CN118416058A - Application of benzimidazole compound - Google Patents
Application of benzimidazole compound Download PDFInfo
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- CN118416058A CN118416058A CN202410546932.XA CN202410546932A CN118416058A CN 118416058 A CN118416058 A CN 118416058A CN 202410546932 A CN202410546932 A CN 202410546932A CN 118416058 A CN118416058 A CN 118416058A
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- -1 benzimidazole compound Chemical class 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 31
- 230000029663 wound healing Effects 0.000 claims abstract description 27
- 206010052428 Wound Diseases 0.000 claims abstract description 24
- 208000027418 Wounds and injury Diseases 0.000 claims abstract description 24
- 230000001737 promoting effect Effects 0.000 claims abstract description 18
- 206010072170 Skin wound Diseases 0.000 claims abstract description 9
- 208000002249 Diabetes Complications Diseases 0.000 claims abstract description 4
- 206010012655 Diabetic complications Diseases 0.000 claims abstract description 4
- 206010040943 Skin Ulcer Diseases 0.000 claims abstract description 4
- 208000014674 injury Diseases 0.000 claims abstract description 4
- 231100000019 skin ulcer Toxicity 0.000 claims abstract description 4
- 230000008733 trauma Effects 0.000 claims abstract description 4
- 210000002950 fibroblast Anatomy 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 14
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- 238000002347 injection Methods 0.000 claims description 2
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- 239000000725 suspension Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000002474 experimental method Methods 0.000 abstract description 8
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- 150000001875 compounds Chemical class 0.000 description 31
- 210000004027 cell Anatomy 0.000 description 29
- 229940079593 drug Drugs 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 210000003953 foreskin Anatomy 0.000 description 12
- 239000013642 negative control Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000006285 cell suspension Substances 0.000 description 6
- 210000001161 mammalian embryo Anatomy 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 230000005012 migration Effects 0.000 description 5
- 238000013508 migration Methods 0.000 description 5
- 230000001684 chronic effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
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- 229940000406 drug candidate Drugs 0.000 description 3
- 239000003777 experimental drug Substances 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- KJXNOHLXULKUIZ-UHFFFAOYSA-N 2-(4-chlorophenyl)-6-nitro-1h-benzimidazole Chemical compound N1C2=CC([N+](=O)[O-])=CC=C2N=C1C1=CC=C(Cl)C=C1 KJXNOHLXULKUIZ-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 208000025865 Ulcer Diseases 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
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- 102000011040 TRPV Cation Channels Human genes 0.000 description 1
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Classifications
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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
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides application of benzimidazole compounds. Experiments prove that the benzimidazole compound can effectively promote cell migration, improve the invasion and penetration capacity of cells, has the effect of promoting wound healing, and has good safety; therefore, the benzimidazole compound is suitable for preparing medicaments for promoting wound healing, and promoting the healing of skin ulcer wounds, skin inflammation wounds, skin wounds caused by mechanical trauma, delivery wounds, skin wounds caused by diabetic complications and the like.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to application of benzimidazole compounds.
Background
The human skin has the functions of resisting the invasion of external pathogens, regulating the body temperature and the like, so that the skin has a protective effect. When the skin is wounded, the treatment measures are needed to be timely taken, the wound healing is promoted, if the intervention is not performed, the wound healing process is slow, the serious conditions such as inflammation, ischemia or necrosis are most likely to be generated, and the functional abnormalities such as scars, pigmentation, ulcers and the like can be caused. However, wound repair is complex and typically requires 4 phases: fibrotic clot formation, inflammatory response, revascularization and connective tissue remodeling, of which revascularization is critical, is an abnormally difficult stage of revascularization for healing of chronic wounds, such as very slow revascularization in wounds of diabetics, where the vascular surface area, branch connection number, total vascular length and total branch number are all significantly reduced, and angiogenesis can effectively support wound closure, while vascular lesions are one of the causes of difficult healing of wounds of diabetics. For healing common skin wounds, especially chronic wounds, traditional skin healing methods such as laser, treatment auxiliary materials, negative pressure treatment, skin transplantation and the like are not ideal in effect, and have limitation in clinical application. Therefore, development of new drugs for accelerating wound healing, especially chronic wound healing for diabetics and the like, is a highly-needed problem.
At present, the development difficulty of a new drug for promoting wound healing is high, the wound healing activity is still low, and the cytotoxicity is difficult to control, so that the development of a new application by adopting a known drug is a rapid and effective drug development path, WO2022/104345Al discloses a 1- (2- (4-cyclopropyl-1H-1, 2, 3-triazol-1-yl) acetyl) -4-hydroxypyrrolidine-2-carboxamide derivative which is used as a VHL inhibitor for treating anemia, the compound can be used for enhancing wound healing, reducing scarring or enhancing angiogenesis or arteriogenesis, and WO2006/078907Al discloses the application of a 2-substituted benzimidazole derivative of capsaicin receptor ligands, which can be used for treating wounds, burns, skin allergy and the like.
However, the prior art disclosed above is not primarily directed to wound healing drugs, which are not significantly effective in the application of the indication. Thus, there remains a need for a strong development of drug screening for indications including ulcers, dermatitis, chronic wounds, childbirth, or wounds in diabetics (e.g., diabetic feet).
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide application of benzimidazole compounds.
In a first aspect, the invention provides an application of benzimidazole compound in preparing a medicine for promoting wound healing, wherein the benzimidazole compound has a molecular structural formula as follows:
Wherein R 1 is any one of Cl, F and Br.
As a preferred embodiment of the present invention, the wound comprises a skin ulcer wound, a skin inflammatory wound, a skin wound caused by mechanical trauma, a delivery wound or a skin wound caused by diabetic complications.
As a preferred embodiment of the present invention, the wound healing promoting drug comprises a pharmaceutically acceptable carrier or excipient.
As a preferred embodiment of the present invention, the dosage form of the wound healing promoting drug includes any one of granules, capsules, tablets, suspensions, emulsions, gels, drop pills, injections, aerosols, drops and solutions.
As a preferred embodiment of the present invention, the concentration of the benzimidazole compound acting on the fibroblasts is 0.01 to 5. Mu.M. The concentration of the benzimidazole compound acting on the epidermal cells may be 0.01. Mu.M, 0.05. Mu.M, 0.1. Mu.M, 0.2. Mu.M, 0.5. Mu.M, 1. Mu.M, 2. Mu.M, 3. Mu.M, 4. Mu.M, 5. Mu.M or a range composed of any two of these values. In the present invention, the unit "μM" means "μmol/L".
In a second aspect, the invention provides an experimental composition for promoting wound healing, which comprises a benzimidazole compound, wherein the benzimidazole compound has a molecular structural formula as follows:
Wherein R 1 is any one of Cl, F and Br.
As a preferred embodiment of the present invention, the experimental composition for promoting wound healing further comprises a pharmaceutically acceptable carrier or excipient.
As a preferred embodiment of the present invention, the experimental composition is a powder, a liquid, a paste, a gel or a spray.
Compared with the prior art, the invention has the beneficial effects that:
Experiments prove that the benzimidazole compound can effectively promote cell migration, improve the invasion and penetration capacity of cells, has the effect of promoting wound healing, and has good safety; therefore, the benzimidazole compound is suitable for preparing medicaments for promoting wound healing, and promoting the healing of skin ulcer wounds, skin inflammation wounds, skin wounds caused by mechanical trauma, delivery wounds, skin wounds caused by diabetic complications and the like.
Drawings
FIG. 1 shows the toxicity test result of the compound TS-2172 provided by the invention on human foreskin fibroblast HFF-1;
FIG. 2 shows the toxicity test result of the compound TS-2172 provided by the invention on mouse embryo fibroblast L-929;
FIG. 3 is a graph showing the results of an in vitro scratch test of the compound TS-2172 provided by the invention on the migration ability of human foreskin fibroblasts HFF-1;
FIG. 4 is statistical data of in vitro scratch experiments of the influence of the compound TS-2172 provided by the invention on the migration capacity of human foreskin fibroblasts HFF-1;
FIG. 5 shows the results of a Transwell experiment for determining the effect of the compound TS-2172 provided by the invention on the invasive capacity of mouse embryonic fibroblasts L-929;
FIG. 6 is a graph showing the statistical data of the effect of compound TS-2172 provided by the present invention on the invasive potential of mouse embryonic fibroblasts L-929;
FIG. 7 is a Transwell test measurement result of the influence of the compound TS-2172 provided by the invention on the invasion capacity of human foreskin fibroblast HFF-1;
Figure 8 is a statistical data of the effect of compound TS-2172 provided by the present invention on the invasive capacity of human foreskin fibroblasts HFF-1.
Detailed Description
The present invention will be further described with reference to specific examples and comparative examples for better illustrating the objects, technical solutions and advantages of the present invention, and the object of the present invention is to be understood in detail, not to limit the present invention. All other embodiments, which can be made by those skilled in the art without the inventive effort, are intended to be within the scope of the present invention.
The experimental reagents and instruments involved in the practice of the present invention are common reagents and instruments unless otherwise specified.
In the application of benzimidazole compound in preparing medicine for promoting wound healing, the compound 2- (4-chlorophenyl) -6-nitro-1H-benzo [ d ] imidazole (with the English name of 2- (4-Chlorophenyl) -6-nitro-1H-1, 3-benzodiazole) is selected for relevant experiments for promoting wound healing, the chemical molecular formula of the benzimidazole compound is C14H10ClN3O2, the CAS number is 1571-87-5, and the molecular structure of the azaindole compound is as follows (in the embodiment of the invention, TS-2172 is used for writing instead of the chemical name of the benzimidazole compound):
wherein R 1 is Cl.
Example 1
The experimental objects adopted in this embodiment are: human foreskin fibroblast HFF-1 and mouse embryonic fibroblast L-929 are subjects.
The experimental drugs used in this example were: compound TS-2172 and dimethyl sulfoxide.
In this example, experimental groups containing compound TS-2172 were set up, each experimental group using the following experimental methods:
the first pm plating: collecting cells in the logarithmic phase, adjusting the concentration of the cell suspension, and adding 90uL of the cell suspension into each hole; if the experimental object is HFF-1 cells, the 90uL cell suspension contains 5000 HFF-1 cells; if the subject is L-929 cells, 8000L-929 cells in 90uL cell suspension);
dosing the next morning: adding 10 μl of drugs with concentration gradient into each hole, wherein each drug is prepared from compound TS-2172 and culture medium, arranging 3 compound holes for each drug concentration, and incubating in incubator at 5% CO 2 and 37deg.C for 48 hr;
plate collection after 48h of dosing: visual inspection under an inverted microscope was followed by addition of 10uLCCK solutions (i.e., cellCountingKit-8 cell counting reagent) per well, and incubation at 37 ℃ for 1h was followed by termination of the reaction.
OD value detection: the absorbance of each well was measured at the wavelength of 450nm of the microplate reader.
In this example, a cell-free medium was used as a blank control, and a Dimethylsulfoxide (DMSO) solution having the same dilution ratio as the compound was added to each well was used as a negative control.
The culture medium used in this example was DMEM medium.
The relative cell viability or drug inhibition was calculated according to the following formula:
relative survival (%) = (compound experimental group OD value-blank group OD value)/(negative control group OD value-blank group OD value) ×100%;
Inhibition (%) = 100% -relative survival.
Non-linear regression analysis is performed using statistical analysis software (e.g., GRAPHPAD PRISM) to calculate IC50 values; IC50 is the half inhibitory concentration, i.e. the concentration of drug that results in half of the cell death by a given time of drug treatment; the results are shown in FIGS. 1-2.
As can be seen from FIGS. 1-2, the IC50 of compound TS-2172 for cell HFF-1 was 26.09. Mu.M, and the IC50 of compound TS-2172 for cell L-929 was 63.77. Mu.M, so that compound TS-2172 was very little toxic to human foreskin fibroblast HFF-1 and mouse embryo fibroblast L-929; based on the IC50 test results, the working concentration of compound TS-2172 in the subsequent examples 2-3 was not greater than 10. Mu.M, which ensured that compound TS-2172 did not affect cytotoxicity.
Example 2
The experimental objects adopted in this embodiment are: human foreskin fibroblast HFF-1.
The experimental drugs used in this example were: compound TS-2172 and dimethyl sulfoxide.
In this example, a control group and two experimental groups were set: the drug of the experimental group A is compound TS-2172 with the working concentration of 0.5 mu M; the drug of the experimental group B is a compound TS-2172 with the working concentration of 1 mu M; the drug of the control group is dimethyl sulfoxide.
The experimental methods of each group were:
Before the plate is paved, a marker pen thin head is used for evenly scribing transverse lines by comparing with a straight ruler, wherein the transverse lines are crossed at intervals of about 0.5 cm to 1cm, three lines are typically scribed, the lines are sequentially named as a line, b line and c line, the b line is crossed at the center, and the other two lines are scribed at two sides of the b line at equal intervals; six well plates were plated, 2mL of complete medium containing 10% fbs (i.e. mass% fetal bovine serum) was added to each well, 2 x 10 6 cells were placed in 2 duplicate wells each and incubated for about 24 hours. The cell number is preferably regulated so that the cells can be covered with the wall over night by more than 90%.
The lid of the well plate is opened the next day, the old culture medium is sucked off, the ruler is perpendicular to the b-line frame on the well plate, the 200uL gun head is tightly attached to the ruler to uniformly move up and down to manufacture cell scratch lines, and two parallel lines are drawn on two sides of the line at equal intervals, and are named as line 1, line 2 and line 3 respectively from left to right. Washing cells with sterile 1 XPBS (i.e., 0.01M phosphate buffer solution) for 3 times, removing the scraped cells, adding complete medium containing 10% FBS, adding medicine to make the concentration of medicine in each well reach working concentration, and culturing in incubator at 37deg.C and 5% CO 2; photographs were taken at 0, 24h samples, and cell scratches were marked in the photographs, and the Scratch areas of 0, 24h samples were counted (SCRATCHAREA) and the percent wound healing (Scratch wound HEALING RATE) was calculated.
As can be seen from fig. 3-4, the migration rate of cells treated with compound TS-2172 was significantly faster, the percentage of wound healing was significantly higher, and it was statistically significant (P < 0.0001), compared to the control group, indicating that compound TS-2172 could significantly promote cell migration, with good promotion of wound healing.
Example 3
The experimental objects adopted in this embodiment are: human foreskin fibroblast HFF-1 and mouse embryonic fibroblast L-929.
The experimental drugs used in this example were: compound TS-2172 and dimethyl sulfoxide.
In this example, a negative control group A, a test group A-1, a test group A-2, a negative control group B, a test group B-1, and a test group B-2 were set.
The plate density of the mouse embryo fibroblast L-929 in the negative control group A, the experimental group A-1 and the experimental group A-2 is 3.5X10 4/200 mu L; the medicine adopted by the negative control group A is dimethyl sulfoxide, and the working concentration is 0.1 mu M; the drug adopted in the experimental group B-1 is a compound TS-2172, and the working concentration is 0.1 mu M; the drug used in experimental group B-2 was compound TS-2172 at a working concentration of 0.2. Mu.M.
The cells adopted in the negative control group B, the experimental group B-1 and the experimental group B-2 are human foreskin fibroblast HFF-1, and the plate density is 6 multiplied by 10 4～10×104/200 mu L; the medicine adopted by the negative control group B is dimethyl sulfoxide, and the working concentration is 0.1 mu M; the medicine adopted in the experimental group B-1 is a compound TS-2172, and the working concentration is 0.05 mu M; the drug used in experimental group B-2 was compound TS-2172 at a working concentration of 0.1. Mu.M.
The experimental methods of each group were:
preparing a cell suspension: digesting cells, centrifuging after stopping digestion, discarding culture solution, washing with PBS (i.e. phosphate buffer solution) for 1 time, re-suspending in serum-free culture medium, and adjusting cell density to proper density;
Inoculating cells: taking a proper amount of cell suspension according to the cell density, adding a proper amount of BSA solution with the volume percentage of 10 percent (namely bovine serum albumin solution), adding a drug, and finally supplementing the mixture with a DMEM culture medium to ensure that the total volume of each hole of the solution is 200 mu L, so that the cell density in each hole of the solution reaches the seed density, the volume percentage of the bovine serum albumin is 0.1 percent, and the concentration of the drug reaches the working concentration; after being evenly mixed, the mixture is gently and evenly added into a Transwell upper chamber; immediately in the 24 hole plate lower chamber is added with 800L medium containing 20% FBS, and the plate is collected about 24 hours after administration;
Cell staining: taking out the Transwell chamber, discarding the culture solution in the hole, gently wiping off the cells which do not migrate in the upper chamber by using a cotton swab, and putting the cells into a clean 24-hole plate; wash 1 time with 1 XPBS, fix with methanol for 30 min, blot methanol, and air dry the chamber in a fume hood. 0.1% crystal violet is dyed for 20min, recovered crystal violet is sucked off, and washed 1 time with PBS; sucking PBS, and airing in a fume hood; cells were observed under 5-fold microscope, randomly five fields under 10-fold microscope, photographed, counted and statistically plotted.
As can be seen from FIGS. 5-6, compared with the negative control group A, the number of the mouse embryo fibroblasts L-929 treated by the TS-2790 treatment is obviously increased, and the number of the L-929 cells invasively migrating through the Transwell chamber has obvious statistical significance (P < 0.01), which indicates that the TS-2790 can promote the movement migration and invasiveness penetration capacity of the mouse embryo fibroblasts L-929.
As can be seen from FIGS. 7-8, compared with the negative control group B, the human foreskin fibroblasts HFF-1 treated by the TS-2790 treatment has significantly increased number of HFF-1 cells invasively migrating through the Transwell chamber, and has significant statistical significance (P < 0.05), which indicates that the TS-2790 can promote the movement migration and invasive penetration capacity of the human foreskin fibroblasts HFF-1.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted equally without departing from the spirit and scope of the technical solution of the present invention.
Claims (8)
1. The application of benzimidazole compound in preparing medicine for promoting wound healing is characterized in that the benzimidazole compound has the following molecular structural formula:
Wherein R 1 is any one of Cl, F and Br.
2. The use of claim 1, wherein the wound comprises a skin ulcer wound, a skin inflammatory wound, a skin wound caused by mechanical trauma, a labor wound, or a skin wound caused by diabetic complications.
3. The use of claim 1, wherein the wound-healing-promoting medicament comprises a pharmaceutically acceptable carrier or excipient.
4. The use according to claim 1, wherein the dosage form of the wound-healing-promoting medicament comprises any one of granules, capsules, tablets, suspensions, emulsions, gels, drop pills, injections, aerosols, drops and solutions.
5. The use according to claim 1, wherein the benzimidazole compound is present at a concentration of 0.01 to 5 μm on the fibroblasts.
6. An experimental composition for promoting wound healing, which is characterized by comprising a benzimidazole compound, wherein the benzimidazole compound has a molecular structural formula as follows:
Wherein R 1 is any one of Cl, F and Br.
7. The test composition for promoting wound healing according to claim 6, further comprising a pharmaceutically acceptable carrier or excipient.
8. The test composition for promoting wound healing according to claim 6, wherein the test composition is a powder, a liquid, a paste, a gel, or a spray.
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| CN (1) | CN118416058A (en) |
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2024
- 2024-05-06 CN CN202410546932.XA patent/CN118416058A/en active Pending
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