Kojic acid triazole derivative with tyrosinase inhibitory activity, alpha-glucosidase inhibitory activity and antioxidant activity

Abstract

The invention discloses an application of a kojic acid triazole derivative in a tyrosinase inhibitor, an alpha-glucosidase inhibitor and an antioxidant. Activity detection results show that the synthesized kojic acid triazole derivative has good tyrosinase inhibitory activity, alpha-glucosidase inhibitory activity and antioxidant activity, and can be used for preparing drugs for treating melanin-related diseases, cosmetic whitening agents, diabetes drugs and food antioxidants. The chemical structural formula of the kojic acid triazole derivative is shown in the specification, wherein R is defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The invention relates to a class of kojic acid triazole derivatives having tyrosinase inhibitory activity, α-glucosidase inhibitory activity and antioxidant activity, and also relates to the application of the compounds in whitening agents, drugs for treating diseases related to melanin, diabetes drugs and food antioxidants. Background Art

[0002] Tyrosinase is a copper-containing oxidase that is widely distributed in microorganisms, animals and plants. It is one of the most important conditions for the synthesis of melanin. In the process of melanin production, tyrosinase catalyzes the oxidation of L-tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), and further oxidizes L-DOPA to o-quinone, ultimately generating melanin. Browning can generally be divided into enzymatic browning and non-enzymatic browning. Tyrosinase inhibitors can prevent enzymatic browning, while antioxidants can prevent non-enzymatic browning. Some tyrosinase inhibitors also have antioxidant properties. Therefore, it is necessary to explore the antioxidant activity and the inhibition of tyrosinase activity together. α-glucosidase is an important hydrolase involved in the sugar metabolism process in the body. It can hydrolyze glucose from polysaccharides and directly affect the blood glucose concentration in the body. Inhibiting α-glucosidase activity is one of the effective strategies for controlling type II diabetes. Studies have shown that the occurrence of melanoma and diabetes is closely related to the imbalance of free radicals in the body. Maintaining the balance between the production and quenching of free radicals in the body can effectively prevent the formation of diabetes and melanoma.

[0003] Due to the wide application of tyrosinase inhibitors in the fields of medicine and food preservation, many scholars at home and abroad are committed to finding efficient, stable and low-toxic tyrosinase inhibitors, including chemically synthesized ones and natural product extracts, and exploring their inhibition kinetics, inhibition mechanisms and related applications. However, so far, no safer and more effective alternatives to tyrosinase inhibitors currently available on the market, such as kojic acid, hydroquinoline, and arbutin, have been found, and kojic acid has recently been restricted in its use due to its carcinogenicity. Therefore, the development of new, efficient and low-toxic tyrosinase inhibitors remains an important research topic in this field.

[0004] At present, there are many types of drugs for the treatment of type II diabetes on the market, including traditional sulfonylureas, biguanides, glinides, thiazolidinediones, α-glucosidase inhibitors, as well as glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase IV (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors that have grown rapidly since 2006. Each type of therapeutic drug has its own characteristics in lowering and controlling blood sugar, and has been widely used in clinical practice. However, they also have more or less shortcomings. Therefore, the development of a new type of anti-type II diabetes drug with high blood sugar reduction and low toxicity and side effects has become an urgent need in the medical community. Summary of the invention

[0005] The purpose of the present invention is to provide a kojic acid triazole derivative having tyrosinase inhibition, α-glucosidase inhibition and antioxidant activity, and application of the derivative in the fields of medicine, cosmetics and food preservation.

[0006] Another object of the present invention is to provide kojic acid triazole derivatives as active ingredients of a pharmaceutical composition, and use of the composition as a tyrosinase inhibitor, an α-glucosidase inhibitor and an antioxidant.

[0007] The present invention is achieved by the following technical scheme: a kojic acid triazole derivative, the structural formula of which is as follows Figure 1 and Figure 2 shown.

[0008] in

[0009] R 1 It is m-methylphenyl, o-methylphenyl, p-fluorophenyl, p-aminophenyl, m-methylbenzyl, o-methylbenzyl, p-fluorophenyl, styrene, and p-chlorostyrene.

[0010] R 2 It is hydrogen, methyl.

[0011] R 3 It is hydrogen, hydroxy, methyl, methoxy, tert-butyl, chlorine, bromine or fluorine.

[0012] The preparation method of a kojic acid triazole derivative, the reaction synthesis route is as follows Figure 3 and Figure 4 shown.

[0013] Figure 3 The specific steps for synthesizing the kojic acid triazole derivatives are as follows:

[0014] (1) Add kojic acid, thionyl chloride and dichloromethane to a reaction flask, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, filter, wash the filter cake with acetone, and dry to obtain a gray solid chlorokojic acid. Add chlorokojic acid and sodium azide to a reaction flask, add DMF, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, add water, extract with ethyl acetate, and back-extract the organic phase with water. Combine the organic phases and add anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure to obtain yellow solid kojic acid hydrazoide.

[0015] (2) Add 2-amino-5-mercapto-1,3,4-thiadiazole, propyne bromide and KOH to a reaction flask, add anhydrous ethanol, heat to 70°C, keep under reflux for reaction, and track the reaction progress with thin layer chromatography. After the reaction is completed, add water, extract with dichloromethane, combine the organic phases, and add anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure to obtain a dark brown solid alkynyl ether compound.

[0016] (3) Add kojic acid azido, acetylene ether compound, sodium ascorbate and copper sulfate pentahydrate into a reaction flask, add THF and water in a ratio of 1:1, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, add water, filter, extract the filtrate with dichloromethane, combine the aqueous phases, and evaporate the solvent under reduced pressure to obtain a yellow solid kojic acid triazole compound.

[0017] (4) Add kojic acid triazole compound, aromatic acids with different substituents, EDCI and HOBT to a reaction bottle, add DMF, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, add water, extract with ethyl acetate, and back-extract the organic phase with water. Combine the organic phases and add anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure, methanol was added to the residue, the mixture was shaken thoroughly, and the mixture was placed in a refrigerator overnight. The crude product was filtered and dried to obtain a crude product. The crude product was separated by preparative chromatography to obtain a kojic acid triazole amide derivative.

[0018] Figure 4 The specific steps for synthesizing the kojic acid triazole derivatives are as follows:

[0019] (1) Add kojic acid, thionyl chloride and dichloromethane to a reaction flask, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, filter, wash the filter cake with acetone, and dry to obtain a gray solid chlorokojic acid. Add chlorokojic acid and sodium azide to a reaction flask, add DMF, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, add water, extract with ethyl acetate, and back-extract the organic phase with water. Combine the organic phases and add anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure to obtain yellow solid kojic acid hydrazoide.

[0020] (2) Add hydroxybenzaldehyde or hydroxyacetophenone with different substituents, propyne bromide and potassium carbonate to a reaction flask, add acetone, raise the temperature to 60°C, keep the temperature under reflux for reaction, and track the reaction progress with thin layer chromatography. After the reaction is completed, filter and evaporate the filtrate under reduced pressure to remove the solvent to obtain a yellow solid alkynyl ether compound.

[0021] (3) Add kojic acid azido, acetylene ether compound, sodium ascorbate and copper sulfate pentahydrate into a reaction flask, add THF and water in a ratio of 1:1, heat to 70°C, keep warm for reaction, and track the reaction progress with thin layer chromatography. After the reaction is completed, add water, filter with suction, add 50% ethanol to the filter cake, stir for 2 hours, filter with suction, and obtain a yellow solid kojic acid triazole phenol ether aldehyde ketone derivative.

[0022] The kojic acid triazole derivatives involved in the present invention can be used to prepare drugs for pigment-related skin diseases, melanoma and Parkinson's disease, and can also be used to prepare cosmetic whitening agents, food preservatives, and diabetes drugs.

[0023] The compounds involved in the present invention have good tyrosinase inhibitory activity, α-glucosidase inhibitory activity and antioxidant activity, have good application prospects, and provide a new development approach for solving whitening cosmetics, medicines, and food preservatives. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is the structure 1 of kojic acid triazole derivative;

[0025] Figure 2 It is the structure 2 of kojic acid triazole derivative;

[0026] Figure 3 It is a synthetic route of kojic acid triazole derivative structure 1;

[0027] Figure 4 yes Figure 3 The synthetic route of kojic acid triazole derivative structure 2; DETAILED DESCRIPTION

[0028] The present invention is further described below by means of synthetic experimental examples and activity experimental examples, but they are not intended to limit the present invention.

[0029] Example 1: Synthesis of N-(5-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-thiadiazol-2-yl)-2-methylbenzamide (QSDZ-1)

[0030] Add 8.52g (60mmol) of kojic acid, 20mL of thionyl chloride and 60mL of dichloromethane to a 250mL reaction bottle, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, filter, wash the filter cake with acetone, and dry to obtain a gray solid chlorokojic acid. Add 8.03g (50mmol) of chlorokojic acid and 3.25g (50mmol) of sodium azide to a reaction bottle, add 60mL of DMF, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, add 60mL of water, extract with ethyl acetate (3×50mL), and then back-extract the organic phase with water (3×30mL). Combine the organic phases and precipitate them with anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure to obtain yellow solid kojic acid hydrazoide.

[0031] 2.664 g (20 mmol) of 2-amino-5-mercapto-1,3,4-thiadiazole, 2.476 g (20 mmol) of bromopropyne and 1.124 g (20 mmol) of KOH were added to a 100 mL reaction bottle, and 60 mL of anhydrous ethanol was added. The temperature was raised to 70 ° C, and the reaction was refluxed. The reaction process was monitored by thin layer chromatography. After the reaction was completed, 60 mL of water was added, and the mixture was extracted with dichloromethane (3 × 50 mL). The organic phases were combined and filtered through anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure to obtain a dark brown solid alkynyl ether compound.

[0032] Add 2.51g (15mmol) of zidazine kojic acid, 2.56g (15mmol) of acetylene ether compound, 0.742g (3.75mmol) of sodium ascorbate and 0.297g (1.2mmol) of copper sulfate pentahydrate into a reaction flask, add 50mL of THF and 50mL of water, stir at room temperature, and track the reaction progress by thin layer chromatography. After the reaction is completed, add 50mL of water, filter with suction, extract the filtrate with dichloromethane (3×50mL), combine the aqueous phases, and evaporate the solvent under reduced pressure to obtain a yellow solid kojic acid triazole compound.

[0033] 0.338 g (1 mmol) of kojic acid triazole compound, 0.163 g (1.2 mmol) of 2-methylbenzoic acid, 0.958 g (5 mmol) of EDCI and 0.162 g (1.2 mmol) of HOBT were added to the reaction bottle, and 10 mL of DMF was added. The mixture was stirred at room temperature and the reaction progress was monitored by thin layer chromatography. After the reaction was completed, 20 mL of water was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic phase was then back-extracted with water (3 × 10 mL). The organic phases were combined and filtered through anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure, 3 mL of methanol was added to the residue and shaken thoroughly, placed in a refrigerator overnight, filtered and dried to obtain a crude product, which was separated by preparative chromatography to obtain a yellow solid with a yield of 28% and a melting point of 162.1-164.5°C.

[0034] IR(KBr,ν / cm -1 )3365,3105,1741,1661,1640,1514,1456,733; 1 H NMR (DMSO-d 6 ,400MHz): δ8.64(s,1H,-OH),8.17(s,1H,=CH),8.00(d,J=7.8Hz,1H,Ph-H),7.59(t,J=7.5 Hz,1H,Ph-H),7.38-7.44(m,2H,Ph-H),7.32(s,2H,=CH),6.57(s,1H,-NH),5.69(s,2H,-CH 2 ),4.39(s,2H,-CH 2 ),2.54(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ157.7,156.4,151.3,150.1,140.2,139.6,135.2,133.0,132.7,127.1,125.9 ,125.1,122.1,121.4,120.1,112.6,60.2,43.5,37.3; MS (ESI): m / z (100%) 457.07 (M+H).

[0035] Example 2: Synthesis of N-(5-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-thiadiazol-2-yl)-3-methylbenzamide (QSDZ-2)

[0036] The preparation method of this embodiment is the same as that of embodiment 1 except that m-toluic acid is used instead of o-toluic acid. A yellow solid is obtained with a yield of 31% and a melting point of 162.8-165.8°C.

[0037] IR(KBr,ν / cm -1 )3367,3111,1740,1665,1640,1514,1468,788,740; 1 H NMR (DMSO-d 6,400MHz): δ8.65(s,1H,-OH),8.17(s,1H,=CH),7.87(d,J=12.3Hz,2H,Ph-H),7.58(d,J=7. 1Hz,1H,Ph-H),7.44-7.53(m,1H,Ph-H),7.32(s,2H,=CH),6.55(s,1H,-NH),5.69(s,2H,-CH 2 ),4.39(s,2H,-CH 2 ),2.40(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ157.6,156.5,150.9,150.2,140.2,139.6,135.2,133.0,131.3,128.5,124.6 ,123.6,122.5,122.1,120.2,112.6,60.2,43.5,37.0; MS (ESI): m / z (100%) 457.07 (M+H).

[0038] Example 3: Synthesis of N-(5-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-thiadiazol-2-yl)-4-fluorobenzamide (QSDZ-3)

[0039] The preparation method of this example is the same as that of Example 1 except that p-fluorobenzoic acid is used instead of o-toluic acid. A yellow solid is obtained with a yield of 26% and a melting point of 230.3-231.9°C.

[0040] IR(KBr,ν / cm -1 )3406,3093,1743,1660,1627,1603,1547,852; 1 H NMR (DMSO-d 6 ,400MHz): δ8.48(s,1H,-OH),8.36(s,1H,=CH),8.09(d,J=8.2Hz,2H,Ph-H),7 .62(d,J=8.3Hz,2H,Ph-H),7.24(s,2H,=CH),6.31(s,1H,-NH),5.57(s,2H,-CH 2 ),4.36(s,2H,-CH 2 ); 13 C NMR (DMSO-d 6,100MHz): δ157.4,156.5,151.5,150.5,140.6,139.6,135.6,133.3,124.2,12 3.7, 122.6, 121.9, 121.0, 113.1, 61.6, 44.0; MS (ESI): m / z (100%) 461.46 (M+H).

[0041] Example 4: Synthesis of N-(5-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-thiadiazol-2-yl)-4-aminobenzamide (QSDZ-4)

[0042] The preparation method of this example is the same as that of Example 1 except that p-aminobenzoic acid is used instead of o-toluic acid. A yellow solid is obtained with a yield of 37% and a melting point of 173.7-174.5°C.

[0043] IR(KBr,ν / cm -1 )3352,3113,1705,1659,1640,1602,1498,846; 1 H NMR (DMSO-d 6 ,400MHz): δ8.50(s,1H,-OH),8.12(s,1H,=CH),7.67(d,J=8.3Hz,2H,Ph-H),7 .29(s,2H,Ph-H),6.56(d,J=8.4Hz,2H,=CH),6.46(s,1H,-NH),6.20(s,2H,-NH 2 ),5.63(s,2H,-CH 2 ),4.34(s,2H,-CH 2 ); 13 C NMR (DMSO-d 6 ,100MHz): δ158.0,156.4,150.8,149.9,144.0,140.1,139.6,135.1,133.1,12 6.1, 120.1, 112.5, 110.8, 110.6, 60.2, 43.5; MS (ESI): m / z (100%) 458.07 (M+H).

[0044] Example 5: Synthesis of N-(5-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-thiadiazol-2-yl)-2-methylphenylacetamide (QSDZ-5)

[0045] The preparation method of this example is the same as that of Example 1 except that o-toluic acid is replaced by o-toluic acid, and a yellow solid is obtained with a yield of 32% and a melting point of 156.0-157.4°C.

[0046] IR(KBr,ν / cm -1 )3328,3136,1760,1673,1642,1548,1494,746; 1 H NMR (DMSO-d 6 ,400MHz): δ8.15(s,1H,-OH),7.32-7.51(m,3H,=CH),7.18-7.30(m,4H,Ph-H),6.69(s,1H,-NH),5.73(s,2H,-CH 2 ),4.66(s,2H,-CH 2 ),3.48(s,2H,-CH 2 ),2.55(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ157.3,156.6,151.3,150.6,140.2,139.6,135.2,133.2,132.7,127.1,126.1,1 25.3, 122.1, 121.4, 120.6, 112.6, 61.3, 43.5, 42.3, 37.6; MS (ESI): m / z (100%) 471.09 (M+H).

[0047] Example 6: Synthesis of N-(5-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-thiadiazol-2-yl)-3-methylphenylacetamide (QSDZ-6)

[0048] The preparation method of this embodiment is the same as that of embodiment 1 except that m-toluic acid is used instead of o-toluic acid. A yellow solid is obtained with a yield of 30% and a melting point of 150.9-152.1°C.

[0049] IR(KBr,ν / cm -1 )3410,3137,1764,1674,1642,1611,1547,796,713; 1 H NMR (DMSO-d 6,400MHz): δ8.27(s,1H,-OH),7.29-7.44(m,3H,=CH),7.12-7.24(m,4H,Ph-H),6.98(s,1H,-NH),5.47(s,2H,-CH 2 ),4.62(s,2H,-CH 2 ),3.57(s,2H,-CH 2 ),2.59(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ157.4,156.0,151.3,149.7,140.4,139.6,135.5,133.2,132.6,127.1,126.2,1 25.3, 122.1, 121.7, 120.3, 113.0, 62.0, 42.6, 42.3, 37.4; MS (ESI): m / z (100%) 471.09 (M+H).

[0050] Example 7: Synthesis of N-(5-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-thiadiazol-2-yl)-4-fluorophenylacetamide (QSDZ-7)

[0051] The preparation method of this example is the same as that of Example 1 except that p-fluorophenylacetic acid is used instead of o-toluic acid. A yellow solid is obtained with a yield of 25% and a melting point of 159.1-160.2°C.

[0052] IR(KBr,ν / cm -1 )3409,3138,1766,1675,1640,1547,1511,825; 1 H NMR (DMSO-d 6 ,400MHz): δ8.39(s,1H,-OH),7.75(d,J=4.2Hz,4H,Ph-H),7.13-7.56(m,3H,=CH),6.69(s,1H,-NH),5.65(s,2H,-CH 2 ),4.34(s,2H,-CH 2 ),3.81(s,2H,-CH 2 ); 13 C NMR (DMSO-d 6,100MHz): δ157.9,156.5,152.4,150.4,142.0,140.3,134.5,133.4,124.2,123.4 ,122.3,121.9,121.0,112.4,63.4,42.2,41.6; MS (ESI): m / z (100%) 475.49 (M+H).

[0053] Example 8: Synthesis of N-(5-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-thiadiazol-2-yl)cinnamamide (QSDZ-8)

[0054] The preparation method of this embodiment is the same as that of embodiment 1 except that cinnamic acid is used instead of o-toluic acid to obtain a yellow solid with a yield of 20% and a melting point of 233.3-236.7°C.

[0055] Example 9: Synthesis of N-(5-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-1,3,4-thiadiazol-2-yl)-4-chlorocinnamamide (QSDZ-9)

[0056] The preparation method of this example is the same as that of Example 1 except that p-chlorocinnamic acid is used instead of o-toluic acid to obtain a yellow solid with a yield of 17% and a melting point of 241.9-247.5°C.

[0057] Example 10: Synthesis of 2-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (QSDZ-10)

[0058] Add 8.52g (60mmol) of kojic acid, 20mL of thionyl chloride and 60mL of dichloromethane to a 250mL reaction bottle, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, filter, wash the filter cake with acetone, and dry to obtain a gray solid chlorokojic acid. Add 8.03g (50mmol) of chlorokojic acid and 3.25g (50mmol) of sodium azide to a reaction bottle, add 60mL of DMF, stir at room temperature, and track the reaction progress with thin layer chromatography. After the reaction is completed, add 60mL of water, extract with ethyl acetate (3×50mL), and then back-extract the organic phase with water (3×30mL). Combine the organic phases and precipitate them with anhydrous MgSO 4 After drying, the solvent was evaporated under reduced pressure to obtain yellow solid kojic acid hydrazoide.

[0059] 0.224 g (2 mmol) of 2-hydroxybenzaldehyde, 0.833 g (7 mmol) of propyne bromide and 0.415 g (3 mmol) of potassium carbonate were added to a reaction flask, 15 mL of acetone was added, the temperature was raised to 60°C, the reaction was refluxed and the reaction process was monitored by thin layer chromatography. After the reaction was completed, the filtrate was filtered and the solvent was evaporated under reduced pressure to obtain a yellow solid alkynyl ether compound.

[0060] Add 0.334g (2mmol) of zidazine kojic acid, 0.320g (1.8mmol) of acetylene ether compound, 0.099g (0.5mmol) of sodium ascorbate and 0.04g (0.16mmol) of copper sulfate pentahydrate into a reaction flask, add 10mL of THF and 10mL of water, heat to 70°C, keep warm for reaction, and track the reaction progress with thin layer chromatography. After the reaction is completed, add 40mL of water, filter with suction, add 6mL of 50% ethanol to the filter cake, stir for 2h, filter with suction, and obtain a yellow solid with a yield of 53% and a melting point of 179.9-181.2°C.

[0061] IR(KBr,ν / cm -1 )3417,3151,2922,1687,1651,1597,1483,770; 1 H NMR (DMSO-d 6 ,400MHz): δ10.32(s,1H,-OH),9.29(s,1H,=CH),8.41(s,1H,=CH),8.03(s,1H,=CH),7.66(dd,J=16.7,7.5 Hz,2H,Ph-H),7.42(d,J=8.1Hz,1H,Ph-H),7.09(t,J=6.9Hz,1H,Ph-H),6.39(s,1H,-CHO),5.60(s,2H,-CH 2 ),5.35(s,2H,-CH 2 ); 13 C NMR (DMSO-d 6 ,100MHz): δ171.7,159.3,148.8,148.6,137.2,134.7,132.4,129.5,122.5,12 0.8, 120.0, 117.4, 111.8, 110.9, 70.1, 60.4; MS (ESI): m / z (100%) 328.09 (M+H).

[0062] Example 11: Synthesis of 3-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (QSDZ-11)

[0063] The preparation method of this embodiment is the same as that of embodiment 10 except that m-hydroxybenzaldehyde is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 60% and a melting point of 159.8-165.9°C.

[0064] IR(KBr,ν / cm -1 )3264,3137,2738,1695,1655,1585,1489,794,681; 1 H NMR (DMSO-d 6 ,400MHz): δ9.94(s,1H,-OH),9.27(s,1H,=CH),8.32(s,1H,=CH),8.02(s,1H,=CH), 7.44-7.58(m,3H,Ph-H),7.28-7.40(m,1H,Ph-H),6.36(s,1H,-CHO),5.58(s,2H,-CH 2 ),5.22(s,2H,-CH 2 ); 13 C NMR (DMSO-d 6 ,100MHz): δ174.7,159.3,148.8,147.2,137.2,134.6,132.4,130.5,124.7,12 0.8, 118.6, 117.6, 111.7, 110.8, 69.3, 60.4; MS (ESI): m / z (100%) 328.09 (M+H).

[0065] Example 12: Synthesis of 4-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)benzaldehyde (QSDZ-12)

[0066] The preparation method of this embodiment is the same as that of embodiment 10 except that p-hydroxybenzaldehyde is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 57% and a melting point of 174.3-175.1°C.

[0067] IR(KBr,ν / cm -1 )3403,3244,2922,1697,1655,1578,1453,849; 1 H NMR (DMSO-d 6,400MHz): δ9.83(s,1H,-OH),9.28(s,1H,=CH),8.35(s,1H,=CH),8.02(s,1H,=CH),7.8 4(d,J=8.1Hz,2H,Ph-H),7.20(d,J=8.1Hz,2H,Ph-H),6.37(s,1H,-CHO),5.58(s,2H,-CH 2 ),5.26(s,2H,-CH 2 ); 13 C NMR (DMSO-d 6 ,100MHz): δ173.5,159.3,150.7,148.8,137.2,134.4,132.4,125.8,124.3,121.0,112.5,110.9,69.4,60.4; MS (ESI): m / z (100%) 328.09 (M+H).

[0068] Example 13: Synthesis of 2-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-methylbenzaldehyde (QSDZ-13)

[0069] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-4-methylbenzaldehyde is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 73% and a melting point of 179.8-180.6°C.

[0070] IR(KBr,ν / cm -1 )3417,3151,2922,1687,1651,1597,1483,884,770; 1 H NMR (DMSO-d 6 ,400MHz): δ10.24(s,1H,-OH),9.30(s,1H,=CH),8.41(s,1H,=CH),8.03(s,1H,=CH),7.57(d,J=7. 2Hz,1H,Ph-H),7.24(s,1H,Ph-H),6.90(d,J=7.1Hz,1H,Ph-H),6.39(s,1H,-CHO),5.61(s,2H,-CH 2 ),5.32(s,2H,-CH 2 ),2.36(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6,100MHz): δ175.1,163.1,152.6,152.5,142.2,141.0,138.5,136.2,126.3,124.6 ,122.0,121.9,115.8,114.7,73.8,64.2,41.6; MS (ESI): m / z (100%) 342.10 (M+H).

[0071] Example 14: Synthesis of 2-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-5-methylbenzaldehyde (QSDZ-14)

[0072] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-5-methylbenzaldehyde is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 68% and a melting point of 151.6-152.1°C.

[0073] IR(KBr,ν / cm -1 )3321,2923,2853,1687,1648,1603,1497,882,803; 1 H NMR (DMSO-d 6 ,400MHz): δ10.27(s,1H,-OH),9.33(s,1H,=CH),8.37(s,1H,=CH),8.01(s,1H,=CH),7.4 5(d,J=7.5Hz,2H,Ph-H),7.29(d,J=8.9Hz,1H,Ph-H),6.38(s,1H,-CHO),5.59(s,2H,-CH 2 ),5.30(s,2H,-CH 2 ),2.24(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ175.6,163.1,152.6,150.9,141.0,138.5,136.2,133.7,128.4,126.2 ,124.6,123.6,115.7,114.6,73.9,64.2,40.0; MS (ESI): m / z (100%) 342.10 (M+H).

[0074] Example 15: Synthesis of 2-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-chlorobenzaldehyde (QSDZ-15)

[0075] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-4-chlorobenzaldehyde is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 78% and a melting point of 182.7-183.9°C.

[0076] IR(KBr,ν / cm -1 )3409,3144,2923,1681,1651,1592,1483,875,800; 1 H NMR (DMSO-d 6 ,400MHz): δ10.99(s,1H,-OH),9.19(s,1H,=CH),8.47(s,1H,=CH),7.74(s,1H,=CH),7.4 3(s,1H,Ph-H),7.15(s,1H,Ph-H),7.06(s,1H,Ph-H),6.13(s,1H,-CHO),5.50(s,2H,-CH 2 ),5.32(s,2H,-CH 2 ); 13 C NMR (DMSO-d 6 ,100MHz): δ171.0,159.3,149.0,148.8,137.3,134.3,133.0,132.4,123.9,12 0.9, 119.1, 117.6, 112.2, 110.9, 70.4, 60.4; MS (ESI): m / z (100%) 362.05 (M+H).

[0077] Example 16: Synthesis of 2-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-bromobenzaldehyde (QSDZ-16)

[0078] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-4-bromobenzaldehyde is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 81% and a melting point of 201.3-202.9°C.

[0079] IR(KBr,ν / cm -1 )3401,3175,2922,1681,1651,1588,1481,875,798; 1 H NMR (DMSO-d 6,400MHz): δ11.21(s,1H,-OH),9.30(s,1H,=CH),8.44(s,1H,=CH),7.69(s,1H,=CH),7.4 8(s,1H,Ph-H),7.21(s,1H,Ph-H),6.85(s,1H,Ph-H),6.19(s,1H,-CHO),5.63(s,2H,-CH 2 ),5.36(s,2H,-CH 2 ); 13 C NMR (DMSO-d 6 ,100MHz): δ172.3,159.6,150.2,148.3,137.5,134.7,134.0,132.6,123.9,12 1.9, 120.2, 117.6, 111.8, 110.6, 71.0, 61.3; MS (ESI): m / z (100%) 407.19 (M+H).

[0080] Example 17: Synthesis of 2-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-fluorobenzaldehyde (QSDZ-17)

[0081] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-4-fluorobenzaldehyde is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 80% and a melting point of 172.3-173.1°C.

[0082] IR(KBr,ν / cm -1 )3405,3113,2923,1682,1652,1594,1496,875,802; 1 H NMR (DMSO-d 6 ,400MHz): δ10.20(s,1H,-OH),9.31(s,1H,=CH),8.43(s,1H,=CH),8.03(s,1H,=CH),7.75(t,J=7.7Hz, 1H,Ph-H),7.37(d,J=11.3Hz,1H,Ph-H),6.94(d,J=7.9Hz,1H,Ph-H),6.39(s,1H,-CHO),5.61(s,2H,-CH 2 ),5.37(s,2H,-CH 2 ); 13 C NMR (DMSO-d 6,100MHz): δ170.6,159.3,154.9,152.9,150.1,148.8,137.2,132.4,124.8,12 4.7, 121.0, 117.6, 107.3, 102.3, 70.4, 60.4; MS (ESI): m / z (100%) 346.29 (M+H).

[0083] Example 18: Synthesis of 2-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-4-methoxybenzaldehyde (QSDZ-18)

[0084] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-4-methoxybenzaldehyde is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 84% and a melting point of 193.3-195.1°C.

[0085] IR(KBr,ν / cm -1 )3410,3136,2836,1657,1631,1604,1499,893,802; 1 H NMR (DMSO-d 6 ,400MHz): δ10.14(s,1H,-OH),9.30(s,1H,=CH),8.42(s,1H,=CH),8.03(s,1H,=CH),7.65(d,J=8. 0Hz,1H,Ph-H),6.91(s,1H,Ph-H),6.65(d,J=7.9Hz,1H,Ph-H),6.39(s,1H,-CHO),5.61(s,2H,-CH 2 ),5.35(s,2H,-CH 2 ),3.85(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ174.0,163.1,156.9,153.9,152.6,141.0,138.4,136.2,127.9,124.6 ,118.9,114.7,110.1,103.9,73.9,68.9,64.2; MS (ESI): m / z (100%) 358.32 (M+H).

[0086] Example 19: Synthesis of 2-((1-((5-hydroxy-4-oxo-4H-pyran-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-3-tert-butylbenzaldehyde (QSDZ-19)

[0087] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-3-tert-butylbenzaldehyde is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 53% and a melting point of 179.8-180.9°C.

[0088] IR(KBr,ν / cm -1 )3366,3154,2885,1683,1654,1593,1487,863,802; 1 H NMR (DMSO-d 6 ,400MHz): δ9.25(s,1H,-OH),8.43(s,1H,=CH),7.75(s,1H,=CH),7.43(s,1H,=CH),7.1 1(t,J=5.8Hz,2H,Ph-H),6.78(t,J=6.1Hz,1H,Ph-H),6.11(s,1H,-CHO),5.50(s,2H,-CH 2 ),5.05(s,2H,-CH 2 ),2.07(s,9H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ172.7,159.3,148.8,148.7,137.2,135.2,134.5,132.4,127.3,124.2,1 22.9, 121.0, 119.9, 110.9, 77.1, 60.4, 48.3, 45.0; MS (ESI): m / z (100%) 384.15 (M+H).

[0089] Example 20: Synthesis of 2-((4-((2-acetylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-20)

[0090] The preparation method of this example is the same as that of Example 10 except that o-hydroxyacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 67% and a melting point of 165.6-168.8°C.

[0091] IR(KBr,ν / cm -1 )3405,3204,1671,1646,1617,1593,1448,760; 1 H NMR (DMSO-d 6,400MHz): δ8.43(s,1H,-OH),7.68(s,1H,=CH),7.41(s,1H,=CH),7.01(dd,J=13.3,6.1Hz,2H,P h-H),6.85(d,J=6.6Hz,1H,Ph-H),6.60(t,J=5.9Hz,1H,Ph-H),6.07(s,1H,=CH),5.48(s,2H,-CH 2 ),5.23(s,2H,-CH 2 ),2.94(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ179.5,159.3,148.9,146.1,137.2,134.7,132.5,127.4,124.0,123.0 ,120.8,117.1,111.5,110.8,69.8,60.4,45.7; MS (ESI): m / z (100%) 342.10 (M+H).

[0092] Example 21: Synthesis of 2-((4-((3-acetylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-21)

[0093] The preparation method of this example is the same as that of Example 10 except that m-hydroxyacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 75% and a melting point of 165.2-167.0°C.

[0094] IR(KBr,ν / cm -1 )3411,3152,1679,1654,1615,1593,1487,791,700; 1 H NMR (DMSO-d 6 ,400MHz): δ9.28(s,1H,-OH),8.32(s,1H,=CH),8.02(s,1H,=CH),7.52(s,2H,Ph-H),7. 42(d,J=7.1Hz,1H,Ph-H),7.27(d,J=6.9Hz,1H,Ph-H),6.36(s,1H,=CH),5.58(s,2H,-CH 2 ),5.21(s,2H,-CH 2 ),2.53(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6,100MHz): δ178.5,159.3,148.8,146.9,137.2,134.7,132.4,131.0,124.3,120.8 ,117.2,116.2,111.4,110.8,69.3,60.4,41.9; MS (ESI): m / z (100%) 342.10 (M+H).

[0095] Example 22: Synthesis of 2-((4-((4-acetylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-22)

[0096] The preparation method of this example is the same as that of Example 10 except that p-hydroxyacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 80% and a melting point of 184.1-188.3°C.

[0097] IR(KBr,ν / cm -1 )3399,3083,1677,1654,1609,1579,1456,835; 1 H NMR (DMSO-d 6 ,400MHz): δ9.28(s,1H,-OH),8.34(s,1H,=CH),8.02(s,1H,=CH),7.89(d,J=8 .6Hz,2H,Ph-H),7.11(d,J=8.6Hz,2H,Ph-H),6.37(s,1H,=CH),5.58(s,2H,-CH 2 ),5.23(s,2H,-CH 2 ),2.48(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ177.4,159.3,149.8,148.8,137.2,134.5,132.4,124.7,124.5 ,120.9,112.0,110.9,69.3,60.4,41.5; MS (ESI): m / z (100%) 342.10 (M+H).

[0098] Example 23: Synthesis of 2-((4-((2-acetyl-5-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-23)

[0099] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-4-methylacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 83% and a melting point of 203.7-205.0°C.

[0100] IR(KBr,ν / cm -1 )3423,3236,1667,1645,1617,1512,1494,873,813; 1 H NMR (DMSO-d 6 ,400MHz): δ9.30(s,1H,-OH),8.37(s,1H,=CH),8.03(s,1H,=CH),7.49(d,J=7.8Hz,1H, Ph-H),7.17(s,1H,Ph-H),6.83(d,J=7.8Hz,1H,Ph-H),6.35(s,1H,=CH),5.62(s,2H,-CH 2 ),5.29(s,2H,-CH 2 ),2.41(s,3H,-CH 3 ),2.33(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ178.7,159.3,148.9,146.4,137.2,136.1,134.7,132.4,124.2,120.8,1 20.7, 117.7, 111.8, 110.7, 69.8, 60.4, 45.8, 37.5; MS (ESI): m / z (100%) 356.12 (M+H).

[0101] Example 24: Synthesis of 2-((4-((2-acetyl-4-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-24)

[0102] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-5-methylacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 86% and a melting point of 185.5-188.2°C.

[0103] IR(KBr,ν / cm -1 )3245,3148,1668,1648,1619,1586,1493,877,808; 1 H NMR (DMSO-d 6,400MHz): δ9.24(s,1H,-OH),8.32(s,1H,=CH),8.00(s,1H,=CH),7.31(d,J=12 .5Hz,2H,Ph-H),7.21(d,J=8.3Hz,1H,Ph-H),6.32(s,1H,=CH),5.58(s,2H,-CH 2 ),5.24(s,2H,-CH 2 ),2.45(s,3H,-CH 3 ),2.21(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ179.5,159.2,148.9,144.5,137.2,134.7,132.4,127.6,124.2,124.1,1 22.8, 120.7, 111.6, 110.7, 69.9, 60.3, 45.7, 36.3; MS (ESI): m / z (100%) 356.12 (M+H).

[0104] Example 25: Synthesis of 2-((4-((4-acetyl-2-methylphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-25)

[0105] The preparation method of this example is the same as that of Example 10 except that 4-hydroxy-3-methylacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 85% and a melting point of 177.2-178.9°C.

[0106] IR(KBr,ν / cm -1 )3345,3177,1669,1635,1600,1578,1505,877,811; 1 H NMR (DMSO-d 6 ,400MHz): δ9.28(s,1H,-OH),8.33(s,1H,=CH),8.02(s,1H,=CH),7.79(d,J=8.5Hz,1H, Ph-H),7.73(s,1H,Ph-H),7.21(d,J=8.6Hz,1H,Ph-H),6.36(s,1H,=CH),5.58(s,1H,-CH 2 ),5.25(s,2H,-CH 2 ),2.46(s,3H,-CH 3 ),2.12(s,3H,-CH 3 );13 C NMR (DMSO-d 6 ,100MHz): δ177.6,159.3,148.8,148.4,137.2,134.8,132.4,124.9,124.2,123.1,1 21.3, 120.7, 110.8, 109.4, 69.6, 60.4, 41.5, 33.2; MS (ESI): m / z (100%) 356.12 (M+H).

[0107] Example 26: Synthesis of 2-((4-((2-acetyl-5-chlorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-26)

[0108] The preparation method of this example is the same as that of Example 10 except that 2'-hydroxy-4'-chloroacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 90% and a melting point of 197.4-199.5°C.

[0109] IR(KBr,ν / cm -1 )3246,3098,1662,1628,1590,1563,1481,908,811; 1 H NMR (DMSO-d 6 ,400MHz): δ8.47(s,1H,-OH),7.74(s,1H,=CH),7.46(s,1H,=CH),7.06(d,J=27.5Hz,2H,Ph-H),6.72(s,1H,Ph-H),6.12(s,1H,=CH),5.53(s,2H,-CH 2 ),5.32(s,2H,-CH 2 ),2.98(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ178.5,159.3,148.9,146.7,137.2,134.3,132.4,130.9,125.3,121.9 ,120.9,117.2,111.9,110.8,70.2,60.4,45.7; MS (ESI): m / z (100%) 376.76 (M+H).

[0110] Example 27: Synthesis of 2-((4-((2-acetyl-5-bromophenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-27)

[0111] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-4-bromoacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 94% and a melting point of 194.6-195.7°C.

[0112] IR(KBr,ν / cm -1 )3265,3148,1651,1627,1610,1582,1468,893,834; 1 H NMR (DMSO-d 6 ,400MHz): δ9.29(s,1H,-OH),8.37(s,1H,=CH),8.03(s,1H,=CH),7.60(s,1H,Ph-H),7. 49(d,J=8.1Hz,1H,Ph-H),7.23(d,J=8.0Hz,1H,Ph-H),6.36(s,1H,=CH),5.62(s,2H,-CH 2 ),5.35(s,2H,-CH 2 ),2.41(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ146.5,128.0,125.9,124.8,121.8,119.8,119.8,118.5,117.0,117.0 ,114.4,107.2,105.0,104.8,67.2,61.7,47.3; MS (ESI): m / z (100%) 421.22 (M+H).

[0113] Example 28: Synthesis of 2-((4-((2-acetyl-5-fluorophenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-28)

[0114] The preparation method of this example is the same as that of Example 10 except that 2'-hydroxy-4'-fluoroacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 89% and a melting point of 178.5-179.9°C.

[0115] IR(KBr,ν / cm -1 )3265,3145,1648,1618,1586,1526,1492,875,804; 1 H NMR (DMSO-d 6,400MHz): δ9.31(s,1H,-OH),8.39(s,1H,=CH),8.03(s,1H,=CH),7.66(t,J=7.6Hz,1H,Ph-H) ,7.29(d,J=10.8Hz,1H,Ph-H),6.87(t,J=7.6Hz,1H,Ph-H),6.35(s,1H,=CH),5.62(s,2H,-CH 2 ),5.33(s,2H,-CH 2 ),2.41(s,3H,-CH 3 ); 13 C NMR (DMSO-d 6 ,100MHz): δ178.1,159.3,151.7,147.6,137.2,134.3,133.7,132.4,126.1,121.0 ,120.1,110.8,106.8,101.7,70.2,60.4,45.7; MS (ESI): m / z (100%) 360.31 (M+H).

[0116] Example 29: Synthesis of 2-((4-((2-acetyl-5-methoxyphenoxy)methyl)-1H-1,2,3-triazol-1-yl)methyl)-5-hydroxy-4H-pyran-4-one (QSDZ-29)

[0117] The preparation method of this example is the same as that of Example 10 except that 2-hydroxy-4-methoxyacetophenone is used instead of o-hydroxybenzaldehyde. A yellow solid is obtained with a yield of 95% and a melting point of 168.1-170.5°C.

[0118] IR(KBr,ν / cm -1 )3288,3056,1667,1644,1606,1500,1443,879,825; 1 H NMR (DMSO-d 6 ,400MHz): δ8.42(s,1H,-OH),7.68(s,1H,=CH),7.41(s,1H,=CH),7.09(d,J=6.9Hz,1H, Ph-H),6.46(s,1H,Ph-H),6.26(d,J=7.0Hz,1H,Ph-H),6.06(s,1H,=CH),5.48(s,2H,-CH 2 ),5.24(s,2H,-CH 2 ),47.04(s,3H,-CH 3 ),2.89(s,3H,-CH 3 ); 13C NMR (DMSO-d 6 ,100MHz): δ177.5,159.3,151.7,148.9,148.0,137.2,134.6,132.4,125.8,120.8,1 16.9, 110.7, 105.6, 100.2, 69.9, 64.9, 60.4, 45.8; MS (ESI): m / z (100%) 372.11 (M+H).

[0119] Example 30: Tyrosinase Inhibitory Activity Test

[0120] Add 168μL 0.05mol / L pH=6.8 phosphate buffer, 2μL sample solution, 10μL enzyme solution to a total of 200μL test system, incubate at 37℃ for 10min, add 20μL Dopa solution, perform time scan at 475nm, and record the OD value for one minute. Change the dosage of the sample solution and test the enzyme catalytic activity respectively. The concentration of the sample can be changed by dilution. The OD / min value of the enzyme catalytic activity without adding the sample is 100%, and the inhibition percentage (the percentage of inhibition and loss of activity) is used to represent the inhibitory activity of samples of different concentrations on the enzyme. The calculation formula for the inhibition rate is as follows:

[0121] Inhibition rate (%) = [(BS) / B] × 100

[0122] Where B is the blank absorbance and S is the sample absorbance.

[0123] The tyrosinase inhibition activity of the target product obtained by the above method is shown in the following table:

[0124]

[0125] From the above table, we can see that, except for QSDZ-1 and QSDZ-2, the kojic acid triazole derivatives inhibited tyrosinase activity better than kojic acid, among which the compound QSDZ-29 had the best inhibitory effect, IC 50 The value is 1.363 μM.

[0126] Example 31: α-Glucosidase Inhibitory Activity Test

[0127] 20 μL α-glucosidase (0.2 U / mL), 2 μL samples of different concentrations and 118 μL PBS solution (0.05 mol / L, PH=6.8) were added to the test system of 200 μL in total, incubated at 37°C for 15 min, and then 20 μL pNPG (2.5 mM) was added to react at 37°C for 15 min, and finally 40 μL sodium carbonate solution (0.2 mol / L) was added to terminate the reaction, and the absorbance was measured at 405 nm, with acarbose as the positive control, and the average value of the three groups was taken. The calculation formula of the inhibition rate is as follows:

[0128]

[0129] The inhibitory α-glucosidase activity of the target product obtained by the above method is as follows:

[0130]

[0131] As shown in the table above, some kojic acid triazole derivatives inhibited α-glucosidase activity better than acarbose, among which compound QSDZ-7 had the best inhibitory effect, IC 50 The value is 18.38μM.

[0132] Example 32: Antioxidant Activity Test

[0133] DPPH method: Add 5 μL of the sample of different concentrations and 95 μL of DPPH solution (50 mg / L) to a 96-well plate, shake at 120 rpm for 6 min at 37°C in the dark, and then keep warm for 30 min. Measure the absorbance A at 517 nm. 1 Under the same conditions, the absorbance of 95 μL 75% ethanol was used instead of DPPH solution. 2 Measure the absorbance A of a mixed solution of 5 μL 75% ethanol solution and 95 μL DDPPH 0 Ascorbic acid was used as a positive control, and the results were repeated three times to obtain the average value. The calculation formula for the scavenging ability of the sample for DPPH free radicals is as follows:

[0134]

[0135] ABTS method: The sample addition method is similar to the DPPH method, and the absorbance is measured at 734nm. Ascorbic acid is used as a positive control, and the average value is obtained by repeating three groups.

[0136] The antioxidant activity of the target product obtained by the above method is as follows:

[0137]

[0138] As shown in the table above, some kojic acid triazole derivatives have better antioxidant activity than ascorbic acid, among which compound QSDZ-25 has the best antioxidant effect. The IC values ​​of DPPH and ABTS are 50 The values ​​were 31.18 μM and 19.6 μM, respectively.

[0139] The invention provides that the kojic acid triazole derivatives have good tyrosinase inhibitory activity, good α-glucosidase inhibitory activity and antioxidant activity, and have good application prospects.

Claims

1. The kojic acid triazole derivatives shown in formula I and II have strong tyrosinase inhibition activity and can be used to prepare drugs for treating melanin-related diseases. in R 1 It is m-methylphenyl, o-methylphenyl, p-fluorophenyl, p-aminophenyl, m-methylbenzyl, o-methylbenzyl, p-fluorophenyl, styrene, and p-chlorostyrene. R 2 It is hydrogen, methyl. R 3 It is hydrogen, hydroxy, methyl, methoxy, tert-butyl, chlorine, bromine or fluorine.

2. The compound of claim 1 has a strong effect of inhibiting tyrosinase activity and can be used to prepare whitening cosmetics with tyrosinase inhibitory effect.

3. The compound of claim 1 has a strong effect of inhibiting the activity of α-glucosidase and can be used to prepare a diabetes drug with the effect of inhibiting α-glucosidase.

4. The compound of claim 1 has strong antioxidant activity and can be used to prepare food antioxidants with antioxidant activity.

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