CN115947731A - Fused heterocyclic compound and application of amylase inhibitor thereof - Google Patents
Fused heterocyclic compound and application of amylase inhibitor thereof Download PDFInfo
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- CN115947731A CN115947731A CN202211646808.8A CN202211646808A CN115947731A CN 115947731 A CN115947731 A CN 115947731A CN 202211646808 A CN202211646808 A CN 202211646808A CN 115947731 A CN115947731 A CN 115947731A
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- 150000002391 heterocyclic compounds Chemical class 0.000 title claims abstract description 20
- 239000003392 amylase inhibitor Substances 0.000 title abstract description 13
- 229940122816 Amylase inhibitor Drugs 0.000 title description 5
- 239000003814 drug Substances 0.000 claims abstract description 25
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 14
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 10
- 239000004382 Amylase Substances 0.000 claims description 6
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
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- 239000003440 toxic substance Substances 0.000 claims 1
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- 229940024171 alpha-amylase Drugs 0.000 abstract description 7
- 231100000053 low toxicity Toxicity 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 6
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 abstract description 3
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- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
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- 230000000291 postprandial effect Effects 0.000 description 2
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- 102000004877 Insulin Human genes 0.000 description 1
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- 229940122355 Insulin sensitizer Drugs 0.000 description 1
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Images
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of a fused heterocyclic compound in treating diabetes, belonging to the technical field of medicines. The compound capable of inhibiting the activity of the alpha-amylase is obtained by screening through a nitro salicylic acid micropore method, and the activity of the alpha-amylase can be obviously inhibited when the concentration is 5 mu g/mL, and the IC of the compound 50 Is 3.27 mu g/mL and is superior to the current clinical medicine acarbose. The fused heterocyclic compounds are simultaneously measured at the cellular level, the animal level and the toxicity, and the results show that the compounds have very low toxicity and are good alpha-amylase inhibitors. The invention finds a high-efficiency low-toxicity alpha-amylase inhibitor which can be used for treating diabetes.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a fused heterocyclic compound and application of an amylase inhibitor thereof.
Background
In recent years, with the rapid increase of people's physical and living standards, diabetes, hyperglycemia and hyperlipidemia have gradually evolved into high-incidence diseases. Diabetes is largely classified into type I diabetes and type ii diabetes, of which type ii diabetes (non-insulin dependent diabetes) is a disease that is likely to occur in almost all ages, even in children, and about nine adults among diabetic patients are diagnosed as type ii diabetes. Disorders in the carbohydrate, protein and fat catabolic mechanisms in diabetic patients, which lead to the long-term hyperglycemic character of the body, can gradually lead to chronic impairment and metabolic dysfunction of various tissues and organs of the body, especially of the eye, kidney, cardiovascular and nervous functions.
At present, the treatment method of diabetes mainly comprises drug therapy, exercise rehabilitation training, diet regulation and the like, wherein a plurality of drugs for treating the diabetes comprise insulin, insulin sensitizers, sulfonylureas, biguanides, glucosidase inhibitors and the like. These drugs, while acting, are associated with more or less side effects. Therefore, the search and development of high-efficiency and low-toxicity hypoglycemic drugs are not easy.
Disclosure of Invention
The invention aims to synthesize a compound with amylase inhibition effect, which has potential function of treating diabetes.
The technical scheme adopted by the invention is as follows:
in one aspect of the invention, an alkaloid compound represented by formula I is provided:
the fused heterocyclic compound shown in the formula I has stronger amylase inhibition activity and the molecular formula is C 17 H 14 N 6 O 2 S。， 1 H and 13 the C-NMR data are:
1 H NMR(400MHz,DMSO-d 6 )δ9.97(s,1H),7.11(s,1H),7.08(d,J＝2.4Hz,1H),6.91(dd,J＝15.4,7.7Hz,2H),6.87(d,J＝6.5Hz,1H),6.71(s,2H),6.65(s,1H),6.63(d,J＝7.1Hz,2H),3.52(s,3H). 13 C NMR(100MHz,DMSO-d 6 )δ167.0,166.5,154.7,153.5,152.4,134.6,134.4,128.6,123.4,122.0,121.6,114.6,114.2,88.8,69.0,43.8,32.9.
the invention provides application of the compound in amylase inhibitor.
Alpha-amylase inhibitors exhibit potent and specific inhibitory activity against amylase in human saliva and the gastrointestinal tract. Its mechanism of action is to inhibit the hydrolysis of starch by amylase, and to prevent the hydrolysis and digestion of some soluble carbohydrates in food, so as to reduce the production of glucose. Because the glucose can be discharged out of the body through the gastrointestinal tract without entering a blood circulation system, the glucose-lowering and postprandial glucose control tablet has relatively high safety, is commonly used for glucose lowering and postprandial glucose control of diabetes patients, and has wide market prospect.
The method comprises the steps of optimizing the concentration of soluble starch, the concentration of alpha-amylase and the reaction time in a 3,5-dinitrosalicylic acid micropore method; then, the experimental method was verified with acarbose; screening the compound by adopting the optimized experimental conditions; HBE cell experiments and zebra fish toxicity experiments are carried out on the compound with better alpha-amylase inhibition effect.
The invention discloses aThe use of fused heterocyclic compounds in the treatment of diabetes. The compound capable of inhibiting the activity of the alpha-amylase is obtained by screening through a nitro salicylic acid micropore method, and the activity of the alpha-amylase can be obviously inhibited when the concentration is 5 mu g/mL, and the IC of the compound 50 Is 3.27 mu g/mL and is superior to the current clinical medicine acarbose. The fused heterocyclic compounds are simultaneously measured at the cellular level, the animal level and the toxicity, and the results show that the compounds have very low toxicity and are good alpha-amylase inhibitors. The invention finds a high-efficiency low-toxicity alpha-amylase inhibitor which can be used for treating diabetes.
Drawings
FIG. 1 is a graph showing the inhibition rate of the inhibitory activity assay.
FIG. 2 is a microscopic image of cells during the cytotoxicity experiments.
FIG. 3 is a diagram showing the incubation and development states of zebrafish in DMSO solution and fused heterocyclic compound 8b at a concentration of 25. Mu.g/mL.
Detailed Description
A fused heterocyclic compound comprises an alkaloid compound with a structure shown in formula I and a derivative thereof;
an application of fused heterocyclic compound in preparing medicine for treating diabetes is disclosed.
The fused heterocyclic compound is a high-efficiency and low-toxicity compound capable of inhibiting amylase.
The medicine is a medicament prepared by taking a compound as an active ingredient and adding pharmaceutical auxiliary materials. The medicine of the present invention is used in lowering blood sugar concentration of diabetics. The medicament is an oral preparation or an injection preparation.
1. Amylase inhibitory Activity assay for fused heterocyclic Compound 8b
mu.L of the original drug stock solution (10 mg/mL) was taken and diluted to 150. Mu.L with PBS buffer for further use. 60 μ L of the drug solution (PBS buffer in the negative group) was added50 mu L of alpha-amylase solution with the concentration of 0.025mg/mL (PBS buffer solution is used for replacing in a blank group), preserving the temperature of the mixed solution for 10 minutes at 37 ℃, adding 250 mu L of starch solution with the concentration of 0.15%, fully and uniformly mixing, reacting for 75 minutes at 25 ℃, adding DNS reagent according to the volume of 1:1, heating for 10 minutes at 100 ℃ to terminate the reaction to obtain reaction solution, finally adding the reaction solution into a 96-well plate, and measuring the absorbance at the wavelength of 520 nm. The fused heterocyclic compound 8b is respectively set with different gradient concentrations for experiments, and the inhibition rate is reduced along with the reduction of the compound concentration. By calculating the IC of the compound 50 The value (half inhibitory concentration) was used to further measure the amylase inhibitory potency of the drug, and the inhibition results are shown in FIG. 1, with an IC of 3.72. Mu.g/mL to 8b calculated from the inhibition data.
2. Cytotoxicity test
After the three drugs with better inhibition effect obtained after rescreening are diluted to 50 mu g/mL by PBS buffer solution, the three drugs are added into the cultured HBE cells (human normal bronchial epithelial cells) to observe the crystal morphology and the influence on the HBE cell growth. As can be seen from the cell microscopic image in fig. 2, the cell morphology of the group administered with compound 8b was almost unchanged and the cell number was not significantly reduced as compared with the control group, indicating that compound No. 8b had no significant inhibitory effect on the growth of HBE cells at this concentration (50 μ g/mL). Wherein A is DMSO solvent control, and B is fused heterocyclic compound 8B.
MTT experiment result shows that the IC of the compound 8b on HBE of human bronchial epithelial cells 50 Greater than 50. Mu.g/mL. The results, combined with cell morphology observations, indicate that compound 8b is less toxic at the cellular level.
3. Toxicity test of Zebra fish
The fused heterocyclic compound 8b is added into a DMSO solution to prepare liquid medicines of 25 mu g/mL respectively for standby. Adding fertilized eggs of the zebra fish into the hatching solution for culturing, adding young zebra fish after hatching for 72 hours into a 96-well plate, removing the original culture solution, and injecting the prepared liquid medicine. Each medicine is divided into two groups according to the concentration of 25 mug/mL, and each group is set to culture 30 juvenile fishes according to the number of the hatched zebra fishes. In the culture process, the influence of the culture medium on the growth of the zebra fish is observed at 0h, 24h, 48h and 72h in terms of body length, heart rate and survival rate respectively.
TABLE 1
As shown in figure 3 and table 1, when the concentration of the fused heterocyclic compound 8b is 25 mug/mL, the incubation and the development of the zebra fish are normal, and no obvious influence is generated on the heartbeat of the zebra fish, and the experimental result shows that the fused heterocyclic compound 8b has low toxicity at the animal level, is a potential amylase inhibitor and is expected to be used for treating diabetes.
Claims (6)
1. A fused heterocyclic compound is characterized by comprising an alkaloid compound with a structure shown in a formula I and a derivative thereof;
2. use of a fused heterocyclic compound according to claim 1 for the manufacture of a medicament for the treatment of diabetes.
3. The use according to claim 2, wherein the compound is a highly potent and low toxic compound capable of inhibiting amylase.
4. The use according to claim 1 or 2, wherein the medicament is a medicament prepared from the compound as an active ingredient, together with pharmaceutically acceptable adjuvants.
5. The use of claim 2, wherein the medicament is a medicament for lowering the blood glucose concentration of a diabetic patient.
6. The use of claim 3, wherein the medicament is an oral formulation or an injectable formulation.
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| CN202211646808.8A CN115947731A (en) | 2022-12-21 | 2022-12-21 | Fused heterocyclic compound and application of amylase inhibitor thereof |
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| CN202211646808.8A CN115947731A (en) | 2022-12-21 | 2022-12-21 | Fused heterocyclic compound and application of amylase inhibitor thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56100789A (en) * | 1980-01-14 | 1981-08-12 | Yoshitomi Pharmaceut Ind Ltd | Imidazole derivative or its acid adduct |
| US20040127519A1 (en) * | 2002-12-12 | 2004-07-01 | Pharmacia Corporation | Method of using aminocyanopyridine compounds as mitogen activated protein kinase-activated protein kinase-2 inhibitors |
| CN108392518A (en) * | 2018-03-13 | 2018-08-14 | 阜阳师范学院 | Chinese toon extract and preparation method thereof and purposes |
| CN108610348A (en) * | 2018-07-24 | 2018-10-02 | 江苏师范大学 | A kind of simultaneously [2,3-b] pyridine -3- carbonitrile derivatives and its preparation and application of the 5H- chromenes containing imidazole substituent |
-
2022
- 2022-12-21 CN CN202211646808.8A patent/CN115947731A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56100789A (en) * | 1980-01-14 | 1981-08-12 | Yoshitomi Pharmaceut Ind Ltd | Imidazole derivative or its acid adduct |
| US20040127519A1 (en) * | 2002-12-12 | 2004-07-01 | Pharmacia Corporation | Method of using aminocyanopyridine compounds as mitogen activated protein kinase-activated protein kinase-2 inhibitors |
| CN108392518A (en) * | 2018-03-13 | 2018-08-14 | 阜阳师范学院 | Chinese toon extract and preparation method thereof and purposes |
| CN108610348A (en) * | 2018-07-24 | 2018-10-02 | 江苏师范大学 | A kind of simultaneously [2,3-b] pyridine -3- carbonitrile derivatives and its preparation and application of the 5H- chromenes containing imidazole substituent |
Non-Patent Citations (1)
| Title |
|---|
| 陈雯 等: "朝格尔碱衍生物的制备及其催化的4H-色烯并[2, 3-b]吡啶-3-腈的合成", 有机化学, vol. 40, no. 4, pages 988 - 996 * |
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