CN107629061B - A kind of fluoro (±)-PenibrugiueramineA and its synthesis and the application as antibacterials - Google Patents
A kind of fluoro (±)-PenibrugiueramineA and its synthesis and the application as antibacterials Download PDFInfo
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Abstract
The invention discloses a kind of fluoro (±)-Penibrugiueramine A and its synthetic method and as the application of antibacterials, its synthetic method is with (2S, 4R/4S) -4- fluoro proline tert-butyl ester and olefin(e) acid compound be starting material successively reacted by condensation, intramolecular aldol, hydrolysis and reduction reaction, obtain fluoro (±)-Penibrugiueramine A；The synthetic method is easy to operate, reaction condition is mild, at low cost, by-product is few, high income, and obtained fluoro (-)-Penibrugiueramine A has better inhibition effect to staphylococcus aureus and Escherichia coli isoreactivity, can be used as antibacterial medicines application.
Description
Technical field
The present invention relates to a kind of antibacterials, in particular to a kind of fluoro (±)-Penibrugiueramine A and its conjunction
At method and as the application of antibacterials, belong to technical field of medicine synthesis.
Background technique
Currently, Drugs Containing Fluorine alreadys exceed 160, in medicinal chemistry arts, Xiang You in the numerous marketed drug in the whole world
It is new anticancer drug, antiviral drugs, anti-inflammation drugs, medicine for central nervous system of exploitation etc. that fluorine atom is introduced in machine molecule
Important directions.Since fluorine atom has the characteristics that small in size and electronegativity is high, the Special Influence that molecule can be generated.Small size
Fluorine atom be typically considered the non-classical bioisostere of hydrogen atom, biological target has slight fluorinated molecule
There is identification identical with its parent drug, and by the adjusting of electronics, makes the Interaction enhanced between prodrugs.
(-)-Penibruguieramine A is a kind of natural ocean pyrrolizidine alkaloids, molecular structure
Have very much particularity, possesses a double pyrrole ring, respectively occur a hydroxyl on C1 and C8, while also having seven carbon on C1
Hydrocarbyl side chain.The absolute configuration of the natural products by Guo and its colleague separated for the first time from Chinese mangrove bruguiera and identify Lai,
It is the effective active composition of Bruguiera conjugata endogenetic fungus Penicillium sp.GD6 (Penicillium), and crude extract, which is shown, to be had
The biological action of certain anti-Staphylococcus aureus, thus it is significant to its bio-mimetic syntheses.2015, Kim etc.
People is using chiral memory tactics P.A fully synthetic for the first time, but its product yield is low, does not carry out relevant biological activity survey to it
It is fixed.
Summary of the invention
In view of the defects existing in the prior art, the first purpose of this invention is to be to provide a kind of pair of Staphylococcus aureus
Bacterium and E. coli Activity all have fluoro (±)-Penibrugiueramine A compound of better inhibition effect.
Another object of the present invention is the synthesizing fluoro (±)-for being to provide that a kind of process is short, step is simple, inexpensive
The method of Penibrugiueramine A.
Third object of the present invention is to be to provide fluoro (±)-Penibrugiueramine A compound as suppression
The application of bacterium drug all has better inhibition effect to staphylococcus aureus and E. coli Activity, especially (6S) -6- fluorine
P.A is better than to the active inhibiting effect of staphylococcus aureus for Penibruguieramine A, and (6R) -6- fluoro
Penibruguieramine A is better than P.A to the inhibiting effect of E. coli Activity.
In order to achieve the above technical purposes, the present invention provides a kind of fluoro (±)-Penibrugiueramine A, tools
There is 1 structure of formula:
Wherein, F substituent group is R configuration or S configuration.
The present invention also provides the preparation methods of fluoro (±)-Penibrugiueramine A a kind of comprising following step
It is rapid:
1) (2S, 4R) -4- fluoro proline tert-butyl ester or (2S, 4S) -4- fluoro proline tert-butyl ester and 2 diluted acid chemical combination of formula
Object carries out condensation reaction and obtains 3 intermediate of formula；
2) 3 intermediate of formula carries out intramolecular aldol reaction, obtains 4 intermediate of formula；
3) 4 intermediate of formula is hydrolyzed and reduction reaction, obtains fluoro (±)-Penibrugiueramine A；
Wherein, F substituent group is R configuration or S configuration.
Preferred scheme, in step 1), (2S, 4R) -4- fluoro proline tert-butyl ester or (2S, 4S) -4- fluoro proline
The tert-butyl ester and 2 diluted acid compound of formula react 18~30h under condensing agent effect at room temperature.Preferred scheme, step 1) will
Diluted acid compound is dissolved in organic solvent, and condensing agent is added, and (2S, 4R) -4- fluoro proline tert-butyl ester is added after stirring 10min
Or (2S, 4S) -4- fluoro proline tert-butyl ester adds DIPEA, the reaction was continued for 24 hours, complete to raw material in room temperature reaction 20min
Portion has been reacted, and with saline solution and distillation water washing, ethyl acetate extraction is dry with anhydrous magnesium sulfate, is filtered, is spin-dried for obtaining formula 3
Intermediate.Wherein, (2S, 4R) -4- fluoro proline tert-butyl ester or (2S, 4S) -4- fluoro proline tert-butyl ester and diluted acid chemical combination
The molar ratio of object, condensing agent and DIPEA is 1:1:1.1:3.Organic solvent be preferably remove water after tetrahydrofuran, methylene chloride,
Methanol, acetonitrile, toluene, dimethyl sulfoxide or N,N-dimethylformamide；Most preferably N,N-dimethylformamide.More preferably
Scheme, the condensing agent include dicyclohexylcarbodiimide, 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea six
Fluorophosphoric acid ester, benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphate or hexafluorophosphoric acid benzotriazole -1- base-oxygroup
Tripyrrole alkyl phosphorus.
Preferred scheme, in step 2), 3 intermediate of formula and alkaline matter react 6~12h at room temperature.More preferably side
3 intermediate of formula is dissolved in organic solvent by case, and alkaline matter is added, and in room temperature reaction 9h, is quenched with saturated ammonium chloride, acetic acid
Ethyl ester extraction merges organic phase, and anhydrous magnesium sulfate is dry, filters, is spin-dried for, obtains 4 intermediate of formula.Preferred organic solvent is first
Alcohol, ethyl alcohol, isopropanol, the tert-butyl alcohol or tetrahydrofuran；Most preferably ethyl alcohol.More preferably scheme, the alkaline matter are methanol
Sodium, sodium ethoxide, sodium isopropylate, sodium tert-butoxide, lithium ethoxide, potassium ethoxide or tetrabutylammonium hydroxide hydrate.
Preferred scheme, in step 3), 4 intermediate of formula and trifluoroacetic acid, after reacting 10~20h at room temperature, separation is thick
Product, gained crude product and BOP, DIPEA and NaBH4, 0.5~3h is reacted at room temperature.More preferably scheme, the crude product
5~20min is stirred at room temperature with BOP, DIPEA, NaBH is added in batches under 0 DEG C of following temperature4, then react at room temperature
0.5~3h.Further preferred scheme, 4 intermediate of formula are dissolved in organic solvent, and TFA is added at a temperature of 0 DEG C, room temperature reaction
16h is all consumed to raw material, is spin-dried for solvent and is obtained crude product, crude product directly casts single step reaction without purifying, by crude product
It is dissolved in organic solvent, BOP, DIPEA is added, after 10min is stirred at room temperature, NaBH is added at a temperature of 0 DEG C4, anti-in room temperature
A hour to be answered, is quenched with saturated ammonium chloride solution, ethyl acetate extraction merges organic phase, and it is dry with anhydrous magnesium sulfate, it takes out
Filter, is spin-dried for, obtains target product.The organic solvent is methylene chloride, tetrahydrofuran, methanol, ethyl alcohol or acetonitrile；Most preferably
Methylene chloride.
The present invention also provides the applications of fluoro (±)-Penibrugiueramine A a kind of, answer as antibacterials
With.
Preferred scheme, using fluoro (±)-Penibrugiueramine A as to staphylococcus aureus and large intestine bar
The inhibited Antibiotics usage of bacterium activity.
Compared with the prior art, technical solution of the present invention bring advantageous effects:
1) fluoro (±)-Penibrugiueramine A of the invention is compared with Penibruguieramine A, 8
Hydroxyl is replaced by fluorine, has the bioactivity similar with Penibruguieramine A, can be used as Antibiotics usage suppression
System, such as to staphylococcus aureus and E. coli Activity inhibiting effect with higher, but after fluorine replaces, pharmacological property hair
Substantial variations have been given birth to, better inhibition effect is all had to staphylococcus aureus and E. coli Activity, especially (6S) -6- fluorine
P.A is better than to the active inhibiting effect of staphylococcus aureus for Penibruguieramine A, and (6R) -6- fluoro
Penibruguieramine A is better than P.A to the inhibiting effect of E. coli Activity.
2) technical solution of the present invention is for the first time with (2S, 4R/S) -4- fluoro proline tert-butyl ester and diluted acid compound for raw material,
It passes sequentially through condensation, intramolecular aldol reaction and hydrolysis and reduction reaction is de-, obtain fluoro (±)-
Penibrugiueramine A has step simple, reaction compared to the method for existing synthesis Penibruguieramine A
Mild condition, the features such as side reaction is few, yield is high.
Detailed description of the invention
[Fig. 1] is the nuclear magnetic resonance spectroscopy of compound 3；
[Fig. 2] is the carbon-13 nmr spectra of compound 3；
[Fig. 3] is the nuclear magnetic resonance spectroscopy of compound 4；
[Fig. 4] is the carbon-13 nmr spectra of compound 4；
[Fig. 5] is the nuclear magnetic resonance spectroscopy of compound 5；
[Fig. 6] is the carbon-13 nmr spectra of compound 5；
[Fig. 7] is the nuclear magnetic resonance spectroscopy of compound 7；
[Fig. 8] is the carbon-13 nmr spectra of compound 7；
[Fig. 9] is the nuclear magnetic resonance spectroscopy of compound 8；
[Figure 10] is the carbon-13 nmr spectra of compound 8；
[Figure 11] is the nuclear magnetic resonance spectroscopy of compound 9；
[Figure 12] is the carbon-13 nmr spectra of compound 9.
Specific embodiment
The following example is intended to further illustrate the content of present invention, rather than limits the protection model of the claims in the present invention
It encloses.
Raw material (2S, 4S) -4- fluoro proline tert-butyl ester of the invention and (2S, 4R) -4- fluoro proline tert-butyl ester are
It is obtained by the synthesis of setting out of (2S, 4R) -4- hydroxy-proline.[reference: (1) M.S.Chorghade, D.K.Mohapatra,
G.Sahoo,M.K.Gurjar,M.V Mandlecha,N.Bhoite,S.Moghe and R.T.Raines,
J.Fluor.Chem.,2008,129,781–784；(2)H.Marusawa,H.Setoi,A.Sawada,A.Kuroda,
J.Seki, Y.Motoyama and H.Tanaka, Bioorg.Med.Chem., 2002,10,1399-1415.], prepared by raw material 2
With reference to [(1) J.H.Kim, S.Lee and S.Kim, Angew.Chemie-Int.Ed., 2015,54,10875-10878.].It will
(2S, 4R) -4- fluoro proline tert-butyl ester and acid 2 react to obtain condensation product 3, then under ethanol as solvent with ethyl alcohol
The aldol that intramolecular occurs for sodium reacts to obtain cyclization product 4, is then passed through a step ester hydrolysis and reduction obtains final product 5.Instead
Answer formula as follows:
This method can efficiently obtain (6S) -6- fluoro Penibrugiueramine A.Simultaneously by (2S, 4R) -4- fluoro
Proline tert-butyl ester is reacted with acid 2, available (the 6R) -6- fluoro Penibruguieramine A of same step.Reaction equation
It is as follows:
Embodiment 1
Compound 2 (120mg, 0.60mmol) is dissolved in the dry DMF of 20ml, addition HATU (250mg,
0.66mmol), compound 1 (113mg, 0.6mmol) is added after stirring 10min, reacts at room temperature 20min, is added into system
DIPEA (0.28mL, 1.74mmol), the reaction was continued for 24 hours, complete to raw material total overall reaction, with saline solution and distillation water washing, acetic acid
Ethyl ester extraction, it is dry with anhydrous magnesium sulfate, it filters, is spin-dried for obtaining product 3 (101mg, 46%).m.p.:73-75℃；(c 0.19,CH3OH)；IR(cm-1):962,1014,1057,1153,1222,1632；1H NMR(400MHz,
(CD3)2SO): δ 5.45-5.24 (m, 5H), 4.47 (d, J=9.9Hz, 1H), 3.97-3.84 (m, 2H), 3.82-3.65 (m,
2H),3.62-3.48(m,1H),2.64-2.53(m,1H),2.53-2.50(m,4H),2.48-2.43(m,3H),2.39(dd,J
=9.3Hz, 5.2Hz, 1H), 2.23 (ddd, J=19.8Hz, 14.6Hz, 5.4Hz, 1H), 1.94-1.89 (m, 3H), 1.60-
1.59(m,5H),1.47-1.43(m,1H),1.42-1.41(m,7H),1.38-1.36(m,11H),1.30-1.20(m,5H),
1.21-1.14(m,3H),1.12-1.09(m,3H)；13C NMR(100MHz,(CD3)2SO):δ206.8,206.5,206.2,
170.9,170.7,170.6,169.9,169.8,169.6,169.6,131.6,131.5,131.5,125.0,124.9,
124.9,93.1 (d, J=174.7Hz), 91.8 (d, J=174.7Hz), 82.1,82.1,81.1,80.9,58.8,58.1,
58.0,54.1,53.9,51.3,51.2,38.1,36.2,35.9,32.3,32.1,28.9,28.8,28.7,28.0,27.9,
27.9,23.2,23.0,22.9,22.8,18.2,13.8,13.2,12.9,12.6；19F NMR(376MHz,(CD3)2SO):δ-
171.2(s,1F),-171.3(s,1F),-171.5(s,1F),-171.9(s,1F)；19F{1H}NMR(376MHz,(CD3)2SO):
δ-171.2；HRMS(ESI):m/z calcd for C20H32 [M+Na]+392.22063,found 392.22076.
Compound 3 (257mg, 0.69mmol) is dissolved in 3ml ethyl alcohol, is added sodium ethoxide (234mg, 3.5mmol), room temperature
9h is reacted, is quenched with saturated ammonium chloride, ethyl acetate extraction merges organic phase, and anhydrous magnesium sulfate is dry, filters, is spin-dried for, obtains
Product 4 (163mg, 65%).m.p.:142-143℃；(c 0.5,CH3OH)；IR(cm-1):668,759,843,
964,1016,1153,1284,1368,1430,1669,2361,2854,2931；1H NMR(400MHz,CD3OD):δ5.51-
5.48 (m, 1/2H, H6), 5.47-5.45 (m, 2H, H15, H16), 5.37-5.35 (m, 1/2H, H1), 3.68 (ddd, J=
34.7Hz, 13.6Hz, 4.4Hz, 1H, H5b), 3.33 (qd, J=3.4Hz, 2.2Hz, 1.6Hz, 1H, H5a), 3.31-3.24 (m,
1H), 2.91 (q, J=7.1Hz, 1H, H2), 2.62 (dd, J=18.3Hz, 14.4Hz, 1H, H7b), 2.46 (ddd, J=
42.5Hz, 14.4Hz, 4.1Hz, 1H, H7a), 2.06 (td, J=7.5Hz, 4.7Hz, 2H), 1.75-1.69 (m, 1H), 1.67-
1.65 (m, 3H, H17), 1.51 (s, 9H, H18), 1.38-1.36 (m, 2H), 1.34-1.31 (m, 2H), 1.03 (d, J=
7.3Hz,3H,H10)；13C NMR(100MHz,CD3OD): δ 176.6,170.8,130.9,124.5,95.6 (d, J=
174.7Hz), 82.5,81.3,79.8,49.6,48.5 (d, J=25.6Hz), 35.2 (d, J=20.8Hz), 32.3,30.1,
26.7,22.7,16.7,6.2；19F NMR(376MHz,CD3OD):δ-169.9(s,1F)；19F{1H}NMR(376MHz,
CD3OD): δ -169.9 (ddddd, J=52.8Hz, 42.3Hz, 34.7Hz, 27.6Hz, 18.3Hz)；HRMS(ESI):m/z
calcd for C20H32 [M+Na]+392.22063,found 392.22076.
Compound 4 (180mg, 0.49mmol) is dissolved in 5ml methylene chloride, TFA (1.6ml) is added at 0 DEG C, room temperature is anti-
Answer 16h, to raw material all consume, be spin-dried for solvent obtain crude product directly throw in next step.Crude product is dissolved in the tetrahydro furan of 2.5ml
It in muttering, is added BOP (150mg, 0.35mmol), DIPEA (30.0 μ L, 0.48mmol) after 10min is stirred at room temperature, is added at 0 DEG C
NaBH4(60.0mg, 1.60mmol) reacts at room temperature a hour, is quenched with saturated ammonium chloride solution, and ethyl acetate extraction is closed
And organic phase, it is dry with anhydrous magnesium sulfate, it filters, is spin-dried for, obtains product 5 (93.0mg, 81%).m.p.:189-190℃；(c 0.5,CH3OH)；IR(cm-1):860,964,1049,1299,1635,2199,3422；1H NMR(400MHz,
CD3OD): δ 5.48-5.45 (m, 2H, H15, H16), 5.42-5.23 (m, 1H, H6), 3.94 (ddd, J=23.9Hz, 13.4Hz,
6.0Hz, 1H, H5a), 3.80 (d, J=12.2Hz, 1H), 3.68 (d, J=12.2Hz, 1H), 3.37-3.31 (m, 1H, H5b),
3.25 (ddd, J=24.4Hz, 12.1Hz, 2.3Hz, 1H, H7a), 3.11 (q, J=7.3Hz, 1H, H2), 2.75-2.62 (m,
2H, H7b), 2.06-2.01 (m, 1H), 1.85-1.80 (m, 1H), 1.78-1.76 (m, 1H), 1.71 (dt, J=8.1Hz,
3.4Hz, 1H), 1.66 (dq, J=2.5Hz, 1.2Hz, 3H), 1.63-1.56 (m, 1H), 1.42 (q, J=7.4Hz, 1H),
1.33-1.24 (m, 2H), 1.02 (d, J=7.3Hz, 3H, H10)；13C NMR(100MHz,CD3OD):δ178.2,131.0,
124.5,94.5 (d, J=177.6Hz), 81.1,76.2,63.6,49.4,48.6 (d, J=27.5Hz, 1C), 33.6 (d, J=
20.0Hz,1C),33.4,32.1,29.9,23.0,16.7,6.2；19FNMR(376MHz,CD3OD):δ-167.1(s,1F)；19F
{1H}NMR(376MHz,CD3OD): δ -167.1 (tt, J=31.6Hz, 24.6Hz)；HRMS(ESI):m/z calcd for
C16H27 [M+Na]+322.17876,found 322.17889.
Embodiment 2
Compound 2 (438mg, 2.2mmol) is dissolved in the dry DMF of 30ml, is added HATU (912mg, 2.4mmol),
Stir 10min after be added compound 6 (416mg, 2.2mmol), react at room temperature 20min, into system addition DIPEA (0.99mL,
6.6mmol), the reaction was continued for 24 hours, complete to raw material total overall reaction, with saline solution and distillation water washing, ethyl acetate extraction, with nothing
Water magnesium sulfate is dry, filters, is spin-dried for obtaining product 7 (270mg, 37%).(c 0.34,CHCl3)；IR(cm-1):
771,846,964,1081,1189,1209,1367,1457,1653,2340,2853,2923；1H NMR(400MHz,CD3OD):
δ5.45-5.41(m,4H),5.39-5.30(m,1H),4.46-4.39(m,1H),4.15-4.01(m,2H),3.93-3.88(m,
1H),3.86-3.82(m,1H),3.81-3.76(m,1H),2.70-2.60(m,2H),2.58-2.48(m,2H),2.24-2.16
(m,1H),2.14-2.05(m,1H),2.14-2.05(m,1H),2.04-1.94(m,3H),1.65-1.63(m,4H),1.61-
1.54 (m, 3H), 1.53-1.52 (m, 2H), 1.50-1.48 (m, 11H), 1.39-1.34 (m, 3H), 1.31 (d, J=6.9Hz,
3H), 1.28 (d, J=6.9Hz, 3H)；13C NMR(100MHz,CD3OD):δ206.5,205.9,170.8,170.7,170.7,
170.5,130.9,130.8,130.7,124.6,124.5,92.9,92.0 (d, J=177.9Hz), 81.7,81.6,58.6,
54.2,53.9,53.7,51.7,51.6,39.9,39.8,35.5,35.3,31.9,28.7,28.6,26.8,26.8,26.7,
22.7,22.6,16.9,11.7,11.4；19F NMR(376MHz,CD3OD):δ-179.1(s,1F),-179.3(s,1F),-
179.4(s,1F)；19F{1H}NMR(376MHz,CD3OD):δ-179.1；HRMS(ESI):m/z calcd for C20H32 [M+Na]+392.22071,found 392.22076.
Compound 8 (150mg, 88%) can be obtained by compound 7 by operation identical in case study on implementation 13 to 4.(c 0.3,CH3OH)；IR(cm-1):758,842,965,984,1078,1156,1255,1287,2855,2934,
3420；1H NMR(400MHz,CD3OD):δ5.50-5.44(m,2H,H15,H16),5.41-5.25(m,1H,H6),3.83(dd,
J=21.9Hz, 13.4Hz, 1H, H5b), 3.14 (dddd, J=28.4Hz, 13.5Hz, 4.9Hz, 1.5Hz, 1H, H5a), 2.90
(qd, J=7.3Hz, 1.3Hz, 1H, H2), 2.80-2.72 (m, 1H, H7a), 2.70-2.62 (m, 1H, H7b), 2.03 (td, J=
7.2Hz,4.1Hz,2H),1.76-1.69(m,1H),1.67-1.65(m,1H),1.51(s,9H,H18),1.40-1.38(m,
2H), 1.36-1.31 (m, 2H), 1.10 (d, J=7.3Hz, 3H, H10)；13C NMR(100MHz,CD3OD):δ176.4,
(171.0,130.9,124.5,93.9 d, J=182.5Hz), 82.9,81.0,79.7,48.8,35.4,34.7 (d, J=
23.4Hz),32.2,30.0,26.7,22.6,16.7,6.5；19F NMR(376MHz,CD3OD):δ-174.7(s,1F)；19F
{1H}NMR(376MHz,CD3OD): δ -174.7 (ddd, J=60.4Hz, 29.0Hz, 23.1Hz)；HRMS(ESI):m/z calcd
for C20H32 [M+Na]+392.22043,found 392.22076.
Compound 9 (43mg, 92%) can be obtained by compound 7 by operation identical in case study on implementation 14 to 5.
m.p.:162-163℃；(c 0.6,CH3OH)；IR(cm-1):559,601,651,724,837,893,966,997,
1055,1101,1136,1168,1250,2851,2985；1H NMR(400MHz,CD3OD):δ5.51-5.45(m,2H,H12,
), H13 5.45-5.44 (m, 1H, H1), 3.82 (ddd, J=23.7Hz, 13.2Hz, 1.5Hz, 1H, H2b), 3.71 (d, J=
11.5Hz, 1H, H7a), 3.48 (d, J=11.6Hz, 1H, 7b), 3.40 (ddd, J=13.4Hz, 5.0Hz, 1.5Hz, 1H,
H2a), 3.34-3.32 (m, 1H), 2.94 (q, J=7.24Hz, 1H, H4), 2.69-2.57 (m, 1H, H3b), 2.08-1.97 (m,
3H),1.71-1.68(m,1H),1.67-1.64(m,3H),1.63-1.59(m,1H),1.42-1.36(m,2H),1.34-1.19
(m, 2H), 1.08 (d, J=7.3Hz, 3H, H5)；13C NMR(100MHz,CD3OD):δ176.8,130.9,124.6,95.2(d,
), J=179.5Hz 80.3,76.9,64.6,49.1 (d, J=4.1Hz), 48.9,34.2 (d, J=23.0Hz), 33.4,32.0,
29.8,22.9,16.9,6.3；19F NMR(376MHz,CD3OD):δ-170.9(s,1F)；19F{1H}NMR(376MHz,
CD3OD): δ -170.9 (dtt, J=55.1Hz, 30.5Hz, 24.2Hz)；HRMS(ESI):m/z calcd for C16H27 [M+Na]+322.17889,found 322.17889.
Embodiment 3
(6S) -6- fluoro Penibrugiueramine A and (6R) -6- fluoro prepared by embodiment 1 and embodiment 2
Penibruguieramine A and Penibrugiueramine A have carried out antibacterial test together, mainly test golden yellow
Staphylococcus and Escherichia coli.
Golden yellow coccus, Escherichia coli bacteriostatic experiment method:
1. raw material
Escherichia coli, staphylococcus aureus, it is outstanding that purchase is prepared as bacterium before China typical culture collection center, experiment
Liquid, concentration are 1 × 108cfu/mL。
MH fluid nutrient medium.
Streptomysin (reference material) 0.25mg/ml.
Experimental drug (Liu Ting and upright sample), is 4mg/ml.
2. experimental method
In 96 hole elisa Plates, 50 μ l MH fluid nutrient mediums are added in the hole 1-8, and No. 1 hole is sample blank, in No. 2 holes
50 μ l experimental drugs or streptomysin is added, pipettes 50 μ l mixtures from No. 2 holes again after mixing to No. 3 holes, so grasps
Make to No. 8 holes, discards 50 μ l mixture in No. 8 holes.Then 150 μ l MH fluid nutrient mediums are added in the hole 1-8, mix
50 μ l Escherichia coli or staphylococcus aureus suspension are added after uniformly.Finally there are 250 μ l solution in such each hole.Sample
To replace bacteria suspension with 50 μ l sterile waters, all samples do three in parallel for control.
ELISA Plate measures its absorbance value A at 410nm with microplate reader at once after adding sample0, then ELISA Plate is set
16h is cultivated at 37 DEG C, then takes out and measures its absorbance value A at 410nm with microplate readers。
Calculate the Δ A in each holes=As-A0, sample controls group is Δ Abs
Blank group is Δ A0, the control group of sample blank is Δ Ab0
According to various concentration sample or the bacteriostasis rate of streptomysin, suppression curve is drawn, the 503nhibiting concentration of sample is calculated
IC50Value.It is as shown in the table to obtain result:
From upper table, it can be concluded that, PA and two fluoro derivatives show preferable antibiotic property.But (6S) -6- fluorine
P.A is better than to the active inhibiting effect of staphylococcus aureus for Penibruguieramine A, and (6R) -6- fluoro
Penibruguieramine A is better than P.A to the inhibiting effect of E. coli Activity.
Claims (1)
1. a kind of application of fluoro (±)-Penibrugiueramine A, it is characterised in that: S configuration fluoro (±)-
Penibrugiueramine A is as the Antibiotics usage inhibited to staphylococcus aureus；R configuration fluoro
(±)-Penibrugiueramine A is as the Antibiotics usage inhibited to E. coli Activity.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01211589A (en) * | 1988-02-19 | 1989-08-24 | Lederle Japan Ltd | (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01211589A (en) * | 1988-02-19 | 1989-08-24 | Lederle Japan Ltd | (5s)-3-substituted thio-8-oxo-1-azabicyclo(3.3.0)octa-2-ene-2-carboxylic acid derivative |
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