CN109223778B - C24H24N6O2S3Application in preparation of anti-tubercle bacillus drugs - Google Patents

C24H24N6O2S3Application in preparation of anti-tubercle bacillus drugs Download PDF

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CN109223778B
CN109223778B CN201811369301.6A CN201811369301A CN109223778B CN 109223778 B CN109223778 B CN 109223778B CN 201811369301 A CN201811369301 A CN 201811369301A CN 109223778 B CN109223778 B CN 109223778B
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tuberculosis
tubercle bacillus
compound
bptes
autophagy
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CN109223778A (en
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戈宝学
陈建霞
刘峰
刘海鹏
李蒿蒿
王菲
刘忠华
唐芬
黄晓辰
王洁
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Shanghai Pulmonary Hospital
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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
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

Abstract

The invention provides C24H24N6O2S3The new application in the preparation of anti-tubercle bacillus drugs and provides a pharmaceutical composition for preventing or treating pulmonary tuberculosis. C24H24N6O2S3Can compensate the expression of the alpha-KG inhibiting macrophage autophagy related gene, recover the autophagy function of the macrophage, effectively inhibit the survival of the tubercle bacillus in vivo, and effectively inhibit the infection of the tubercle bacillus. Thus, C24H24N6O2S3Can be used as lead compound for treating pulmonary tuberculosis and/or extrapulmonary tuberculosis, and C24H24N6O2S3The compound is particularly suitable for preparing the drugs for preventing or treating tuberculosis, thereby having wide clinical application prospect and huge market potential.

Description

C24H24N6O2S3In the preparation of anti-tuberculosisApplication of bacteria medicine
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, in particular to a compound C24H24N6O2S3The application in preparing anti-tubercle bacillus medicine, and also relates to a medicine composition for preventing or treating pulmonary tuberculosis.
Background
Mycobacterium tuberculosis (m.tuberculosis) is simply referred to as mycobacterium tuberculosis (tuberculosis bacillus) or tubercle bacillus. As early as 1882, Mycobacterium tuberculosis was demonstrated by Koch (Robert Koch, 1843-1910) as a causative agent of tuberculosis by German bacteriologists. The bacteria can invade various tissues and organs of the whole body, but lung infection is most common. Tubercle bacillus does not produce endo-and exotoxins, and the pathogenicity of tubercle bacillus may be related to inflammation caused by mass propagation of bacteria in tissue cells, toxicity of thallus components and metabolites and immune damage of organism to thallus components. Tubercle bacillus can invade susceptible organisms through respiratory tract, digestive tract or skin injury, and cause tuberculosis of various tissues and organs, wherein pulmonary tuberculosis is caused through the respiratory tract at most. Because of the large number of normal flora inhabitation in the intestinal tract, tubercle bacillus can survive only through competition and is easy to adhere to susceptible cells; while the alveoli have no normal flora, tubercle bacillus can be inhaled by droplet droplets or bacteria-containing dust, so that tuberculosis is common.
Clinical findings indicate that open tuberculosis is most common in the lung (in about 90% of cases, see Lawn, SD; Zumla, AI. Tuberculosis. Lancet.2011-07-02,378(9785): 57-72. and Behera, D. textbook of Pulmony medicine2nd. New Delhi: Jaype Brothers Medical publishers 2010: 457.). Symptoms of tuberculosis may include chest pain and prolonged cough with sputum, while about 25% of people may not exhibit any symptoms; occasionally, the patient may have small amounts of hemoptysis, coughing, and in very rare cases, the infection may also erode the pulmonary artery and the lescent aneurysm, resulting in massive hemorrhage. Further, tuberculosis may develop into a chronic disease and cause large scars on the upper lung lobes. Clinical studies have shown that the upper lobe is more susceptible to tuberculosis than the lower lobe, but the reason for this difference is not known at present; a possible explanation is that the upper lung lobes are better ventilated or have a poorer lymphatic drainage capacity.
Furthermore, in 15% to 20% of cases of open tuberculosis, tubercle bacillus infection can spread outside the lungs, causing other kinds of tuberculosis, and these conditions are classified as "extrapulmonary tuberculosis" (Golden MP, Vikram hr. extrapulmony tuberculosis: an overview. american Family physicians.2005, 72(9): 1761-8). Among them, common extrapulmonary tuberculosis includes: lymphoid tuberculosis (commonly called scrofula) is the most common extrapulmonary tuberculosis), tuberculous meningitis, tuberculous peritonitis, intestinal tuberculosis (commonly called 'wuliangxing'), renal tuberculosis, epididymis tuberculosis, female reproductive tuberculosis (including fallopian tube, endometrium and ovarian tuberculosis), bone joint tuberculosis and the like.
It is seen that various tuberculosis seriously endangers human health.
According to related literatures, the compound BPTES is a potent glutaminase inhibitor, and has certain anticancer activity. The CAS number of BPTES is 314045-39-1, and the chemical formula is C24H24N6O2S3And its chemical name is N, N' - [ thiobis (2,1-ethanediyl-1,3, 4-thiadiazol-5, 2-diyl)]bis-benzazeneacetamide. The results of the present experiments demonstrated that the compound BPTES is able to inhibit glutaminase with an IC50 of 0.18. mu.M in human kidney cells and glutamate inhibition by microglia with an IC50 of 80-120nM (see Newcomb R.2002.U.S. Pat.6,451, 828B 1.). In D54 cells containing mutant IDH1, the compound BPTES preferentially slowed cell growth. In addition, the compound BPTES also inhibits glutaminase activity, decreases glutamate and α -KG levels, and increases glycolytic intermediates (see Seltzer MJ, et al. cancer Res.2010,70(22), 8981-8987.). The compound BPTES (at a concentration of 10. mu.M) also inhibited the growth of mHCC 3-4 cells derived from LAP/MYC tumors. Recent studies have shown that the compound BPTES also inhibits growth of MYC-dependent P493 cells by blocking DNA replication, leading to cell death and lysis. In LAP/MYC mice, the compound BPTES (12.5mg/kg, i.p.) prolonged survival, while no significant effect was seen at MYC, GLS, or GLS2 levelsUsing; the compound BPTES (200. mu.g/mouse, i.p.) also inhibited tumor cell growth in P493 tumor xenograft-loaded mice (see Xiaong Y, et al.J. Clin invest.2015,125(6), 2293-2306.).
Thus, the prior art only discloses the effect of the compound BPTES in inhibiting tumors, and does not mention that the compound BPTES can be used for preventing or treating tuberculosis.
Disclosure of Invention
The invention aims to provide a new application of the known compound BPTES in the aspect of being used as an anti-tubercle bacillus medicament. In the process of researching and screening the anti-tubercle bacillus compound, the inventor of the invention unexpectedly finds that the compound BPTES can effectively inhibit the survival of tubercle bacillus in vivo by supplementing alpha-KG to inhibit the expression of macrophage autophagy related genes.
Accordingly, the first aspect of the present invention provides C24H24N6O2S3The application in the preparation of anti-tubercle bacillus drugs; wherein, C24H24N6O2S3The structural formula of (A) is as follows:
Figure BDA0001869402890000031
the CAS number of the compound is 314045-39-1, and the chemical name is as follows:
n, N' - [ thiobis (2,1-ethanediyl-1,3, 4-thiadiazol-5, 2-diyl) ] bis-benzanecetamide. The compound BPTES of the present invention can be prepared by chemical synthesis or can be obtained directly from Selleck.
In a preferred embodiment of the invention, C24H24N6O2S3In combination with a second anti-tubercular agent.
In a further preferred embodiment of the invention, the second anti-tubercular drug is selected from the group consisting of any one or more of the following: isoniazid, rifampin, rifapentine, pyrazinamide, ethambutol, p-aminosalicylic acid, capreomycin, thiosemicarbazide, ethionamide, gatifloxacin, moxifloxacin, ciprofloxacin, levofloxacin.
Also, the present invention provides, in a second aspect, a pharmaceutical composition for preventing or treating tuberculosis, comprising an effective amount of C24H24N6O2S3And a pharmaceutically acceptable carrier; wherein, C24H24N6O2S3The structural formula of (A) is as follows:
Figure BDA0001869402890000032
preferably, the pharmaceutical composition for preventing or treating tuberculosis further comprises a second anti-tubercle bacillus drug.
Further preferably, the second anti-tubercular drug is selected from the group consisting of any one or more of the following: isoniazid, rifampin, rifapentine, pyrazinamide, ethambutol, p-aminosalicylic acid, capreomycin, thiosemicarbazide, ethionamide, gatifloxacin, moxifloxacin, ciprofloxacin, levofloxacin.
Preferably, the dosage form of the pharmaceutical composition for preventing or treating pulmonary tuberculosis is selected from any one of the following: tablets, capsules, pills, granules, suspensions, oral liquids, transdermal preparations, aerosols and injections.
In order to avoid the first-pass effect, it is further preferred that the above pharmaceutical composition for preventing or treating tuberculosis is in a dosage form selected from any one of the following: transdermal preparations, aerosols and injections.
The inventor proves that the compound BPTES (namely C) through experiments24H24N6O2S3) Can effectively inhibit the intracellular survival of tubercle bacillus infected macrophages. Meanwhile, the results of the related animal experiments showed that, after one week of infection of mice with tubercle bacillus, C was administered at a dose of 5 mg/kg/day24H24N6O2S3And after continuous oral administration for three weeks, pathological injury of the lung of a mouse is obviously relieved, and the amount of bacteria in the lung is obviously reduced.
To sum upIn the invention, C is provided24H24N6O2S3New use in preparation of anti-tubercle bacillus medicine, wherein, C24H24N6O2S3The expression of macrophage autophagy related genes is inhibited by supplementing the alpha-KG back, so that the autophagy function of the macrophages is recovered, the in-vivo survival of the tubercle bacillus is effectively inhibited, and the infection of the tubercle bacillus can be effectively inhibited. Thus, C24H24N6O2S3Can be used as lead compound for treating pulmonary tuberculosis and/or extrapulmonary tuberculosis, and C24H24N6O2S3The compound is particularly suitable for preparing the drugs for preventing or treating tuberculosis, thereby having wide clinical application prospect and huge market potential.
Drawings
FIG. 1 is a graph of intracellular CFU of WT and DB/DB mouse macrophages after treatment with DMSO, compound BPTES, respectively, 24 hours after tubercle bacillus infection;
FIG. 2 is a graph showing the results of hematoxylin-eosin staining (H & E) performed on mouse lung sections;
FIG. 3 is a statistical chart of the bacterial load of M.tuberculosis in the lung of mice;
FIG. 4 is a graph showing the results of realtime PCR detection of mouse autophagy-related gene LC3 b;
FIG. 5 is a graph showing the results of realtime PCR detection of mouse autophagy-related gene ATG 5;
FIG. 6 is a graph showing the results of realtime PCR detection of mouse autophagy-related gene ATG 7;
FIG. 7 is a graph showing the result of realtime PCR detection of mouse autophagy-related gene Beclin 1;
FIG. 8 is a graph of the results of realtime PCR detection of mouse autophagy-related gene ULK 1.
Detailed Description
The present invention will be further described with reference to specific embodiments, but the present invention is not limited to the following embodiments. The experimental operations in the following examples are all conventional operations unless otherwise specified; materials, reagents and the like used in the following examples are commercially available from public unless otherwise specified.
Example 1
C57BL/6 mice and DB/DB mice Db/Db (leptin receptor (Lepr) mutant) peritoneal primary macrophages with 1 × 105One/well was seeded in 48-well cell culture plates, and after about 2h for cells to adhere, the complete medium 1640 was removed and fresh complete medium was added for overnight culture. The following day, 1H before infection, cells were treated with DMSO and compound BPTES (150nM) for 1H before infection with tubercle bacillus, replaced with fresh 1640 containing 10% serum without diabody, and then infected with tubercle bacillus at a dose of MOI 5 (H37 Rv). After 2-3h of infection, the supernatant was discarded, followed by culturing the cells in amikacin containing medium for 2h, discarding the supernatant and replacing with 1640 containing 10% serum without diabody and continuing at 37 ℃ with 5% CO2Cells were cultured in an incubator for 24 h. The supernatant was discarded, and the cells were washed with PBS, lysed with PBS containing 1% triton-100, and the cell lysate was spread on a MiddleBook 7H10 agar plate containing amphotericin B, cultured in an incubator at 37 ℃ for 2-3 weeks, and then colony counting was performed.
The results of the counting are shown in FIG. 1, and the experimental results show that the compound BPTES (i.e., C)24H24N6O2S3) Can obviously inhibit the intracellular survival of tubercle bacillus infected Db/Db mouse macrophage.
Example 2
C57BL/6 mice were divided into two groups and Db/Db mice were divided into two groups of 6 mice each, and each was titrated with tubercle bacillus rhinofectus (H37Rv) at a dose of 200 CFU/mouse for 1 week, and after infection, compound BPTES at a dose of 5 mg/kg/day was administered continuously for 3 weeks, with purified water as a negative control. The mice were sacrificed by cervical dislocation, one leaf of the lung was removed, fixed with 4% paraformaldehyde, and after paraffin sectioning, H & E staining was performed to observe the pathological injury condition of the lung.
Referring to fig. 2, it can be seen that the pathological lung lesions of mice treated with compound BPTES are significantly reduced; thus, the experimental results of this example show that the compound BPTES (i.e., C)24H24N6O2S3) Can effectively reducePathological damage to the lung in light mice.
Example 3
One-third of the lung tissues of the mice administered one month after infection in example 2 were treated by grinding with 1ml of 1% triton-100-containing PBS, and diluted in a gradient to 10-3、10-4100ml of the tissue suspension was uniformly spread on a MiddleBook 7H10 agar plate containing amphotericin B, and then placed in an incubator at 37 ℃ for 2-3 weeks, and colony counting was completed, as shown in FIG. 3.
The experimental results of this example show that the compound BPTES (i.e., C)24H24N6O2S3) The strain loading of the tubercle bacillus in the lung of the mouse is obviously reduced.
Example 4
Extraction of cellular RNA: treating normal uninfected mouse macrophage with DMSO, alpha-KG, BPTES and alpha-KG + BPTES respectively, then infecting with tubercle bacillus with MOI of 5 for 0, 3h and 6h, discarding supernatant, adding 1ml trizol, adding 200ul chloroform, reversing, mixing, standing for 10 min, centrifuging at 4 deg.C and 12000rpm for 15 min, and taking supernatant to a new RNase free EP tube; then, an equal volume of isopropanol was added, the mixture was left at-20 ℃ for 10 minutes and centrifuged at 12000rpm for 15 minutes at 4 ℃, the supernatant was discarded, 1ml of cold 75% ethanol was added to wash the precipitate, and the mixture was centrifuged at 7500rpm for 10 minutes at 4 ℃, the supernatant was discarded, and the RNA precipitate was dried.
Synthesis of cDNA: taking 1ug RNA, adding RNase free water to 14ul, acting at 65 ℃ for 5 minutes, adding 1ul primer, 4ul 5 × RT buffer and 1ul enzyme into the RNA with the total volume of 20ul, acting the reaction solution at 37 ℃ for 15 minutes, and finally, inactivating the enzyme at 95 ℃ for 5 minutes to synthesize cDNA.
Detection of autophagy-related genes: the realtime PCR detects the expression level of mRNA of autophagy-related genes LC3b, ATG5, ATG7, Beclin1 and ULK1, and the detection results are sequentially shown in figure 4, figure 5, figure 6, figure 7 and figure 8.
The experimental result of the embodiment shows that the alpha-KG can obviously inhibit the expression of the macrophage autophagy related gene, thereby inhibiting the autophagy function of the macrophage; the compound BPTES can supplement alpha-KG to inhibit the expression of macrophage autophagy related genes, so that the autophagy function of macrophages is recovered, and the survival of tubercle bacillus in the macrophages is effectively inhibited.
Analysis of the above examples shows that C24H24N6O2S3Can effectively inhibit the infection of tubercle bacillus, thereby being beneficial to the clinical treatment of tuberculosis.
The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.

Claims (4)

1.C24H24N6O2S3The application in the preparation of anti-tubercle bacillus drugs; wherein, C24H24N6O2S3The structural formula of (A) is as follows:
Figure FDA0003024815280000011
2. use according to claim 1, characterized in that C24H24N6O2S3In combination with a second anti-tubercular agent.
3. The use of claim 2, wherein the second anti-tubercular drug is selected from the group consisting of any one or more of the following: isoniazid, rifampin, rifapentine, pyrazinamide, ethambutol, p-aminosalicylic acid, capreomycin, thiosemicarbazide, ethionamide, gatifloxacin, moxifloxacin, ciprofloxacin, levofloxacin.
4. The use according to claim 1, wherein the anti-tubercle bacillus drug is in a dosage form selected from any one of: tablets, capsules, pills, granules, suspensions, oral liquids, transdermal preparations, aerosols and injections.
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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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CN107663182A (en) * 2016-07-28 2018-02-06 杭州健昵福生物科技有限公司 A kind of glutamine metabolism inhibitor compound
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Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102143748A (en) * 2008-09-03 2011-08-03 辉瑞大药厂 Combination therapy for tuberculosis
CN105960405A (en) * 2014-01-06 2016-09-21 理森制药股份公司 Novel inhibitors of glutaminase
CN106890184A (en) * 2015-12-18 2017-06-27 侯以琳 Antineoplastic glutamine enzyme inhibitor and angiogenesis inhibitor pharmaceutical composition and its application
CN107663182A (en) * 2016-07-28 2018-02-06 杭州健昵福生物科技有限公司 A kind of glutamine metabolism inhibitor compound
CN107714650A (en) * 2016-08-11 2018-02-23 杭州健昵福生物科技有限公司 A kind of inhibitors liposomes containing glutamine metabolism and its pharmaceutical composition and purposes

Non-Patent Citations (2)

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Title
BPTES inhibition of hGA124–551, a truncated form of human kidney-type glutaminase;Erik W.Hartwick et al.;《Journal of Enzyme Inhibition and Medicinal Chemistry》;20111015;第27卷(第6期);第861-867页 *
Design, synthesis, and evaluation of substituted nicotinamide adenine;Xu Wang et al.;《Bioorganic & Medicinal Chemistry Letters》;20170808;第4426–4430页 *

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