quinoline ketone (fluoroqiunolones), tsiklomitsin and quaternary ammonium salts be respectively by MsrA, NorA[1], TekA[2] and QacA[3] outer chlG forms 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 anti-microbial effect in intracellular concentration.
Therefore, the MRSA bacterial strain of selecting to contain the NorA gene is an important channel [4] of seeking medicines for inhibiting drug-resistant bacteria as a screening target.
The prior art reference:
[1]Ng，E.Y.W.et?al.(1994).Quinolone?resistance?mediated?by?norA：physiolocgiccharacterization?and?relationship?to?flqB，a?quinolone?resistance?locus?on?the?Staphylococcusaureus?chromosome.Antimicrob?Agents?Chemother，38：1345.
[2]Guay，G.G.，et?al.(1993).The?tet(K)gene?of?plasmid?pT181of?Staphylococcus?aures?encodesand?efflux?protein?that?contains?14?transmembrane?helices.Plasmid.30(2)：163-6.
[3]Marshall，N.J.et?al.(1997).Antibacterial?efflux?systems.Microbiologia.13：285-300.
[4]Yu，J.L.，et?al，2002，NorA?Functions?as?a?Multidrug?Efflux?Protein?in?both?CytoplasmicMembrane?Vesicles?and?Reconstituted?Proteoliposomes，J.Bacteriology，184(5)：1370-77.
Summary of the invention
The purpose of this invention is to provide a kind of compound that suppresses multi-medicine medicine-resistant staphylococcus aureus activity that has; relate to compound 1S*; 2R*; 7R*-3-benzoyl-2-hydroxyl-8,8-dimethyl-1,5; 7-three (3-methyl-2-butene base)-dicyclo [3.3.1] ninth of the ten Heavenly Stems-2-alkene-4; the 9-diketone, (to call HSRO1-1 in the following text), and the purposes in the anti-anti-fluorine promise quinoline ketone methicillin-resistant staphylococcus aureus medicine of preparation.
The invention provides the natural inhibitor HRSO1-1 that can be used for suppressing anti-fluorine promise quinoline ketone methicillin-resistant staphylococcus aureus (multidrug resistant MRSA).Described compound has identical molecular formula and two dimensional structure with compound 7-epiclusianone, but wherein the three-dimensional chemical configuration of chiral carbon atom is the enantiomer of 7-epiclusianone, called after ent-7-epiclusianone.
Compound H SRO1-1 provided by the invention, its molecular formula is C
33H
42O
4, have the benzophenone two dimensional structure structure of the bicyclic nonane of formula (I),
In acetone or chloroformic solution, this compound has many ketone structure of enol form resonance structure.
Compound H SRO1-1 of the present invention prepares by following method,
Adopt the root of Hypericum (Hypericum) plant Sampson St.John's wort Herb (H.sampsonii), pulverize, 95% ethanol soaks extraction below 45 degrees centigrade, and united extraction liquid is evaporated to the whole volatilizations of ethanol and finishes, and adds water to the medicinal extract suspendible, uses ethyl acetate extraction.Obtaining HSRO1-1 with silica gel and the positive reversed phase column chromatography separating for several times of RP-18 after the organic phase evaporated under reduced pressure is clear crystal shape compound.
The physical properties of described compound H SRO1-1 and Wave Spectrum character are:
Clear crystal, [α]
D 19+ 83.1 ° of (c0.372, CHCl
3), 98～100 ° of fusing points, molecular weight are 502.EI-MSm/z(rel.int.)：502[M]
+(2)，433(90.6)，309(100)，105(49.7)；UV(CHCl
3)λ
max(logε)302(3.06)，248(3.09)，206(2.55)nm；IR(KBr)v
max3352，2962，1782，1727，1672cm
-1。
Compound H SRO1-1 of the present invention has carried out pharmacological evaluation, the bacteriostatic experiment of determining and X-1497 class antibiotic medicine is had chemical sproof staphylococcus aureus (MRSA) through minimum inhibitory concentration, the result shows, The compounds of this invention has pharmacologically active, for methicillin-resistant staphylococcus aureus strain SA1199B (the Kaatz G.W that contains the genoid of anti-fluoroquinolone NorA, Seo S.M.Antimicrob Agents Chemother41:2733-2737.1997), when the minimum inhibitory concentration MIC of positive control medicine norfloxicin is 32 μ g/mL (100 μ M), and the MIC of The compounds of this invention HSRO1-1 only is 4 μ g/mL (7.3 μ M), and activity is better than contrast medicine medicine.
Related anti-first XiLin staphylococcus aureus has the resistance to fluorine promise quinoline ketone antibiotic medicine simultaneously.
The compounds of this invention HSRO1-1 can be used for preparing antiseptic injection, external medicine preparation.
Description of drawings
Fig. 1 is a compound H SRO1-1 crystal X-diffractogram.
Embodiment
Get 1.2 kilograms of the roots of Hypericum (Hypericum) plant Sampson St.John's wort Herb (H.sampsonii), pulverize, soaking extraction five times below 45 degrees centigrade with 1 liter of 95% ethanol, united extraction liquid is evaporated to the whole volatilizations of ethanol and finishes, add 800 milliliters in water to the medicinal extract suspendible, use ethyl acetate extraction.Chromatographic separation after the organic phase evaporated under reduced pressure.The sample silica gel column chromatography, 200-300 order silica gel (Chinese Haiyang Chemical Plant, Qingdao) 800 grams, petroleum ether-ethyl acetate (9:1) wash-out, every flow point is 75 milliliters, silica gel thin-layer chromatography detects.Merge 10 to 25 flow point and evaporates to dryness, go up silica gel column chromatography again, 200-300 order silica gel 200 grams place 4 * 40 centimetres chromatography column, and sherwood oil-acetone (98:2) is eluent, obtains slightly brown solid compound.Use reverse phase silica gel RP-18 column chromatography (2 * 15 centimetres) again, methanol-water (9:1) wash-out purifying.Obtaining 125 milligrams of white crystals, take off thin-layer chromatography and anti-phase RP-18 efficient liquid phase chromatographic analysis through silicon, is a pure compound, is accredited as HSRO1-1.
The physical properties of HSRO1-1 and Wave Spectrum character are:
Clear crystal, [α]
D 19+ 83.1 ° of (c0.372, CHCl
3), 98～100 ° of fusing points, molecular weight are 502.EI-MSm/z(rel.int.)：502[M]
+(2)，433(90.6)，309(100)，105(49.7)；UV(CHCl
3)λ
max(logε)302(3.06)，248(3.09)，206(2.55)nm；IR(KBr)v
max3352，2962，1782，1727，1672cm
-1。
The pharmacologically active experiment of embodiment 2 compound H SRO1-1
Determine minimum inhibitory concentration: norfloxicin (Norfloxacin) is purchased in Sigma company (SigmaChemical 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.Norfloxicin and compound H SRO1-1 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 compounds or norfloxicin (control drug) are added No. 1 hole and serial dilution, stay that No. 11 holes do not add 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 minimum 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-phenylbenzene ditetrazolium chloride 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 bacterium SA-1199B overexpression NorA multidrug resistance, it is MIC32 microlitre/milliliter to the resistance of norfloxicin.Described NorA albumen is the main medicine efflux pump (efflux pump) of golden Portugal bacterium.
For Resistant strain SA-1199B, when control drug norfloxicin minimum inhibitory concentration is MIC32 mcg/ml (100 μ M), the minimum inhibitory concentration of compound H SRO1-1 is 4 mcg/ml (7.3 μ M), shows that the bacteriostatic activity of compound H SRO1-1 is better than the control drug norfloxicin.
Claims (7)
1. a compound that suppresses multi-medicine medicine-resistant staphylococcus aureus activity has the benzophenone two dimensional structure of the bicyclic nonane of formula (I), and molecular formula is C
33H
42O
4,
2. according to the compound of claim 1, it is characterized in that described compound in acetone or chloroformic solution, have many ketone structure of enol form resonance structure.
3. the compound of claim 1 is preparing the purposes that suppresses in the multi-medicine medicine-resistant staphylococcus aureus activity medicine.
4. according to the purposes of claim 3, it is characterized in that described golden Portugal bacterium is that X-1497 class antibiotic medicine is had chemical sproof staphylococcus aureus.
5. according to the purposes of claim 3, it is characterized in that described methicillin-resistant staphylococcus aureus has the resistance to fluorine promise quinoline ketone antibiotic medicine simultaneously.
6. according to the purposes of claim 3, it is characterized in that described inhibition multi-medicine medicine-resistant staphylococcus aureus activity pharmaceutical dosage form is an injection.
7. according to the purposes of claim 3, it is characterized in that described inhibition multi-medicine medicine-resistant staphylococcus aureus activity pharmaceutical dosage form is an external medicine preparation.
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