Chalconamide alpha-glucosidase inhibitors, and methods of making and using the same

Abstract

The present application relates to a kind of chalcone amide alpha-glucosidase inhibitors and its preparation and application, the inhibitor structural formula is: preparation method specifically is (1) after 2-hydroxyacetophenone, sodium hydroxide and methyl p-formylbenzoate are reacted, intermediate in formula (a) is obtained after post-processing;(2) intermediate in formula (a) is dissolved in organic solvent and potassium hydroxide is reacted, after reaction, intermediate in formula (b) is obtained after post-processing;(3) intermediate in formula (b) and substituted aniline are dissolved in organic solvent, after reaction, the inhibitor shown in formula (c) is obtained after post-processing.Compared with prior art, the compound of the present application is novel, and experiments show that it has good alpha-glucosidase inhibitory activity, and can be used for preparing alpha-glucosidase activity inhibiting drug.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a chalconeamide α-glucosidase inhibitor, its preparation method, and its application. Background Technology

[0002] Alpha-glucosidase (AG) is an intestinal hydrolase found in small intestinal cells. It catalyzes the cleavage of the α-1,4 glycosidic bond at the non-reducing end of oligosaccharides, forming α-glucose which is absorbed by the small intestine and enters the bloodstream. Therefore, α-glucosidase is one of the important targets for the development of drugs for type 2 diabetes.

[0003] Currently established medications for treating type 2 diabetes include DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas, thiazolidinediones, and alpha-glucosidase inhibitors. The main alpha-glucosidase inhibitors used clinically and commercially available include acarbose, voglibose, and miglitol. However, with increasing time on the market, these three classes of inhibitors have shown varying side effects at higher doses, typically including gastrointestinal discomfort, flatulence, diarrhea, abdominal pain, and hypoglycemia when used in combination with other hypoglycemic agents such as insulin, sulfonylureas, and metformin.

[0004] Patent application 202310472396.9 discloses a chalcone α-glucosidase inhibitor, its preparation method, and its application. The chalcone α-glucosidase inhibitor is the chalcone compound xanthohumol G, which is derived from plant extracts by directly introducing hydroxyl, methoxy, and double bond groups onto the chalcone skeleton. The positive control drug has an IC50 value of [missing information]. 50 The value is 594.1 μM. Patent CN111747881A discloses the application of isopentenyl-substituted indole alkaloids in the preparation of α-glucosidase inhibitors. The isopentenyl-substituted indole alkaloids described in this invention have good inhibitory effects on α-glucosidase and can be used for the treatment or adjunctive treatment of type 2 diabetes. The IC50 of the isopentenyl-substituted indole alkaloids having the structure shown in formula (1) is... 50 The IC50 values ​​of isopentenyl-substituted indole alkaloids with the structure shown in formula (2) are in the range of 105 ± 4.7 μM. 50 The value can reach the range of 35.2 ± 3.2 μM. Patent CN112225740A discloses the application of a pyrazolopyrimidinone derivative in the preparation of α-glucosidase inhibitors and its application in the preparation of drugs for the prevention and treatment of α-glucosidase-related diseases. The pyrazolopyrimidinone derivative described in this invention has a good inhibitory effect on α-glucosidase. The IC50 of pyrazolopyrimidinone compounds having the structure shown in Formula I... 50The value was 45.74 μM, significantly better than the positive control (IC50). 50 The value is 52.02 μM.

[0005]

[0006] Therefore, the existing technology has a good inhibitory effect on α-glucosidase activity, but it can still be further improved. Summary of the Invention

[0007] The purpose of this invention is to provide a chalconeamide α-glucosidase inhibitor, its preparation method, and its application in order to solve the above-mentioned problems. The inhibitor has a novel structure and experiments have shown that it has good α-glucosidase inhibitory activity. It can be used to prepare drugs that inhibit α-glucosidase activity.

[0008] The objective of this invention is achieved through the following technical solution:

[0009] A chalconeamide α-glucosidase inhibitor having the structure shown in formula (I):

[0010]

[0011] Where Ar is selected from any of the following structural formulas:

[0012] Ar for In the above structural formulas This indicates that the Ar group is connected to the N phase.

[0013] Further preferably, the inhibitor has the following structure:

[0014]

[0015] The present invention also provides a method for preparing the chalconeamide α-glucosidase inhibitor as described above, the equation of which is shown below:

[0016]

[0017] The preparation method specifically includes the following steps:

[0018] (1) A reaction system was formed by 2-hydroxyacetophenone, sodium hydroxide and methyl p-formylbenzoate, and the intermediate of formula (a) was obtained after post-treatment after the reaction.

[0019] (2) Take the intermediate of formula (a) obtained in step (1) and dissolve it in an organic solvent and potassium hydroxide solution to form a reaction system. After the reaction, the intermediate of formula (b) is obtained.

[0020] (3) Take the intermediate of formula (b) obtained in step (2), substituted aniline, HOBt (1-hydroxybenzotriazole), and EDCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) and dissolve them in an organic solvent to form a reaction system. After the reaction, the chalcone inhibitor shown in formula (c) is obtained by post-treatment.

[0021] In step (1), the sodium hydroxide is prepared into a 30% sodium hydroxide solution using distilled water to make the reaction system alkaline, and the organic solvent is anhydrous methanol.

[0022] In step (1), the temperature of the reaction system is 25-60℃, preferably 25℃, and the reaction time is 8-16h, preferably 12h.

[0023] In step (1), the post-processing process is as follows: the reaction system is filtered and the filter cake is washed with an appropriate amount of distilled water, the filter cake is dried at room temperature to obtain the crude product, and then recrystallized with ethanol to obtain the pure intermediate of formula (a).

[0024] In step (1), the ratio of the amount of 2-hydroxyacetophenone, sodium hydroxide, methyl paraben and organic solvent added is (50-80) mmol: (5-10) g: (50-80) mmol: (70-100) mL, preferably 60 mmol: 9 g: 60 mmol: 80 mL.

[0025] In step (2), potassium hydroxide is used to make the reaction system alkaline, and anhydrous ethanol is used as the organic solvent.

[0026] In step (2), the reaction system is placed at room temperature, preferably 25°C, and the reaction time is 4-6 hours, preferably 4 hours.

[0027] In step (2), the post-treatment process is as follows: add 1-2 mol / L (preferably 1.5 mol / L) hydrochloric acid to neutralize the reaction system to neutral, stir at room temperature for 1-2 h, preferably 2 h, to generate a large amount of yellow precipitate. Filter the precipitate under reduced pressure and wash it with an appropriate amount of distilled water, dry it at room temperature to obtain the crude product, and then recrystallize it with ethanol to obtain the pure intermediate of formula (b).

[0028] In step (2), the ratio of the intermediate of formula (a), KOH and organic solvent added is 10 mmol: 30 mmol: 100 mL.

[0029] In step (3), the organic solvent is dichloromethane or DMF, preferably DMF.

[0030] In step (3), the reaction system is placed at room temperature, preferably 25°C, and the reaction time is 2-6 hours, preferably 3 hours. Nitrogen protection is required during the reaction stirring.

[0031] In step (3), the post-processing process is as follows: after the reaction is completed, 100 mL of distilled water is added to the system, stirred to obtain a precipitate, filtered and washed with saturated saline to obtain a crude product, recrystallized with 95% aqueous ethanol, and finally purified by column chromatography to obtain the pure inhibitor shown in formula (c).

[0032] In step (3), the ratio of the intermediate of formula (b), HOBt, EDCl, substituted aniline and organic solvent added is 2 mmol: (4-5) mmol: (4-6) mmol: (3-4) mmol: (10-20) mL, preferably 2 mmol: 4 mmol: 4 mmol: 4 mmol: 12 mL.

[0033] The present invention also provides the use of the chalconeamide α-glucosidase inhibitor as described above in the preparation of a drug capable of inhibiting α-glucosidase activity.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] 1. This invention provides an α-glucosidase inhibitor with a novel skeletal structure, its preparation method, and its application. The synthesis method is simple, and the obtained inhibitor has good α-glucosidase inhibitory activity and excellent α-glucosidase inhibitory effect. It can be applied to the preparation of drugs that inhibit α-glucosidase activity.

[0036] 2. This invention introduces aniline with different substituents onto the benzoic acid at the end of the skeleton of chalcone derivatives through amide condensation, synthesizing a series of chalcone derivatives with amide substituents. The amide skeleton facilitates a more stable binding of the compound to the active site during virtual docking, thereby inhibiting the activity of α-glucosidase and becoming a series of more promising novel α-glucosidase inhibitors.

[0037] 3. This invention successfully introduced amide groups into the structure of chalcone derivatives, which was verified by 1H NMR, 13C NMR and HRMS, and the purity was detected by high performance liquid chromatography. The purity of all newly synthesized compounds was above 95%.

[0038] 4. Theoretically speaking, the IC of a compound 50 The lower the value, the better the inhibitory activity of the compound. The compound IC of this invention... 50 The value can reach 8.36 μM, which is much lower than the existing technology, indicating that the compound synthesized in this invention has a good inhibitory effect on α-glucosidase activity and has better application and development prospects. Detailed Implementation

[0039] The present invention will now be described in detail with reference to specific embodiments, but these are by no means limitations on the present invention.

[0040] The present invention comprises a chalconeamide α-glucosidase inhibitor having the structure shown in formula (I):

[0041]

[0042] Where Ar is selected from any of the following structural formulas:

[0043] Ar for In the above structural formulas This indicates that the Ar group is connected to the N phase.

[0044] The above-mentioned method for preparing chalconeamide α-glucosidase inhibitors is illustrated by the following equation:

[0045]

[0046] The preparation method specifically includes the following steps:

[0047] (1) A reaction system was formed by 2-hydroxyacetophenone, sodium hydroxide and methyl p-formylbenzoate, and the intermediate of formula (a) was obtained after post-treatment after the reaction.

[0048] (2) Take the intermediate of formula (a) obtained in step (1) and dissolve it in an organic solvent and potassium hydroxide solution to form a reaction system. After the reaction, the intermediate of formula (b) is obtained.

[0049] (3) Take the intermediate of formula (b) obtained in step (2) and the substituted aniline and dissolve them in an organic solvent to form a reaction system. After the reaction, the chalcone inhibitor shown in formula (c) is obtained by post-treatment.

[0050] In step (1), a 30% sodium hydroxide solution is used to place the reaction system in an alkaline environment, and anhydrous methanol is used as the organic solvent. The reaction system is placed at a temperature of 25-60℃, preferably 25℃, and the reaction time is 8-16h, preferably 12h. The post-treatment process is as follows: the reaction system is filtered and the filter cake is washed with an appropriate amount of distilled water. The filter cake is dried at room temperature to obtain a crude product, and then recrystallized with ethanol to obtain a pure intermediate of formula (a). The addition ratio of 2-hydroxyacetophenone, sodium hydroxide, distilled water, methyl paraformylbenzoate and organic solvent is (50-80) mmol, (5-10) g, (10-40) mL, (50-80) mmol, (70-100) mL, preferably 60 mmol, 9 g, 30 mL, 60 mmol, 80 mL.

[0051] In step (2), the reaction system is placed at room temperature, preferably 25°C, and the reaction time is 4-6 hours, preferably 4 hours. The post-treatment process is as follows: 1.5 mol / L hydrochloric acid is added to neutralize the reaction system to neutrality, and the mixture is stirred at room temperature for 2 hours, generating a large amount of yellow precipitate. The precipitate is filtered and washed with an appropriate amount of distilled water, dried at room temperature to obtain a crude product, and then recrystallized with ethanol to obtain a pure intermediate of formula (b). The amounts of intermediate of formula (a), KOH, and organic solvent added are 10 mmol, 30 mmol, and 100 mL, respectively.

[0052] In step (3), the organic solvent is dichloromethane and DMF, preferably DMF. The reaction system is placed at room temperature, preferably 25°C, and the reaction time is 2-6 hours, preferably 3 hours. Nitrogen protection is required during stirring. The post-treatment process is as follows: After the reaction is completed, 100 mL of distilled water is added to the system, stirred to obtain a precipitate, filtered and washed with saturated brine to obtain a crude product, recrystallized with 95% aqueous ethanol, and finally purified by column chromatography to obtain a pure inhibitor of formula (c). The addition ratio of the intermediate of formula (b), HOBt, EDCl, substituted aniline and organic solvent is 2 mmol, (4-5) mmol, (4-6) mmol, (3-4) mmol, (10-20) mL, preferably 2 mmol, 4 mmol, 4 mmol, 4 mmol, 12 mL.

[0053] The prepared inhibitors were tested for their α-glucosidase activity. The specific test method is as follows:

[0054] 1. Experimental instruments and materials

[0055] Multifunctional microplate reader, Spark model, Tecan Australia GmbH;

[0056] Clean bench;

[0057] Bond A3Pipette manual single-channel adjustable pipette, 0.5-10μL, 10-100μL, 100-1000μL Titan Technology;

[0058] 96-well plate (transparent), sterilized, Corning;

[0059] α-Glucosidase was purchased from Beijing Innocare Technology Co., Ltd.; the fluorescent substrate p-nitrobenzene-α-D-glucopyranoside (PNPG) used in the enzyme inhibition experiment was purchased from Shanghai Myriel Biochemical Technology Co., Ltd.; disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate dihydrate, and sodium carbonate were purchased from Titan Technology.

[0060] Positive control drug: acarbose, Shanghai Myrui Biochemical Technology Co., Ltd.

[0061] 2. Reagent preparation

[0062] a. 0.1 mol / L, pH 6.8 phosphate buffer (PBS): Mix 0.1 mM sodium dihydrogen phosphate solution with 0.1 mM disodium hydrogen phosphate solution and adjust the pH of the solution to 6.80.

[0063] b. Substrate solution: Accurately weigh 1.5 mg PNPG and dissolve it in 1 mL of PBS buffer to prepare a 5 mM PNPG solution. Prepare fresh before use.

[0064] c. Enzyme solution: Add 100U of lyophilized enzyme powder to PBS buffer to prepare a stock solution with a concentration of 10U / mL. Store at -20℃. Dilute to 0.4U / mL before use. Prepare fresh before use.

[0065] d. Termination solution: Weigh anhydrous sodium carbonate and dissolve it in distilled water to prepare a 0.2 mol / L sodium carbonate solution.

[0066] e. Positive control and sample solutions: Acarbose and ten target compounds were dissolved in DMSO and the initial concentration was prepared to be 300 μM / L. The solution was then serially diluted to five concentration gradients: 100 μM / L, 30 μM / L, 10 μM / L, 3 μM / L, and 1 μM / L. Three sets of each concentration gradient were prepared in sequence.

[0067] 3. Experimental Methods

[0068] This experiment was conducted in a 96-well plate with a total reaction volume of 200 μL. 100 μL of PBS buffer was added to each well, followed by 10 μL of different concentrations of the α-glucosidase inhibitor sample or positive control sample solution. Then, 20 μL of α-glucosidase solution was added, and the plate was incubated at 37°C for 15 min. Next, 20 μL of PNPG solution was added, and incubation continued for another 15 min. Finally, 50 μL of sodium carbonate solution was added to each well to terminate the reaction. The absorbance of each well was measured at 405 nm. The experiment was performed in triplicate.

[0069] The experiment was set up in four groups, namely

[0070] Sample group A (enzyme solution + substrate solution + buffer solution + test sample solution / acarbose solution + stop solution)

[0071] Sample background group A0 (sample solution + substrate solution + buffer solution + stop solution)

[0072] Negative control group B (enzyme solution + substrate solution + buffer + DMSO + stop solution)

[0073] Negative background control group B0 (substrate solution + buffer solution + DMSO + stop solution)

[0074] The reagent amounts added to each group are shown in Table 2. After measuring the absorbance, the corresponding inhibition rate was calculated using a formula. The data were then processed using GraphPadprism software to fit curves and the corresponding IC50 values. 50 Value. The formula for the inhibition rate of the sample against α-glucosidase is as follows:

[0075]

[0076] Table 2: Amount of reagents added to the four experimental groups

[0077] reagents Group A / μL <![CDATA[A0 group / μL]]> Group B / μL <![CDATA[Group B / μL]]> α-glycosidase 20 － 20 － Sample to be tested 10 10 － － PNPG solution 20 20 20 20 PBS buffer 100 120 100 120 DMSO － － 10 10 <![CDATA[Sodium carbonate solution]]> 50 50 50 50

[0078] A represents the absorbance of the substrate and α-glucosidase after incubation at 37°C for 30 min in the presence of the sample solvent.

[0079] A0 represents the background absorbance of the system after 30 minutes of reaction without the addition of α-glucosidase, in the presence of the sample and solvent.

[0080] B represents the absorbance of the substrate and α-glucosidase after 30 minutes of incubation.

[0081] B0 represents the absorbance after incubation for 30 minutes with only the substrate and solvent system added.

[0082] This invention utilizes a receptor-based molecular docking virtual screening method to screen 450,000 compounds from the TCMSP database of traditional Chinese medicines, obtaining one compound theoretically possessing α-glucosidase inhibitory activity. Subsequently, its structure was modified to design more rational compounds, and α-glucosidase tests were performed on ten of these compounds, using acarbose as a positive control. The IC50 of acarbose was... 50 The value is 8.36 μM. The following is a detailed explanation using specific examples:

[0083] Example 1

[0084] A chalconeamide α-glucosidase inhibitor, the structural formula of which is shown below:

[0085]

[0086] The specific synthesis steps are as follows:

[0087] (1) Accurately weigh 9.00 g of sodium hydroxide and pour it into a 250 mL round-bottom flask. Measure 30 mL of distilled water using a graduated cylinder and add it to the round-bottom flask. Stir to dissolve. Accurately measure 8.16 g (60 mmol) of 2-hydroxyacetophenone and 9.84 g (60 mmol) of methyl p-formylbenzoate and add them to the round-bottom flask. Pour in 80 mL of methanol and stir. Place the mixture at room temperature (25 °C) and stir to react for 12 hours. After the reaction is complete, a large amount of yellow solid is produced in the system solution. Filter the yellow precipitate and wash the filter cake with an appropriate amount of distilled water. Dry it at room temperature and recrystallize it with ethanol to obtain intermediate (a).

[0088] (2) Accurately weigh 2.82 g (10 mmol) of intermediate (a) into a 250 mL round-bottom flask, add 100 mL of ethanol, and add a solution of 1.68 g (30 mmol) of potassium hydroxide dissolved in 5 mL of distilled water to the round-bottom flask under ice bath conditions. React at 25 °C for 4 hours. After the reaction is complete, add 1.5 mol / L hydrochloric acid to the system to neutralize it, stir at room temperature for 2 hours, and a large amount of yellow precipitate is generated. Filter the precipitate and wash it with an appropriate amount of distilled water. Dry it at room temperature to obtain the crude product, and then recrystallize it with ethanol to obtain the pure intermediate (b).

[0089] (3) Take 0.54 g (2 mmol) of intermediate (b), 0.54 g (4 mmol) of HOBt, and 0.76 g (4 mmol) of EDCl in a 25 mL round-bottom flask, add 12 mL of DMF, and stir at room temperature for 10 min under nitrogen flow. Then slowly add 4 mmol of piperoethylamine to the flask and stir at room temperature for 3 h under nitrogen flow. After the reaction is complete, add 100 mL of distilled water to the system, stir to obtain a precipitate, filter and wash with saturated brine to obtain the crude product, recrystallize with 95% aqueous ethanol, and finally purify by column chromatography to obtain the pure inhibitor L1 shown in formula (c).

[0090] The obtained inhibitor L1 was tested using the above experimental method, and the results are as follows:

[0091] (E)-N-(2-benzo[d][1,3]dioxacyclopenten-4-yl)ethyl)-4-(3-(2-hydroxyphenyl)-3-oxopropyl-1-enyl)benzamide, a pale yellow solid, in 93% yield, with an IC50 value of 100%. 50 The value was 8.28 μM, and the IC50 of the positive control drug was... 50 The value is 8.36 μM.

[0092] 1 H NMR (401MHz, DMSO-d6) δ12.49(s,1H),8.67(t,J=5.6Hz,1H),8.28(dd,J=8.3,1.6Hz,1H),8.13(d,J=15.5Hz,1H),8.04–7.84(m,5H),7.62–7.55 (m,1H),7.02(dd,J=8.1,5.3Hz,2H),6.87–6.80(m,2H),6.71(dd,J=7.9,1.6Hz,1H),5.98(s,2H),3.50(d,J=6.8Hz,2H),2.80(t,J=7.3Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ194.02,166.00,162.41,147.71,146.03,144.04,137.41,136.94,136.74,133.78 ,131.46,129.49,128.19,123.72,122.05,121.26,119.70,118.27,109.55,108.60,101.16,41.66,35.24.

[0093] Example 2

[0094] (E)-N-(4-hydroxyphenylethyl)-4-(3-(2-hydroxyphenyl)-3-oxopropyl-1-en-1-ylbenzamide, the structural formula of which is as follows, is prepared in a similar manner to Example 1, except that the piperoethylamine in step (3) is replaced with p-hydroxyphenylethylamine.

[0095]

[0096] The obtained inhibitor L2 was a pale yellow solid with a yield of 92% and an IC50 value of 100%. 50 The value is 8.86 μM.

[0097] 1 H NMR (501MHz, DMSO-d6) δ12.46(s,1H),9.20(s,1H),8.64(t,J=5.5Hz,1H),8.27(d,J=7.9Hz,1H),8.12(d,J=15.5Hz,1H),8.03–7 .78(m,5H),7.57(t,J=7.8Hz,1H),7.04(dd,J=13.9,7.8Hz,4H),6.72(d,J=7.9Hz,2H),3.46(d,J=7.3Hz,2H),2.81–2.69(m,2H). 13 C NMR(126MHz,DMSO-d6)δ194.02,165.94,162.37,156.16,144.03,137.36,136.90,136.80 ,131.43,130.00,129.45,128.17,123.74,121.28,119.68,118.24,115.64,41.82,34.78.

[0098] Example 3

[0099] 3,4-Dimethoxyphenylethyl-4-(3-(2-hydroxyphenyl)-3-oxopropyl-1-enylbenzamide, with the following structural formula, is prepared in a similar manner to Example 1, except that the piperoethylamine in step (3) is replaced with 2-(3,4-dimethoxyphenyl)ethylamine.

[0100]

[0101] The obtained inhibitor L3 was a pale yellow solid with a yield of 89% and an IC50 value of 100%. 50 The value is 11.56 μM.

[0102] 1H NMR (401MHz, DMSO-d6) δ12.47(s,1H),8.70(t,J=5.6Hz,1H),8.25(d,J=7.8 Hz,1H),8.10(d,J=15.6Hz,1H),7.99(d,J=8.1Hz,2H),7.95–7.81(m,3H),7 .58(t,J=7.8Hz,1H),7.03(dd,J=8.0,6.0Hz,2H),6.86(d,J=8.2Hz,2H),6. 79–6.72(m,1H),3.72(d,J=4.8Hz,6H),3.50(q,J=6.9Hz,2H),2.94(s,2H). 13 C NMR (101MHz, DMSO-d6) δ194.01,170.42,166.13,162.29,149.01,147.66,144.01,137.40,137.01,136.67,132.37,131. 41,129.49,128.19,123.73,121.25,121.00,119.79,118.25,112.92,112.24,55.92,55.77,41.64,37.94,35.03,21.83.

[0103] Example 4

[0104] 3-Hydroxy-4-methoxyphenyl-4-(3-(2-hydroxyphenyl)-3-oxopropyl-1-enyl)benzamide, with the following structural formula, is prepared in a similar manner to Example 1, except that the piperoethylamine in step (3) is replaced with 2-methoxy-5-aminophenol.

[0105]

[0106] The obtained inhibitor L4 was a brownish-yellow solid with a yield of 90% and an IC50 value of 100%. 50 The value is 11.99 μM.

[0107] 1H NMR (401MHz, DMSO-d6) δ12.50(s,1H),10.15(s,1H),9.21–9.05(m,1H),8.29(d,J=8.0Hz,1H),8.16(d,J=15.5Hz,1H),8.06(s,4H),7.91(d,J=1 5.5Hz,1H),7.58(t,J=7.7Hz,1H),7.42(d,J=2.5Hz,1H),7.21(dd,J=8.6,2.5Hz,1H),7.03(t,J=7.0Hz,2H),6.91(d,J=8.7Hz,1H),3.78(s,3H). 13 C NMR(101MHz,DMSO-d6)δ194.02,164.84,162.41,146.82,144.80,144.01,137.61,137.28,136.96, 133.07,131.47,129.48,128.65,123.85,121.27,119.72,118.28,112.75,111.93,109.55,56.35.

[0108] Example 5

[0109] (E)-4-(3-(2-hydroxyphenyl)-3-oxopropyl-1-enyl)-N-phenylethylbenzamide, the structural formula of which is as follows, is prepared in a similar manner to Example 1, except that the piperoethylamine in step (3) is replaced with 2-phenylethylamine.

[0110]

[0111] The obtained inhibitor L5 was a pale yellow solid with a yield of 86% and an IC50 value of 100%. 50 The value is 13.29 μM.

[0112] 1 H NMR(501MHz, DMSO-d6)δ12.47(s,1H),8.70(t,J=5.6Hz,1H),8.27(d,J=7.9Hz,1H),8.12(d,J=15.5Hz,1H),8.03–7.81(m,5H), 7.58(t,J=7.7Hz,1H), 7.26(td,J=21.9,20.3,7.2Hz,5H), 7.02(d,J=7.8Hz,2H), 3.53(q,J=6.9Hz,2H), 2.88(t,J=7.5Hz,2H). 13C NMR(126MHz,DMSO-d6)δ194.01,165.99,162.38,144.02,139.98,137.40,136.93,136.71,131 .44,129.47,129.15,128.82,128.17,126.58,123.73,121.26,119.69,118.24,41.45,35.55.

[0113] Example 6

[0114] 4-(3-hydroxyphenyl)-3-oxopropyl-1-en-1-ylbenzamide has the following structural formula. The preparation method is similar to that in Example 1, except that the piperoethylamine in step (3) is replaced with 4-fluorophenylethylamine.

[0115]

[0116] The obtained inhibitor L6 was a pale yellow solid with a yield of 78% and an IC50 value of 100%. 50 The value is 15.59 μM.

[0117] 1 H NMR (401MHz, DMSO-d6) δ12.52(s,1H),8.73(t,J=5.5Hz,1H),8.29(dd,J=8.3,1.7Hz,1H),8.14(d,J=15.6Hz,1H),8.01(d,J=8.1Hz,2H),7.96–7.81 (m,3H),7.68–7.54(m,1H),7.34(td,J=8.0,6.2Hz,1H),7.17–7.07(m,2H) ,7.03(q,J=6.8,6.3Hz,3H),3.56(q,J=6.7Hz,2H),2.91(t,J=7.2Hz,2H). 13 CNMR(101MHz,DMSO-d6)δ194.00,166.07,163.93,162.45,161.52,144.02,143.01,142.94,137.45,136.95,136.64,131.47,130.65 ,130.57,129.51,128.19,126.88,125.38,125.35,123.73,121.25,119.68,118.28,115.99,115.78,113.49,113.29,41.06,35.14.

[0118] Example 7

[0119] 3-Chlorobenzyl-4-(3-hydroxyphenyl)-3-oxopropyl-1-en-1-ylbenzamide has the following structural formula. The preparation method is similar to that in Example 1, except that the piperoethylamine in step (3) is replaced with 3-chlorobenzylamine.

[0120]

[0121] The obtained inhibitor L7 was a yellow solid with a yield of 84% and an IC50 value of 100%. 50 The value is 46.56 μM.

[0122] 1 H NMR(500MHz,Chloroform-d)δ8.76(t,J=5.7Hz,1H),8.08(dd,J=8.1,1.6Hz,1H),7.99–7.93(m,2H),7.75–7.68(m,1H),7.63–7.52( m,3H),7.48–7.38(m,2H),7.34–7.25(m,3H),7.02(dd,J=8.3,1.5Hz,1H),6.97(td,J=8.1,1.5Hz,1H),4.53(dt,J=5.6,0.8Hz,2H). 13 C NMR(126MHz,DMSO-d6)δ194.01,166.13,162.32,143.92,142.63,137.68,136.92,136.18,133.48, 131.45,130.70,129.54,128.32,127.61,127.25,126.46,123.96,121.32,119.70,118.24,42.74.

[0123] Example 8

[0124] (F)-4-(3-(2-hydroxyphenyl)-3-oxopropyl-1-en-1-yl)-N-(4-methoxyphenylethyl)benzamide, the structural formula of which is as follows, is prepared in a similar manner to Example 1, except that the piperoethylamine in step (3) is replaced with 2-(4-methoxyphenyl)ethylamine.

[0125]

[0126] The obtained inhibitor L8 was a pale yellow solid with a yield of 75% and an IC50 value of 100%. 50 The value is 50.25 μM.

[0127] 1H NMR (401MHz, DMSO-d6) δ12.52(s,1H),8.71(t,J=5.5Hz,1H),8.29(dd,J=8.4,1.8Hz,1H),8.14(d,J=15.5Hz,1H),8.05–7.85(m,6H),7.58(td,J=7. 6,1.6Hz,1H),7.22(t,J=8.0Hz,1H),7.03(d,J=7.9Hz,2H),6.87–6.82(m ,2H),3.55(q,J=7.1Hz,3H),2.87(t,J=7.3Hz,2H),2.52(p,J=1.8Hz,1H). 13 CNMR(101MHz,DMSO-d6)δ194.02,166.02,162.45,159.80,144.04,141.59,137.43,136.94,136.75,131.4 6,129.83,129.49,128.21,123.72,121.44,121.26,119.69,118.28,114.77,112.10,55.34,41.40,35.60.

[0128] Example 9

[0129] (E)-4-(3-(2-hydroxyphenyl)-3-oxopropyl-1-en-1-yl)-N-(3,4,5-trimethoxyphenyl)benzamide, the structural formula of which is as follows, is prepared in a similar manner to Example 1, except that the piperoethylamine in step (3) is replaced with 3,4,5-trimethoxyaniline.

[0130]

[0131] The obtained inhibitor L9 was a brownish-yellow solid with a yield of 82% and an IC50 value of 100%. 50 The value is 64.98 μM.

[0132] 1 H NMR (401MHz, DMSO-d6) δ12.48(s,1H),10.27(s,1H),8.32–8.27(m,1H),8.16(d,J=15.5Hz,1H),8.08(s,4H),7. 91(d,J=15.6Hz,1H),7.59(t,J=7.4Hz,1H),7.29(s,2H),7.04(dt,J=7.6,3.3Hz,2H),3.81(s,6H),3.68(s,3H). 13CNMR(101MHz,DMSO-d6)δ194.00,165.07,162.40,153.14,143.89,137.86,136.95,135.6 9,134.36,131.47,129.52,128.63,124.03,121.30,119.71,118.27,98.66,60.62,56.23.

[0133] Example 10

[0134] (E)-5-bromo-N'-(4-(3-(2-hydroxyphenyl)-3-oxopropyl-1-en-1-yl)benzoyl)nicotinamide, the structural formula of which is as follows, is prepared in a similar manner to Example 1, except that the piperoethylamine in step (3) is replaced with 5-bromopyridine-3-carboxylhydrazine.

[0135]

[0136] The obtained inhibitor L10 was a pale yellow solid with a yield of 80% and an IC50 value of 100%. 50 The value is 67.12 μM.

[0137] 1 H NMR (401MHz, DMSO-d6) δ12.43(s,1H),10.84(s,2H),9.08(d,J=1.8Hz,1H),8.95(d,J=2.2Hz,1H),8.51(t,J=2.1Hz,1H),8.27(dd,J =8.3,1.7Hz,1H),8.16(d,J=15.6Hz,1H),8.06(q,J=8.3Hz,4H),7.98–7.87(m,3H),7.63–7.56(m,1H),7.04(dd,J=8.2,5.5Hz,2H). 13 C NMR(101MHz,DMSO-d6)δ193.99,165.71,163.66,162.89,162.31,153.81,147.50,143.72,138.32,138.11 ,137.02,134.24,131.47,130.19,129.68,128.59,124.35,121.32,120.76,119.78,118.27,36.31,31.29.

[0138] The IC50 values ​​of the following four compounds (L1-L4) among the L1-L10 compounds synthesized in the above embodiments are as follows: 50 The values ​​were all low (as shown in Table 1), indicating good α-glucosidase inhibitory activity. Among them, compound L1 showed the best inhibitory effect, with an IC50 value of [missing value].50 The value is 8.26 μM, which is less than that of acarbose (8.36 μM), indicating that it has excellent α-glucosidase inhibitory activity.

[0139] Table 1: Structures and IC50 values ​​of compounds L1-L10 50 value

[0140]

[0141]

[0142] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A chalconeamide α-glucosidase inhibitor, characterized in that, The inhibitor has the chemical structural formula shown in formula (I): (I)， Where Ar is selected from any of the following structural formulas: ， In the above structural formulas, it is indicated that the Ar group is connected to the N phase.

2. The chalconeamide α-glucosidase inhibitor according to claim 1, characterized in that, The inhibitor has one of the following chemical structural formulas: 。 3. A method for preparing a chalconeamide α-glucosidase inhibitor as described in any one of claims 1-2, characterized in that, Specifically, the following steps are included: (1) Add 2-hydroxyacetophenone, sodium hydroxide and methyl p-formylbenzoate to an organic solvent to form a reaction system. After the reaction, the intermediate of formula (a) is obtained by post-treatment. (2) Take the intermediate of formula (a) obtained in step (1) and dissolve it in an organic solvent and potassium hydroxide solution to form a reaction system. After the reaction, the intermediate of formula (b) is obtained by post-treatment. (3) Take the intermediate of formula (b) obtained in step (2) and Ar-NH2, HOBt (1-hydroxybenzotriazole), EDCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride) in an organic solvent to form a reaction system. After the reaction, the chalcone amide inhibitor shown in formula (c) is obtained by post-treatment. The equation for the preparation method is shown below: ； Wherein, the Ar group is as described in either claim 1 or 2.

4. The method for preparing a chalconeamide α-glucosidase inhibitor according to claim 3, characterized in that, In step (1), the reaction temperature is 25-60 ℃, the reaction time is 8-16 h, the sodium hydroxide is prepared into a 30% sodium hydroxide solution using distilled water to make the reaction system alkaline, and the organic solvent is anhydrous methanol. The ratio of the amount of 2-hydroxyacetophenone, sodium hydroxide, methyl paraben, and organic solvent added is (50-80) mmol: (5-10) g: (50-80) mmol: (70-100) mL.

5. The method for preparing a chalconeamide α-glucosidase inhibitor according to claim 3, characterized in that, In step (1), the post-processing process is as follows: the material obtained from the reaction is filtered, the filter cake is washed with distilled water, the filter cake is dried at room temperature to obtain the crude product, and then recrystallized with ethanol to obtain the intermediate of formula (a).

6. The method for preparing a chalconeamide α-glucosidase inhibitor according to claim 3, characterized in that, In step (2), potassium hydroxide is used to make the reaction system alkaline, and anhydrous ethanol is used as the organic solvent; the reaction system is placed at room temperature and the reaction time is 4-6 h. The ratio of the intermediate of formula (a), potassium hydroxide and organic solvent added is 10 mmol: (20-30) mmol: (80-100) mL.

7. The method for preparing a chalconeamide α-glucosidase inhibitor according to claim 3, characterized in that, In step (2), the post-processing process is as follows: the reaction system is neutralized to neutral with 1~2 mol / L hydrochloric acid, stirred at room temperature for 1~3 h to generate a yellow precipitate, the precipitate is filtered under reduced pressure and washed with distilled water, dried at room temperature to obtain the crude product, and then recrystallized with ethanol to obtain the intermediate of formula (b).

8. The method for preparing a chalconeamide α-glucosidase inhibitor according to claim 3, characterized in that, In step (3), the reaction temperature is 20~30℃, the reaction time is 2-6 h, the reaction is carried out under nitrogen protection and the organic solvent is dichloromethane or DMF; The ratio of the intermediate of formula (b), HOBt, EDCl, substituted aniline and organic solvent added is 2 mmol: (4-5) mmol: (4-6) mmol: (3-4) mmol: (10-20) mL.

9. The method for preparing a chalconeamide α-glucosidase inhibitor according to claim 3, characterized in that, In step (3), the post-processing process is as follows: after the reaction is completed, distilled water is added to the system, the precipitate is obtained by stirring, the product is filtered and washed with saturated brine to obtain the crude product, recrystallized with 95% aqueous ethanol, and finally purified by column chromatography to obtain the inhibitor shown in formula (c).

10. The use of a chalconeamide α-glucosidase inhibitor as described in any one of claims 1-2 in the preparation of a medicament capable of inhibiting α-glucosidase activity.

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