CN102872152B - Application of Houttuynoid D in tubercle bacillus resistant medicament - Google Patents
Application of Houttuynoid D in tubercle bacillus resistant medicament Download PDFInfo
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- CN102872152B CN102872152B CN 201210419708 CN201210419708A CN102872152B CN 102872152 B CN102872152 B CN 102872152B CN 201210419708 CN201210419708 CN 201210419708 CN 201210419708 A CN201210419708 A CN 201210419708A CN 102872152 B CN102872152 B CN 102872152B
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- houttuynoid
- tubercle bacillus
- tubercle
- tuberculosis
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- 241000193830 Bacillus <bacterium> Species 0.000 title claims abstract description 21
- 239000003814 drug Substances 0.000 title claims abstract description 14
- ROCYDQPSKYPRJK-KXDBBDCJSA-N 2-[3,4-dihydroxy-2-(2-oxoundecyl)phenyl]-5,7-dihydroxy-3-[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxychromen-4-one Chemical compound CCCCCCCCCC(=O)CC1=C(O)C(O)=CC=C1C1=C(O[C@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 ROCYDQPSKYPRJK-KXDBBDCJSA-N 0.000 title abstract description 67
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 229940079593 drug Drugs 0.000 claims description 8
- 229930190556 houttuynoid Natural products 0.000 claims description 4
- 201000008827 tuberculosis Diseases 0.000 abstract description 14
- 238000002360 preparation method Methods 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 241000304886 Bacilli Species 0.000 abstract 3
- 206010060976 Bacillus infection Diseases 0.000 abstract 1
- 230000002265 prevention Effects 0.000 abstract 1
- 239000001963 growth medium Substances 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 9
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 8
- 241000894006 Bacteria Species 0.000 description 6
- 206010059866 Drug resistance Diseases 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 230000002365 anti-tubercular Effects 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 229920001817 Agar Polymers 0.000 description 4
- 208000009889 Herpes Simplex Diseases 0.000 description 4
- 241000700584 Simplexvirus Species 0.000 description 4
- 239000008272 agar Substances 0.000 description 4
- 230000003602 anti-herpes Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 240000000691 Houttuynia cordata Species 0.000 description 3
- 235000013719 Houttuynia cordata Nutrition 0.000 description 3
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 229930003935 flavonoid Natural products 0.000 description 3
- 150000002215 flavonoids Chemical class 0.000 description 3
- 235000017173 flavonoids Nutrition 0.000 description 3
- 230000010355 oscillation Effects 0.000 description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 3
- 229920000053 polysorbate 80 Polymers 0.000 description 3
- 238000007790 scraping Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 229910021642 ultra pure water Inorganic materials 0.000 description 3
- 239000012498 ultrapure water Substances 0.000 description 3
- 241000725303 Human immunodeficiency virus Species 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- 150000002611 lead compounds Chemical class 0.000 description 2
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000036981 active tuberculosis Diseases 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 description 1
- 229960001225 rifampicin Drugs 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
Abstract
The invention discloses an application of Houttuynoid D in preparation of a tubercle bacillus resistant medicament. According to the current situation that the incidence and the mortality of tuberculosis rise due to high incidence of the conventional tuberculosis and appearance of multi-resistant strains of tubercle bacilli, the Houttuynoid D has the activity of remarkably inhibiting the tubercle bacilli and has a good application prospect. The invention discloses the application of the Houttuynoid D in preparation of the tubercle bacillus resistant medicament for the first time, the skeleton type belongs to a brand-new skeleton type, the Houttuynoid D has unexpected strong inhibiting activity on the tubercle bacilli, the probability of giving any revelation by other compounds does not exist, and the Houttuynoid D has predominant substantial characteristics and obviously makes a remarkable progress on prevention and treatment of tubercle bacillus infection.
Description
Technical field
The present invention relates to the medical compounds application, be specifically related to the application of Houttuynoid D in preparing anti-tubercle bacillus drugs.
Background technology
Global morbidity lungy in recent years is increases trend, according to the World Health Organization (WHO), estimate, the population that the whole world is infected by mycobacterium tuberculosis (Mycobacterium tuberculosis, MTB) at present accounts for 1/3rd of world population, and wherein the infected of 5 ~ 10% becomes tuberculosis patient.Active tuberculosis patient 1,300,000 examples every year appears in China, about 600,000 examples of infectiousness pulmonary tuberculosis wherein, and wherein about 600,000 examples of infectiousness pulmonary tuberculosis, be one of the high burden of global tuberculosis country.
Come out one after another from antituberculotics, make treatment lungy play epoch-making variation.Yet due to the treatment of tuberculosis patient management standard very not still, irregular chemotherapy, the abuse antituberculotics, make the drug resistance of tuberculosis situation day by day serious, and the variation of drug resistance more trends towards multi-medicament drug resistance simultaneously, and this causes very big difficulty to preventing and controlling lungy.Therefore find new antituberculotics, the antituberculotics of especially anti-multidrug resistance is to the protection people's health, significant.
Summary of the invention
The compound H outtuynoid D the present invention relates to is one and within 2012, delivers (Chen, S. D. et al., 2012. Houttuynoid D_E, Anti-Herpes Simplex Virus Active Flavonoids with Novel Skeletons from Houttuynia cordata. Organic Letters 14 (7), 1772 – 1775.) New skeleton compound, this compound has brand-new framework types, current purposes only relates to anti-herpes simplex virus activity (Chen, S. D. et al., 2012. Houttuynoid D_E, Anti-Herpes Simplex Virus Active Flavonoids with Novel Skeletons from Houttuynia cordata. Organic Letters 14 (7), 1772 – 1775.), purposes for the Houttuynoid D the present invention relates in preparation treatment anti-tubercle bacillus drugs belongs to open first, because framework types belongs to brand-new framework types, and it suppresses active unexpectedly strong for tulase, there do not is the possibility that is provided any enlightenment by other compounds, possesses outstanding substantive distinguishing features, control for tubercle bacillus affection simultaneously obviously has significant progress.
Summary of the invention
The object of the invention is to, according in existing Houttuynoid D research, not finding that it has the present situation of the report of tuberculosis activity, provides the application of Houttuynoid D in preparing anti-tubercle bacillus drugs.
Described compound H outtuynoid D structure is as shown in formula I:
Formula I
The object of the invention is achieved by the following technical programs:
The inventor first does the examination bacterial strain with bacillus calmette-guerin vaccine, adopt disk diffusion method to carry out preliminary test to the anti-tubercle bacillus activity of Houttuynoid D, result according to preliminary test, the present invention use again the solid medium By Dilution this compound to bacillus calmette-guerin vaccine, the minimal inhibitory concentration of three kinds of tulases of the H37Rv strain of mycobacterium tuberculosis type strain and substance of medicines-resistant branched tubercle bacillus (MDR MTB), experimental result confirms that Houttuynoid D has very strong anti-tubercle bacillus and anti-drug resistance tulase activity, can be used as the lead compound for the treatment of tubercle bacillus affection disease, also can be used for preparation treatment tuberculosis medicine.
Compared with prior art, the present invention has following beneficial effect:
1. the invention provides a kind of Houttuynoid D that can be used for the sick treatment of tuberculosis, thereby enlarged the kind of anti-tubercle bacillus drugs;
2. the appearance of, tubercule bacillus multiple antibiotic resistant strain high for current incidence of tuberculosis and HIV (human immunodeficiency virus) double infection, make incidence of tuberculosis and mortality rate present situation in rising trend, the present invention finds that Houttuynoid D has the characteristics of anti-tubercle bacillus and drug resistance tulase activity, can be used for the preparation of antituberculotics, there is boundless application prospect;
3. the purposes of the Houttuynoid D the present invention relates in preparation treatment anti-tubercle bacillus drugs belongs to open first, because framework types belongs to brand-new framework types, and it suppresses active unexpectedly strong for tulase, there do not is the possibility that is provided any enlightenment by other compounds, possess outstanding substantive distinguishing features, the control for tubercle bacillus affection simultaneously obviously has significant progress.
The specific embodiment
The preparation method of compound H outtuynoid D involved in the present invention is referring to document (Chen, S. D. et al., 2012. Houttuynoid D_E, Anti-Herpes Simplex Virus Active Flavonoids with Novel Skeletons from Houttuynia cordata. Organic Letters 14 (7), 1772 – 1775.).
The present invention is further detailed explanation by the following examples, but protection scope of the present invention is not subject to any restriction of specific embodiment, but be limited by claim.
Embodiment 1: the preparation of compound H outtuynoid D tablet involved in the present invention:
Get 20 and digest compound Houttuynoid D, add conventional adjuvant 180 grams that prepare tablet, mix, conventional tablet machine is made 1000.
Embodiment 2: the preparation of compound H outtuynoid D capsule involved in the present invention:
Get 20 and digest compound Houttuynoid D, add the conventional adjuvant for preparing capsule as starch 180 grams, mix, encapsulatedly make 1000.
Further illustrate its pharmaceutically active below by pharmacodynamic experiment.
The experimental example 1 anti-bacillus calmette-guerin vaccine of solid medium By Dilution Houttuynoid D (BCG) absolute concentration
Scraping bacillus calmette-guerin vaccine culture from inclined-plane, join in 3ml Middlebrook7H9 broth bouillon, add a small amount of bead, screw test tube cap, on the vortex oscillation device, high vibration grinds, than turbid, be made into bacillus calmette-guerin vaccine (BCG) bacteria suspension of 1mg/ml with standard Maxwell opacity tube (MacFarland No.1).
Houttuynoid D is made into to the stock solution of high concentration with DMSO, dilute stock solution to desired concn with the aseptic ultra-pure water of the tween 80 containing 5%, the Houttuynoid D that diluted is joined to 4ml Middlebrook7H11 agar culture medium by required dosage, and (this culture medium is 121 ℃ of high pressure steam sterilizations 15 minutes, be cooled to 50 ~ 55 ℃), mix, make containing Houttuynoid D, concentration is respectively 6.0 ug/ml, 4.0 ug/ml, 3.0 ug/ml, 2.0 ug/ml, 1.5 ug/ml, 1.0 ug/ml, 0.75 ug/ml, 0.5 the isocyatic slant medium of ug/ml.
The bacillus calmette-guerin vaccine that is 1 mg/ml by concentration (BCG) bacteria suspension dips ring of numbers with inoculating loop, be inoculated in respectively on the culture medium and blank medium slant containing Houttuynoid D series concentration, be placed in 37 ℃ and cultivate 4 ~ 8 weeks, the observation experiment result, result is as shown in table 1.
Culture medium commonly used when in the present embodiment, Middlebrook7H9 broth bouillon used and Middlebrook7H11 agar culture medium carry out the tulase cultivation for those skilled in the art, its formula adopts conventional formulation to get final product.
Experimental example 2 solid medium By Dilution Houttuynoid D Killing Mycobacterium Tuberculosis type strain H37Rv strain absolute concentrations
Scraping mycobacterium tuberculosis type strain H37Rv strain culture from inclined-plane, join in 3 ml Middlebrook7H9 broth bouillons, add a small amount of bead, screw test tube cap, on the vortex oscillation device, high vibration grinds, than turbid, be made into the H37Rv strain bacteria suspension of 1 mg/ml with standard Maxwell opacity tube (MacFarland No.1).
Houttuynoid D is made into respectively to the stock solution of high concentration with DMSO, dilute stock solution to desired concn with the aseptic ultra-pure water of the tween 80 containing 5%, the Houttuynoid D that diluted is joined to 4ml Middlebrook7H11 agar culture medium by required dosage, and (this culture medium is 121 ℃ of high pressure steam sterilizations 15 minutes, be cooled to 50 ~ 55 ℃), mix, make containing Houttuynoid D, concentration is respectively 6.0 ug/ml, 4.0 ug/ml, 3.0 ug/ml, 2.0 ug/ml, 1.5 ug/ml, 1.0 ug/ml, 0.75 ug/ml, 0.5 the isocyatic slant medium of ug/ml.
The H37Rv strain bacteria suspension that is 1mg/ml by concentration dips ring of numbers with inoculating loop, is inoculated in respectively on the culture medium and blank medium slant containing Houttuynoid D series concentration, and be placed in 37 ℃ and cultivate 4 ~ 8 weeks, the observation experiment result, result is as shown in table 1.
The clinical separation of the experimental example 3 solid medium By Dilution Houttuynoid D tuberculosis mycobacterium MTB of anti-ISRE strain absolute concentration
The clinical separation of the scraping mycobacterium tuberculosis MTB of anti-ISRE strain (anti-isoniazid, streptomycin, rifampicin, the clinical detached dowel of ethambutol mycobacterium tuberculosis) culture from inclined-plane, join in 3ml Middlebrook7H9 broth bouillon, add a small amount of bead, screw test tube cap, on the vortex oscillation device, high vibration grinds, than turbid, be made into the bacteria suspension of 1mg/ml with standard Maxwell opacity tube (MacFarland No.1).
Houttuynoid D is made into respectively to the stock solution of high concentration with DMSO, dilute stock solution to desired concn with the aseptic ultra-pure water of the tween 80 containing 5%, the Houttuynoid D that diluted is joined to 4ml Middlebrook7H11 agar culture medium by required dosage, and (this culture medium is 121 ℃ of high pressure steam sterilizations 15 minutes, be cooled to 50 ~ 55 ℃), mix, make containing Houttuynoid D, concentration is respectively 6.0 ug/ml, 4.0 ug/ml, 3.0 ug/ml, 2.0 ug/ml, 1.5 ug/ml, 1.0 ug/ml, 0.75 ug/ml, 0.5 the isocyatic slant medium of ug/ml.
The clinical separation of the mycobacterium tuberculosis MTB of the anti-ISRE strain bacteria suspension that is 1mg/ml by concentration dips ring of numbers with inoculating loop, be inoculated in respectively on the culture medium and blank medium slant containing Houttuynoid D series concentration, being placed in 37 ℃ cultivates 4 ~ 8 weeks, the observation experiment result, result is as shown in table 1.
Table 1 solid medium By Dilution Houttuynoid D anti-tubercle bacillus absolute concentration result
Conclusion: Houttuynoid D has very strong anti-tubercle bacillus and anti-drug resistance tulase activity, can be used as the lead compound for the treatment of tubercle bacillus affection disease, also can be used for preparation treatment tuberculosis medicine.
Claims (1)
1.Houttuynoid the application of D in preparing anti-tubercle bacillus drugs, described compound H outtuynoid D structure as
formula Ishown in:
formula I.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201210419708 CN102872152B (en) | 2012-10-27 | 2012-10-27 | Application of Houttuynoid D in tubercle bacillus resistant medicament |
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| CN 201210419708 CN102872152B (en) | 2012-10-27 | 2012-10-27 | Application of Houttuynoid D in tubercle bacillus resistant medicament |
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| CN102872152A CN102872152A (en) | 2013-01-16 |
| CN102872152B true CN102872152B (en) | 2013-12-18 |
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| JP5339840B2 (en) * | 2008-10-02 | 2013-11-13 | 公益財団法人微生物化学研究会 | Anti-XDR-TB drug, anti-MDR-TB drug, and concomitant anti-tuberculosis drug |
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