CN101597230B - Beta,beta-dimethyl-acry-lalkannin and application in preparing medicines for inhibiting drug-resistant bacteria - Google Patents
Beta,beta-dimethyl-acry-lalkannin and application in preparing medicines for inhibiting drug-resistant bacteria Download PDFInfo
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- CN101597230B CN101597230B CN 200910054418 CN200910054418A CN101597230B CN 101597230 B CN101597230 B CN 101597230B CN 200910054418 CN200910054418 CN 200910054418 CN 200910054418 A CN200910054418 A CN 200910054418A CN 101597230 B CN101597230 B CN 101597230B
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Abstract
The invention belongs to the pharmaceutical field, relates to beta,beta-dimethyl-acry-lalkannin and an application in preparing medicines for inhibiting drug-resistant bacteria. The invention can provide a natural inhibitor for inhibiting efflux pump multidrug methicillin-resistant staphylococcus aureus. The compound has good inhibiting effect on multidrug staphylococcus aureus resistance strain with NorA efflux pump protein and the antibacterial effect is 13 times of positive contrastive drug norfloxacin. The compound can both inhibit tetracycline-resistant staphylococcus aureus strain Xu212 with TetK tetracycline efflux pump protein and macrolide-resistant staphylococcus aureus strain RN4220 with MsrA macrolide efflux pump protein, and the minimal inhibitory concentration is 10.8mu m. The compound of the invention can be prepared to medicines for inhibiting multidrug resistance bacteria and produced to antibacterial injection or external medicine preparation.
Description
Technical field
The invention belongs to pharmaceutical field, relate to the natural naphthoquinone compound that suppresses outer pump type multidrug resistance bacterium, relate in particular to compound β, beta-dimethyl-acry-lalkannin and the purposes in preparation inhibition multidrug resistance bacterium medicine thereof
Background technology
The infectious diseases that antibiotic discovery of earlier 1900s makes some scripts such as leprosy, typhoid fever, cholera, tuberculosis be difficult to treat no longer becomes incurable disease.But along with the continuous appearance of antibacterials and extensive extensive application in the world thereof, the resistance of bacterial antibiotic becomes increasingly conspicuous, and has developed into serious public health problem to the end of the eighties.It is reported that methicillin-resistant staphylococcus aureus (Methicillin-Resistant Staphylococcus aureus, MRSA) has become a kind of common serious infectivity pathogenic bacterium in the hospital at present.MRSA is except to the methicillin resistance, beta-lactam and the equal resistance of cephalosporin analog antibiotic of all and X-1497 same structure to other.MRSA also can produce modifying enzyme by changing the microbiotic target site, reduces the different mechanisms such as membrane permeability, and aminoglycoside, Macrolide, tetracyclines, fluorine quinlone class, sulfamido, Rifampin are all produced resistance in various degree.Think that in the past vancomycin is the last line of defense of resisting MRSA, but occurs the MRSA bacterial strain of vancomycin resistance in 2002 in the U.S..Up-to-date anti-MRSA azoles quinoline ketone medicine Linezoid (Zyvox
TM) and streptogramine class medicine quinupristin/dalfostin mixture calendar year 2001 just throw in into market, but Linezoid drug-resistant type MRSA has appearred.This multidrug resistance of MRSA is so that treat the infection that is caused by it and control its spread and epidemic very difficult.
Clinical practice shows, the speed that increases to slow down resistance MRSA by the restriction abuse of antibiotics except taking measures, 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.
Prior art discloses bacterial resistance number of mechanisms.Wherein, reducing medicine, to take in cell be a kind of in several important resistance mechanisms of bacterium.Reduce medicine absorption cell and have again following several mode: the change of membrane structure; The variation of epicyte protein; Medicine is initiatively effluxed (outer pump efflux) from cell.Present generally accepted cell is initiatively outer pump mechanism 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.
Therefore, the MRSA bacterial strain of selecting to contain the NorA gene is an important channel seeking medicines for inhibiting drug-resistant bacteria as a Screening target.
Prior art related to the present invention has:
[1]CDC.Staphylococcus areus resistant to vancomycin-United states.Morbidity and Mortality Weekly Reports,2002,51:565-567.
[2]PublicHealth Dispatch.Vancomycin-resistan Staphylococcus arueus-Pennsylvannia.Morbidity and Mortality Weekly Reports,2002,51:902-903.
[3]Tsiodras S,Gold HS,Sakoulas G.,Eliopoulos GM,Wennersten C,Venkataraman L,Moellering RC,Ferraro MJ.Linezolid resistance in a clinical isolate of Staphylococcus aureus.Lancet,2001,358:207-208.
[4]Potoski BA,Mangino JE,Goff DA.Clinical Filures of Linezolid and Implications for the Clinical Microbiology Laboratory,CDC.Emerging Infectious Diseases,2002,8(12):1519-1520.
[5]Yu,JL,et al.2002,NorA Functions as a Multidrug Efflux Protein in both Cytoplasmic Membrane Vesicles and Reconstituted Proteoliposomes,J.Bacteriology,184(5):1370-1377.
[6]Kaatz G.W，Seo SM,Ruble CA.Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus.Antimicrobial Agents and Chemotherapy,1993,37:1086-1094.
[7]Gibbons S,Udo EE.The effect of reserpine,a modulator of multidrug efflux pumps,on the in vitro activity of tetracycline against clinical isolates of methicillin-resistant Staphylococcus aureus(MRSA)possessing the tet(K)determinant.Phytotherapy Research,2000,14:139-140.
[8]Richardson JF,Reith S.Characterization of a strain of methicillin-resistant Staphylococcus aureus(EMRSA-15)by conventional and molecular methods.Journal of Hospital Infection,1993,25:45-52.
Summary of the invention
Purpose of the present invention provides a kind of natural naphthoquinone compound that suppresses outer pump type multidrug resistance bacterium, be specifically related to natural naphthoquinone compound β, beta-dimethyl-acry-lalkannin (β, β-dimethylacrylalkannin), relate in particular to compound β, beta-dimethyl-acry-lalkannin and the purposes in preparation inhibition multidrug resistance bacterium medicine thereof.
Among the present invention, the multidrug resistance bacterium is that X-1497 class antibiotic medicine is had resistance, simultaneously the fluoroquinolone antibiotics medicine is had chemical sproof staphylococcus aureus.
Among the present invention, described staphylococcus aureus contains the outer pump drug resistant gene norA that fluoroquinolone antibiotics is discharged.
The invention provides and can be used for suppressing anti-fluorine promise quinoline ketone methicillin-resistant staphylococcus aureus (multidrug resistant MRSA) natural inhibitor AE02-7-2.Described compound, chemistry β by name, beta-dimethyl-acryl-5,8-dihydroxyl-1,4-naphthoquinone.
Compd A E02-7-2 provided by the invention, its molecular formula is C
21H
22O
6, specific rotatory power [α]
D 22.7-143 ° (c 0.01, acetone) have the structure of formula (I).
Among the present invention, described compound has 5,8-dihydroxyl naphthoquinones parent nucleus skeleton, has the methylpentene side chain that an acyloxy replaces on the 2-position carbon of naphthoquinones.
Among the present invention, described acyloxy is the methyl butene acyloxy, and 1 '-position is the S configuration.
Compd A E02-7-2 of the present invention prepares by following method,
Adopt the root of Boraginaceae (Boraginaceae) Lithospermum (Arnebia) plant lithospermum euchromum Royle (Arnebia euchroma), pulverize, 95% ethanol soaks extraction below 45 degrees centigrade, united extraction liquid is evaporated to ethanol, and all volatilization is complete, add water to the medicinal extract suspendible, use ethyl acetate extraction.Obtain red-purple solid chemical compound AE02-7-2 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.
The physical properties of described compd A E02-7-2 and Wave Spectrum character are:
The red-purple solid, [α]
D 22.7-143 ° (c, 0.01, acetone); Molecular formula is C
21H
22O
6(370); EI-MS m/z (%) 302,288 (2.71), 270 (100), and 255 (45.91), 229 (6.99), 220 (15.87), 100 (2.60), 83 (72.88), 69 (11.81); IR (KBr) ν
Max: 3446,3408,2959,2920,2843,1726,1605,1457cm
-1
The inhibition resistant organism activity of compd A E02-7-2 that the present invention has adopted lowest bacteria fogging-resistant concentration determining
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.
Compd A E02-7-2 of the present invention has carried out pharmacological evaluation.
Employing has chemical sproof staphylococcus aureus (Methicillin-Resistant Staphylococcus aureus, MRSA) to X-1497 class antibiotic medicine and carries out bacteriostatic experiment, and the result shows that the compounds of this invention has pharmacologically active.Although for standard gold staphylococcus aureus strain ATCC25943, the bacteriostatic activity of compd A E02-7-2 (minimum inhibitory concentration MIC 10.8 μ M) is lower than microbiotic norfloxicin (noflorxacin), minimum inhibitory concentration MIC 1.6 μ M, but it is to having the outer chlG of NorA, the multi-medicine medicine-resistant staphylococcus aureus bacterial strain SA1199B that has tolerated fluorine promise quinoline ketone antibiotic medicine shows good restraining effect (MIC 2.7 μ M), and inhibitory effect is 13 times of positive control medicine norfloxicin (MIC 50 μ M).Simultaneously, described compd A E02-7-2 all has restraining effect to the anti-tsiklomitsin gold bacteria strain Xu212 of Portugal with the outer chlG of TetK tsiklomitsin and the anti-macrolide gold bacteria strain RN4220 of Portugal with the outer chlG of MsrA macrolide, and minimum inhibitory concentration is 10.8 μ M.
The compounds of this invention AE02-7-2 can be used for preparing the medicine that suppresses the multidrug resistance bacterium, it is characterized in that containing this compound of effective antibacterial amount.
Described medicine can be made into antiseptic injection, or external medicine preparation.
The instrument that the present invention adopts and experiment material are commercial, wherein:
Infrared spectrometer: Avatar
TM360E.S.P.
TM, Thermo Nicolet Corporation; Nuclear magnetic resonance analyser: Varian Mercury Plus 400MHz NMR spectrometer with superconducting magnet, CDCl
3, DMSO, Acetone; Mass spectrum: EI-MS:Agilent 5973N MSD type mass spectrograph; Optically-active: Polarimeter P-1020, JASCO Corporation.
Chromatographic silica gel (the yellow affair silica gel of Yantai City's Zhifu development experiments factory; Subsidiary factory of Haiyang Chemical Plant, Qingdao); Silica gel H (60 type): 10～40 subsidiary factories of μ m(Haiyang Chemical Plant, Qingdao); TCL plate (the yellow affair silica gel of Yantai City's Zhifu development experiments factory); Reverse phase silica gel: C-18(Fluka company).
Embodiment
Embodiment 1 preparation compd A E02-7-2
1.0 kilograms of the roots of Lithospermum (Arnebia) plant lithospermum euchromum Royle (Arnebia euchroma) are pulverized, and 95% ethanol soaks extraction below 45 degrees centigrade, and united extraction liquid is evaporated to ethanol, and all volatilization is complete, uses the chloroform Solid-Phase Extraction.Remainder obtains red-purple solid chemical compound AE02-7-2 with silica gel and the positive reversed phase column chromatography separating for several times of RP-18.Sample 2.0 grams and 100-200 order silica gel mixed sample, residual solvent is removed in volatilization.Take 200-300 order silica gel 250 and restrain the 2.0 centimetres of glass columns of diameter of packing into, add the above-mentioned sample of having mixed silica gel and having volatilized, add moving phase and separate.Silica gel column chromatography moving phase is chloroform-sherwood oil (1:1); Merge identical flow point, reduction vaporization removes out solvent.Detect the gained sample purity with thin layer chromatography, the Rf value is 0.6 (chloroform-sherwood oil 3:7); Repeat above-mentioned flow process and sample is carried out purifying carry out anti-phase silicon layer with same method and analyse, the moving phase of reverse-phase chromatography is methanol-water (9:1).
The physical properties of AE02-7-2 and Wave Spectrum character are:
The red-purple solid, [α]
D 22.7-143 ° (c, 0.01, acetone); Molecular formula is C
21H
22O
6(370); EI-MS m/z (%) 302,288 (2.71), 270 (100), and 255 (45.91), 229 (6.99), 220 (15.87), 100 (2.60), 83 (72.88), 69 (11.81); IR (KBr) ν
Max: 3446,3408,2959,2920,2843,1726,1605,1457cm
-1 1H NMR δ (ppm, J in Hz): 6.98s (3-H), 12.43s (5-OH), 7.18s (2H, 6-H, 7-H), 12.59s (8-OH), 6.01dd, 4.7,7.2 (1 '-H), 2.60m; 2.47m; (2H, 2 '-H) 5.12t, 7.3 (3 '-H), 1.68s (5 '-H), 1.57s, 6 '-H; 5.85s (2 "-H), 2.15s (4 "-H), 1.94s (5 "-H).
13C NMR δ (ppm): 177.5 (C-1), 149.0 (C-2), 131.6 (C-3), 179.0 (C-4), 166.2 (C-5), 132.6 (C-6), 132.4 (C-7), 166.8 (C-8), 111.8 (C-9), 111.6 (C-10), 68.6 (C-1 '), 32.9 (C-2 '), 118.0 (C-3 '), 135.9 (C-4 '), 25.8 (C-5 '), 18.0 (C-6 '), 165.3 (C-1 "), 115.2 (C-2 "), 159.0 (C-3 "); 20.4 (C-4 "), 27.6 (C-5 ").
Embodiment 2 compd A E02-7-2 are to the pharmacologically active experiment of SA1199B
Determine minimum inhibitory concentration: norfloxicin (norfloxacin) is purchased from Sigma company (Sigma Chemical Co.) Muller-Hendon's meat soup (Mueller-Hinton broth, MHB; Oxoid) transfer to every liter and contain 20 milligrams of calcium ions and magnesium ion.By comparing the McFarland standard, bacterial cultures is mixed with 5 * 10
5The inoculum of cfu/ml density.Norfloxicin and compd A E02-7-2 are dissolved in dimethyl sulfoxide solvent and dilute among the MHB initial concentration to 512 ug/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 respectively the 1-11 hole, and should coil 37 ℃ of lower cultivations 18 hours.Minimum inhibitory concentration (MIC) is the minimum concentration that has no 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) blue by the color xanthochromia, for detection of the growth of bacterium.
The experiment bacterium SA-1199B that the present invention adopts is staphylococcus aureus (the Gibbons S that contains the outer chlG of overexpression NorA multidrug resistance, Udo EE.Phytotherapy Research, 2000,14:139-140.), its resistance to norfloxicin is MIC 16 microlitre/milliliters or 50 μ M.Described NorA albumen is the main drug efflux pump (efflux pump) of golden Portugal bacterium.
The result shows, for Resistant strain SA-1199B, when control drug norfloxicin minimum inhibitory concentration is MIC 16 ug/ml (50 μ M), the minimum inhibitory concentration of compd A E02-7-2 is 1 ug/ml (2.7 μ M), shows that the bacteriostatic activity of compd A E02-7-2 is better than the control drug norfloxicin.
Embodiment 3 compd A E02-7-2 to resistant organism Xu212 and pharmacological activity test
Same procedure culturing bacterium among employing and the embodiment 2, the positive control drug of norfloxicin, the experimental procedure that repeats embodiment 2 detects AE02-7-2 to the minimum inhibitory concentration of Resistant strain Xu212.Described strain X u212 be anti-tsiklomitsin gold Portugal bacteria strain with the outer chlG of TetK tsiklomitsin (Richardson JF, Reith S.Journal of Hospital Infection, 1993,25:45-52.).
The result shows, compd A E02-7-2 has restraining effect to the anti-tsiklomitsin gold bacteria strain Xu212 of Portugal with the outer chlG of TetK tsiklomitsin, minimum inhibitory concentration is 4 ug/ml (10.8 μ M), this intensity is suitable with positive control medicine norfloxicin bacteriostatic activity, 4 ug/ml (12.5 μ M).
Embodiment 4 compd A E02-7-2 are to the pharmacological activity test of standard gold staphylococcus aureus strain ATCC25943
Same procedure culturing bacterium among employing and the embodiment 2, the positive control drug of norfloxicin, the experimental procedure that repeats embodiment 2 detects AE02-7-2 to the minimum inhibitory concentration of standard gold staphylococcus aureus strain ATCC25943.Experimental result shows that AE02-7-2 (MIC 2 ug/ml (5.4 μ M)) is weaker than positive control medicine norfloxicin (MIC 0.5 ug/ml (1.6 μ M)) to the inhibition activity of standard gold staphylococcus aureus strain ATCC25943.
Embodiment 5 compd A E02-7-2 are to the pharmacological activity test of clinical drug-resistant bacterial strain
Same procedure culturing bacterium among employing and the embodiment 2, the positive control drug of norfloxicin, the experimental procedure that repeats embodiment 2 detects AE02-7-2 to clinical common Methicillin-resistant Staphylococcus aureus strain EMRSA16(Richardson JF, Reith S.Journal of Hospital Infection, 1993, minimum inhibitory concentration 25:45-52.).EMRSA16EMRSA16 is a kind of in the Britain hospital [8].Experimental result finds that the bacteriostatic activity of compd A E02-7-2 (MIC 2 ug/ml (5.4 μ M)) obviously is better than positive control medicine norfloxicin (MIC 128 ug/ml (400 μ M)).
Claims (4)
1. the compound of formula I, its molecular formula is C
21H
22O
6, molecular weight is 370, specific rotatory power [α]
D 22.7-143 ° (c0.01, acetone),
2. the compound of formula I claimed in claim 1 is preparing the purposes that suppresses in the multidrug resistance bacterium medicine, wherein, described multidrug resistance bacterium is that X-1497 class antibiotic medicine is had resistance, simultaneously the fluoroquinolone antibiotics medicine is had chemical sproof staphylococcus aureus.
3. by purposes claimed in claim 2, it is characterized in that described staphylococcus aureus contains the outer pump drug resistant gene norA that fluoroquinolone antibiotics is discharged.
4. medicine that suppresses the multidrug resistance bacterium, it is characterized in that containing the compound of the claim 1 of establishment drug-resistant bacteria amount, wherein, described drug-resistant bacteria is that X-1497 class antibiotic medicine is had resistance, simultaneously the fluoroquinolone antibiotics medicine is had chemical sproof staphylococcus aureus.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101269060A (en) * | 2007-03-21 | 2008-09-24 | 复旦大学 | Use of compound HSR01-4-9 in preparing multi-drug resistant aureus restrainer |
| CN101293821A (en) * | 2007-04-28 | 2008-10-29 | 复旦大学 | Compounds for inhibiting multi-medicine medicine-resistant staphylococcus aureus activity |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101269060A (en) * | 2007-03-21 | 2008-09-24 | 复旦大学 | Use of compound HSR01-4-9 in preparing multi-drug resistant aureus restrainer |
| CN101293821A (en) * | 2007-04-28 | 2008-10-29 | 复旦大学 | Compounds for inhibiting multi-medicine medicine-resistant staphylococcus aureus activity |
Non-Patent Citations (1)
| Title |
|---|
| Yu，JL，et al..NorA Functions as a Multidrug Efflux Protein in both CytoplasmicMembrane Vesicles and Reconstituted Proteoliposomes.《J.Bacteriology》.2002,第184卷(第5期),1370-1377. * |
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