CN104230938A - Marine fungus-derived piperazine derivative and application of derivative in preparation of antituberculosis drugs - Google Patents
Marine fungus-derived piperazine derivative and application of derivative in preparation of antituberculosis drugs Download PDFInfo
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- CN104230938A CN104230938A CN201410465696.5A CN201410465696A CN104230938A CN 104230938 A CN104230938 A CN 104230938A CN 201410465696 A CN201410465696 A CN 201410465696A CN 104230938 A CN104230938 A CN 104230938A
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/182—Heterocyclic compounds containing nitrogen atoms as the only ring heteroatoms in the condensed system
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Abstract
The invention discloses a marine fungus-derived piperazine derivative and an application of the derivative in preparation of antituberculosis drugs. The piperazine compound has a structural formula shown in a formula (I) described in the specification, has the activity of remarkably inhibiting mycobacterium protein tyrosine phosphatase B (mPTPB) and the IC50 value of (7.07+/-2.761) microns, can be used for preparing novel antituberculosis drugs, and has wide application prospects.
Description
Technical field
The present invention relates to medical compounds field, specifically, relate to a kind of piperazine compounds and preparing the application in antitubercular agent.
Background technology
Tuberculosis is a kind of disease of serious harm human body health, belongs to chronic infectious disease, and main peak infection population was 15 ~ 35 one full year of life, and comparatively refractory more.Mycobacterium tuberculosis (Mycobacterium tuberculosis, MTB), it is the pathogenic bacteria of tubercule bacillus, after respiratory infectious, can encroach on each histoorgan of whole body, in the immunity system of human body, pathogenic bacteria is cells infected in human body, the most common with pulmonary infection, be secondly at meninx, neck lymph and peritonaeum etc.The clinical symptom of its main manifestations is cough, sometimes also can with phlegm and blood, also has pectoralgia, weak, weight loss, heating and night sweat etc.
Mycobacterium tuberculosis self can secrete tyrosine phosphatase PTPs, wherein current research mainly concentrates on the homologous protein tyrosine phosphatase (PTP1B) of tyrosine phosphatase A (mPTPA) and tyrosine phosphatase-1 b (mPTPB) and its people, being the important and necessary virulence factor of mycobacterium tuberculosis, is cause phthisical important reason.The tyrosine phosphatase-1 b (mPTPB) gone out by mycobacterium tuberculosis secretory, the tenuigenin entering scavenger cell is total, regulates the survival of mycobacterium tuberculosis in host, and the part making interferon-γ active is in scavenger cell, vigor declines greatly, the immunity system of opposing host.
Because the homology of mPTPB and people PTPB only has 6%, so mPTPB is very worth further investigation as medicinal design target.The avtive spot of mPTPB is a double-helical cap structure and two tyrosine phosphorylation binding sites, it has a P-Loop circulation, in this circulation, the asparagicacid residue (Asp165) of 165 that have and the lysine residue (Lys164) of 164 are its main catalytic site.
The research of the newtype drug being target spot with the tyrosine phosphatase mPTPB of mycobacterium tuberculosis secretory is very important.The interactional research of newtype drug and chemical substance and enzyme is research very popular at present, and the inhibitor of screening mPTPB is work main at present.
Summary of the invention
The object of this invention is to provide above-mentioned bridged piperazine derivatives and prepare the application in antitubercular agent.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
One class piperazine derivative, its structural formula is as shown in (I):
The preparation method of piperazine derivative of the present invention comprises the steps:
(1) bacterial strain of thalassiomycetes aspergillus Aspergillussp.HNY16-5C is accessed seed culture medium from slant medium, shaking table is cultivated, (depositary institution of described thalassiomycetes aspergillus Aspergillussp.HNY16-5C is China typical culture collection center to obtain seed culture fluid, preservation address is Wuhan University of Wuhan, China city, preserving number is CCTCC M 2012358, and preservation date is on September 19th, 2012);
(2) seed culture fluid is accessed in fermention medium, quiescent culture;
(3) tunning filtration is obtained thalline, thalline methyl alcohol soaks, and concentrating under reduced pressure obtains medicinal extract, then through chromatographic separation, obtains piperazine derivative 1.
As a kind of preferred version, in above-mentioned preparation method, the component of step (1) described seed culture medium is: potato 200g, glucose 20g, water 1L.
As a kind of preferred version, in above-mentioned preparation method, the component of step (2) described fermention medium is: northeast rice 7000g, sea salt 210g, water 7L.
As a kind of preferred version, in above-mentioned preparation method, the described shaking table culture condition of step (1) is: rotating speed 200rpm, temperature 28 DEG C, incubation time 72h.
As a kind of preferred version, in above-mentioned preparation method, the described quiescent culture temperature of step (2) is 25 DEG C, and incubation time is 28 days.
As a kind of preferred version, in above-mentioned preparation method, the described medicinal extract silica gel column chromatography of step (3) is separated, and is separated the ethyl acetate/petroleum ether gradient elution with 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 100%.
As a kind of preferred version, in above-mentioned preparation method, described 30%-40% ethyl acetate--sherwood oil elution fraction is through purification on normal-phase silica gel column chromatography for separation, and eluent is chloroform--methanol gradient drip washing, collect chloroform--the methyl alcohol component of 5%, eventually pass and obtain compound 1.
Piperazine compounds of the present invention 1 pair of tubercule bacillus tyrosine phosphatase (mPTPB) has restraining effect, can be used for preparing antitubercular agent.
Compared with prior art, the present invention has following beneficial effect: the class piperazine compounds 1 deriving from South Sea mangrove fungi Aspergillussp.HNY16-5C, this compound has and significantly suppresses tubercule bacillus tyrosine phosphatase (mPTPB) active, has good market outlook preparing in Newer Antibuberculotics.Piperazine compounds 1 of the present invention derives from thalassiomycetes, simple, with low cost from the method for fungi extraction and isolation.
Embodiment
Explain the present invention further below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.
Embodiment 1:
Compound of the present invention, can be separated and obtain from the thalline of thalassiomycetes aspergillus Aspergillussp.HNY16-5C.Thalassiomycetes aspergillus Aspergillussp.HNY16-5C is separated to obtain from the leaf of marine site, Haikou Mangrove Sonneratia apetala Buch. Ham S.apetala.Concrete steps are as follows:
1. seed culture:
(1) seed culture medium is prepared: potato 200g, glucose 20g, tap water 1L, average mark is loaded on 5 500mL Erlenmeyer flasks, and 121 DEG C go out 30 minutes.
(2) cultivation of seed: by the bacterial strain of thalassiomycetes aspergillus Aspergillussp.HNY16-5C access seed culture medium, at the temperature of 28 DEG C, put with the rotating speed of 200rpm on shaking table, cultivate 72 hours to obtain seed culture fluid.
2. fermentation culture:
(1) fermention medium is prepared: northeast rice 7000g, sea salt 210g, tap water 7L, 121 DEG C go out 30 minutes.
(2) fermentation culture:
Seed liquor 5mL access is equipped with in the Erlenmeyer flask of fermention medium, in 25 DEG C of quiescent culture 28 days by aseptic technique.
3. extraction and isolation:
Fermented product methyl alcohol soaks, and soak solution concentrating under reduced pressure at lower than 50 DEG C obtains medicinal extract 12.2g.This medicinal extract is separated through silica gel column chromatography, uses 5% respectively, and 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, the ethyl acetate-light petrol gradient elution of 100%, wherein 30%-40% ethyl acetate--sherwood oil elution fraction is through purification on normal-phase silica gel column chromatography for separation, and eluent is chloroform--methanol gradient drip washing, collect chloroform--the methyl alcohol component of 5%, eventually pass and obtain compound 1.
Embodiment 2: carry out structural analysis test to the compound in embodiment 1, obtains following physico-chemical property data:
Compound 1: yellow needle-like crystals, fusing point 157-158 DEG C (thermometer does not correct), EI-MS (m/z): 347 [M]
+.
The NMR data of compound 1 are in table 1.
The NMR data (100MHz/400MHz, TMS, ppm) of table 1 compound 1
Embodiment 3: mycobacterium tuberculosis tyrosine phosphatase (mPTPB) Inhibition test is carried out to the compound 1 in embodiment 1:
Adopt p-nitrophenyl phosphoric acid (pNPP) to be substrate, carry out in 50mM Tris, 100mM NaCl damping fluid (37 DEG C, pH 7.8).PNPP is p-NP by mPTPB enzymolysis, to measure the change of its absorbancy and calculate the activity of enzyme with ultraviolet-visible spectrophotometer at 405nm wavelength place.Reaction initial system 200 μ L, wherein comprises the enzyme of 5 μ L, the substrate pNPP of 2.5mM, the inhibitor of different concns.Reaction starts the light absorption value measuring 405nm wavelength place after starting 5min, within continuous 5 minutes, reads absorption value.
Enzymic activity is calculated: inhibiting rate (%)=[(A with following formula
0– A)/A
0] × 100%, wherein A
0the absorbancy changing value of blank, A is the absorbancy changing value of sample.Measure the sample of 5 concentration, draw dosage--inhibiting rate curve, draw its IC
50value.Each sample replication three times, result mean value ± standard deviation represents.
It is inhibited that result records compound 1 pair of mycobacterium tuberculosis tyrosine phosphatase (mPTPB), its IC
50for (7.07 ± 2.761) μM.
Claims (3)
1. the piperazine compounds in thalassiomycetes source, is characterized in that structural formula is as shown in formula I:
。
2. piperazine compounds described in claim 1 is preparing the application in mycobacterium tuberculosis tyrosine phosphatase enzyme inhibitors.
3. the application of piperazine compounds according to claim 2, is characterized in that described mycobacterium tuberculosis tyrosine phosphatase enzyme inhibitors is for preventing and treating tuberculosis.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410465696.5A CN104230938A (en) | 2014-09-13 | 2014-09-13 | Marine fungus-derived piperazine derivative and application of derivative in preparation of antituberculosis drugs |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110724149A (en) * | 2019-10-17 | 2020-01-24 | 中山大学 | Indole alkaloid dimer compound derived from marine fungi, preparation method and application of indole alkaloid dimer compound in marine fouling organism resistant control agent |
| CN114934084A (en) * | 2022-05-23 | 2022-08-23 | 浙江工业大学 | Preparation method of indole diketopiperazine alkaloid |
-
2014
- 2014-09-13 CN CN201410465696.5A patent/CN104230938A/en active Pending
Non-Patent Citations (5)
| Title |
|---|
| FENG-PING MIAO ET AL.: ""Secondary Metabolites from an Algicolous Aspergillus versicolor Strain"", 《MARINE DRUGS》 * |
| FUHANG SONG ET AL.: ""Brevianamides with Antitubercular Potential from a Marine-Derived Isolate of Aspergillus versicolor"", 《ORGANIC LETTERS》 * |
| GUO-YOU LI ET AL.: ""Brevianamide J, A New Indole Alkaloid Dimer from Fungus Aspergillus versicolor"", 《ORGANIC LETTERS》 * |
| KONG XIANGLAN ET AL.: ""Secondary Metabolites of a Deep Sea Derived Fungus Aspergillus versicolor CXCTD-06-6a and Their Bioactivity"", 《J. OCEAN UNIV. CHINA》 * |
| 李国友: ""五种毛壳霉属和曲霉属真菌代谢产物及细胞毒活性"", 《中国博士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110724149A (en) * | 2019-10-17 | 2020-01-24 | 中山大学 | Indole alkaloid dimer compound derived from marine fungi, preparation method and application of indole alkaloid dimer compound in marine fouling organism resistant control agent |
| CN110724149B (en) * | 2019-10-17 | 2022-04-05 | 中山大学 | Indole alkaloid dimer compound derived from marine fungi, preparation method and application of indole alkaloid dimer compound in marine fouling organism resistant control agent |
| CN114934084A (en) * | 2022-05-23 | 2022-08-23 | 浙江工业大学 | Preparation method of indole diketopiperazine alkaloid |
| CN114934084B (en) * | 2022-05-23 | 2024-03-26 | 浙江工业大学 | Preparation method of indole diketopiperazine alkaloid |
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