CN102138917A - Application of dimethyl xanthocillin to preparation of antitubercular medicaments - Google Patents
Application of dimethyl xanthocillin to preparation of antitubercular medicaments Download PDFInfo
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- CN102138917A CN102138917A CN 201010104669 CN201010104669A CN102138917A CN 102138917 A CN102138917 A CN 102138917A CN 201010104669 CN201010104669 CN 201010104669 CN 201010104669 A CN201010104669 A CN 201010104669A CN 102138917 A CN102138917 A CN 102138917A
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Abstract
The invention relates to application of dimethyl xanthocillin to the preparation of intracorporal or extracorporal medicaments for resisting mycobacterium tuberculosis, and application of dimethyl xanthocillin to the preparation of antitubercular medicaments. The mycobacterium tuberculosis is mycobacterium tuberculosis H37Rv.
Description
Technical field
The present invention relates to application and dimethyl yellow penicillin the application in preparation antituberculotics of dimethyl yellow penicillin (xanthocillin X dimethyl ether) in the against mycobacterium tuberculosis medicine of preparation.
Background technology
Tuberculosis (Tuberculosis is designated hereinafter simply as " TB ") is to infect the chronic infection disease that causes by mycobacterium tuberculosis (Mycobacterium tuberculosis), and human life's health in serious harm.Now the population in the whole world 1/3rd has infected mycobacterium tuberculosis, and annual newly-increased tuberculosis case 9,270,000 examples, and is dead 3,000,000, becomes and AIDS, malaria and the three big infectious disease that claim.China is one of the high burden of 22 tuberculosis in whole world country, has 5.5 hundred million populations to infect TB, and patient's number occupies the second place of the world up to 5,500,000, increases tuberculosis patient 4000 many cases every day newly.
The drug resistance of mycobacterium tuberculosis becomes one of the most serious problem that is faced in the current tuberculotherapy, the mycobacterium tuberculosis of single medicine drug resistance, multidrug resistance even serious drug resistance (extreme drug resistance) constantly occurs and propagates, and makes traditional anti-TB medicine lose original curative effect.In in the past three, 40 years, fail to develop real effectively novel anti TB medicine, and the protective rate of bacillus calmette-guerin vaccine also has been lower than 50% in developed country, then lower in China.Threaten in order to tackle tuberculosis, press for the new anti-TB medicine of development.
At present, microbial medicine has become the important source of clinical medicine, and many treatments important drugs lungy is all directly or indirectly from microorganism, as isoniazid, streptomycin, rifampicin, kanamycin, capreomycin, viomycin etc.Therefore, the lead compound of the new and effective antituberculotics of screening also is the emphasis of present antituberculotics research and development from microbial fermentation product.
Dimethyl yellow penicillin (shown in following formula 1) is separated from the fermentation liquid liquid of soil fungi Aspergillus sp. first in nineteen sixty-eight by people such as Takatsuki and obtains, and find that it has antiviral activity (Takatsuki A, et al.New antiviral antibiotics, Xanthocillin X mono-and dimethylether, and methoxyxanthocillin Xdimethylether.I.J Antibiot 1968 (21): 671-675; Takatsuki A, et al.New antiviral antibiotics; Xanthocillin X mono-and dimethylether, and methoxyxanthocillin X dimethylether.II.J Antibiot 1968 (21): 676-680).Afterwards, people such as Japan scientist Tsutomu find that the dimethyl yellow penicillin has better antitumor activity and has lower toxicity (Kurihara H, et al.Method ofinhibiting tumor growth using Xanthocillin x dimethylether.U.S.5,210,097, May 11 (1993) .).People such as Sakai separate from marine fungi Basipetospora sp. and obtain the dimethyl yellow penicillin, and find that it has activity (Sakai R, et al.Xanthocillin as thrombopoietin mimetic smallmolecules.Bioorg Med Chem 2005 (13): 6388-6395) that platelet generates receptor activators.
The inventor found and measured the dimethyl yellow penicillin in vivo with the activity of Killing Mycobacterium Tuberculosis in vitro.The inventor finds that first this chemical compound all has tangible against mycobacterium tuberculosis activity with external in vivo, thereby for against mycobacterium tuberculosis medicine of development and antituberculotics, provides a kind of new selection.
Summary of the invention
One aspect of the invention provides the application of dimethyl yellow penicillin in the against mycobacterium tuberculosis medicine of preparation.
In one embodiment of the invention, the dimethyl yellow penicillin is used to prepare against mycobacterium tuberculosis medicine in the body.
In one embodiment of the invention, the dimethyl yellow penicillin is used to prepare the medicine of Killing Mycobacterium Tuberculosis in vitro.
In one embodiment of the invention, described mycobacterium tuberculosis is mycobacterium tuberculosis H
37Rv.
The inventor adopts microwell plate Alamar Blue method (MABA method) and mice aerosol infection acute tuberculosis disease model to measure dimethyl yellow penicillin Killing Mycobacterium Tuberculosis H
37The activity of Rv (available from Beijing Tuberculosis and Thoracic Tumor Research Institute, or available from ATCC27294), the result shows that this chemical compound all has against mycobacterium tuberculosis effect in vitro and in vivo.
Another aspect of the present invention provides the application of described dimethyl yellow penicillin in the preparation antituberculotics.Verified that by mice aerosol infection acute tuberculosis disease model the dimethyl yellow penicillin is to therapeutical effect lungy.Can be active ingredient with the dimethyl yellow penicillin, and acceptable accessories, the preparation antituberculotics.
The beneficial effect of the invention
The inventor finds first:
1) the dimethyl yellow penicillin all has a tangible against mycobacterium tuberculosis effect with external in vivo.
2) application of dimethyl yellow penicillin in the preparation antituberculotics.
Description of drawings
Fig. 1: infect in the acute tuberculosis disease model and respectively organized the full lung count plate of mice in 30 days.
The specific embodiment
Below in conjunction with embodiment embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only is used to illustrate the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person among the embodiment carries out according to the condition of normal condition or manufacturer's suggestion.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
In an embodiment of the present invention, use rifampicin and isoniazid medicine in contrast.Wherein, isoniazid has very strong antibacterial action, extensive use clinically to tulase; Rifampicin is artificial semisynthetic Ryfamycin derivative, and tulase is had very strong killing action, is just to control indispensable composition medicine in the tuberculosis treatment scheme at present.The dimethyl yellow penicillin can be according to prior art for preparing, for example, and can be with reference to following document: Hagedorn, I.; Eholzer, U.Synthesis of xanthocillin dimethyl ether.[Synthese desXanthocillin-
], Angew.Chem.74 (1962), p215; Hagedorn, I.; Eholzer, U.and Etling H., Isonitriles.V.Preparation of α, β-unsaturated isonitriles, β-keto-and β-chloro-isonitriles.Synthesisof xanthocillin dimethyl ether.[Isonitrile.V.Darstellung von α, β
β-Keto-und β-Chlor-Isonitrilen.], Chem.Ber.98 (1965), pp193-201.
The test of embodiment 1 dimethyl yellow penicillin Killing Mycobacterium Tuberculosis in vitro
Adopt microwell plate Alamar Blue method (MABA method) (Lu Yu, Wang Bin, Zheng Meiqin etc. use the research that Alamar Blue and MTT measure the antituberculotics minimum inhibitory concentration. middle national defence consumptive disease magazine, 2007 (29): 499～501) measure the dimethyl yellow penicillin to mycobacterium tuberculosis H
37The minimum inhibitory concentration of Rv (MIC) value.Aseptic 96 orifice plates add aquesterilisa in each hole around 96 orifice plates, and 200 μ l/ holes are to prevent the composition evaporation of each experimental port in the incubation.With isoniazid (INH, Sigma company) with the aseptic distillation water dissolution, chemical compound of the present invention and rifampicin (RFP, Sigma company) with dmso solution, making concentration respectively is the first solution of 128 μ g/ml, for each required two times of concentration, make chemical compound final concentration of the present invention be: 0.5,1,2,4,8,16,32 μ g/ml with 7H9 culture medium (buy ready-made culture medium, do not contain tween 80) dilution in Difco company; INH and RFP final concentration are: 0.006,0.0125,0.025,0.05,0.1,0.2 μ g/ml.Mycobacterium tuberculosis H
37Rv (available from Beijing Tuberculosis and Thoracic Tumor Research Institute), 100 μ l are inoculated in every hole, and the final concentration of bacterium is 1 * 10
6CFU/ml.Hatched 5 days for 37 ℃, add the 10 * Alamarblue of 20 μ l and the 5%Tween80 mixed liquor of 50 μ l, 37 ℃ hatch 24 hours again after, record stops the lowest concentration of drug of change color (becoming pink from blueness) as the MIC value.
Adopt the MABA method, record the dimethyl yellow penicillin mycobacterium tuberculosis type strain H
37The MIC of Rv is 0.5 μ g/ml (MIC of I NH and RFP is respectively 0.025 μ g/ml and 0.0125 μ g/ml).The dimethyl yellow penicillin shows tangible Killing Mycobacterium Tuberculosis activity external.
Killing Mycobacterium Tuberculosis test in the embodiment 2 dimethyl yellow penicillin bodies
Adopt the interior tuberculosis activity of body of chmice acute aerosol infection tuberculosis model evaluation dimethyl yellow penicillin.According to the standard operating procedure infecting mouse of aerosol infection device (099C A4224 Inhalation ExposureSystem) (available from Beijing Tuberculosis and Thoracic Tumor Research Institute, SPF male BALB/c), infective dose 50～100CFU/ only, coinfection 30 mices.30 mice infected are divided into 5 groups, 6 every group.As follows:
First group: infect back 3 days, dead 3 mices in 10 natural gift other places, do the lung tissue count plate.
Second group: infect and began to give Drug therapy on the 10th day, be subjected to reagent thing dimethyl yellow penicillin 25mg/kg.
The 3rd group: positive control, infect and began to give Drug therapy on the 10th day, be subjected to reagent thing rifampicin 10mg/kg.
The 4th group: positive control, infect and began to give Drug therapy on the 10th day, be subjected to reagent thing isoniazid 25mg/kg.
The 5th group: no medicine matched group, hydroxy methocel.
More than second to five group of equal oral administration gavage administration, administration is 5 times weekly, totally 15 dosage.
Infect the 3rd day, the full lung count plate of mice was 1.98 ± 0.19log
10CFU proves and infects successfully.
Infect back execution in the 30th day and respectively organize mice, weigh, dissect down the sterile working, does the lung tissue count plate, and wherein, preceding four groups counting is shown in table 1 and accompanying drawing 1:
Table 1: infect mice body weight and the full lung count plate situation respectively organized in 30 days in the acute tuberculosis disease model
Found that, adopt chmice acute aerosol infection tuberculosis model to record the dimethyl yellow penicillin and under the dosage of 25mg/kg, have tuberculosis activity in the body, active approaching with rifampicin (10mg/kg).The dimethyl yellow penicillin shows tangible against mycobacterium tuberculosis activity in vivo.The dimethyl yellow penicillin can be used to prepare antituberculotics.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (5)
1. the application of dimethyl yellow penicillin in the against mycobacterium tuberculosis medicine of preparation.
2. application according to claim 1, wherein, described against mycobacterium tuberculosis medicine is an against mycobacterium tuberculosis medicine in the body.
3. application according to claim 1, wherein, described against mycobacterium tuberculosis medicine is the medicine of Killing Mycobacterium Tuberculosis in vitro.
4. according to each described application in the claim 1 to 3, wherein said mycobacterium tuberculosis is mycobacterium tuberculosis H
37Rv.
5. the application of dimethyl yellow penicillin in the preparation antituberculotics.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113730550A (en) * | 2021-04-06 | 2021-12-03 | 中国医学科学院医药生物技术研究所 | Application of boningmycin in treating drug-resistant tuberculosis |
| CN115894307A (en) * | 2022-11-07 | 2023-04-04 | 中国科学院南海海洋研究所 | Isonitrile-based compound, preparation method thereof and application thereof in preparation of antibacterial drugs |
-
2010
- 2010-02-02 CN CN 201010104669 patent/CN102138917A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113730550A (en) * | 2021-04-06 | 2021-12-03 | 中国医学科学院医药生物技术研究所 | Application of boningmycin in treating drug-resistant tuberculosis |
| CN113730550B (en) * | 2021-04-06 | 2023-08-18 | 中国医学科学院医药生物技术研究所 | Application of boningmycin in treating drug-resistant tuberculosis |
| CN115894307A (en) * | 2022-11-07 | 2023-04-04 | 中国科学院南海海洋研究所 | Isonitrile-based compound, preparation method thereof and application thereof in preparation of antibacterial drugs |
| CN115894307B (en) * | 2022-11-07 | 2024-06-11 | 中国科学院南海海洋研究所 | Isonitrile compound, preparation method thereof and application thereof in preparation of antibacterial drugs |
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Application publication date: 20110803 |