Pyrimidine derivative containing thiosemicarbazide structure and application thereof
By designing pyrimidine derivatives containing an aminothiourea structure, the limitations of existing α-glucosidase inhibitors and the poor efficacy of antioxidants have been addressed, achieving more efficient antioxidant and α-glucosidase inhibition, and demonstrating greater potential for treating type 2 diabetes.
Patent Information
- Application Number
- CN202511534860.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-27
- Publication Date
- 2026-01-30
AI Technical Summary
Existing alpha-glucosidase inhibitors have limited efficacy and significant side effects in treating type 2 diabetes, while there is room for improvement in the antioxidant effects of antioxidants such as vitamin C and vitamin E.
A class of pyrimidine derivatives containing an aminothiourea structure were developed, such as 2-(4,6-dimethylpyrimidin-2-yl)-N-methylhydrazine-1-methylthioamide. By optimizing the structural design, their antioxidant capacity and α-glucosidase inhibitory effect were improved.
Some compounds outperform vitamin C and vitamin E in antioxidant capacity and are superior to acarbose in inhibiting α-glucosidase, resulting in higher efficacy and fewer side effects.
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Figure CN121426751A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical technology, specifically to a pyrimidine derivative containing an aminothiourea structure, and also to the application of this pyrimidine derivative containing an aminothiourea structure in anti-oxidation and anti-α-glucosidase activities. Background Technology
[0002] The human body is equipped with a complex enzymatic and non-enzymatic antioxidant defense system that effectively counteracts the harmful effects of free radicals and other oxidizing substances. Free radicals are linked to the progression of various health conditions, such as cancer, heart disease, neurodegenerative diseases, and Alzheimer's disease; increasing the consumption of antioxidants through diet can enhance the body's defense against these harmful substances. Numerous studies have shown that foods rich in antioxidants, especially those containing essential antioxidant nutrients, are crucial for disease prevention; furthermore, a growing consensus among scientists is that antioxidants can improve overall health by slowing or preventing the development of degenerative diseases and age-related illnesses.
[0003] Diabetes, especially type 2 diabetes, is characterized by insufficient insulin secretion and reduced insulin activity, leading to disorders of carbohydrate, protein, and fat metabolism. It has become a global epidemic, affecting more than 350 million people worldwide and is considered a leading cause of death. Treatment for type 2 diabetes involves a variety of approaches, including stimulating endogenous insulin secretion, reducing insulin requirements, and inhibiting carbohydrate digestion. Alpha-glucosidase inhibitors are an important class of drugs for treating type 2 diabetes; common alpha-glucosidase inhibitors, such as acarbose, miglitol, and voglibose, are widely used in clinical practice to delay carbohydrate digestion, thereby reducing postprandial blood glucose spikes and improving blood glucose levels. Developing novel alpha-glucosidase inhibitors with higher efficacy and fewer side effects is an ongoing research direction in the field of medicinal chemistry. Summary of the Invention
[0004] The purpose of this invention is to provide a pyrimidine derivative containing an aminothiourea structure that has good antioxidant and anti-α-glucosidase activity.
[0005] A pyrimidine derivative containing an aminothiourea structure according to the present invention has the following general formula:
[0006]
[0007] In formula (I): R1 is selected from substituents such as methyl and trifluoromethyl; R2 is selected from substituents such as methyl, ethyl, propyl, isopropyl, allyl, butyl, hexyl, ethoxycarbonyl, phenyl, 4-fluorophenyl, benzoyl, etc.
[0008] The specific compound is:
[0009] Compound 1: 2-(4,6-dimethylpyrimidin-2-yl)-N-methylhydrazine-1-methylthioamide;
[0010] Compound 2: 2-(4,6-dimethylpyrimidin-2-yl)-N-ethylhydrazine-1-methylthioamide;
[0011] Compound 3: 2-(4,6-dimethylpyrimidin-2-yl)-N-propylhydrazine-1-methylthioamide;
[0012] Compound 4: 2-(4,6-dimethylpyrimidin-2-yl)-N-isopropylhydrazine-1-methylthioamide;
[0013] Compound 5: 2-(4,6-dimethylpyrimidin-2-yl)-N-allylhydrazine-1-methylthioamide;
[0014] Compound 6: 2-(4,6-dimethylpyrimidin-2-yl)-N-butylhydrazine-1-methylthioamide;
[0015] Compound 7: 2-(4,6-dimethylpyrimidin-2-yl)-N-hexylhydrazine-1-methylthioamide;
[0016] Compound 8: 2-(4,6-dimethylpyrimidin-2-yl)-N-ethoxycarbonylhydrazine-1-methylthioamide;
[0017] Compound 9: 2-(4,6-dimethylpyrimidin-2-yl)-N-phenylhydrazine-1-methylthioamide;
[0018] Compound 10: 2-(4,6-dimethylpyrimidin-2-yl)-N-(4-fluorophenylhydrazine)-1-methylthioamide;
[0019] Compound 11: 2-(4,6-dimethylpyrimidin-2-yl)-N-benzoylhydrazine-1-methylthioamide;
[0020] Compound 12: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N-methylhydrazine-1-methylthioamide;
[0021] Compound 13: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N-ethylhydrazine-1-methylthioamide;
[0022] Compound 14: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N-propylhydrazine-1-methylthioamide;
[0023] Compound 15: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N-isopropylhydrazine-1-methylthioamide;
[0024] Compound 16: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N-butylhydrazine-1-methylthioamide;
[0025] Compound 17: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N-hexylhydrazine-1-methylthioamide;
[0026] Compound 18: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N-ethoxycarbonylhydrazine-1-methylthioamide.
[0027] The present invention describes the application of a class of pyrimidine derivatives containing an aminothiourea structure in antioxidant activities, wherein the IC50 of the compounds scavenging activity against DPPH and ABTS is [not specified in the original text]. 50 The values ranged from 3.96 to 21.36 and from 2.01 to 12.68 μg / mL, respectively. Some compounds were superior to the control agents vitamin C and vitamin E. Among them, the IC50 values of compound 2-(4,6-dimethylpyrimidin-2-yl)-N-methylhydrazine-1-methylthioamide showed the best DPPH and ABTS scavenging activity. 50 The values were 3.96 and 2.01 μg / mL, respectively, with the best results.
[0028] The present invention relates to the application of a class of pyrimidine derivatives containing an aminothiourea structure in the inhibition of α-glucosidase. At a concentration of 200 μg / mL, the inhibitory activity of these compounds against α-glucosidase ranges from 17.27% to 86.45%, with some compounds showing superior activity compared to the control drug acarbose. Specifically, the IC50 of 2-(4,6-dimethylpyrimidin-2-yl)-N-benzoylhydrazine-1-methylthioamide against α-glucosidase is [not specified in the original text]. 50 The value was 38.62 μg / mL, which showed the best effect. Detailed Implementation
[0029] The invention will be further explained below with reference to specific experimental examples.
[0030] Experimental Example 1: Determination of the scavenging activity of the target compound against DPPH and ABTS
[0031] DPPH scavenging activity assay: 5 mg of the target compound was dissolved in 100 mL of methanol to prepare a stock solution with a concentration of 50 μg / mL. Then, 160 μL of the stock solution and 40 μL of DPPH solution were added to a 96-well plate. The DPPH solution had a mass concentration of 0.5 μM, resulting in a reaction mixture with a concentration of 40 μg / mL. After reacting in the dark for 30 min, the absorbance was measured at 517 nm using a full-wavelength multi-mode microplate reader. Dimethyl sulfoxide was used as a negative control, and vitamin C was used as a positive control.
[0032] ABTS scavenging activity assay: 0.2 mL of 2.6 mM K₂S₂O₈ solution was mixed with 0.2 mL of 7.4 mM ABTS solution and reacted in the dark at room temperature for 12 h. The mixture was then diluted 50-fold with PBS buffer. 6.25 mg of the target compound was dissolved in 100 mL of methanol to obtain a stock solution with a concentration of 62.5 μg / mL. Subsequently, 160 μL of the stock solution and 40 μL of ABTS solution were added to each well of a 96-well plate to obtain a reaction mixture with a concentration of 50 μg / mL. After reacting in the dark for 30 min, the absorbance was measured at 734 nm using a multi-wavelength microplate reader. Dimethyl sulfoxide was used as a negative control, and vitamin E was used as a positive control.
[0033] The formulas for calculating the scavenging activity of the target compound against DPPH and ABTS are as follows:
[0034] Scavenging activity (%) = (OD value of control group - OD value of treatment group) / OD value of control group × 100%;
[0035] The scavenging activity and IC50 of the target compound were determined using the methods described above. 50 The values are shown in Table 1.
[0036] Table 1. DPPH scavenging activity of the target compounds
[0037]
[0038] Table 1 shows that the IC50 values of the target compound for scavenging DPPH and ABTS are: 50 The values ranged from 3.96 to 21.36 and from 2.01 to 12.68 μg / mL, respectively, with some compounds showing superior performance compared to the control agents vitamin C and vitamin E. Among them, compound 2-(4,6-dimethylpyrimidin-2-yl)-N-methylhydrazine-1-methylthioamide (1) exhibited IC50 values for DPPH scavenging activity and ABTS scavenging activity. 50 The values were 3.96 and 2.01 μg / mL, respectively, showing the best effect and being superior to the control drugs vitamin C and vitamin E.
[0039] Experimental Example 2: Determination of the anti-α-glucosidase activity of the target compound
[0040] 4 mg of the target compound was dissolved in 100 μL of dimethyl sulfoxide and 900 μL of PBS buffer to prepare a stock solution with a concentration of 400 μg / mL. Then, 20 μL of α-glucosidase, 70 μL of PBS buffer, 80 μL of 0.2 M sodium carbonate solution and 10 μL of the test compound stock solution were added sequentially to a 96-well plate. After reacting at 37 °C for 10 min, 20 μL of p-nitrobenzene-β-D-glucopyranoside was added, and after reacting at 37 °C for 30 min, the absorbance was measured at 405 nm using a full-wavelength multi-mode microplate reader. Dimethyl sulfoxide was used as a negative control and acarbose was used as a positive control.
[0041] The formula for calculating the anti-α-glucosidase activity of the target compound is as follows:
[0042] Anti-α-glucosidase activity (%) = (OD value of control group - OD value of treatment group) / OD value of control group × 100%;
[0043] The inhibitory activity and IC50 of the target compound were determined using the methods described above. 50 The values are shown in Table 2.
[0044] Table 2 Anti-α-glucosidase activity of target compounds
[0045] compound Inhibitory activity (%) <![CDATA[IC 50 (μg / mL)]]> 1 17.27±2.03 / 2 25.75±1.08 / 3 28.87±0.95 / 4 23.59±2.19 / 5 23.51±2.22 / 6 14.75±1.65 / 7 25.61±1.84 / 8 18.63±1.49 / 9 47.83±1.65 / 10 39.45±1.67 / 11 86.45±1.17 38.62±2.25 12 21.24±1.24 / 13 26.32±1.65 / 14 43.88±2.25 / 15 35.70±1.24 / 16 25.98±1.65 / 17 17.50±1.54 / 18 26.32±0.95 / Acarbose 53.00±1.65 237.48±1.56
[0046] Table 2 shows that at a concentration of 200 μg / mL, the inhibitory activity of these compounds against α-glucosidase ranged from 17.27% to 86.45%, with some compounds showing better performance than the control drug acarbose. Among them, compound 2-(4,6-dimethylpyrimidin-2-yl)-N-benzoylhydrazine-1-methylthioamide (11) showed the best IC50 inhibitory activity against α-glucosidase. 50 The value was 38.62 μg / mL, which showed the best effect and was superior to the control drug acarbose.
Claims
1. A pyrimidine derivative having an aminothiourea structure, which is represented by the following general formula (I) : ###0001### wherein R1 is selected from the group consisting of methyl, trifluoromethyl and the like; and R2 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, allyl, butyl, hexyl, ethoxycarbonyl, phenyl, 4-fluorophenyl, benzoyl and the like. The specific compounds are: Compound 1: 2-(4,6-dimethylpyrimidin-2-yl)-N-methylhydrazine-1- thioamide; Compound 2: 2-(4,6-dimethylpyrimidin-2-yl)-N-ethylhydrazine-1- thioamide; Compound 3: 2-(4,6-dimethylpyrimidin-2-yl)-N-propylhydrazine-1- thioamide; Compound 4: 2-(4,6-dimethylpyrimidin-2-yl)-N-isopropylhydrazine-1- thioamide; Compound 5: 2-(4,6-dimethylpyrimidin-2-yl)-N-allylhydrazine-1- thioamide; Compound 6: 2-(4,6-dimethylpyrimidin-2-yl)-N-butylhydrazine-1- thioamide; Compound 7: 2-(4,6-dimethylpyrimidin-2-yl)-N-hexylhydrazine-1- thioamide; Compound 8: 2-(4,6-dimethylpyrimidin-2-yl)-N-ethoxycarbonylhydrazine- 1-thioamide; Compound 9: 2-(4,6-dimethylpyrimidin-2-yl)-N-phenylhydrazine-1- thioamide; Compound 10: 2-(4,6-dimethylpyrimidin-2-yl)-N-(4-fluorophenylhydrazine)- 1-thioamide; Compound 11: 2-(4,6-dimethylpyrimidin-2-yl)-N-benzoylhydrazine-1- thioamide; Compound 12: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N- methylhydrazine-1-thioamide; Compound 13: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N- ethylhydrazine-1-thioamide; Compound 14: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N- propylhydrazine-1-thioamide; Compound 15: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N- isopropylhydrazine-1-thioamide; Compound 16: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N- butylhydrazine-1-thioamide; Compound 17: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N- hexylhydrazine-1-thioamide; Compound 18: 2-(4-trifluoromethyl-6-methylpyrimidin-2-yl)-N- ethoxycarbonylhydrazine-1-thioamide.
2. The pyrimidine derivative having an aminothiourea structure according to claim 1 for use in antioxidation.
3. The pyrimidine derivative having an aminothiourea structure according to claim 1 for use in anti-α-glucosidase. The antioxidation is the scavenging activity against DPPH and ABTS.
4. The use of the aminothiourea structured pyrimidine derivatives according to claim 2 for antioxidation, characterized by: 5. The use of a thiosemicarbazone-structured pyrimidine derivative according to claim 4 for the antioxidation, characterized by: The IC50 of the compound's scavenging activity against DPPH and ABTS 50 The values ranged from 3.96 to 21.36 and from 2.01 to 12.68 μg / mL, respectively. Some compounds were superior to the control agents vitamin C and vitamin E. Among them, the IC50 values of compound 2-(4,6-dimethylpyrimidin-2-yl)-N-methylhydrazine-1-methylthioamide showed the best DPPH and ABTS scavenging activity. 50 The values were 3.96 and 2.01 μg / mL, respectively.
6. Use of a thiosemicarbazide structured pyrimidine derivative according to claim 3 for the inhibition of α-glucosidases, characterized in that, The inhibition activity of the compounds on α-glucosidase is in the range of 17.27% to 86.45% at the concentration of 200 μg / mL, and some of the compounds are superior to the control agent acarbose, wherein the IC 50 value of the compound 2-(4,6-dimethylpyrimidin-2-yl)-N-phenylcarbonylhydrazine-1- methanesulfonamide on α-glucosidase is 38.62 μg / mL.