CN103044439B - De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug - Google Patents
De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug Download PDFInfo
- Publication number
- CN103044439B CN103044439B CN201210560944.5A CN201210560944A CN103044439B CN 103044439 B CN103044439 B CN 103044439B CN 201210560944 A CN201210560944 A CN 201210560944A CN 103044439 B CN103044439 B CN 103044439B
- Authority
- CN
- China
- Prior art keywords
- azalomycin
- malonyl
- preparation
- malonate
- mrsa
- 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.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention discloses a de-malonate monoacyl azalomycin F, a preparation method thereof and the application thereof to preparation of an MRSA (Methicillin-resistant Staphylococcus aureus) infection therapeutic drug. Azalomycin F reacts in an alkaline methanol solution to produce de-malonate azalomycin F, the de-malonate azalomycin F is separated to obtain the de-malonate monoacyl azalomycin F. The MRSA activity test shows that the MIC (Minimal Inhibitory Concentration) of the obtained de-malonate monoacyl azalomycin F to MRSA tester strain is 0.25-0.50 Mug/mL, which is 8-16 times of that of azalomycin F, and the de-malonate monoacyl azalomycin F has enhanced stability and water solubility. The de-malonate monoacyl azalomycin F has remarkable MRSA activity and a favorable development prospect and can be used for preparing an MRSA infection therapeutic drug.
Description
Technical field
The present invention relates to malonyl azalomycin F and preparation method thereof and the application in preparation treatment MRSA infection medicine.
Background technology
In recent years, methicillin-resistant staphylococcus aureus (Methicillin-resistant
staphylococcus aureus, MRSA) and infect extend over the entire globe various places, infection rate is in continuing ascendant trend, and in succession resistance is occurred to the clinical antibiotics of various structures type, its speed has exceeded the research and development speed of current new antibiotic, and become super wide spectrum resistant organism, the life and health of the mankind in serious threat.The resistance of pathogenic bacteria is innately intrinsic, and people, in the use procedure of antibiotic medicine, serve inrichment to these resistant organisms, and makes it become Dominantpathogen to carry out wide-scale distribution and infection.Long-term clinical and research practice shows: a lot of antibacterials have responsive pathogenic bacteria to be killed or restraining effect, but can not kill or suppress resistant organism, even the antibacterials of never contacted pathogenic bacteria, so the discovery of drug-resistance bacteria medicine must pass through screening, and simply cannot infer according to existing antibiotic anti-microbial effect.The widest popular resistant organism is MRSA at present, because it is to the antibiotics resistance of various structures type, is called " super pathogenic bacteria " by people.Therefore the discovery of anti-MRSA medicine and research and development seem particularly urgent.
Azalomycin F is 36 membered macrolides, mainly comprises azalomycin F
5a, F
4aand F
3a.Successively from
streptomyces hygrpscopicusvar.
azalomyceticuswith
streptomycessp. be separated in 211726 liang of bacterial strains and identify, they have resisting gram-positive bacteria, fungi and immunosuppressive activity, and have certain application clinically.But activity needs to be improved further, and structural instability, easily degrade, be insoluble in water, thus limit its widespread use clinically.Within 2011, we obtain 17 by structural modification and alkylatingly remove malonyl azalomycin F derivative (application number: 201110314705.7), and prove that its anti-microbial activity strengthens to some extent, but do not prove that it has the activity of antimicrobial agent.Conventionally; before sloughing 23 malonyls, alkylation protection must be carried out to the hydroxyl of 17, otherwise while alkaline hydrolysis sloughs malonyl; to the open loop of hemiketal ring in structure be caused, and then cause the forfeiture of anti-microbial activity.And to after 17 hydroxyl protections; deprotection will cause the degraded of compound; therefore azalomycin F found so far from nineteen fifty-nine; do not obtain yet and remove malonyl azalomycin F; the present invention, by changing hydrolysising condition, obtains and removes malonyl azalomycin F while not protecting 17 hemiketal hydroxyls, and it is active to prove that gained compound has significant anti-MRSA by test; strengthening 8 ~ 16 times than the azalomycin F before modifying, is positive clinical contrast medicine Linezolid 2 ~ 8 times.And stability and water-solublely to improve, show good application prospect, useful application is in the preparation of anti-many MRSA medicine.
Summary of the invention
The object of this invention is to provide a kind of new compound and go malonyl azalomycin F and preparation method thereof and the application in the anti-MRSA medicine of preparation.
Of the present inventionly remove malonyl azalomycin F, its molecular structure is such as formula shown in I:
Formula I
Wherein, R
1for methyl or hydrogen; R
2for methyl or hydrogen.
Work as R
1and R
2when being methyl, formula I is for removing malonyl azalomycin F
5a(
1);
Work as R
1for methyl, R
2during for hydrogen, formula I is for removing malonyl azalomycin F
4a(
2);
Work as R
1and R
2when being hydrogen, formula I is for removing malonyl azalomycin F
3a(
3);
The preparation method of malonyl azalomycin F derivative that goes of the present invention is: get a certain amount of sodium hydride and be dissolved in methyl alcohol; a certain amount of azalomycin F is added under stirring; splash bar reaction 8 ~ 18 h at-5 ~ 5 DEG C; reaction mixture aqueous hydrochloric acid neutralizes; concentrating under reduced pressure; enriched material is separated through RPLC (HPLC); with a certain proportion of methanol-water solution wash-out; collect and be rich in the elutriant of malonyl azalomycin F, concentrating under reduced pressure, dryly must remove malonyl azalomycin F.
The described molecular structure of raw materials used azalomycin F in malonyl azalomycin F preparation method that goes is such as formula shown in II:
Formula II
Wherein, R
1for methyl or hydrogen, R
2for methyl or hydrogen; Work as R
1, R
2when being methyl, be azalomycin F
5a; R
1for methyl, R
2during for hydrogen, be azalomycin F
4a; R
1, R
2when being hydrogen, be azalomycin F
3a, above compound all can be bought by business and obtain, also can by the obtainable streptomycete of business
streptomyces hygrpscopicusvar.
azalomyceticusin accordance with known methods and technology, through fermentation, be separated and prepare, also by streptomycete
streptomycessp. 211726 according to document (Yuan Ganjun,
et al.
magn Reson Chem, 2011,49 (1): 30-37.) method through fermentation, be separated prepare.
Describedly go raw material azalomycin F used in malonyl azalomycin F preparation method can select azalomycin F
5a, F
4aand F
3ain any one, also can be the mixture of any two or three compounds.
It is described that to go to be hydrolyzed malonyl alkali used in malonyl azalomycin F preparation method be sodium hydride.
Synthetic route of going malonyl azalomycin F derivative to prepare of the present invention is as follows:
。
The present invention is in the methanol solution of sodium hydride, is hydrolyzed the malonyl of in azalomycin F molecular structure 23, obtains and remove malonyl azalomycin F.Overcome the open loop that direct NaOH or KOH basic hydrolysis causes hemiketal ring in molecular structure on the one hand; On the other hand, avoid because hydrolysis malonyl first need protect 17 hydroxyls and bring 29 easy alkylating shortcomings of hydroxyl.Gained goes the stability of malonyl azalomycin F molecular structure to strengthen, water-soluble remarkable increase simultaneously.The experiment proved that: go malonyl azalomycin F to have significant the suppression and killing action to MRSA, its minimum inhibitory concentration (MIC) is 0.25 ~ 0.50 μ g/mL, and activity is azalomycin F
5a, F
4aand F
3a8 ~ 16 times, be positive clinical contrast medicine Linezolid 2 ~ 8 times.Show its good prospect as anti-MRSA drug development, can be used for preparing the medicine that treatment MRSA infects.
Embodiment
embodiment 1:
Get 100 mg sodium hydrides to be dissolved in 100 ml methyl alcohol, under stirring, add 1.1 g(1 mmol) azalomycin F
5a, at 0 DEG C, splash bar reacts 12 h.The reaction mixture aqueous hydrochloric acid of 5 M neutralizes, concentrating under reduced pressure at 40 DEG C, and enriched material is separated through C-18 RPLC, is the methanol-water solution wash-out of 80:20 by volume ratio, collects and is rich in malonyl azalomycin F
5aelutriant, concentrating under reduced pressure, lyophilize at 37 DEG C, obtain 0.83 g and remove malonyl azalomycin F
5a(
1).
Remove malonyl azalomycin F
5a(
1): molecular formula is C
54h
95n
3o
14, water-soluble, be soluble in methyl alcohol, ethanol, m.p. 126.0 ~ 128.0 DEG C, ESI-MS (
m/z): 1010.7 [M+H]
+.
13C?NMR（MeOH-
d 4,?100?MHz）
δppm：169.2(s),?157.4(s),?145.0(d),?139.3(s),?137.0(s),?135.3(d),?132.0(d),?129.4(d),?128.6(d),?127.4(d),?127.0(d),?126.3(d),?99.7(s),?80.3(d),?77.2(d),?75.3(d),?74.8(d),?74.2(d),?72.3(d),?71.5(d),?69.7(d),?67.4(d),?66.3(d),?65.8(d),?65.4(d),?47.7,?46.7,?46.0,?44.8,?44.2,?44.1,?42.7,?41.7,?41.2,?41.0,?40.6,?39.3,?35.0,?34.5,?33.5,?33.2,?30.3,?30.1,?29.7,?28.2,?28.2,?27.8,?17.6,?16.9,?14.8,?14.0,?13.3,?12.8,?10.7。
embodiment 2:
Get 100 mg sodium hydrides to be dissolved in 100 ml methyl alcohol, under stirring, add 1.1 g(1 mmol) azalomycin F
4a, at 5 DEG C, splash bar reacts 8 h.The reaction mixture aqueous hydrochloric acid of 5 M neutralizes, concentrating under reduced pressure at 40 DEG C, and enriched material is separated through C-18 RPLC, is the methanol-water solution wash-out of 78:22 by volume ratio, collects and is rich in malonyl azalomycin F
4aelutriant, concentrating under reduced pressure, lyophilize at 37 DEG C, obtain 0.79 g and remove malonyl azalomycin F
4a(
2).
Remove malonyl azalomycin F
4a(
2): molecular formula is C
53h
93n
3o
14, water-soluble, be soluble in methyl alcohol, ethanol, m.p. 126.5 ~ 127.7 DEG C, ESI-MS (
m/z): 996.7 [M+H]
+.
13C?NMR（MeOH-
d 4,?100?MHz）
δppm：169.1(s)、158.3(s)、145.1(d)、139.3(s)、137.0(s)、135.2(d)、132.0(d)、129.4(d)、128.5(d)、127.4(d)、127.0(d)、126.3(d)、99.8(s)、80.3(d)、77.1(d)、75.3(d)、74.9(d)、74.1(d)、72.3(d)、71.5(d)、69.7(d)、67.4(d)、66.3(d)、65.8(d)、65.3(d)、47.7、46.7、46.0、44.7、44.2、44.1、42.6、41.7、41.2、41.0、40.6、39.3、35.0、34.5、33.5、33.2、30.3、30.1、29.7、28.2、27.9、17.6、16.9、14.8、14.0、13.3、12.8、10.7。
embodiment 3:
Get 200 mg sodium hydrides to be dissolved in 250 ml methyl alcohol, under stirring, add 2.1 g(2 mmol) azalomycin F
3a, at-5 DEG C, splash bar reacts 18 h.The reaction mixture aqueous hydrochloric acid of 5 M neutralizes, concentrating under reduced pressure at 40 DEG C, and enriched material is separated through C-18 RPLC, is the methanol-water solution wash-out of 78:22 by volume ratio, collects and is rich in malonyl azalomycin F
3aelutriant, concentrating under reduced pressure, lyophilize at 37 DEG C, obtain 1.5 g and remove malonyl azalomycin F
3a(
3).
Remove malonyl azalomycin F
3a(
3): molecular formula is C
52h
91n
3o
14, water-soluble, be soluble in methyl alcohol, ethanol, m.p. 126.3 ~ 127.5 DEG C, ESI-MS (
m/z): 982.6 [M+H]
+.
13C?NMR（MeOH-
d 4,?100?MHz）
δppm：169.1(s)、158.7(s)、145.1(d)、139.3(s)、137.0(s)、135.2(d)、132.0(d)、129.4(d)、128.5(d)、127.4(d)、127.0(d)、126.3(d)、99.9(s)、80.3(d)、77.2(d)、75.3(d)、74.9(d)、74.1(d)、72.3(d)、71.5(d)、69.8(d)、67.4(d)、66.3(d)、65.8(d)、65.3(d)、47.7、46.7、46.0、44.7、44.2、44.1、42.6、41.6、41.2、41.0、40.6、39.3、35.0、34.5、33.5、33.2、30.3、30.1、29.7、27.9、17.6、16.9、14.8、14.0、13.3、12.8、10.7。
embodiment 4:
Get streptomycete
streptomyces hygrpscopicusvar.
azalomyceticusbacterial strain is appropriate, is inoculated on ISP2 plate culture medium, cultivates 4d, and the bacterial strain getting activation is appropriate, is inoculated in the 500 mL Erlenmeyer flasks that 50 mL ISP2 nutrient solutions are housed, 28 DEG C, 72 h cultivated by shaking table under 200 rpm conditions, obtain the seed culture fluid of bacterial strain.This seed culture fluid is inoculated in respectively by 10% inoculum size 500 mL productive culture liquid [substratum composition (g/L): glycerine 5 g is housed, glucose 5 g, yeast powder 15 g, analysis for soybean powder 5 g, Succinic acid ammonium salt 2 g, sodium-chlor 3 g, deionized water 1L, pH 7.1 ~ 7.3] 3000 mL Erlenmeyer flasks in, 28 DEG C, 7 d cultivated by shaking table under the condition of 225 rpm.Repeat aforesaid operations to obtaining fermenting mixture 100 L.With centrifugal method by mycelium and separation of fermentative broth.Mycelium methyl alcohol lixiviate 3 times, obtains methanol extract liquid, and be evaporated to not containing methyl alcohol, freeze-drying, obtains lyophilized powder 282.3 g.By document (Yuan Ganjun,
et al.
magn Reson Chem, 2011,49 (1): 30-37) and method obtained azalomycin F respectively
5a(12.1 g), azalomycin F
4a(7.3 g) and azalomycin F
3a(3.6 g).
Azalomycin F
5a: molecular formula is C
57h
97n
3o
17, white amorphous powder is soluble in methyl alcohol, is dissolved in DMSO, is slightly soluble in water, is insoluble to chloroform, ethyl acetate, m.p. 130 ~ 132 DEG C (Dec.), UV
nm(lg
ε): 240(4.6), 269(4.4), IR(
cm
-1): 3385,2964,2936,1701,1636,1597,1378,1243,1089,1056,969, ESI-MS:1096.7 [M+H]
+,
13c NMR(MeOH-
d 4, 100 MHz)
δppm:174.0, 171.6, 170.1, 157.3, 146.2, 140.3, 140.2, 136.2, 132.5, 130.3, 128.6, 127.6, 126.7, 125.1, 99.7, 80.7, 77.2, 75.7, 74.8, 74.2, 72.3, 72.3, 70.7, 69.7, 66.0, 65.5, 65.4, 46.6, 46.1, 44.6, 44.5, 44.4, 44.2, 42.1, 41.8, 41.7, 41.2, 41.1, 40.8, 39.3, 35.1, 34.5, 33.6, 33.6, 30.7, 30.7, 29.8, 28.4, 28.4, 27.9, 17.6, 17.2, 14.8, 14.3, 13.3, 12.9, 10.4.
Azalomycin F
4a: molecular formula is C
56h
95n
3o
17, white amorphous powder, is soluble in methyl alcohol, is dissolved in DMSO, is slightly soluble in water, is insoluble to chloroform, ethyl acetate, m.p. 130 ~ 132 DEG C (Dec.), UV
nm(lg
ε): 240(4.6), 269(4.4), IR(
cm
-1): 3385,2964,2936,1701,1638,1597,1378,1243,1089,1056,969, ESI-MS:1082.7 [M+H]
+,
13c NMR(MeOH-
d 4, 100 MHz)
δppm:173.9, 171.6, 170.1, 158.3, 146.1, 140.2, 140.1, 136.2, 132.5, 130.3, 128.6, 127.6, 126.8, 125.2, 99.8, 80.7, 77.1, 75.7, 75.0, 74.2, 72.3, 72.2, 70.7, 69.7, 66.1, 65.5, 65.4, 46.5, 46.1, 44.6, 44.6, 44.5, 44.1, 42.1, 42.0, 41.7, 41.2, 41.0, 40.5, 39.2, 35.1, 34.6, 33.6, 33.6, 30.8, 30.8, 29.8, 28.4, 27.9, 17.6, 17.1, 14.8, 14.3, 13.3, 12.9, 10.5.
Azalomycin F
3a: molecular formula is C
55h
93n
3o
17, white amorphous powder, is soluble in methyl alcohol, is dissolved in DMSO, is slightly soluble in water, is insoluble to chloroform, ethyl acetate, m.p. 132 ~ 133 DEG C (Dec.), UV
nm(lg
ε): 240(4.6), 269(4.4), IR(
cm
-1): 3385,2964,2936,1701,1638,1597,1378,1243,1089,1056,969, ESI-MS:1068.6 [M+H]
+,
13c NMR(MeOH-
d 4, 100 MHz)
δppm:174.0, 171.8, 170.1, 158.7, 146.2, 140.3, 140.1, 136.2, 132.6, 130.3, 128.5, 127.6, 126.8, 125.2, 99.9, 81.2, 77.2, 75.7, 75.0, 73.9, 72.3, 72.2, 70.8, 69.8, 66.2, 65.5, 65.4, 46.2, 45.8, 44.6, 44.6, 44.5, 44.1, 42.1, 41.9, 41.7, 41.2, 40.7, 40.5, 39.3, 35.2, 34.6, 33.6, 33.6, 30.7, 30.7, 29.9, 27.9, 17.7, 17.0, 14.8, 14.4, 13.3, 12.8, 10.5.
Get 300 mg sodium hydrides to be dissolved in 400 ml methyl alcohol, under stirring, add 3.3 g(3 mmol) azalomycin F
5a, at 0 DEG C, splash bar reacts 12 h.The reaction mixture aqueous hydrochloric acid of 5 M neutralizes, concentrating under reduced pressure at 40 DEG C, and enriched material is separated through C-18 RPLC, is the methanol-water solution wash-out of 80:20 by volume ratio, collects and is rich in malonyl azalomycin F
5aelutriant, concentrating under reduced pressure, lyophilize at 37 DEG C, obtain 2.4 g and remove malonyl azalomycin F
5a(
1).
embodiment 5:
Get streptomycete
streptomyces hygrpscopicusvar.
azalomyceticusbacterial strain is appropriate, is inoculated on ISP2 plate culture medium, cultivates 4d, and the bacterial strain getting activation is appropriate, is inoculated in the 500 mL Erlenmeyer flasks that 50 mL ISP2 nutrient solutions are housed, and by method described in embodiment 4, preparation seed liquor, fermentation, to obtaining fermented liquid 50 L.With centrifugal method by mycelium and separation of fermentative broth.Mycelium methyl alcohol lixiviate 3 times, obtains methanol extract liquid, and be evaporated to not containing methyl alcohol, freeze-drying, obtains lyophilized powder 135.9 g.Then use chloroform-methanol (1:1) mixed solvent to dissolve, after crossing elimination nonsoluble, volatilize solvent, dry method loading, carries out silica gel column chromatography (silica gel 200 ~ 300 order), with chloroform-methanol (5:1,2:1) for solvent carries out gradient elution, collect part (the azalomycin F being rich in azalomycin F
5a, azalomycin F
4awith azalomycin F
3a), concentrating under reduced pressure at 37 DEG C, 40% dissolve with methanol, filters, crystallization 24 h at 4 DEG C, obtains 15.3 g azalomycin F(containing 57.2% azalomycin F
5a, 25.7% azalomycin F
4awith 13.6% azalomycin F
3a)
Get 500 mg sodium hydrides to be dissolved in 700 ml methyl alcohol, add the azalomycin F of the above-mentioned preparation of 5.4 g under stirring, at 0 DEG C, splash bar reacts 12 h.The reaction mixture aqueous hydrochloric acid of 5 M neutralizes, concentrating under reduced pressure at 40 DEG C, and enriched material is separated through C-18 RPLC, is the methanol-water solution wash-out of 75:25,80:20 successively by volume ratio, collects respectively and is rich in malonyl azalomycin F
3a, F
4aand F
3aelutriant, at 37 DEG C, respectively concentrating under reduced pressure, lyophilize, obtains 1.42 g and removes malonyl azalomycin F
5a(
1), 0.56 g removes malonyl azalomycin F
4a(
2) and 0.34 g remove malonyl azalomycin F
5a(
3).
embodiment 6:
By embodiment 5 method, use streptomycete
streptomyces hygrpscopicusvar.
azalomyceticusbacterial strain prepares seed liquor, fermentation, to obtaining fermented liquid 30 L.Then the obtained 9.2 g azalomycin F(of example 5 method are pressed containing 60.5% azalomycin F
5a, 23.1% azalomycin F
4awith 12.8% azalomycin F
3a)
Get 100 mg sodium hydrides to be dissolved in 100 ml methyl alcohol, add 1.1 g azalomycin F under stirring, at 0 DEG C, splash bar reacts 12 h.The reaction mixture aqueous hydrochloric acid of 5 M neutralizes, concentrating under reduced pressure at 40 DEG C, and enriched material is separated through C-18 RPLC, is the methanol-water solution wash-out of 80:20 successively by volume ratio, and collection is rich in malonyl azalomycin F(and is comprised
1,
2with
3) elutriant, at 37 DEG C, respectively concentrating under reduced pressure, lyophilize, obtains 0.77 g and removes malonyl azalomycin F(
1content be 60.2%,
2content be 21.7% He
3content be 15.1%).
embodiment 7:
Go the anti-MRSA activity test of malonyl azalomycin F
1, experiment material and method
Test strain:
Methicillin-resistant staphylococcus aureus reference culture: MRSA ATCC 33592(Methicillin-resistant
staphylococcus aureusaTCC 33592); Methicillin-resistant staphylococcus aureus clinical strains: MRSA 01; MRSA 02 and MRSA 03.
Beef-protein medium:
Extractum carnis 3 g, peptone 10 g, sodium-chlor 5 g, pure water 1000 mL, pH 7.4.
Positive control drug: Linezolid (Linezolid).
Test sample solution preparation: accurately take respectively Linezolid,
1,
2,
3, azalomycin F
5a, azalomycin F
4awith azalomycin F
3ain right amount, add a small amount of DMSO and dissolve, be then mixed with pure water the test reference substance solution and sample solution (DMSO concentration is less than 5%) that final concentration is 256 μ g/mL.
The anti-MRSA activity of above-claimed cpd all adopts micro-broth dilution method to test, process is as follows: be added to by beef-protein medium in 96 good hole polystyrene plates of sterilizing, every hole adds 100 μ L, then respectively 100 μ L reference substance solution and sample solution are added the 1st hole of corresponding row on the same plate, last 1 row does solvent blank contrast, mixing, then dilute by coubling dilution, the 1st hole is made to be respectively 128 to the concentration of the 11st hole compound, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.13 μ g/mL, growth control is done in 12nd hole, do not add any sample and reference substance solution.Last adding in every hole is diluted to through beef-protein medium the test organisms suspension that spore concentration is 1.0 × 107 CFU/mL, every hole adds 100 μ L, namely obtains the bacterium sample mixture that compound concentration is respectively 64,32,16,8,4,2,1,0.5,0.25,0.13 and 0.06 μ g/mL.In the constant-temperature table of the rearmounted temperature of cap seal 37 DEG C, rotating speed 150 rpm, hatch 20 h judged results.When in growth control hole and solvent control hole, test strain obviously grows, be the minimum inhibitory concentration (MIC) of this compound to test strain with the minimum compound concentration of inhibition test strain growth complete in aperture.
2, experimental result
Remove malonyl azalomycin F
5a(
1), F
4a(
2), F
3a(
3)
,azalomycin F
5a, F
4a, F
3awith anti-MRSA activity (representing with the minimum inhibitory concentration) test-results of Linezolid in table 1.
table 1 goes the activity of the anti-MRSA of malonyl azalomycin F
。
3, conclusion
As shown in Table 1, compound
1,
2with
3azalomycin F is obviously better than to the restraining effect of above-mentioned MRSA test strain growth
5a,f
4aand F
3a, be azalomycin F
5a,f
4aand F
3a8 ~ 16 times; And activity is 2 ~ 8 times of positive clinical contrast medicine Linezolid.Therefore, the malonyl azalomycin F that goes shown in formula I of the present invention has significant anti-MRSA effect, and activity is obviously better than the azalomycin F before modification
5a,f
4aand F
3a, be better than clinical positive control drug Linezolid, therefore can be used for the medicine preparing treatment MRSA infection.In addition, compound 1,2 is very similar with physico-chemical property with the structure of 3, and the anti-MRSA that table 1 shows three compounds is active in significant difference.Therefore wherein any one can be selected, the mixture of two or three also can be selected to prepare anti-MRSA medicine, be used for the treatment of the disease that MRSA infects.
embodiment 7:
Remove malonyl azalomycin F
5athe preparation of tablet
1. the every sheet consumption of prescription 300 consumptions
Remove malonyl azalomycin F
5a0.0500g 15g
Starch 0.0200g 6g
10% starch slurry is appropriate
Talcum powder is appropriate.
2. method for making:
The preparation of (1) 10% starch slurry: added by 2g starch in about 20ml purified water, Heat Gelatinization, makes the starch slurry of 10%.
(2) granulate: get recipe quantity and remove malonyl azalomycin F
5amix with starch, add appropriate 10% starch slurry softwood, cross 16 mesh sieves and granulate, the grain that will wet, in 40 ~ 50 DEG C of dryings, mixes with talcum powder with the whole grain of 16 mesh sieve.
(3) compressing tablet: remove malonyl azalomycin F by above-mentioned
5aparticle is compressing tablet on tabletting machine, must remove malonyl azalomycin F
5asheet.
3. tablet quality measures
(1) inspection item and method: the weight differential and the disintegration that measure above-mentioned tablet respectively according to current edition Pharmacopoeia of the People's Republic of China annex I A and Ⅹ A.
(2) result: above-mentionedly prepare the content difference of tablet and the results are shown in Table 2 disintegration,
table 2 prepares weight differential and the disintegration of tablet
embodiment 8:
Go the preparation of malonyl azalomycin F tablet
1. the every sheet consumption of prescription 300 consumptions
Remove malonyl azalomycin F 0.0500g 15g
Starch 0.0200g 6g
10% starch slurry is appropriate
Talcum powder is appropriate
Note: go in prescription malonyl azalomycin F be prepare by embodiment 6 method remove malonyl azalomycin F, comprise malonyl azalomycin F
5a, F
4aand F
3a.
2. method for making:
The preparation of (1) 10% starch slurry: added by 2g starch in about 20ml purified water, Heat Gelatinization, makes the starch slurry of 10%.
(2) granulate: get recipe quantity and go malonyl azalomycin F to mix with starch, add appropriate 10% starch slurry softwood, the granulation of mistake 16 mesh sieves, the grain that will wet, in 40 ~ 50 DEG C of dryings, mixes with talcum powder with the whole grain of 16 mesh sieve.
(3) compressing tablet: remove malonyl azalomycin F particle compressing tablet on tabletting machine by above-mentioned, malonyl azalomycin F sheet must be removed.
3. tablet quality measures
(1) inspection item and method: the weight differential and the disintegration that measure above-mentioned tablet respectively according to current edition Pharmacopoeia of the People's Republic of China annex I A and Ⅹ A.
(2) result: above-mentionedly prepare the content difference of tablet and the results are shown in Table 3 disintegration,
table 3 prepares weight differential and the disintegration of tablet
Claims (4)
1. remove a malonyl azalomycin F, it is characterized in that: its molecular structural formula is as follows:
Wherein, R
1for methyl or hydrogen: work as R
1during for methyl, R
2for methyl or hydrogen; Work as R
1during for hydrogen, R
2for hydrogen.
2. according to claim 1ly go a malonyl azalomycin F preparation method, it is characterized in that:
Getting a certain amount of sodium hydride is dissolved in methyl alcohol; a certain amount of azalomycin F is added under stirring; splash bar reaction 8 ~ 18 h at-5 ~ 5 DEG C; reaction mixture aqueous hydrochloric acid neutralizes, concentrating under reduced pressure, and enriched material is separated through RPLC; with a certain proportion of methanol-water solution wash-out; collect the elutriant being rich in malonyl azalomycin F, concentrating under reduced pressure, drying, must remove malonyl azalomycin F.
3. go malonyl azalomycin F preparation method as claimed in claim 2, it is characterized in that: raw material azalomycin F can select azalomycin F
5a, F
4aand F
3ain any one, also can be the mixture of any two or three.
4. one kind is gone the application of malonyl azalomycin F in preparation treatment methicillin-resistant staphylococcus aureus infection medicine as claimed in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210560944.5A CN103044439B (en) | 2012-12-21 | 2012-12-21 | De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210560944.5A CN103044439B (en) | 2012-12-21 | 2012-12-21 | De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103044439A CN103044439A (en) | 2013-04-17 |
| CN103044439B true CN103044439B (en) | 2015-01-28 |
Family
ID=48057322
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210560944.5A Active CN103044439B (en) | 2012-12-21 | 2012-12-21 | De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103044439B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103690526B (en) * | 2013-12-16 | 2016-05-11 | 江西农业大学 | One is removed malonyl azalomycin F and vitamin K3Antibacterial combination |
| CN105919995B (en) * | 2016-06-24 | 2018-05-29 | 江西农业大学 | Azalomycin F is preparing the application in treating atopic dermatitis drug |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4703128A (en) * | 1984-10-15 | 1987-10-27 | Takahara Shuzo Co., Ltd. | Guanidylfungin derivatives and their production |
| CN101720772A (en) * | 2008-10-13 | 2010-06-09 | 云南大学 | Macrolide composition for preventing and controlling fungal disease of crop and preparation process thereof |
| CN101792474A (en) * | 2009-11-30 | 2010-08-04 | 中国热带农业科学院热带生物技术研究所 | Novel AzalomycinF microlide compounds and preparation method thereof and application thereof |
| CN102503999A (en) * | 2011-10-18 | 2012-06-20 | 江西农业大学 | Demalonyl azalomycin F derivatives, preparation method thereof and use in preparing microbicides |
-
2012
- 2012-12-21 CN CN201210560944.5A patent/CN103044439B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4703128A (en) * | 1984-10-15 | 1987-10-27 | Takahara Shuzo Co., Ltd. | Guanidylfungin derivatives and their production |
| CN101720772A (en) * | 2008-10-13 | 2010-06-09 | 云南大学 | Macrolide composition for preventing and controlling fungal disease of crop and preparation process thereof |
| CN101792474A (en) * | 2009-11-30 | 2010-08-04 | 中国热带农业科学院热带生物技术研究所 | Novel AzalomycinF microlide compounds and preparation method thereof and application thereof |
| CN102503999A (en) * | 2011-10-18 | 2012-06-20 | 江西农业大学 | Demalonyl azalomycin F derivatives, preparation method thereof and use in preparing microbicides |
Non-Patent Citations (5)
| Title |
|---|
| Azalomycin F4a 2-ethylpentyl ester, a new macrocyclic lactone, from mangrove actinomycete Streptomyces sp. 211726;Gan Jun Yuan,等;《Chinese Chemical Letters》;20101231;第21卷(第8期);第947-950页 * |
| Ganjun Yuan,等.1H and 13C assignments of two new macrocyclic lactones isolated from Streptomyces sp. 211726 and revised assignments of azalomycins F3a, F4a and F5a.《Magnetic Resonance in Chemistry》.2010,第49卷(第1期),第30-37页. * |
| Ganjun Yuan,等.The relative configurations of azalomycins F5a, F4a and F3a.《Journal of Molecular Structure》.2012,第1035卷第31-37页. * |
| 刘为营,等.放线菌1161代谢产物分离纯化及其菌种鉴定.《药物生物技术》.2011,第18卷(第4期),第322-327页. * |
| 杨晓洪,等.红树林土壤微生物与其代谢产物研究进展.《国外医药抗生素分册》.2011,第32卷(第3期),第97-100页. * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103044439A (en) | 2013-04-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103665071B (en) | Elaiophylin derivative and the application in antimicrobial agent and resistance m tuberculosis infection thereof | |
| CN103044439B (en) | De-malonate monoacyl azalomycin F, preparation method thereof and application thereof to preparation of MRSA infection therapeutic drug | |
| CN101544661B (en) | Cefobutazine sodium compound and pharmaceutical composition made therefrom | |
| CN101720772A (en) | Macrolide composition for preventing and controlling fungal disease of crop and preparation process thereof | |
| CN109082445A (en) | The metabolite product of one plant of gingko endogenous fungus and its application in antibacterial | |
| CN102746376A (en) | Cyclopeptide antibiotics and preparation method thereof and application of cylopeptide antibiotics in preparation of antibacterial agents | |
| CN103214547B (en) | A kind of compound and the application in preparation antibacterials thereof | |
| CN109988129A (en) | Compound and its preparing the application in antituberculotic | |
| JPH0232092A (en) | Antibiotics bu-3608d and bu-3608e | |
| CN111494364B (en) | Application of isopentenyl substituted phenol compound in resisting staphylococcus aureus and methicillin-resistant staphylococcus aureus | |
| CN102503999B (en) | Demalonyl azalomycin F derivatives, preparation method thereof and use in preparing microbicides | |
| CN105476983B (en) | A kind of purposes of deep-sea originated from fungus compound Prenylcandidusin C | |
| CN106905342B (en) | Structure of two active metabolites of streptomyces roseoflavus and preparation thereof | |
| CN101863895B (en) | Polyketide and preparation method and application thereof | |
| CN109320527A (en) | Deer chromomycin (cervinomycin) B1, B2, B3, B4 and its production method and application | |
| CN109180593A (en) | Phenol piperazine alkaloids secondary metabolite and its application | |
| CN114014832B (en) | Disc Mao Baojun ketone compound, preparation method thereof and application thereof in preparation of antibacterial drugs | |
| CN103421084A (en) | Antibacterial compound | |
| CA2811635A1 (en) | Improved procedure for the production of tiacumicin b | |
| CN109053836B (en) | Luteolin 7-O-succinyl glucoside and apigenin-7-O-succinyl glucoside and application thereof | |
| CN105037479B (en) | A kind of antimicrobial compound of fungal transformation and preparation method and application | |
| CN100567299C (en) | New antifungal compound, Preparation method and use | |
| CN101429202B (en) | Cephalosporium acremonium corda rhzomorph, production method and uses thereof | |
| CN109096349A (en) | A kind of bar of bifilomycin and its preparation and application and the bacterial strain for producing it | |
| CN115710167A (en) | Two diphenyl ether compounds, preparation method thereof and application thereof in preparation of antibacterial drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |