CN108685908A - Applications of the celecoxib derivative OSU-03012 in preparing anti-tubercle bacillus drugs - Google Patents
Applications of the celecoxib derivative OSU-03012 in preparing anti-tubercle bacillus drugs Download PDFInfo
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- CN108685908A CN108685908A CN201810917450.5A CN201810917450A CN108685908A CN 108685908 A CN108685908 A CN 108685908A CN 201810917450 A CN201810917450 A CN 201810917450A CN 108685908 A CN108685908 A CN 108685908A
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- tubercle bacillus
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- celecoxib
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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Abstract
The present invention relates to field of pharmaceutical chemistry technology, more particularly to applications of the celecoxib derivative OSU-03012 in preparing anti-tubercle bacillus drugs, and celecoxib derivative OSU-03012 is being prepared for treating the application in phthisical drug, and a kind of anti-tubercle bacillus drugs composition is further related to.The celecoxib derivative OSU-03012 has the activity of anti-tubercle bacillus and anti-drug resistance tulase, therefore it can be used as the lead compound for the treatment of tubercle bacillus affection disease (such as pulmonary tuberculosis), certainly, the celecoxib derivative OSU-03012 itself also can be used for preparing treatment tuberculosis, to have good potential applicability in clinical practice.
Description
Technical field
The present invention relates to field of pharmaceutical chemistry technology, and in particular to celecoxib derivative OSU-03012 is preparing resistive connection
Application and celecoxib derivative OSU-03012 in pyrenomycetes drug are being prepared for treating answering in phthisical drug
With further relating to a kind of anti-tubercle bacillus drugs composition.
Background technology
Mycobacterium tuberculosis (M.tuberculosis) is referred to as tubercle bacillus (tubercle bacilli) or tulase.
Early in 1882, it was tuberculosis that German bacteriologist Ke He (Robert Koch, 1843-1910), which is just proved mycobacterium tuberculosis,
The pathogen of disease.This bacterium can invade each histoorgan of whole body, but most common with pulmonary infection.
Tulase does not generate inside and outside toxin, it is pathogenic may with bacterium in histocyte caused by mass propagation it is scorching
The immunologic mjury that the toxicity and body of disease, drive member and metabolite generate drive member is related.Tulase can pass through
Respiratory tract, alimentary canal or skin injury invade susceptible body, cause the tuberculosis of Various Tissues organ, wherein to pass through respiratory tract
It is most to cause pulmonary tuberculosis.Because there is a large amount of normal floras to live away from home in enteron aisle, tulase must could be survived simultaneously and easy by competition
Feel cell adherence;And without normal flora in alveolar, tulase can be sucked by droplet droplet or germ-laden Dust, thus pulmonary tuberculosis compared with
It is common.
After the 1980s, since the appearance of AIDS and drug resistance of mycobacterium tuberculosis bacterial strain, immunosuppressor are answered
With, take drugs, the factors such as poor and movement of population, epidemic situation lungy deteriorates suddenly in global range.It is counted according to WHO, the whole world
Just there is 1 people to infect mycobacterium tuberculosis in about every 3 people, mycobacterium tuberculosis carries in certain developing countries are grown up
Rate is up to 80%, wherein about 5%~10% carrier can develop into active tuberculosis.Since 21 century, the whole world about goes out every year
Existing 8,000,000 tuberculosis new cases, and cause about 3 million peoples dead;It is reported that China die of every year people lungy about 250,000 it
More, therefore, tuberculosis is clearly to threaten the global hygienic issues of human health.
Celecoxib derivative OSU-03012 is also referred to as AR-12, is usually considered a kind of effective recombination PDK-1
Inhibitor.Recent studies indicate that OSU-03012 can also effectively inhibit hydrophobin, chikungunya virus, measles
Poison, rubella virus, Respiratory Syncytial Virus(RSV), Marburg virus, Lassa virus (Lassa virus), cytomegalovirus, Coxsack
Virus, adenovirus, dengue fever virus, West Nile Virus, flavivirus and enterovirns type 71 replication capacity.
In a newest research (Journal of Cell Physiology, in October, 2016), from the U.S.,
The anti-virus ability of OSU-03012 is described in detail in Australia, Argentina and Hispanic researcher, reconfirms
OSU-03012 is effective against a series of viruses, including a variety of drug resistance HIV strains, Ebola virus, influenza virus, the parotid gland
Scorching virus and measles virus.Accordingly, related researcher feels the need to carry out further clinical test to prove OSU-
03012 can be used as a kind of antiviral drugs use.It can be seen that report OSU-03012 not can be used as resistive connection in the prior art
Pyrenomycetes drug uses.
Invention content
The present invention is intended to provide new applications of the known compound OSU-03012 in terms of as anti-tubercle bacillus drugs.This hair
Bright inventor is during studying and screening the compound of anti-tubercle bacillus, it has unexpectedly been found that celecoxib derivative OSU-
03012 (i.e. AR-12) can generate apparent inhibiting effect to tulase.
Specifically, first aspect present invention provides celecoxib derivative OSU-03012 and is preparing anti-tubercle bacillus drugs
In application;Wherein, the structural formula of the celecoxib derivative OSU-03012 is:
Meanwhile second aspect of the present invention provides celecoxib derivative OSU-03012 and is preparing for treating pulmonary tuberculosis
Drug in application;Wherein, the structural formula of the celecoxib derivative OSU-03012 is:
In addition, third aspect present invention additionally provides a kind of anti-tubercle bacillus drugs composition, it includes a effective amount of plugs to come
Former times cloth derivative OSU-03012 and pharmaceutically acceptable carrier;Wherein, the knot of the celecoxib derivative OSU-03012
Structure formula is:
Wherein, celecoxib derivative OSU-03012 (i.e. AR-12) of the present invention can be by chemical synthesis process system
.
In a preferred embodiment of the present invention, the pharmaceutically acceptable carrier is selected from following any or more
Kind:Filler, adhesive, solubilizer, disintegrant and glidant.Wherein, the filler includes but not limited to:Lactose, crystallite
Cellulose, starch, dextrin, fructose, sucrose, mannitol, sorbierite, xylitol, maltitol or combinations thereof.Wherein, described viscous
Mixture includes but not limited to:Polyvinylpyrrolidone, hydroxypropyl methylcellulose, carboxymethyl cellulose (sodium), hydroxypropyl cellulose, hydroxyl
Ethyl cellulose, gelatin, Arabic gum, guar gum, xanthans, dextrin, starch or combinations thereof.Wherein, the solubilizer includes
But it is not limited to:Lauryl sodium sulfate, poloxamer, beta-cyclodextrin, hydroxypropylβ-cyclodextrin, hydroxyethylβcyclodextrin, α-ring
Dextrin, polysorbate, polyethylene glycol, polyvinylpyrrolidone or combinations thereof.Wherein, the disintegrant includes but not limited to:It hands over
Join povidone, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose or its group
It closes.Wherein, the glidant includes but not limited to:Magnesium stearate, calcium stearate, stearic acid, silica, talcum powder, poly- second
Glycol, sodium stearyl fumarate or combinations thereof.
In another preferred embodiment of the present invention, the dosage form of the anti-tubercle bacillus drugs composition is selected from following
It is a kind of:Tablet, capsule, pill, granule, suspension, oral solution, paint, cataplasm, spray, powder-injection and liquid drugs injection.
Inventor experiments prove that, the celecoxib derivative OSU-03012 (i.e. AR-12) can reduce tulase
Infect the Intracellular survival after macrophage.Also, relevant animal experimental study shows with tubercle bacillus affection mouse after a week, to give
The OSU-03012 of 100-200mg/kg dosage is given, after three weeks, mouse lung pathology damage is substantially reduced, intrapulmonary lotus for oral medication
Bacterium amount is substantially reduced, and the expression of the intrapulmonary segmental inflammation factor substantially reduces.
In conclusion the present invention provides celecoxib derivative OSU-03012 is new in preparing anti-tubercle bacillus drugs
Purposes, the celecoxib derivative OSU-03012 can effectively inhibit the infection of tulase, to be carried for treatment lungy
It is supported for effective drug.In short, the celecoxib derivative OSU-03012 has anti-tubercle bacillus and anti-drug resistance tulase
Activity, therefore its can be used as treatment tubercle bacillus affection disease (such as pulmonary tuberculosis) lead compound, certainly, it is described plug come
Former times cloth derivative OSU-03012 itself also can be used for preparing treatment tuberculosis, to before good clinical application
Scape.
Description of the drawings
Fig. 1 is the intracellular CFU figures of tubercle bacillus affection macrophage;
Fig. 2 is to be sliced to implement hematoxylin to mouse lung --- eosin stains (hematoxylin-eosin staining,
H&E result figure);
Fig. 3 is the statistical chart of the lotus bacterium amount of tulase in mouse lung;
Fig. 4 is the realtime PCR testing result figures of mouse lung inflammatory factor iNOS;
Fig. 5 is the realtime PCR testing result figures of mouse lung inflammatory factor TNF-α;
Fig. 6 is the realtime PCR testing result figures of mouse lung inflammatory factor IL-12mRNA.
Specific implementation mode
The present invention is further elaborated With reference to embodiment, but the present invention is not limited to following embodiment party
Formula.Experimental method in following embodiments is unless otherwise specified conventional method;Material as used in the following examples, examination
Agent etc. can obtain unless otherwise specified from open commercial sources.
Embodiment 1
By C57BL/6 mouse peritoneal primary macrophages with 1*105A/hole is inoculated in 48 porocyte culture plates, about 2h
After cell is adherent, complete medium 1640 is removed, fresh complete medium overnight incubation is then added.Second day, feeling
Dye before 1h change it is fresh without dual anti-and containing 10% serum 1640, along with final concentration 1uM AR-12 in cell culture
In clear;With the holes as a contrast DMSO, cell is placed in incubator after cultivating 1h, tulase is infected with the dosage of MOI=5
(H37Rv).After infecting 2-3h, discards supernatant, then, with the medium culture cell 2h containing amikacin, discard supernatant simultaneously
It changes 1640 without dual anti-and containing 10% serum and continues at 37 DEG C, 5%CO2Cell is cultivated in incubator for 24 hours.It discards
Clearly, PBS is used in combination to wash cell, then with the PBS lytic cells containing 1%triton-100, take cell pyrolysis liquid be applied to containing
On the Middle Brook 7H10 agar plates of amphotericin B, it is placed in culture 2-3 weeks in 37 DEG C of incubators, then carries out bacterium
Fall counting.
Count results as shown in Figure 1, the experimental results showed that, AR-12 (i.e. celecoxib derivative OSU-03012) can drop
Intracellular survival after low tubercle bacillus affection macrophage.
Embodiment 2
C57BL/6 mouse are divided into two groups, every group 6, tulase (H37Rv), dosage 2* are infected in intraperitoneal injection respectively
106After infecting 1 week, 25mg/kg and PBS is administered orally as a contrast, successive administration 3 weeks in a bacterium/mouse.Cervical dislocation is put to death
Mouse takes out the leaf in lungs, is fixed with 4% paraformaldehyde, after paraffin section, implements H&E is dyed, observation lung pathologies damage
Condition of the injury condition.
Referring to Fig. 2, the AR-12 of 100-200mg/kg dosage is given, after three weeks, mouse lung pathology damage is bright for oral medication
It is aobvious to mitigate;Therefore, the present embodiment the experimental results showed that, AR-12 can effectively mitigate the pathology damage of mouse lung.
Embodiment 3
Three weeks mouse lung tissues are administered after being infected in embodiment 2 and take its one third, 1ml is used in combination to contain 1%triton-
100 PBS milled processeds, gradient dilution take 10 respectively-3,10-4Tissue suspension 100ml be spread evenly across it is mould containing both sexes
It on the Middle Brook 7H10 agar plates of plain B, is subsequently placed in 37 DEG C of incubators and cultivates 2-3 weeks, carry out bacterium colony meter
Number, the results are shown in Figure 3.
The present embodiment the experimental results showed that, AR-12 significantly reduces the lotus bacterium amount of tulase in mouse lung.
Embodiment 4
The extraction of mouse lung tissue RNA:Three weeks mouse lung tissues are administered after infecting in embodiment 2 to take thirdly dividing it
One, it shreds, 1ml trizol is added, and 200ul chloroforms are added, overturn mixing and stand 10 minutes, 4 DEG C, 12000rpm centrifugations 15
Minute, it takes in supernatant to new RNase free EP pipes;Then, isometric isopropanol is added, -20 DEG C are placed 10 minutes, and
In 4 DEG C, 12000rpm is centrifuged 15 minutes, abandons supernatant, and the cold 75% ethyl alcohol washing precipitations of 1ml are added, then at 4 DEG C, 7500rpm from
The heart 10 minutes, discards supernatant, dry RNA precipitate.
The synthesis of cDNA:1ugRNA is taken, RNase free water is added to 14ul, after five minutes in 65 DEG C of effects, into RNA
Be added 1ul primer, 4ul 5*RT buffer, 1ul enzymes, total volume 20ul, place reaction liquid into 37 DEG C act on 15 minutes, most
It is placed on 95 DEG C of enzymes to inactivate 5 minutes, that is, synthesizes cDNA.
The detection of inflammatory factor:The expression water of realtime PCR detection inflammatory factors iNOS, TNF-α, IL-12mRNA
Flat, testing result is successively as shown in Fig. 4, Fig. 5, Fig. 6.
The present embodiment the experimental results showed that, AR-12 can reduce the expression of the inflammation factor in mouse lung.
Therefore, AR-12 (celecoxib derivative OSU-03012) can effectively inhibit the infection of tulase, to be knot
The treatment of core disease provides effective drug and supports.
Specific embodiments of the present invention are described in detail above, but it is intended only as example, the present invention is simultaneously unlimited
It is formed on particular embodiments described above.To those skilled in the art, it is any to the equivalent modifications that carry out of the present invention and
It substitutes also all among scope of the invention.Therefore, without departing from the spirit and scope of the invention made by impartial conversion and
Modification, all should be contained within the scope of the invention.
Claims (5)
1. applications of the celecoxib derivative OSU-03012 in preparing anti-tubercle bacillus drugs;Wherein, the celecoxib derives
The structural formula of object OSU-03012 is:
2. celecoxib derivative OSU-03012 is being prepared for treating the application in phthisical drug;Wherein, the plug comes
The former times structural formula of cloth derivative OSU-03012 is:
3. a kind of anti-tubercle bacillus drugs composition, which is characterized in that comprising a effective amount of celecoxib derivative OSU-03012 and
Pharmaceutically acceptable carrier;Wherein, the structural formula of the celecoxib derivative OSU-03012 is:
4. anti-tubercle bacillus drugs composition according to claim 3, which is characterized in that the pharmaceutically acceptable carrier
Selected from following any one or more:Filler, adhesive, solubilizer, disintegrant and glidant.
5. anti-tubercle bacillus drugs composition according to claim 3, which is characterized in that the anti-tubercle bacillus drugs composition
Dosage form be selected from it is following any:Tablet, capsule, pill, granule, suspension, oral solution, paint, cataplasm, spraying
Agent, powder-injection and liquid drugs injection.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810917450.5A CN108685908A (en) | 2018-08-13 | 2018-08-13 | Applications of the celecoxib derivative OSU-03012 in preparing anti-tubercle bacillus drugs |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810917450.5A CN108685908A (en) | 2018-08-13 | 2018-08-13 | Applications of the celecoxib derivative OSU-03012 in preparing anti-tubercle bacillus drugs |
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| CN108685908A true CN108685908A (en) | 2018-10-23 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112322695A (en) * | 2020-11-03 | 2021-02-05 | 上海市肺科医院 | Experimental method for in-vitro antibacterial activity of AR-12 on MABC |
| CN113082025A (en) * | 2021-04-14 | 2021-07-09 | 上海市肺科医院 | Application of dihydroxybenzamide derivatives in preparation of SerC inhibitor and antituberculosis drug |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090111799A1 (en) * | 2007-07-24 | 2009-04-30 | The Ohio State University Research Foundation | Anti-infective agents against intracellular pathogens |
| CN105007916A (en) * | 2012-07-30 | 2015-10-28 | 俄亥俄州大学 | Antibacterial protein kinase inhibitors |
-
2018
- 2018-08-13 CN CN201810917450.5A patent/CN108685908A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090111799A1 (en) * | 2007-07-24 | 2009-04-30 | The Ohio State University Research Foundation | Anti-infective agents against intracellular pathogens |
| CN105007916A (en) * | 2012-07-30 | 2015-10-28 | 俄亥俄州大学 | Antibacterial protein kinase inhibitors |
Non-Patent Citations (3)
| Title |
|---|
| JANG-EUN CHO ET AL.: "c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) are involved in Mycobacterium tuberculosis-induced expression of Leukotactin-1", 《BMB REPORTS》 * |
| MICHIEL VAN DER VAAR ET AL.: "The DNA Damage-Regulated Autophagy Modulator DRAM1 Links Mycobacterial Recognition via TLR-MYD88 to Autophagic Defense", 《CELL HOST & MICROBE》 * |
| SANTOSH B. SALUNKE ET AL.: "Design and synthesis of novel anti-tuberculosis agents from the celecoxib pharmacophore", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112322695A (en) * | 2020-11-03 | 2021-02-05 | 上海市肺科医院 | Experimental method for in-vitro antibacterial activity of AR-12 on MABC |
| CN113082025A (en) * | 2021-04-14 | 2021-07-09 | 上海市肺科医院 | Application of dihydroxybenzamide derivatives in preparation of SerC inhibitor and antituberculosis drug |
| CN113082025B (en) * | 2021-04-14 | 2023-01-20 | 上海市肺科医院 | Application of dihydroxy benzamide derivative in preparation of SerC inhibitor and antituberculosis drug |
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Application publication date: 20181023 |
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