CN110664811B - Application of afatinib in anti-mycobacterium tuberculosis drugs - Google Patents
Application of afatinib in anti-mycobacterium tuberculosis drugs Download PDFInfo
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- CN110664811B CN110664811B CN201910882146.6A CN201910882146A CN110664811B CN 110664811 B CN110664811 B CN 110664811B CN 201910882146 A CN201910882146 A CN 201910882146A CN 110664811 B CN110664811 B CN 110664811B
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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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
Abstract
The invention relates to application of afatinib in an anti-mycobacterium tuberculosis drug. In clinic, afatinib is mainly used for treating malignant lymphoma and acute lymphocytic leukemia; the research of the invention finds that the compound has the anti-tuberculosis effect and has good development value; the application of afatinib in the mycobacterium tuberculosis resistant medicine and the obvious mycobacterium tuberculosis resistant effect of afatinib are disclosed for the first time.
Description
Technical Field
The invention relates to the technical field of bioengineering, and particularly relates to application of afatinib in an anti-mycobacterium tuberculosis drug.
Background
In the treatment of tuberculosis, the main challenges are: 1) The cure success rate of the multi-drug resistant tuberculosis (MDR-TB) is extremely low; 2) The treatment time of the existing antituberculosis standard short-term treatment scheme is still too long; and the patient compliance and the treatment deficiency are caused by toxic and side effects and other reasons, and the recurrence rate of the initially treated sensitive tuberculosis is as high as 3-9 percent. For the reasons mentioned above, this ancient infectious disease is again faced with the serious challenge of no drug being available. The first-line antituberculosis drugs used at present are developed more than 40 years ago, the novel effective antituberculosis drugs are slowly developed, and the drugs directly act on tubercle bacillus, so that the risk of cross drug resistance always exists.
Afatinib is a 4-anilinoquinazoline tyrosine kinase inhibitor in the form of a dibenzoate salt, afatinib tablets are first-line (initial) therapeutic drugs for patients with metastatic non-small cell lung cancer (NSCLC), with common Epidermal Growth Factor Receptor (EGFR) mutations, afatinib is a potent and selective, irreversible ErbB family blocker; afatinib covalently binds and irreversibly blocks signaling by all homodimers and heterodimers formed by the ErbB family members EGFR (ErbB 1), HER2 (ErbB 2), erbB3 and ErbB4, afatinib covalently binds to the kinase domains of EGFR (ErbB 1), HER2 (ErbB 2) and HER4 (ErbB 4) and irreversibly inhibits tyrosine kinase autophosphorylation, resulting in down-regulation of ErbB signaling. Certain mutations in EGFR, including non-resistant mutations in its kinase domain, result in increased autophosphorylation of the receptor, resulting in receptor activation, which can also support cell proliferation in NSCLC in the absence of ligand binding. Non-resistant mutations are defined as occurring in exons making up the EGFR kinase domain, which result in increased receptor activation, and where efficacy is predicted by clinically meaningful tumor shrinkage and recommended doses of afatinib and/or inhibition of cell proliferation; the most common of these mutations are exon 21 L858R substitutions and exon 19 deletions.
The molecular formula of afatinib is C 24 H 25 ClFN 5 O 3 Molecular weight is 485.94, and the structural formula is as follows:
the research finds that the medicine has the effect of resisting tuberculosis and has good development value.
Disclosure of Invention
The invention aims to research and develop a novel efficient antitubercular medicament, finds the antitubercular effect of afatinib and the application of afatinib in antitubercular mycobacteria medicaments, has high safety and good development value.
The technical scheme of the invention mainly relates to the application of afatinib in the anti-mycobacterium tuberculosis drugs.
Further, the Mycobacterium tuberculosis is specifically Mycobacterium tuberculosis H 37 Rv。
The invention also provides application of afatinib in preparation of anti-tuberculosis drugs.
In one embodiment of the present invention, an anti-tuberculosis drug with afatinib as an active ingredient is provided. The antituberculosis drug can be used for treating tuberculosis.
The invention has the advantages that:
(1) The invention discovers for the first time that afatinib has an obvious anti-mycobacterium tuberculosis effect, and as a potential HDT-targeting drug, afatinib is approved by FDA, has high safety and has good development value;
(2) The invention provides the application of afatinib in the preparation of anti-tuberculosis drugs for the first time;
(3) The invention discovers that afatinib can remarkably enhance the cell killing of tubercle bacillus in cells.
Drawings
FIG. 1 is a graph of the effect of various concentrations of afatinib on cell viability in example 1 of the present invention;
FIG. 2 is a graph showing the effect of afatinib on the survival of Mycobacterium tuberculosis in cells in example 2 of the present invention.
Detailed Description
The invention is further described with reference to the following figures and detailed description, which are intended to illustrate, but not to limit the invention further.
The technical means used in the following examples are conventional means well known to those skilled in the art, and all the raw materials are general-purpose materials.
Example 1
Differentiation of u937 macrophages (accession number BNCC 100967): culturing suspended U937 in RPMI-1640 medium containing 10% FBS, and standing at 37 deg.C, containing 5% CO 2 Adding PMA with the final concentration of 20ng/ml into the cell culture box, culturing overnight, differentiating the PMA into macrophages, washing the macrophages twice by PBS, digesting and resuspending by pancreatin, and adding the macrophages into a 96-hole cell culture plate to ensure that the number of cells in each hole is 1x 104;
2. determination of cell viability: culturing the U937 macrophage for 24h, adding medicines with different concentrations to make the final concentrations of the medicines 100uM, 10uM and 1uM, repeating each concentration for 3 times, using DMSO as a parallel control experiment, adding DMSO with the same volume as the medicines into a control group, repeating the experiments for 3 times, adding 10ul of WST-1 solution into each hole after 48h, continuously culturing for 4h at 37 ℃, and measuring the OD450 nm light absorption value by using an enzyme labeling instrument;
cell viability was calculated according to the following formula: cell survival% = [ A/A% 0 ]X 100, wherein A 0 Absorbance for DMSO control, a is absorbance for different concentrations of drug treatment.
Figure 1 shows the effect of different concentrations of afatinib on cell viability; where "×" represents significant difference and "ns" represents no statistical difference.
The experimental results show that the afatinib concentration is 100uM, 10uM and 1uM, and the corresponding cell survival rates are respectively as follows: 40%, 95%, 103%; when the drug concentration was 10uM, the cell survival rate was not statistically different from that of the control group.
Example 2:
differentiation of u937 macrophages: the suspended U937 was cultured in RPMI-1640 containing 10% FBS and placed at 37 ℃ 5% CO 2 Adding PMA with the final concentration of 20ng/ml, culturing overnight, differentiating into macrophage, washing twice with PBS, digesting with pancreatin, resuspending, and adding into 96-well cell culture plate to make the number of cells in each well be 1x 104;
2. determination of intracellular bactericidal activity: culturing the U937 macrophages for 24 hours, adding afatinib to enable the final concentration to be 1uM, repeating the experiment for 3 times respectively for each concentration, using DMSO as a parallel control experiment, adding DMSO with the same volume as the medicine into a control group, repeating the experiment for 3 times respectively, sucking the culture medium after 4 hours, washing twice with PBS, adding a fresh culture medium for 72 hours, adding a lysate, coating the lysate on a 7H10 plate after gradient dilution, and calculating bacterial colonies after 3 weeks;
the results are shown in figure 2, the survival rate of the cells treated by 1uM afatinib is only 2.72% compared with that of the control group, and the cells treated by the method have no obvious cytotoxicity at the concentration, so that the method can be used for developing high-efficiency and low-toxicity antituberculosis drugs.
Finally, it should be noted that: the above embodiments are only used to illustrate the present invention and do not limit the technical solutions described in the present invention; it will be understood by those skilled in the art that the present invention may be modified and equivalents substituted; all technical solutions and modifications thereof which do not depart from the spirit and scope of the present invention should be construed as being included in the scope thereof as defined in the appended claims.
Claims (4)
1. Application of afatinib in preparation of anti-mycobacterium tuberculosis drugs.
2. The use of claim 1, wherein said anti-mycobacterium tuberculosis drug is an in vivo anti-mycobacterium tuberculosis drug.
3. The use according to claim 1, wherein the mycobacterium tuberculosis is mycobacterium tuberculosis H37Rv.
4. Application of afatinib in preparing antituberculosis drugs.
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| "外周血CD3+CD161+淋巴细胞检测在结核病诊断中的价值";张洁云等;《临床肺科杂志》;20201120;第25卷(第11期);第1626-1630页 * |
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