Curcumol derivatives containing triazole structure, synthesis method and application thereof in preparing anti-inflammatory drugs

Abstract

The present invention provides a curcumin derivative containing a triazole structure, a synthesis method and its application in the preparation of anti-inflammatory drugs, and belongs to the technical field of pharmaceutical chemistry. The present invention obtains a plurality of curcumin derivatives containing a triazole structure by modifying the 8-hydroxyl group and the 10-double bond structure of curcumin. The synthesis method of the curcumin derivative containing a triazole structure disclosed in the present invention is simple, the reaction conditions are mild, and it is easy to operate. In addition, the raw materials are easily available during the synthesis process, the production cost is low, and it is suitable for industrial production and application. In vitro cell experiments show that the curcumin derivative containing a triazole structure exhibits good anti-inflammatory biological activity. In vivo studies have shown that compound h1 has a therapeutic effect on acute lung injury. At a dose of 5 mg / kg, it can improve LPS-induced acute lung injury and reduce lung inflammation, providing a clue for the development of specific anti-acute lung injury drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of medicinal chemistry and relates to a curcuminol derivative containing a triazole structure, a synthesis method and an application thereof in the preparation of anti-inflammatory drugs. Background Art

[0002] Acute lung injury (ALI) is an inflammatory disease characterized by damage to alveolar epithelial and vascular endothelial cells, often accompanied by non-cardiogenic pulmonary edema and hypoxemia. In severe cases, it can progress to acute respiratory distress syndrome (ARDS), with a mortality rate as high as 40%. Current clinical treatment relies primarily on glucocorticoids and mechanical ventilation support. However, glucocorticoids lack specificity, and long-term use can easily lead to side effects such as immunosuppression and metabolic disorders. Existing anti-inflammatory drugs (such as dexamethasone) have limited regulatory effects on key inflammatory targets and are subject to drug resistance and toxicity issues. Therefore, the development of novel, highly effective, low-toxic drugs that target key inflammatory pathways is urgently needed for the treatment of ALI. Summary of the Invention

[0003] The purpose of the present invention is to provide a curcuminol derivative containing a triazole structure, a synthesis method and its use in the preparation of anti-inflammatory drugs. The curcuminol derivative containing a triazole structure of the present invention exhibits good anti-inflammatory activity on RAW264.7 cells, especially the curcuminol derivative h1 has a therapeutic effect on acute lung injury at an effective dose, revealing the mechanism of action and molecular target of the curcuminol derivative h1 in treating acute lung injury.

[0004] To achieve the above object, the present invention provides the following technical solutions:

[0005] The curcuminol derivative containing a triazole structure has a structure shown in the following formula (ai):

[0006] In formula (ai), R is selected from benzyl, p-benzoyl, ethanol, o-benzoyl, o-benzyl alcohol, methyl acetate, p-anisole, ethyl acetate, ethylene glycol-1-methyl ether-2-ethyl ether, ethylene glycol monoethyl ether, propanol, acetate, and propionate.

[0007] Preferably, the curcumol derivative containing a triazole structure is selected from any one of the compounds represented by formula a1-a10, b1-b6, c1-c3, d1, e1-e5, f1-f7, g1-g9, h1, and i1:

[0008]

[0009] The present invention also provides a method for synthesizing the above-mentioned curcuminol derivatives containing a triazole structure. When the curcuminol derivatives are compounds a1-a10 and b1-b6, the synthetic route is:

[0010] The synthesis method comprises the following steps:

[0011] Curcumol and NaH were mixed in dimethylformamide and stirred at room temperature for 0.5 h. Then, 2 equivalents of halogenated alkyne were added and stirred at room temperature for 3 h. After the reaction, the reaction was quenched with water and extracted with ethyl acetate. The upper layer was recovered and separated and purified to obtain yellow oily intermediates a and b. In a reaction flask, intermediates a and b, azide, copper sulfate pentahydrate, and sodium ascorbate were added in sequence and dissolved in dichloromethane solvent. The mixture was stirred at room temperature to react. After the reaction, the reaction was quenched with water and extracted with dichloromethane. The lower layer was recovered and separated and purified to obtain products a1-a10 and b1-b6.

[0012] Furthermore, when the curcumol derivative is compound c1-c3, the synthetic route is:

[0013] The synthesis method comprises the following steps:

[0014] Curcumol derivative G1 was mixed with NaHCO3 in dimethylformamide and stirred at room temperature for 0.5 h. Then, 1 equivalent of propargyl bromide was added and stirred at room temperature for 3 h. After the reaction, the reaction was quenched with water and extracted with ethyl acetate. The upper layer was recovered and separated and purified to obtain a yellow oily intermediate c. In a reaction flask, intermediate c, azide compound, copper sulfate pentahydrate, and sodium ascorbate were added in sequence and dissolved in dichloromethane solvent. The mixture was stirred at room temperature to react. After the reaction, the reaction was quenched with water and extracted with dichloromethane. The lower layer was recovered and separated and purified to obtain products c1-c3.

[0015] Furthermore, when the curcumol derivative is compound d1, the synthetic route is:

[0016] The synthesis method comprises the following steps:

[0017] Curcumol derivative G1 was mixed with NaH in dimethylformamide and stirred at room temperature for 0.5 h. Then, propargyl bromide was added and stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with water and extracted with ethyl acetate. The upper layer was recovered and separated and purified to obtain a yellow oily intermediate product d. In a reaction flask, intermediate d, 2-azidobenzyl alcohol, copper sulfate pentahydrate, and sodium ascorbate were added in sequence and dissolved in dichloromethane solvent. The mixture was stirred at room temperature to react. After the reaction was completed, the reaction was quenched with water and extracted with dichloromethane. The lower layer was recovered and separated and purified to obtain product d1.

[0018] Furthermore, when the curcumol derivative is compound e1-e5, f1-f7, g1-g9, i1, the synthetic route is:

[0019] The synthesis method comprises the following steps:

[0020] Alkynyl acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were dissolved in CH2Cl2 and stirred at room temperature for 0.5 h. Then, curcuminol derivative G1 and 4-dimethylaminopyridine were added to the reaction system and continued to stir at room temperature for 3 h. After the reaction was completed, the reaction was quenched with water, extracted with CH2Cl2, and the lower layer was recovered. After separation and purification, yellow oily intermediates e, f, g, and i were obtained. In the reaction flask, the intermediate, azide compound, copper sulfate pentahydrate, and sodium ascorbate were added in sequence and dissolved in dichloromethane solvent. The mixture was stirred at room temperature to react. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, and the lower layer was recovered. After separation and purification, products e1-e5, f1-f7, g1-g9, and i1 were obtained.

[0021] Furthermore, when the curcumol derivative is compound h1, the synthetic route is:

[0022] The synthesis method comprises the following steps:

[0023] The intermediate product g was dissolved in tetrahydrofuran, and the air in the reaction apparatus was evacuated and the reaction apparatus was filled with nitrogen. Ethylmagnesium bromide was added, and the mixture was refluxed at 55°C for 30 min. Succinic anhydride was then added, and the mixture was refluxed at 75°C for 4 h. Water was added to stop the reaction, and the pH was adjusted to 4 with hydrochloric acid. After extraction with ethyl acetate, the upper layer was purified by silica gel column chromatography to obtain a yellow oily substance h. In a reaction flask, the intermediate h, benzyl azide, copper sulfate pentahydrate, and sodium ascorbate were added in sequence and dissolved in dichloromethane solvent. The mixture was stirred at room temperature to react. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, and the lower layer was recovered. After separation and purification, the product h1 was obtained.

[0024] The present invention also provides the use of the above-mentioned curcumol derivative containing a triazole structure in the preparation of anti-inflammatory drugs.

[0025] Preferably, the anti-inflammatory drug can inhibit the inflammatory response of M1 macrophages.

[0026] Preferably, the application includes the application of the curcuminol derivative h1 in the preparation of a drug for improving acute lung injury, and the structural formula of the curcuminol derivative h1 is as follows: .

[0027] More preferably, the curcumin derivative h1 can significantly inhibit the expression of inflammatory factors IFN-γ and IL-17A; the curcumin derivative h1 exerts an anti-acute lung injury effect by inhibiting the activation of NLRP3 inflammasome.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] The present invention obtains multiple curcuminol derivatives containing a triazole structure by modifying the 8-hydroxyl group and the 12-double bond structure of curcumin. In vitro cell experiments show that the curcuminol derivatives containing a triazole structure exhibit good anti-inflammatory activity against RAW264.7 cells, can be used to treat or prevent inflammatory diseases, and have good application prospects.

[0030] The synthesis method of the curcumol derivative containing a triazole structure disclosed in the present invention is simple, the reaction conditions are mild, and the operation is easy. In addition, the raw materials are readily available during the synthesis process, the production cost is low, and the curcumol derivative is suitable for industrial production and application.

[0031] The curcumol derivative h1 obtained in this study can improve LPS-induced acute lung injury and reduce lung inflammation at a dose of 5 mg / kg. Molecular docking, surface plasmon resonance (SPR), and Western blot experiments confirmed that curcumol derivative h1 exerts its anti-inflammatory effects primarily by inhibiting activation of the NLRP3 inflammasome. NLRP3 is a direct target of curcumol derivative h1. This study demonstrates the potential of curcumol derivative h1 as a lead compound and provides insights into the development of specific anti-ALI drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 is the H NMR spectrum of the curcumol derivative h1 obtained in Example 8;

[0033] Figure 2 is the C NMR spectrum of the curcumol derivative h1 obtained in Example 8;

[0034] Figure 3 This is the high-resolution mass spectrum of the curcumol derivative h1 obtained in Example 8;

[0035] Figure 4 Figure A is the molecular docking model of curcuminol derivative h1 and NLRP3, and Figure B is the 2D interaction diagram of curcuminol derivative h1 and NLRP3;

[0036] Figure 5 The experimental results of Western blot (WB) in Application Example 3 are shown;

[0037] Figure 6 This is the experimental result of surface plasmon resonance (SPR) in application example 4. DETAILED DESCRIPTION

[0038] The present invention will be described in detail below with reference to specific embodiments. The following specific embodiments will help those skilled in the art to further understand the present invention, but will not limit the present invention in any form.

[0039] Example 1: Synthesis of curcumol derivatives a1-a10 containing triazole structure

[0040]

[0041] Curcumol (0.2 mmol) and NaH (0.2 mmol) were mixed in 2 mL of dimethylformamide and stirred at room temperature for 0.5 h. Two equivalents of propargyl bromide were then added, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored by thin-layer chromatography (TLC). After completion, the reaction was quenched with 10 mL of water and extracted three times with ethyl acetate. The upper layer was recovered and purified by silica gel column chromatography or preparative thin-layer chromatography to obtain intermediate a as a yellow oil in a 70% yield. To a reaction flask, intermediate a (0.2 mmol), azide (0.2 mmol), copper sulfate pentahydrate (0.02 mmol), and sodium ascorbate (0.02 mmol) were added sequentially and dissolved in 2 mL of solvent (CH₂Cl₂:H₂O 3:1). The mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction, the reaction was quenched with 10 mL of water and extracted three times with dichloromethane. The lower layer was recovered and separated and purified by silica gel column chromatography or preparative thin layer chromatography to obtain products a1-a10 in a yield of 80-85%.

[0042] Compound a1: 11H NMR (500 MHz, CDCl3) δ 7.45 (s, 1H, H-18), 7.36 (s, 3H), 7.26 (d, J = 2.8 Hz, 2H), 5.51 (d, J = 3.2 Hz, 2H), 4.85 (d, J = 9.8 Hz, 3H), 4.79 (d, J = 12.4 Hz, 1H), 2.50 (q, J = 14.8 Hz, 2H), 2.16 (t, J = 10.3 Hz, 1H), 2.07 (t, J = 12.3 Hz, 1H), 1.88 (tq, J = 17.2, 9.9 Hz, 3H), 1.73 – 1.60 (m, 3H), 1.44 – 1.36 (m, 1H), 1.18 – 1.12 (m, 1H), 0.94 – 0.91 (m, 3H), 0.91 – 0.86 (m, 3H), 0.84 (t, J = 4.3 Hz, 3H).

[0043] 13 13C NMR (125 MHz, CDCl3) δ 145.12, 129.08, 128.70, 128.14, 122.37, 112.78, 107.42, 87.57, 55.78, 54.72, 54.19, 48.98, 39.48, 38.22, 34.33, 31.05, 28.70, 28.33, 23.05, 21.08, 12.31.

[0044] HRMS (ESI): Calcd for C 25 H 34 N3O2 (M + H): 408.2651; found: 408.2690.

[0045] Compound a2: 11H NMR (600 MHz, CDCl3) δ 8.25 (d, J = 8.3 Hz, 2H), 8.05 (s,1H), 7.87 (d, J = 8.3 Hz, 2H,), 5.02 (d, J = 12.6 Hz, 1H), 4.93 – 4.85 (m,3H), 2.65 (d, J = 14.9 Hz, 1H), 2.56 (d, J = 14.8 Hz, 1H), 2.25 – 2.18 (m,1H), 2.14 (t, J = 12.4 Hz, 1H), 1.98-1.89 (m, 3H), 1.78-1.69 (m, 3H), 1.48(d, J = 11.0 Hz, 1H), 1.24 – 1.18 (m, 1H), 1.00 (dd, J = 11.9, 6.5 Hz, 6H),0.89 (d, J = 6.5 Hz, 3H).

[0046] 13 13C NMR (150 MHz, CDCl3) δ 169.25, 148.00, 144.89, 140.78, 131.95,129.13, 120.34, 119.88, 113.04, 107.60, 87.85, 55.76, 54.75, 49.05, 39.51,38.23, 34.33, 31.10, 28.73, 28.34, 23.07, 21.15, 12.38.

[0047] HRMS (ESI): Calcd for C 25 H 32 N3O4 (M + H): 438.2393; found: 438.2394.

[0048] Compound a3: 11H NMR (600 MHz, CDCl3) δ 7.65 (s, 1H), 4.92 – 4.85 (m, 3H), 4.79 (d, J = 12.2 Hz, 1H), 4.47 (s, 2H), 4.07 (s, 2H), 2.61 – 2.46 (m, 2H), 2.19 (t, J = 10.0 Hz, 1H), 2.09 (t, J = 12.2 Hz, 1H), 1.98 – 1.84 (m, 3H,), 1.77 – 1.63 (m, 3H), 1.51 – 1.42 (m, 1H), 1.19 (dd, J = 11.9, 6.1 Hz, 1H), 0.96 (dd, J = 21.3, 5.8 Hz, 6H), 0.86 (d, J = 5.7 Hz, 3H).

[0049] 13 13C NMR (150 MHz, CDCl3) δ 145.08, 123.57, 112.86, 107.42, 87.63, 61.28, 55.66, 54.74, 52.56, 49.04, 39.51, 38.19, 34.34, 31.10, 28.72, 28.35, 23.07, 21.13, 12.35.

[0050] HRMS (ESI): Calcd for C 20 H 32 N3O3 (M + H): 362.2444; found: 362.2463.

[0051] Compound a4: 11H NMR (600 MHz, CDCl3) δ 8.06 (d, J = 7.7 Hz, 1H), 7.85 (s,1H), 7.67 (t, J = 7.7 Hz, 1H), 7.59 (t, J = 7.6 Hz), 7.48 (d, J = 7.8 Hz),4.98 (d, J = 12.3 Hz, 1H), 4.93 – 4.83 (m, 3H), 2.60 (d, J = 14.8 Hz, 1H),2.53 (d, J = 14.7 Hz, 1H), 2.22 – 2.16 (m, 1H), 2.11 (t, J = 12.3 Hz, 1H),1.98 – 1.84 (m, 3H), 1.78 – 1.62 (m, 3H), 1.51 – 1.41 (m, 1H), 1.20 (dd, J =12.4, 6.4 Hz, 1H), 0.98 (dd, J = 17.7, 6.5 Hz, 6H), 0.87 (d, J = 6.5 Hz, 3H).

[0052] 13 13C NMR (150 MHz, CDCl3) δ 168.61, 145.05, 132.79, 131.68, 129.82,126.71, 112.90, 107.56, 87.76, 55.59, 54.75, 49.04, 39.52, 38.18, 34.35,31.07, 28.74, 28.34, 23.07, 21.15, 12.36.

[0053] HRMS (ESI): Calcd for C 25 H 32 N3O4 (M + H): 438.2393; found: 438.1973.

[0054] Compound a5: 11H NMR (600 MHz, CDCl3) δ 7.92 (s, 1H), 7.63 (dd, J = 7.3, 1.8 Hz, 1H), 7.49 (dtd, J = 17.5, 7.5, 1.6 Hz, 2H), 7.38 (dd, J = 7.6, 1.6 Hz, 1H), 5.01 (d, J = 12.4 Hz, 1H), 4.94 – 4.85 (m, 3H), 4.48 (s, 2H), 2.65 – 2.51 (m, 2H), 2.21 (dd, J = 11.3, 8.8 Hz, 1H), 2.13 (t, J = 12.4 Hz, 1H), 1.99 – 1.88 (m, 3H), 1.72 (m, J = 25.3, 12.6, 7.4, 2.9 Hz, 3H), 1.48 (dtd, J = 11.6, 8.4, 4.3 Hz, 1H), 1.22 (dd, J = 12.4, 6.5 Hz, 1H), 0.99 (dd, J = 15.3, 6.5 Hz, 6H), 0.89 (d, J = 6.4 Hz, 3H).

[0055] 13 13C NMR (150 MHz, CDCl3) δ 147.14, 144.98, 136.16, 135.74, 131.59, 129.84, 129.05, 124.28, 123.76, 112.96, 107.52, 87.75, 61.92, 55.�0, 54.75, 49.19, 39.52, 38.21, 34.36, 31.12, 28.73, 28.37, 23.07, 21.18, 12.38.

[0056] HRMS (ESI): Calcd for C 25 H 34 N3O3 (M + H): 424.2600; found: 424.2618.

[0057] Compound a6: 11H NMR (600 MHz, CDCl3) δ 7.67 (s, 1H), 5.16 (d, J = 2.0 Hz, 2H), 4.95 – 4.79 (m, 4H), 3.81 (s, 3H), 2.61 – 2.47 (m, 2H), 2.19 (dd, J = 11.4, 8.8 Hz, 1H), 2.10 (t, J = 12.4 Hz, 1H), 1.99 – 1.85 (m, 3H), 1.76 – 1.64 (m, 3H), 1.47 (tdd, J = 11.4, 8.2, 3.5 Hz, 1H), 1.20 (dd, J = 12.5, 6.4 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H).

[0058] 13 13C NMR (150 MHz, CDCl3) δ 166.72, 147.23, 145.15, 123.67, 112.80, 107.41, 87.63, 55.74, 54.75, 52.96, 50.72, 49.14, 39.53, 38.17, 34.36, 31.09, 28.72, 28.36, 23.06, 21.13, 12.32.

[0059] HRMS (ESI): Calcd for C 21 H 32 N3O4 (M + H): 390.2393; found: 390.2396.

[0060] Compound a7: 11H NMR (600 MHz, CDCl3) δ 7.41 (s, 1H), 7.23 (d, J = 8.5 Hz, 2H), 6.91 – 6.87 (m, 2H), 5.44 (d, J = 2.4 Hz, 2H), 4.88 – 4.81 (m, 3H), 4.77 (d, J = 12.4 Hz, 1H), 3.81 (d, J = 0.9 Hz, 3H), 2.50 (q, J = 14.8 Hz, 2H), 2.16 (dd, J = 11.3, 8.9 Hz, 1H), 2.07 (t, J = 12.3 Hz, 1H), 1.95 – 1.81 (m, 3H), 1.73 – 1.60 (m, 3H), 1.44 – 1.36 (m, 1H), 1.17 (dd, J = 12.4, 6.4 Hz, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H).

[0061] 13 13C NMR (150 MHz, CDCl3) δ 159.91, 146.91, 145.13, 129.71, 126.69, 122.14, 114.45, 112.78, 107.41, 87.5, 55.77, 55.34, 54.72, 53.71, 48.93, 39.48, 38.24, 34.32, 31.05, 28.70, 28.33, 23.06, 21.08, 12.31.

[0062] HRMS (ESI): Calcd for C 26 H 36 N3O3 (M + H): 438.2757; found: 438.2876.

[0063] Compound a8: 11H NMR (600 MHz, CDCl3) δ 7.67 (s, 1H), 5.14 (d, J = 2.3 Hz, 2H), 4.93 (d, J = 12.4 Hz, 1H), 4.87 (d, J = 2.7 Hz, 2H), 4.82 (d, J = 12.4 Hz, 1H), 4.27 (q, J = 7.2 Hz, 2H), 2.60 – 2.48 (m, 2H), 2.22 – 2.16 (m, 1H), 2.12 – 2.04 (m, 1H), 1.97 – 1.84 (m, 3H), 1.77 – 1.63 (m, 3H), 1.48 (dt, J = 11.8, 8.3 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.20 (dd, J = 12.4, 6.5 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H).

[0064] 13 13C NMR (150 MHz, CDClz) δ 166.29, 145.17, 123.07, 112.81, 107.41, 87.05, 62.36, 55.74, 54.75, 50.89, 49.07, 39.53, 38.19, 34.36, 31.08, 28.73, 28.36, 23.08, 21.14, 14.07, 12.34.

[0065] HRMS (ESI): Calcd for C 22 H 34 N3O4(M + H): 404.2549; found: 404.2549.

[0066] Compound a9: 11H NMR (600 MHz, CDCl3) δ 7.70 (s, 1H), 4.95 – 4.84 (m, 3H), 4.80 (d, J = 12.2 Hz, 1H), 4.54 (t, J = 5.2 Hz, 2H), 3.87 (t, J = 5.2 Hz, 2H), 3.63 – 3.56 (m, 2H), 3.56 – 3.47 (m, 2H), 3.37 (s, 3H), 2.58 (dp, J = 14.9, 2.1 Hz, 1H), 2.50 (d, J = 14.7 Hz, 1H), 2.19 (dd, J = 11.3, 8.8 Hz, 1H), 2.10 (t, J = 12.3 Hz, 1H), 1.99 – 1.86 (m, 3H), 1.77 – 1.64 (m, 3H), 1.48 (tdd, J = 11.3, 8.2, 3.5 Hz, 1H), 1.19 (dd, J = 12.4, 6.4 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.86 (d, J = 6.4 Hz, 3H).

[0067] 13 13C NMR (150 MHz, CDCl3) δ 146.38, 145.20, 123.57, 112.77, 107.39, 87.56, 71.77, 70.58, 69.60, 59.05, 55.73, 54.75, 50.20, 49.02, 40.05, 38.21, 34.36, 31.09, 28.73, 28.35, 23.09, 21.13, 12.35.

[0068] HRMS (ESI): Calcd for C 23 H 38 N3O4 (M + H): 420.2862; found: 420.2866.

[0069] Compound a10: 1H NMR (600 MHz, CDCl3) δ 7.69 (s, 1H), 4.94 – 4.85 (m, 3H), 4.80 (d, J = 12.2 Hz, 1H), 4.54 (t, J = 5.1 Hz, 2H), 3.89 (t, J = 5.1 Hz, 2H), 3.70 (dd, J = 5.3, 3.7 Hz, 2H), 3.56 (dd, J = 5.2, 3.8 Hz, 2H), 2.61 –2.46 (m, 2H), 2.19 (dd, J = 11.3, 8.8 Hz, 1H), 2.14 – 2.01 (m, 1H), 2.00 –1.84 (m, 3H), 1.71 (dtdd, J = 25.0, 12.8, 6.9, 2.5 Hz, 3H), 1.47 (tdd, J =11.5, 8.3, 3.5 Hz, 1H), 1.20 (dd, J = 12.4, 6.4 Hz, 1H), 0.99 (d, J = 6.6 Hz,3H), 0.93 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H).

[0070] 13 C NMR (150 MHz, CDCl3) δ 146.40, 145.06, 123.50, 112.86, 107.43,87.62, 72.56, 69.39, 61.61, 55.67, 54.72, 50.22, 49.06, 39.50, 38.21, 34.33,31.08, 28.70, 28.33, 23.07, 21.11, 12.35.

[0071] HRMS (ESI): Calcd for C 22 H 36 N3O4 (M + H): 406.2706; found: 406.2724.

[0072] Example 2: Synthesis of curcumol derivatives b1-b6 containing triazole structure

[0073]

[0074] Curcumol (0.2 mmol) and NaH (0.2 mmol) were mixed in 2 mL of dimethylformamide and stirred at room temperature for 0.5 h. Two equivalents of iodopentyne were then added, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After completion, the reaction was quenched with 10 mL of water and extracted three times with ethyl acetate. The upper layer was recovered and purified by silica gel column chromatography or preparative thin-layer chromatography to obtain intermediate b as a yellow oil in 70% yield. To a reaction flask, intermediate b (0.2 mmol), azide (0.2 mmol), copper sulfate pentahydrate (0.02 mmol), and sodium ascorbate (0.02 mmol) were added sequentially and dissolved in 2 mL of a solvent (CH₂Cl₂:H₂O₃:1). The mixture was stirred at room temperature and the reaction progress was monitored by TLC. After completion, the reaction was quenched with 10 mL of water and extracted three times with dichloromethane. The lower layer was recovered and purified by silica gel column chromatography or preparative thin-layer chromatography to obtain products b1-b6 in 80-85% yields.

[0075] Compound b1: 1 H NMR (600 MHz, CDCl3) δ 7.76 (s, 1H), 7.62 (dd, J = 7.5,1.7 Hz, 1H), 7.56 – 7.40 (m, 2H), 7.36 (d, J = 7.6 Hz, 1H), 4.85 (d, J = 2.6Hz, 2H), 4.46 (s, 2H), 3.76 (dt, J = 9.4, 6.3 Hz, 1H), 3.63 (dt, J = 9.3, 6.0Hz, 1H), 2.94 (td, J = 7.4, 3.6 Hz, 2H), 2.58 – 2.40 (m, 2H), 2.16 (dd, J =11.4, 8.7 Hz, 1H), 2.06 – 1.97 (m, 3H), 1.94 – 1.79 (m, 3H ), 1.75 – 1.61 (m,3H), 1.38 (dtd, J = 11.6, 8.4, 4.3 Hz, 1H), 1.16 (dd, J = 12.4, 6.4 Hz, 1H), 0.96 (d, J = 6.4 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H).

[0076] 1313C NMR (150 MHz, CDCl3) δ 148.22, 145.41, 136.24, 135.71, 131.51, 129.70, 128.97, 124.26, 122.61, 112.58, 107.12, 87.20, 61.88, 59.74, 54.76, 48.88, 39.46, 38.11, 34.37, 31.03, 29.55, 28.74, 28.35, 23.12, 22.27, 21.12, 12.29.

[0077] HRMS (ESI): Calcd for C 27 H 38 N3O3 (M + H): 452.2913; found: 452.2981.

[0078] Compound b2: 1 1H NMR (600 MHz, CDCl3) δ 7.46 (s, 1H), 4.85 (d, J = 2.5 Hz, 2H), 4.47 – 4.39 (m, 2H), 4.05 (t, J = 5.0 Hz, 2H), 3.71 (dt, J = 9.3, 6.3 Hz, 1H), 3.57 (dt, J = 9.3, 6.1 Hz, 1H), 2.78 (td, J = 7.4, 5.1 Hz, 2H), 2.56 – 2.40 (m, 2H,), 2.16 (dd, J = 11.3, 8.8 Hz, 1H), 2.03 (t, J = 12.3 Hz, 1H), 1.97 – 1.84 (m, 3H), 1.84 – 1.76 (m, 2H), 1.75 – 1.61 (m, 3H), 1.45 (tdd, J = 11.7, 8.5, 3.5 Hz, 1H), 1.15 (dd, J = 12.4, 6.4 Hz, 1H), 0.95 (t, J = 6.2 Hz, 6H), 0.85 (d, J = 6.4 Hz, 3H).

[0079] 1313C NMR (150 MHz, CDCl3) δ 147.7, 145.45, 122.24, 112.54, 107.10, 87.18, 61.13, 59.94, 54.77, 52.52, 48.87, 39.50, 38.08, 34.37, 31.11, 29.71, 28.73, 28.35, 23.11, 22.30, 21.10, 12.33.

[0080] HRMS (ESI): Calcd for C 22 H 36 N3O3 (M + H): 390.2757; found: 390.2797.

[0081] Compound b3: 1 1H NMR (600 MHz, CDCl3) δ 7.49 (s, 1H), 5.12 (d, J = 2.5 Hz, 2H), 4.85 (d, J = 2.6 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.73 (dt, J = 9.2, 6.3 Hz, 1H), 3.59 (dt, J = 9.2, 6.0 Hz, 1H), 2.85 (td, J = 7.4, 2.4 Hz, 2H), 2.60 – 2.40 (m, 2H), 2.16 (dd, J = 11.4, 8.8 Hz, 1H), 2.03 (t, J = 12.3 Hz, 1H), 1.95 (q, J = 6.9 Hz, 3H), 1.92 – 1.76 (m, 3H), 1.74 – 1.60 (m, 3H), 1.45 (tdd, J = 11.9, 8.5, 3.6 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.15 (dd, J = 12.4, 6.4 Hz, 1H), 0.95 (dd, J = 6.6, 4.2 Hz, 6H), 0.85 (d, J = 6.4 Hz, 3H).

[0082] 1313C NMR (150 MHz, CDCl3) δ 166.41, 148.41, 145.53, 122.35, 112.49, 107.09, 87.16, 61.97, 59.89, 54.78, 50.81, 48.97, 39.50, 38.04, 34.38, 31.13, 29.68, 28.74, 28.34, 23.11, 22.37, 21.10, 14.06, 12.34.

[0083] HRMS (ESI): Calcd for C 24 H 38 N3O4 (M + H): 432.2862; found: 432.2398.

[0084] Compound b4: 1 1H NMR (600 MHz, CDCl3) δ 7.49 (s, 1H), 5.14 (d, J = 2.2 Hz, 2H), 4.85 (d, J = 2.5 Hz, 2H), 3.80 (s, 3H), 3.73 (dt, J = 9.4, 6.3 Hz, 1H), 3.59 (dt, J = 9.4, 6.1 Hz, 1H), 2.85 (td, J = 7.3, 2.3 Hz, 2H), 2.58 – 2.40 (m, 2H), 2.16 (dd, J = 11.4, 8.7 Hz, 1H), 2.08 – 1.96 (m, 2H), 1.96 – 1.86 (m, 3H), 1.86 – 1.75 (m, 2H), 1.68 (dddd, J = 25.4, 16.9, 12.0, 7.6 Hz, 3H), 1.44 (tdd, J = 11.8, 8.5, 3.5 Hz, 1H), 1.16 (dd, J = 12.4, 6.4 Hz, 1H), 0.95 (dd, J = 6.5, 3.9 Hz, 6H), 0.85 (d, J = 6.4 Hz, 3H).

[0085] 1313C NMR (150 MHz, CDCl3) δ 166.87, 148.46, 145.51, 122.34, 112.48, 107.08, 87.15, 59.88, 54.77, 52.91, 50.63, 48.98, 39.50, 38.03, 34.38, 31.13, 29.65, 28.73, 28.34, 23.10, 22.36, 21.09, 12.33.

[0086] HRMS (ESI): Calcd for C 23 H 36 N3O4 (M + H): 418.2706; found: 418.2746.

[0087] Compound b5: 1 1H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 7.1 Hz, 3H), 7.26 (s, 3H), 5.54 – 5.43 (m, 2H), 4.83 (d, J = 2.6 Hz, 2H), 3.69 (dt, J = 9.4, 6.3 Hz, 1H), 3.55 (dt, J = 9.4, 6.2 Hz, 1H), 2.80 (dd, J = 8.6, 6.6 Hz, 2H), 2.53 – 2.35 (m, 2H), 2.14 (dd, J = 11.3, 8.8 Hz, 1H), 2.01 (t, J = 12.3 Hz, 1H), 1.90 (dq, J = 15.2, 7.9, 7.3 Hz, 3H), 1.86 – 1.72 (m, 2H), 1.72 – 1.59 (m, 3H), 1.42 (tdd, J = 11.6, 8.5, 3.6 Hz, 1H), 1.13 (dd, J = 12.4, 6.4 Hz, 1H), 0.92 (dd, J = 13.9, 6.5 Hz, 6H), 0.83 (d, J = 6.4 Hz, 3H).

[0088] 1313C NMR (150 MHz, CDCl3) δ 148.42, 145.53, 134.94, 129.06, 128.6, 127.95, 120.93, 112.49, 107.05, 87.12, 59.95, 54.77, 48.83, 39.50, 38.06, 34.38, 31.11, 29.71, 28.72, 28.34, 23.12, 22.42, 21.09, 12.35.

[0089] HRMS (ESI): Calcd for C 27 H 36 N3O2(M - H): 434.2964; found: 434.2398.

[0090] Compound b6: 1 1H NMR (600 MHz, CDCl3) δ 7.69 (s, 1H), 4.94 – 4.85 (m, 3H), 4.80 (d, J = 12.2 Hz, 1H), 4.54 (t, J = 5.1 Hz, 2H), 3.89 (t, J = 5.1 Hz, 2H), 3.70 (dd, J = 5.3, 3.7 Hz, 2H), 3.56 (dd, J = 5.2, 3.8 Hz, 2H), 2.61 – 2.46 (m, 2H), 2.19 (dd, J = 11.3, 8.8 Hz, 1H), 2.14 – 2.01 (m, 1H), 2.00 – 1.84 (m, 3H), 1.71 (dtdd, J = 25.0, 12.8, 6.9, 2.5 Hz, 3H), 1.47 (tdd, J = 11.5, 8.3, 3.5 Hz, 1H), 1.20 (dd, J = 12.4, 6.4 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H).

[0091] 13C NMR (150 MHz, CDCl3) δ 148.43, 145.53, 134.94, 129.07, 128.63,127.96, 120.94, 112.51, 107.05, 87.13, 59.95, 54.77, 54.05, 48.80, 39.50,38.08, 34.38, 31.11, 29.71, 28.73, 28.34, 23.13, 22.43, 21.09, 12.36.

[0092] HRMS (ESI): Calcd for C 28 H40N3O4 (M + H): 466.6406; found: 466.6424.

[0093] Example 3: Synthesis of Curcumol Derivatives C1-C3 Containing Triazole Structure

[0094]

[0095] Curcumol derivative G1 (0.2 mmol) and NaHCO₃ (0.2 mmol) were mixed in 2 mL of dimethylformamide and stirred at room temperature for 0.5 h. One equivalent of propargyl bromide was then added, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After completion, the reaction was quenched with 10 mL of water and extracted three times with ethyl acetate. The upper layer was recovered and purified by silica gel column chromatography or preparative thin-layer chromatography to obtain intermediate c as a yellow oil in 60% yield. To a reaction flask, intermediate c (0.2 mmol), azide (0.2 mmol), copper sulfate pentahydrate (0.02 mmol), and sodium ascorbate (0.02 mmol) were added sequentially and dissolved in 2 mL of solvent (CH₂Cl₂:H₂O 3:1). The mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction, quench the reaction with 10 mL of water and extract with dichloromethane three times. Recover the lower layer and separate and purify it by silica gel column chromatography or preparative thin layer chromatography to obtain products c1-c3 with a yield of 80-85%.

[0096] Compound c1: 11H NMR (600 MHz, CDCl3) δ 7.47 (s, 1H), 7.36 (d, J = 6.7 Hz, 3H), 7.28 (d, J = 6.6 Hz, 2H), 5.85 (s, 1H), 5.49 (s, 2H), 4.81 (q, J = 12.8 Hz, 2H), 4.12 – 4.03 (m, 2H), 2.14 (t, J = 11.8 Hz, 2H), 1.99 (t, J = 8.5 Hz), 1.90 – 1.81 (m, 3H), 1.55 – 1.39 (m, 3H), 1.24 – 1.19 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H), 0.84 (d, J = 6.5 Hz, 3H).

[0097] 13 13C NMR (150 MHz, CDCl3) δ 146.90, 145.05, 134.64, 129.08, 128.69, 128.14, 122.78, 122.57, 106.92, 86.88, 64.44, 58.23, 55.99, 54.14, 49.48, 40.16, 36.11, 31.34, 30.78, 27.77, 22.59, 21.15, 11.76.

[0098] HRMS (ESI): Calcd for C 25 H 34 N3O3 (M + H): 424.2600; found: 424.2592.

[0099] Compound c2: 11H NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 7.62 (dd, J = 7.4, 1.7 Hz, 1H), 7.48 (dtd, J = 20.0, 7.5, 1.6 Hz, 2H), 7.36 (dd, J = 7.7, 1.5 Hz, 1H), 5.91 (q, J = 1.6 Hz, 1H), 4.99 – 4.86 (m, 2H), 4.47 (s, 2H), 4.16 – 4.04 (m, 2H), 2.19 (dd, J = 12.6, 10.9 Hz, 1H), 2.06 – 1.96 (m, 1H), 1.94 – 1.81 (m, 4H), 1.58 – 1.45 (m, 3H), 1.31 – 1.21 (m, 1H), 0.98 (dd, J = 18.5, 6.5 Hz, 6H), 0.87 (d, J = 6.5 Hz, 3H).

[0100] 13 13C NMR (150 MHz, CDCl3) δ 146.94, 145.26, 136.07, 135.71, 131.51, 129.89, 129.05, 124.34, 124.05, 122.62, 107.02, 87.05, 64.44, 61.79, 58.11, 56.14, 49.54, 40.19, 36.16, 31.41, 30.81, 27.83, 22.59, 21.24, 11.82.

[0101] HRMS (ESI): Calcd for C 25 H 34 N3O4 (M + H): 440.2549; found: 440.2563.

[0102] Compound c3: 1H NMR (600 MHz, CDCl3) δ 7.42 (s, 1H), 7.25 – 7.17 (m, 2H), 6.91 – 6.82 (m, 2H,), 5.84 (q, J = 1.5 Hz, 1H), 5.42 (s, 2H), 4.85 – 4.74 (m,2H), 4.13 – 4.01 (m, 2H), 3.80 (s, 3H), 2.14 (dd, J = 12.7, 11.0 Hz, 1H), 1.98 (d, J = 9.0 Hz, 1H), 1.84 (tddd, J = 24.8, 15.2, 10.0, 2.5 Hz, 4H), 1.54– 1.39 (m, 3H), 1.22 (dt, J = 12.6, 6.7 Hz, 1H), 0.90 (dd, J = 13.5, 6.5 Hz, 6H), 0.84 (d, J = 6.5 Hz, 3H).

[0103] 13 C NMR (150 MHz, CDCl3) δ 159.91, 146.76, 144.96, 129.75, 126.60,122.93, 122.35, 114.46, 106.88, 86.84, 64.51, 58.21, 55.91 55.35, 53.72,49.47, 40.16, 36.11, 31.34), 30.80, 27.76, 22.58, 21.14, 11.75.

[0104] HRMS (ESI): Calcd for C 26 H 36 N3O4 (M + H): 454.2706; found: 454.2717.

[0105] Example 4: Synthesis of curcumol derivative d1 containing a triazole structure

[0106]

[0107] Curcumol derivative G1 (0.2 mmol) and NaH (0.2 mmol) were mixed in 2 mL of dimethylformamide and stirred at room temperature for 0.5 h. Two equivalents of propargyl bromide (0.3 mmol) were then added, and the mixture was stirred at room temperature for 3 h. The reaction progress was monitored by TLC. After completion, the reaction was quenched with 10 mL of water and extracted three times with ethyl acetate. The upper layer was recovered and purified by silica gel column chromatography or preparative thin-layer chromatography to obtain intermediate d as a yellow oil in a 70% yield. To a reaction flask, intermediate d (0.2 mmol), 2-azidobenzyl alcohol (0.2 mmol), copper sulfate pentahydrate (0.02 mmol), and sodium ascorbate (0.02 mmol) were added sequentially and dissolved in 2 mL of solvent (CH₂Cl₂:H₂O 3:1). The mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction, the reaction was quenched with 10 mL of water and extracted with dichloromethane three times. The lower layer was recovered and separated and purified by silica gel column chromatography or preparative thin layer chromatography to obtain product d1 in a yield of 80-85%.

[0108] Compound d1: 1H NMR (600 MHz, CDCl3) δ 8.03 (s, 1H), 7.95 (s, 1H), 7.68 –7.58 (m, 2H), δ 7.53 – 7.47 (m, 2H), δ 7.48 – 7.44 (m, 2H), δ 7.42 (d, J =7.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 6.01 (s, 1H), 4.95 (q, J = 12.8 Hz,2H), 4.74 (q, J = 12.3 Hz, 2H), 4.49 (s, 2H), 4.46 (s, 2H, ), δ 4.17 – 4.03(m, 2H), 2.23 (t, J = 11.8 Hz, 1H), 2.08 (t, J = 7.4 Hz, 1H), 1.96 (dd, J =10.7, 7.2 Hz, 1H), 1.93 (d, J = 3.0 Hz, 1H), 1.92 – 1.89 (m, 1H), 1.86 (t, J= 6.8 Hz, 1H), 1.59 (s, 1H), 1.56 (t, J = 4.1 Hz, 1H), 1.53 (t, J = 5.5 Hz,1H), δ 1.31 (dd, J = 12.7, 7.4 Hz, 1H), 1.02 (d, J = 6.2 Hz, 3H), 0.99 (d, J= 6.5 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H).

[0109] 13 C NMR (150 MHz, CDCl3) δ 146.84, 145.43, 141.99, 136.06, 135.97,135.69, 135.53 , 131.45, 131.41, 129.99, 129.87, 129.07, 129.03, 125.33,124.57, 124.36, 124.16, 124.03, 106.91 , 87.04, 72.11, 63.62, 61.76, 61.64,58.18, 56.23, 49.74, 40.23, 36.25, 31.38, 30.97, 27.74, 22.67 , 21.28, 11.83.

[0110] HRMS (ESI): Calcd for C35 H 43 N6O5 (M + H): 627.3295; found: 627.3309.

[0111] Example 5: Synthesis of curcumol derivatives e1-e5 containing triazole structure

[0112]

[0113] Hexynyl acid (0.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) (0.3 mmol) were dissolved in 2 mL of CHCl and stirred at room temperature for 0.5 h. Curcumol derivative G1 (0.2 mmol) and 4-dimethylaminopyridine (DMAP) (0.2 mmol) were then added to the reaction system, and stirring continued at room temperature for 3 h. The reaction progress was monitored by TLC. After completion, the reaction was quenched with 10 mL of water and extracted three times with CHCl. ​​The lower layer was recovered and purified by silica gel column chromatography or preparative thin-layer chromatography to obtain intermediate e as a yellow oil in 60% yield. The intermediate, azide (0.2 mmol), copper sulfate pentahydrate (0.02 mmol), and sodium ascorbate (0.02 mmol) were added sequentially to a reaction flask and dissolved in 2 mL of solvent (CHCl:HO 3:1). The reaction was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction, the reaction was quenched with 10 mL of water and extracted with dichloromethane three times. The lower layer was recovered and separated and purified by silica gel column chromatography or preparative thin layer chromatography to obtain products e1-e5 with a yield of 80-85%.

[0114] Compound e1: 11H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 6.9 Hz, 3H), 7.28 –7.21 (m, 3H), 5.83 (s, 1H), 5.49 (s, 2H), 4.54 – 4.45 (m, 2H), 2.74 (t, J =7.6 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.22 – 2.16 (m, 1H), 2.04 – 1.94 (m,3H), 1.85 (dq, J = 21.5, 7.7, 7.0 Hz, 3H), 1.66 – 1.50 (m, 3H), 1.45 (dt, J =10.9, 6.5 Hz, 1H), 1.26 – 1.19 (m, 1H), 0.99 (dd, J = 12.9, 6.5 Hz, 6H), 0.86(d, J = 6.5 Hz, 3H).

[0115] 13 13C NMR (150 MHz, CDCl3) δ 172.84, 147.50, 139.02, 134.78, 129.10,128.70, 128.04, 126.40, 120.87, 103.22, 86.96, 65.27, 59.67, 五十四点一零, 49.79,40.22, 36.39, 33.48, 31.17, 30.72, 27.51, 24.93, 24.62, 22.63, 21.41, 11.66.

[0116] HRMS (ESI): Calcd for C 28 H 38 N3O4(M + H): 480.2862; found: 480.2398.

[0117] Compound e2: 11H NMR (600 MHz, CDCl3) δ 7.24 – 7.18 (m, 3H), 6.89 (d, J = 8.2 Hz, 2H), 5.83 (s, 1H), 5.42 (s, 2H), 4.55 – 4.45 (m, 2H), 3.81 (s, 3H), 2.73 (t, J = 7.6 Hz, 2H), 2.40 (t, J = 7.3 Hz, 2H), 2.20 (dd, J = 12.8, 10.8 Hz, 1H), 1.98 (q, J = 7.5 Hz, 3H), 1.91 – 1.79 (m, 3H), 1.67 – 1.52 (m, 3H), 1.48 – 1.41 (m, 1H), 1.26 – 1.20 (m, 1H), 1.00 (dd, J = 12.8, 6.5 Hz, 6H), 0.87 (d, J = 6.6 Hz, 3H).

[0118] 13 13C NMR (150 MHz, CDCl3) δ 172.86, 159.89, 147.67, 139.01, 129.62, 126.78, 126.42, 120.60, 114.47, 103.21, 86.96, 65.26, 59.65, 55.33, 53.63, 49..79, 40.22, 36.39, 33.49, 31.18, 30.71, 27.51, 24.95, 24.64, 22.63, 21.41, 11.66.

[0119] HRMS (ESI): Calcd for C 29 H 40 N3O5 (M + H): 510.2968; found: 510.2975.

[0120] Compound e3: 11H NMR (600 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (dd, J = 7.3, 1.8 Hz, 1H), 7.49 (dtd, J = 18.0, 7.5, 1.6 Hz, 2H), 7.38 (dd, J = 7.6, 1.6 Hz, 1H), 5.86 (d, J = 1.8 Hz, 1H), 4.54 (q, J = 13.5 Hz, 2H), 4.48 (s, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.50 (t, J = 7.2 Hz, 2H), 2.21 (dd, J = 12.8, 10.8 Hz, 1H), 2.12 (p, J = 7.4 Hz, 2H, H-1), 1.99 (t, J = 8.3 Hz, 1H), 1.94 – 1.80 (m, 3H), 1.69 – 1.54 (m, 3H), 1.46 (ddt, J = 17.2, 13.3, 6.7 Hz, 1H), 1.26 – 1.22 (m, 1H), 1.00 (dd, J = 10.8, 6.5 Hz, 6H), 0.87 (d, J = 6.5 Hz, 3H).

[0121] 13 13C NMR (150 MHz, CDCl3) δ 172.82, 147.36, 138.99, 136.11, 135.57, 131.58, 129.85, 129.08, 126.35, 124.35, 122.59, 103.25, 87.00, 65.36, 61.84, 59.67, 49.86, 40.22, 36.39, 33.42, 31.18, 30.73, 27.54, 24.78, 24.49, 22.63, 21.41, 11.65.

[0122] HRMS (ESI): Calcd for C 28 H 38 N3O5 (M + H): 496.2811; found: 496.2803.

[0123] Compound e4: 11H NMR (600 MHz, CDCl3) δ 7.46 (s, 1H), 5.83 (t, J = 1.4 Hz, 1H), 5.12 (s, 2H), 4.51 (qd, J = 13.5, 1.5 Hz, 2H), 4.25 (q, J = 7.2 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.19 (dd, J = 12.7, 10.9 Hz, 1H), 2.05 – 2.01 (m, 2H), 2.01 – 1.94 (m, 1H), 1.82 (ddd, J = 19.7, 10.4, 4.0 Hz, 3H), 1.67 – 1.52 (m, 3H), 1.44 (dq, J = 10.9, 6.5 Hz, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.24 – 1.19 (m, 1H), 0.99 (dd, J = 9.9, 6.5 Hz, 6H), 0.86 (d, J = 6.6 Hz, 3H).

[0124] 13 13C NMR (150 MHz, CDCl3) δ 172.85, 166.42, 147.49, 139.01, 126.44, 122.36, 103.22, 86.98, 65.28, 62.36, 59.62, 50.80, 49.78, 40.21, 36.38, 33.37, 31.18, 30.71, 27.50, 24.83, 24.53, 22.63, 21.40, 14.06, 11.65.

[0125] HRMS (ESI): Calcd for C 25 H 38 N3O6 (M + H): 476.2761; found: 476.2771.

[0126] Compound e5: 1H NMR (600 MHz, CDCl3) δ 7.48 (s, 1H), 5.82 (d, J = 1.7 Hz,1H), 4.52 – 4.40 (m, 4H), 4.09 – 3.94 (m, 2H), 2.78 – 2.71 (m, 2H), 2.47 –2.38 (m, 2H), 2.20 (dd, J = 12.8, 10.9 Hz, 1H), 2.05 – 1.93 (m, 3H), 1.93 –1.76 (m, 3H), 1.69 – 1.51 (m, 3H), 1.44 (ddt, J = 17.1, 13.0, 6.5 Hz, 1H),1.22 (dd, J = 12.9, 7.5 Hz, 1H), 0.99 (t, J = 6.1 Hz, 6H), 0.87 (d, J = 6.6Hz, 3H).

[0127] 13 C NMR (150 MHz, CDCl3) δ 172.93, 138.83, 126.51, 122.58, 103.25, 87.00, 65.13, 61.11, 59.40, 52.61, 49.83, 40.24, 36.36, 33.33, 31.23,30.74, 27.49, 24.80, 24.46, 22.63, 21.43, 11.65.

[0128] HRMS (ESI): Calcd for C 23 H 35 N3O5 (M + H): 434.2655; found: 434.2660.

[0129] Example 6: Synthesis of Curcumol Derivatives f1-f7 Containing Triazole Structure

[0130]

[0131] Pentynoic acid (0.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.3 mmol) were dissolved in 2 mL of CHCl and stirred at room temperature for 0.5 h. Curcumol derivative G1 (0.2 mmol) and 4-dimethylaminopyridine (0.2 mmol) were then added to the reaction system, and stirring continued at room temperature for 3 h. The reaction progress was monitored by TLC. After completion, the reaction was quenched with 10 mL of water and extracted three times with CHCl. ​​The lower layer was recovered and purified by silica gel column chromatography or preparative thin-layer chromatography to obtain intermediate f as a yellow oil in 60% yield. The intermediate, azide (0.2 mmol), copper sulfate pentahydrate (0.02 mmol), and sodium ascorbate (0.02 mmol) were added sequentially to a reaction flask and dissolved in 2 mL of solvent (CHCl:HO 3:1). The reaction was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction, the reaction was quenched with 10 mL of water and extracted with dichloromethane three times. The lower layer was recovered and separated and purified by silica gel column chromatography or preparative thin layer chromatography to obtain products f1-f7 with a yield of 80-85%.

[0132] Compound f1: 1 H NMR (600 MHz, CDCl3) δ 172.30, 138.78, 136.01, 135.59,131.41, 129.88, 129.01, 126.68, 124.44, 103.23, 87.06, 65.64, 59.55, 49.82,40.19, 36.35, 33.41, 31.15, 30.72, 27.55, 22.62, 21.40, 20.90, 11.65.

[0133] 13 C NMR (150 MHz, CDCl3) δ 172.30, 138.78, 136.01, 135.59, 131.41,129.88, 129.01, 126.68, 124.44, 103.23, 87.06, 65.64, 59.55, 49.82, 40.19,36.35, 33.41, 31.15, 30.72, 27.55, 22.62, 21.40, 20.90, 11.65.

[0134] HRMS (ESI): Calcd for C 27 H 36 N3O5 (M + H): 482.2655; found: 482.2683.

[0135] Compound f2: 1 H NMR (600 MHz, CDCl3) δ 7.25 – 7.17 (m, 3H), 6.89 (d, J =8.2 Hz, 2H), 5.81 (s, 1H), 5.42 (s, 2H), 4.57 – 4.41 (m, 2H), 3.80 (s, 3H),3.01 (t, J = 7.3 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H), 2.20 (t, J = 11.8 Hz,1H), 1.95 (t, J = 9.2 Hz, 1H), 1.92 – 1.76 (m, 4H), 1.68 – 1.50 (m, 3H), 1.44(dq, J = 12.7, 6.5 Hz, 1H), 1.27 – 1.18 (m, 1H), 1.00 (dd, J = 9.0, 6.6 Hz, 6H), 0.88 (d, J = 6.5 Hz, 3H).

[0136] 13 C NMR (150 MHz, CDCl3) δ 172.33, 159.89, 146.53, 138.90, 129.63,126.75, 126.58, 120.94, 114.45, 103.20, 86.96, 65.48, 59.70, 55.34, 53.64,49.72, 40.21, 36.37, 33.55, 31.17, 30.71, 27.47, 22.65, 21.42, 21.02, 11.67.

[0137] HRMS (ESI): Calcd for C 28 H 38 N3O5 (M + H): 496.2811; found: 496.2815.

[0138] Compound f3: 11H NMR (600 MHz, CDCl3) δ 7.41 – 7.32 (m, 3H), 7.27 – 7.24 (m, 2H,), 5.81 (d, J = 1.8 Hz, 1H), 5.49 (s, 2H), 4.59 – 4.41 (m, 2H), 3.03 (t, J = 7.3 Hz, 2H), 2.77 (t, J = 7.4 Hz, 2H), 2.20 (dd, J = 12.8, 10.8 Hz, 1H), 1.96 (t, J = 9.2 Hz, 1H), 1.93 – 1.78 (m, 4H), 1.68 – 1.48 (m, 3H), 1.44 (dq, J = 10.7, 6.6 Hz, 1H), 1.22 (dd, J = 12.8, 7.4 Hz, 1H), 1.00 (dd, J = 9.0, 6.5 Hz, 6H), 0.88 (d, J = 6.5 Hz, 3H).

[0139] 13 13C NMR (150 MHz, CDCl3) δ 172.31, 146.62, 138.89, 134.75, 129.10, 128.71, 128.04, 126.61, 121.22, 103.19, 86.96, 65.49, 59.70, 54.11, 49.72, 40.21, 36.37, 33.53, 31.17, 30.70, 27.46, 22.64, 21.42, 21.00, 11.67.

[0140] HRMS (ESI): Calcd for C 27 H 36 N3O4 (M + H): 466.2706; found: 466.2718.

[0141] Compound f4: 11H NMR (600 MHz, CDCl3) δ 7.50 (s, 1H), 5.80 (d, J = 1.5 Hz, 1H), 5.12 (s, 2H), 4.61 – 4.42 (m, 2H), 4.25 (q, J = 7.2 Hz, 2H), 3.08 (t, J = 7.3 Hz, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.19 (dd, J = 12.8, 10.9 Hz, 1H), 1.96 (t, J = 9.1 Hz, 1H), 1.94 – 1.78 (m, 4H), 1.65 – 1.48 (m, 3H), 1.45 (tdd, J = 13.0, 8.4, 5.4 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.24 – 1.18 (m, 1H), 0.99 (dd, J = 9.8, 6.5 Hz, 6H), 0.87 (d, J = 6.6 Hz, 3H).

[0142] 13 13C NMR (150 MHz, CDClz) δ 172.29, 166.41, 138.89, 126.62, 122.57, 103.20, 86.97, 65.50, 62.39, 59.67, 50.82, 49.92, 40.20, 36.37, 33.51, 31.18, 30.69, 27.48, 22.64, 21.40, 21.13, 14.06, 11.66.

[0143] HRMS (ESI): Calcd for C 24 H 36 N3O6(M + H): 462.2604; found: 462.2653.

[0144] Compound f5: 11H NMR (600 MHz, CDCl3) δ 7.51 (s, 1H), 5.81 (d, J = 1.5 Hz, 1H), 5.15 (s, 2H), 4.59 – 4.44 (m, 2H), 3.81 (s, 3H), 3.08 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.20 (dd, J = 12.8, 10.8 Hz, 1H), 1.97 (t, J = 9.0 Hz, 1H), 1.92 – 1.77 (m, 3H), 1.68 – 1.49 (m, 3H), 1.45 (ddd, J = 13.0, 10.8, 6.6 Hz, 1H), 1.26 – 1.20 (m, 1H), 1.00 (dd, J = 9.5, 6.6 Hz, 6H), 0.88 (d, J = 6.6 Hz, 3H).

[0145] 13 13C NMR (150 MHz, CDCl3) δ 172.29, 166.88, 138.82, 126.70, 122.74, 103.2, 86.99, 65.51, 59.60, 53.02, 50.66, 49.78, 40.20, 36.36, 33.48, 31.18, 30.70, 27.46, 22.64, 21.40, 20.98, 11.67.

[0146] HRMS (ESI): Calcd for C 23 H 34 N3O6(M + H): 448.2448; found: 448.2460.

[0147] Compound f6: 11H NMR (600 MHz, CDCl3) δ 7.44 (s, 1H), 5.85 (s, 1H), 4.56 –4.42 (m, 4H), 3.61-3.52 (m, 2H), 3.05 (dt, J = 8.6, 4.7 Hz, 2H), 2.92 – 2.68(m, 2H), 2.20 (dd, J = 12.8, 10.9 Hz, 1H), 2.09 (tt, J = 11.5, 5.8 Hz, 1H),1.97 – 1.76 (m, 4H), 1.68 (td, J = 10.7, 7.3 Hz, 1H), 1.60 – 1.45 (m, 3H),1.46 – 1.41 (m, 1H), 1.22 (dd, J = 12.8, 7.4 Hz, 1H), 1.00 (dd, J = 6.6, 4.1Hz, 6H), 0.88 (d, J = 6.5 Hz, 3H).

[0148] 13 13C NMR (150 MHz, CDCl3) δ 172.31, 138.69, 126.42, 121.98, 103.29,87.07, 65.18, 59.24, 58.32, 49.81, 46.77, 40.20, 36.30, 33.47, 32.47,31.16, 30.74, 27.49, 22.64, 21.43, 20.96, 11.66.

[0149] HRMS (ESI): Calcd for C 23 H 36 N3O5 (M + H): 434.2655; found: 434.2675.

[0150] Compound f7: 1H NMR (600 MHz, CDCl3) δ 7.51 (s, 1H), 5.80 (d, J = 1.5 Hz,1H), 4.51 (qd, J = 13.5, 1.5 Hz, 2H), 4.44 (t, J = 4.9 Hz, 2H), 4.10 – 3.96(m, 2H), 3.04 (t, J = 7.1 Hz, 2H), 2.78 (tq, J = 16.5, 8.4, 7.1 Hz, 2H), 2.20 (dd, J = 12.8, 10.8 Hz, 1H), 1.98 – 1.76 (m, 4H), 1.66 (td, J = 10.8, 7.4 Hz,1H), 1.58 – 1.40 (m, 3H), 1.22 (dd, J = 12.8, 7.4 Hz, 1H), 0.99 (dd, J = 6.6,4.2 Hz, 6H), 0.88 (d, J = 6.5 Hz, 3H).

[0151] 13 C NMR (150 MHz, CDCl3) δ 172.34, 138.79, 126.58, 122.85, 103.26, 87.13, 65.33, 60.93, 59.32, 52.50, 49.94, 40.18, 36.34, 33.50, 31.16, 30.73,27.54, 22.64, 21.41, 20.94, 11.67.

[0152] HRMS (ESI): Calcd for C 22 H 34 N3O5 (M + H): 420.2498; found: 420.2499.

[0153] Example 7: Synthesis of curcumol derivatives g1-g9 containing triazole structure

[0154]

[0155] 3-Alkynylbenzoic acid (0.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.3 mmol) were dissolved in 2 mL of CHCl and stirred at room temperature for 0.5 h. Curcumol derivative G1 (0.2 mmol) and 4-dimethylaminopyridine (0.2 mmol) were then added to the reaction system, and stirring continued at room temperature for 3 h. The reaction progress was monitored by TLC. After completion, the reaction was quenched with 10 mL of water and extracted three times with CHCl. ​​The lower layer was recovered and purified by silica gel column chromatography or preparative thin-layer chromatography to obtain intermediate g as a yellow oil in 60% yield. The intermediate, azide (0.2 mmol), copper sulfate pentahydrate (0.02 mmol), and sodium ascorbate (0.02 mmol) were added sequentially to a reaction flask and dissolved in 2 mL of solvent (CHCl:HO 3:1). The reaction was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction, the reaction was quenched with 10 mL of water and extracted with dichloromethane three times. The lower layer was recovered and separated and purified by silica gel column chromatography or preparative thin layer chromatography to obtain products g1-g9 with a yield of 80-85%.

[0156] Compound g1: 1H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 2.2 Hz, 1H), 8.15 (d,J = 7.8 Hz, 1H), 8.03 (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.53 (td, J = 7.8,2.2 Hz, 1H), 5.97 (s, 1H), 5.24 (s, 2H), 4.88 – 4.64 (m, 2H), 4.29 (qd, J =7.1, 2.1 Hz, 2H), 2.23 (dd, J = 13.3, 11.0 Hz, 1H), 2.09 (t, J = 8.9 Hz, 1H),1.95 (d, J = 10.9 Hz, 1H), 1.92 (d, J = 9.5 Hz, 1H), 1.86 (dt, J = 15.4, 7.9Hz, 1H), 1.70 (dd, J = 10.7, 7.5 Hz, 1H), 1.65 (dd, J = 11.1, 2.6 Hz, 1H),1.60 (d, J = 15.2 Hz, 1H), 1.55 – 1.49 (m, 1H), 1.32 (td, J = 7.2, 2.0 Hz,3H), 1.30 – 1.27 (m, 1H), 1.01 (t, J = 6.3 Hz, 6H), 0.89 (d, J = 6.4 Hz, 3H).

[0157] 13 C NMR (150 MHz, CDCl3) δ 166.24, 165.90, 147.24, 138.90, 130.88,130.65, 130.30, 129.24, 129.10, 127.16, 126.94, 121.52, 103.28, 87.18, 66.20,62.54, 59.58, 51.00, 49.97, 40.20, 36.40, 31.21, 30.74, 27.67, 22.66, 21.42,14.08, 11.68.

[0158] HRMS (ESI): Calcd forC 31 H 36 N3O4 (M + H): 514.2704; found: 514.2706.

[0159] Compound g2: 1 H NMR (600 MHz, CDCl3) δ 8.33 (d, J = 2.1 Hz, 1H), 8.13 (d,J = 7.8 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.50 (t, J = 7.7 Hz,1H), 7.29 (s, 2H), 6.92 (d, J = 8.2 Hz, 2H), 5.95 (s, 1H), 5.52 (s, 2H), 4.86– 4.69 (m, 2H), 3.82 (s, 3H), 2.22 (t, J = 11.8 Hz), 2.06 (d, J = 9.6 Hz,1H), 1.96 – 1.92 (m, 1H), 1.90 (d, J = 9.2 Hz, 1H), 1.86 – 1.80 (m, 1H, 1H),1.68 (dd, J = 10.8, 7.4 Hz, 1H), 1.63 (d, J = 6.5 Hz, 1H), 1.60 (d, J = 14.7Hz, 1H), 1.50 (dt, J = 11.5, 6.3 Hz, 1H), 1.28 (d, J = 7.7 Hz, 1H), 1.02 (d,J = 6.4 Hz, 3H, 3H), 0.99 (d, J = 6.4 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H).

[0160] 13 C NMR (150 MHz, CDCl3) δ 165.95, 160.05, 147.14, 139.00, 131.12,130.52, 130.22, 129.79, 129.09, 129.08, 126.95, 126.81, 126.39, 119.73,114.61, 103.26, 87.15, 66.17, 59.72, 55.36, 53.93, 49.97, 40.21, 36.42,31.21, 30.74, 27.68, 22.6, 21.42, 11.68.

[0161] HRMS (ESI): Calcd for C 32 H 38N3O5 (M + H): 544.2811; found: 544.2822.

[0162] Compound g3: 1 H NMR (600 MHz, CDCl3) δ 8.43 (s, 1H), 8.14 (s, 1H), 8.03(s, 1H),8.00 (d, 1H), 7.53 (t, 1H), 5.97 (s, 1H), 5.26 (s, 2H), 4.93 – 4.66(m, 2H), 4.12 (q, 1H), 3.83 (s, 3H), 2.23 (dd, 1H), 2.07 (m, 1H), 2.00 – 1.94(m, 1H), 1.92 (m, 1H), 1.89 – 1.81 (m, 1H), 1.72 – 1.67 (m, 1H), 1.67 – 1.63(m, 1H), 1.63 – 1.57 (m, 1H), 1.51 (m, 1H), 1.31 – 1.26 (m, 1H), 1.02 (d, J =5.4 Hz, 3H), 1.01 (d, J = 5.2 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H).

[0163] 13 C NMR (150 MHz, CDCl3) δ 166.69, 165.90, 147.29, 138.89, 130.84,130.65, 130.31, 129.26, 129.11, 127.14, 126.94, 121.53, 103.29, 87.19, 66.20,59.58, 53.14, 50.85, 49.97, 40.20, 36.40, 31.21, 30.74, 27.67, 22.66, 21.42,11.68.

[0164] HRMS (ESI): Calcd for C 27 H 34 N3O6 (M + H): 496.2448; found: 496.2462.

[0165] Compound g4: 11H NMR (600 MHz, CDCl3) δ 8.49 (t, J = 1.8 Hz, 1H, H-18), 8.29 (s, 1H), 8.21 (dt, J = 7.7, 1.5 Hz, 1H), 8.04 (dt, J = 7.8, 1.4 Hz, 1H), 7.66 (dd, J = 7.4, 1.7 Hz, 1H), 7.60 – 7.45 (m, 4H), 5.98 (d, J = 1.6 Hz, 1H), 4.91 – 4.71 (m, 2H), 4.56 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.23 (dd, J = 12.8, 10.8 Hz, 1H), 2.08 (t, J = 8.9 Hz, 1H), 2.05 (s, 1H), 2.00 – 1.81 (m, 3H), 1.73 – 1.58 (m, 3H), 1.57 – 1.45 (m, 1H), 1.31 – 1.26 (m, 1H), 1.01 (t, J = 6.2 Hz, 6H), 0.89 (d, J = 6.6 Hz, 3H).

[0166] 13 13C NMR (150 MHz, CDCl3) δ 171.22, 165.85, 147.06, 138.90, 135.85, 135.52, 131.56, 130.78, 130.50, 130.33, 130.16, 129.53, 129.29, 129.19, 127.02, 126.96, 124.49, 121.55, 103.30, 87.17, 66.23, 61.74, 59.68, 50.01, 40.21, 36.42, 31.22, 30.76, 27.71, 22.66, 21.43, 21.06, 14.20, 11.68.

[0167] HRMS (ESI): Calcd for C 32 H 38 N3O5 (M + H): 544.281; found: FOUND: 544.2801.

[0168] Compound g5: 11H NMR (600 MHz, CDCl3) δ 8.39 (s, 1H), 8.09 (d, J = 7.9 Hz, 1H), 7.97 (d, J = 7.7 Hz, 2H), 7.50 (t, J = 7.8 Hz, 1H), 5.99 (s, 1H), 4.88 – 4.67 (m, 2H), 4.59 (t, J = 6.7 Hz, 2H), 3.69 (t, J = 5.8 Hz, 2H), 2.27 – 2.15 (m, 3H), 2.06 (d, J = 7.3 Hz, 1H), 1.98 – 1.92 (m, 1H), 1.89 (dd, J = 14.9, 6.1 Hz, 1H), 1.86 – 1.80 (m, 1H), 1.70 (td, J = 10.8, 7.4 Hz, 1H), 1.63 (d, J = 11.5 Hz, 1H), 1.61 – 1.55 (m, 1H), 1.51 (dt, J = 10.8, 6.3 Hz, 1H1), 1.31 – 1.27 (m, 1H), 1.04 – 0.98 (m, 6H), 0.88 (d, J = 6.5 Hz, 3H).

[0169] 13 13C NMR (150 MHz, CDCl3) δ 165.94, 146.65, 138.79, 131.04, 130.60, 130.19, 129.13, 126.98, 126.78, 120.86, 103.32, 87.16, 66.12, 59.44, 58.55, 50.01, 47.15, 40.20, 36.38, 32.57, 31.23, 30.76, 27.71, 22.66, 21.43, 11.67.

[0170] HRMS (ESI): Calcd for C<o:p>0000146< / o:p>H 36 N3O5 (M + H): 482.2655; found: 482.2663.

[0171] Compound g6: 1 It should be noted that there might be some issues with the tags in the original text like <o:p> in ID=8 which might not be standard XML tags. If this is a specific format requirement in a particular system, it's important to ensure the translation tool can handle such non - standard elements correctly. The above translation attempts to maintain the integrity of the text as much as possible while converting the Chinese part to English.H NMR (600 MHz, CDCl3) δ 8.43 (d, J = 2.2 Hz, 1H), 8.15 (d,J = 7.8 Hz, 1H, H-22), 8.03 (s, 1H, H-20), 8.00 (d, J = 7.8 Hz, 1H, H-21),7.53 (td, J = 7.8, 2.2 Hz, 1H4), 5.97 (s, 1H), 5.24 (s, 2H), 4.88 – 4.64 (m,2H), 4.29 (qd, J = 7.1, 2.1 Hz, 2H), 2.23 (dd, J = 13.3, 11.0 Hz, 1H), 2.09(t, J = 8.9 Hz, 1H), 1.95 (d, J = 10.9 Hz, 1H), 1.92 (d, J = 9.5 Hz, 1H),1.86 (dt, J = 15.4, 7.9 Hz, 1H), 1.70 (dd, J = 10.7, 7.5 Hz, 1H), 1.65 (dd, J= 11.1, 2.6 Hz, 1H), 1.60 (d, J = 15.2 Hz, 1H), 1.55 – 1.49 (m, 1H), 1.32(td, J = 7.2, 2.0 Hz, 3H), 1.30 – 1.27 (m, 1H), 1.01 (t, J = 6.3 Hz, 6H),0.89 (d, J = 6.4 Hz, 3H).

[0172] 13 C NMR (150 MHz, CDCl3) δ 166.24, 165.90, 147.24, 138.90, 130.88,130.65, 130.30, 129.24, 129.10, 127.16, 126.94, 121.52, 103.28, 87.18, 66.20,62.54, 59.58, 51.00, 49.97, 40.20, 36.40, 31.21, 30.74, 27.67, 22.66, 21.42,14.08, 11.68.

[0173] HRMS (ESI): Calcd forC 28 H 36 N3O6 (M + H): 510.2604; found: 510.2617.

[0174] Compound g7: 1 H NMR (600 MHz, CDCl3) δ 8.45 (d, J = 1.8 Hz, 1H), 8.17 (dt,J = 7.8, 1.5 Hz, 1H), 8.02 (q, J = 3.5, 2.5 Hz, 2H), 7.55 (t, J = 7.8 Hz,1H), 5.98 (d, J = 1.5 Hz, 1H), 5.25 (d, J = 11.3 Hz, 2H), 4.88 – 4.71 (m,2H), 4.36 – 4.22 (m, 1H), 2.24 (dd, J = 12.8, 10.8 Hz, 1H), 2.10 (t, J = 8.8Hz, 1H), 1.96 (ddd, J = 14.5, 6.1, 3.7 Hz, 1H), 1.94 – 1.89 (m, 1H), 1.89 –1.83 (m, 1H), 1.68 (d, J = 3.9 Hz, 1H), 1.66 – 1.63 (m, 1H), 1.63 – 1.59 (m,1H), 1.55 – 1.50 (m, 1H), 1.29 (d, J = 5.9 Hz, 1H), 1.03 – 0.99 (m, 6H), 0.90(d, J = 6.5 Hz, 3H).

[0175] 13 C NMR (150 MHz, CDCl3) δ 166.22, 165.95, 147.32, 139.05, 130.84,130.65, 130.35, 129.32, 129.16, 126.97, 126.89, 121.48, 103.30, 87.17, 66.21,62.62, 59.72, 50.88, 49.97, 40.2, 36.42, 31.20, 30.77, 29.72, 27.68, 22.69,21.44, 11.70.

[0176] HRMS (ESI): Calcd forC 26 H 32 N3O6 (M + H): 482.2291; found: 482.2291.

[0177] Compound g8: 11H NMR (600 MHz, CDCl3) δ 8.38 (s, 1H, H-18), 8.15 – 8.06 (m,1H), 8.02 (s, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.50 (t, J = 7.7 Hz, 1H), 5.97(d, J = 1.7 Hz, 1H), δ 4.87 – 4.76 (m, 2H), 4.73 (q, J = 6.1, 4.9 Hz, 2H),3.07 (d, J = 6.2 Hz, 2H), 2.24 (dd, J = 12.8, 10.8 Hz, 1H), 2.12 – 2.06 (m,1H), 1.95 (d, J = 12.4 Hz, 1H), 1.92 – 1.88 (m, 1H), 1.85 (td, J = 8.8, 8.3,6.3 Hz, 1H), 1.75 – 1.69 (m, 1H), 1.69 – 1.62 (m, 1H), 1.62 – 1.56 (m, 1H),1.56 – 1.48 (m, 1H), 1.32 – 1.27 (m, 1H), 1.00 (t, J = 6.8 Hz, 6H), 0.88 (d,J = 6.5 Hz, 3H).

[0178] 13 13C NMR (150 MHz, CDCl3) δ 165.92, 138.96, 130.86, 130.60, 130.28,129.20, 129.16, 127.00, 126.89, 121.38, 103.63, 87.71, 66.07, 59.30, 50.15,45.69, 40.18, 36.37, 31.16, 30.73, 29.69, 27.70, 22.59 21.39, 11.64.

[0179] HRMS (ESI): Calcd forC 27 H 34 N3O6 (M + H): 496.2448; found: 496.2492.

[0180] Compound g9: 1H NMR (600 MHz, CDCl3) δ 8.39 (d, J = 1.9 Hz, 1H), 8.15 (d,J = 7.7 Hz, 1H), 8.10 (s, 1H), 7.98 (d, J = 7.7 Hz, 1H), 7.51 (t, J = 7.7 Hz,1H), 5.98 (d, J = 1.4 Hz, 1H), 4.88 – 4.71 (m, 2H), 4.62 (t, J = 4.9 Hz, 2H),3.93 (t, J = 4.9 Hz, 2H), 3.77 (t, J = 4.4 Hz, 2H), 3.61 (t, J = 4.4 Hz, 2H),2.23 (dd, J = 12.8, 10.8 Hz, 1H), 2.07 (t, J = 8.9 Hz, 1H), 2.00 – 1.94 (m,1H), 1.94 – 1.89 (m, 1H), 1.89 – 1.81 (m, 1H), 1.73 – 1.67 (m, 1H), 1.67 –1.62 (m, 1H), 1.62 – 1.56 (m, 1H), 1.55 – 1.47 (m, 1H), 1.32 – 1.27 (m, 1H),1.02 (d, J = 6.5 Hz, 3H), 1.00 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 6.6 Hz, 3H).

[0181] 13 C NMR (150 MHz, CDCl3) δ 165.96, 138.96, 131.15, 130.60, 130.22,129.10, 126.99, 126.83, 121.34, 103.30, 87.17, 72.52, 69.29, 66.13, 61.6059.61, 50.40, 50.1, 40.20, 36.41, 31.24, 30.73, 27.77, 22.64, 21.42, 11.67.

[0182] HRMS (ESI): Calcd for C 28 H 38 N3O6(M + H): 512.2761; found: 512.2764.

[0183] Example 8: Synthesis of curcumol derivative h1 containing a triazole structure

[0184]

[0185] Intermediate product g (0.4 mmol) was dissolved in 2.5 mL of tetrahydrofuran. The air in the reaction apparatus was evacuated and the reaction chamber was filled with nitrogen. Ethylmagnesium bromide (0.4 mmol) was added and the mixture was refluxed at 55°C for 30 min. Succinic anhydride (1.2 mmol) was then added and the mixture was refluxed at 75°C for 4 h. The reaction was quenched with water and the pH was adjusted to 4 with hydrochloric acid. After extraction with ethyl acetate, the upper layer was purified by silica gel column chromatography to obtain a yellow oil, product h, in 82% yield. To the reaction flask, intermediate h, benzyl azide (0.2 mmol), copper sulfate pentahydrate (0.02 mmol), and sodium ascorbate (0.02 mmol) were added in sequence and dissolved in 2 mL of a solvent (CH₂Cl₂:H₂O₃:1). The mixture was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction, the reaction was quenched with 10 mL of water and extracted with dichloromethane three times. The lower layer was recovered and separated and purified by silica gel column chromatography or preparative thin layer chromatography to obtain product h1 in a yield of 80-85%.

[0186] Compound h1: 1H NMR (500 MHz, CDCl3) δ 8.39 (t, J = 1.8 Hz, 1H), 8.00 (dt,J = 7.8, 1.5 Hz, 1H, H-18), 7.95 (dt, J = 7.9, 1.5 Hz, 1H, H-24), 7.75 (s,1H, H-20), 7.48 (t, J = 7.8 Hz, 1H), 7.43 – 7.37 (m, 3H), 7.32 (dd, J = 7.5,2.1 Hz, 2H), 6.04 (d, J = 1.6 Hz, 1H), 5.59 (s, 2H), 4.87 – 4.67 (m, 2H),2.82 – 2.66 (m, 2H), 2.66 – 2.55 (m, 2H), 2.19 (t, J = 11.7 Hz, 1H), 2.09 (s,1H), 2.02 (t, J = 8.9 Hz, 1H), 1.97 – 1.92 (m, 1H), 1.92 – 1.89 (m, 1H), 1.89– 1.83 (m, 1H), 1.75 (qd, J = 9.7, 8.1, 3.1 Hz, 1H), 1.69 – 1.61 (m, 1H), 1.54 (dt, J = 10.7, 6.5 Hz, 1H), 1.27 – 1.24 (m, 1H), 1.01 (d, J = 6.3 Hz,3H), 0.94 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 6.6 Hz, 3H). Figure 1 shown.

[0187] 13 C NMR (125 MHz, CDCl3) δ 175.97, 169.91, 165.92, 147.18 135.94,134.26, 130.84, 130.35, 129.62, 129.26, 129.03, 128.99, 128.21, 126.68,124.59, 120.28, 105.55, 88.99, 65.91, 57.86, 54.52, 49.72, 40.13, 34.97,31.05, 30.42, 29.90, 29.03, 27.67, 22.54, 21.19, 11.57. Figure 2 shown.

[0188] HRMS (ESI): Calcd for C 35 H 40 N3O7 (M + H): 614.2866; found: 614.2898. Figure 3 shown.

[0189] Example 9: Synthesis of curcumol derivative i1 containing a triazole structure

[0190]

[0191] p-Alkynylbenzoic acid (0.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.3 mmol) were dissolved in 2 mL of CHCl and stirred at room temperature for 0.5 h. Curcumol derivative G1 (0.2 mmol) and 4-dimethylaminopyridine (0.2 mmol) were then added to the reaction system, and stirring continued at room temperature for 3 h. The reaction progress was monitored by TLC. After completion, the reaction was quenched with 10 mL of water and extracted three times with CHCl. ​​The lower layer was recovered and purified by silica gel column chromatography or preparative thin-layer chromatography to obtain intermediate i as a yellow oil in 60% yield. Intermediate i, methyl azidoacetate (0.2 mmol), copper sulfate pentahydrate (0.02 mmol), and sodium ascorbate (0.02 mmol) were added sequentially to a reaction flask and dissolved in 2 mL of solvent (CHCl:HO 3:1). The reaction was stirred at room temperature and the reaction progress was monitored by TLC. After the reaction, the reaction was quenched with 10 mL of water and extracted with dichloromethane three times. The lower layer was recovered and separated and purified by silica gel column chromatography or preparative thin layer chromatography to obtain product i1 in a yield of 80-85%.

[0192] Compound i1: 1H NMR (500 MHz, CDCl3) δ 8.11 – 8.06 (m, 2H), 8.05 (s, 1H), 7.96 – 7.87 (m, 2H), 5.97 (d, J = 1.6 Hz, 1H), 5.26 (s, 2H), 4.92 – 4.55 (m,2H), 3.83 (s, 3H), 2.23 (dd, J = 12.8, 10.8 Hz, 1H), 2.09 (t, J = 8.7 Hz,1H), 2.00 – 1.80 (m, 3H), 1.74 – 1.57 (m, 3H), 1.51 (dq, J = 10.7, 6.4 Hz,1H), 1.32 – 1.27 (m, 1H), 1.02 (t, J = 6.7 Hz, 6H), 0.89 (d, J = 6.6 Hz, 3H).

[0193] 13 C NMR (125 MHz, CDCl3) δ 166.67, 165.82, 147.13, 138.86, 134.81,130.24, 129.59, 127.14, 125.65, 122.04, 103.30, 87.19, 66.10, 59.51, 53.12,50.83, 50.01, 40.21, 36.41, 31.23, 30.74, 27.67, 22.62, 21.39, 11.66.

[0194] HRMS (ESI): Calcd for C 27 H 34 N3O6 (M + H): 496.2448; found: 496.2454.

[0195] Application Example 1: In vitro anti-inflammatory experiment

[0196] The anti-inflammatory activity of the present invention was evaluated using a lipopolysaccharide (LPS)-induced RAW 264.7 macrophage model: the cells were cultured at a rate of 8×10 5Cells were seeded at a density of 1 μg / mL in 48-well plates and LPS (final concentration 1 μg / mL) was added to establish an inflammatory model. Experimental groups were treated with 25-100 nM concentrations of a curcumol derivative, the parent compound, or the positive control drug dexamethasone, with a concentration gradient of 100 nM, 50 μM, and 25 μM. Four replicate wells were set up for each concentration gradient and incubated for 48 hours. Cells were stimulated with a mixture of phorbol 12-myristate 13-acetate (PMA) (50 μg / mL) and ionomycin (1 mg / mL). TNF-α expression levels were determined by flow cytometry using a fluorescently labeled anti-TNF-α antibody. Data were analyzed using FlowJo software. Experiments were repeated three times independently, and statistical analysis was performed using one-way analysis of variance (P < 0.05 was considered significant).

[0197] Table 1

[0198]

[0199] Evaluation in the LPS-induced RAW 264.7 macrophage inflammation model revealed that the curcumol derivatives exhibited dose-dependent anti-inflammatory activity within the 25-100 nM concentration range. At 100 nM, 29 derivatives significantly inhibited TNF-α expression (inhibition rate ≥50%, P < 0.05), comparable to the parent compound curcumol and the positive control dexamethasone. When the concentration was reduced to 50 nM, 28 derivatives maintained significant inhibitory activity, with compound h1 exhibiting superior TNF-α inhibition compared to curcumol and dexamethasone. Further reducing the concentration to 25 nM, 22 derivatives maintained significant activity, with h1's inhibition rate remaining significantly higher than that of the parent compound and the control (P < 0.05). These data demonstrate that the triazole curcumol derivatives, particularly h1, exhibit low-dose, highly effective inhibition of M1 macrophage inflammatory responses, with the enhanced activity attributed to structural optimization through synergistic modifications at the C-8 / C-10 positions.

[0200] Application Example 2: Curcumol derivative h1 with a triazole ring improves LPS-induced acute lung injury

[0201] The curcumol derivative h1 was dissolved in 5% sodium bicarbonate injection to prepare the corresponding administration concentration.

[0202] Thirty-six C57BL / 6 mice were selected for the experiment. After one week of acclimatization, they were randomly divided into 6 groups (n=6): blank control group (Control), model group (Model), high-dose group (h1-H, 25 mg / kg), medium-dose group (h1-M, 10 mg / kg), low-dose group (h1-L, 5 mg / kg) of curcumin derivative h1 with a triazole ring, and dexamethasone positive control group (DEX, 5 mg / kg).

[0203] The model was established as follows: mice were anesthetized with an intraperitoneal injection of tribromoethanol (1 μL / g). Subsequently, 50 μL of LPS solution (15 mg / kg) was instilled into the trachea to establish an acute lung injury model. A blank control group was instilled with an equal volume of saline. Twenty-four hours after modeling, the mice were sacrificed, and lung tissue was harvested. Bronchoalveolar lavage fluid was collected for later use.

[0204] Table 2

[0205]

[0206] The results showed that the curcuminol derivative h1 with a triazole ring could inhibit the expression of inflammatory factors in the bronchoalveolar lavage fluid of mice with LPS-induced acute lung injury, and at a dose of 5 mg / kg it could significantly inhibit the expression of IFN-γ and IL-17A, which was better than the positive drug dexamethasone (DEX).

[0207] Application Example 3: Molecular docking and protein imprinting experiments determine the mechanism of action of curcuminol derivative h1 with a triazole ring in the treatment of acute lung injury

[0208] This study used the Discovery Studio 2020 molecular simulation platform (Dassault Systèmes, v19.1.0) to conduct molecular docking analysis of the interaction between the target compound, a curcuminol derivative h1, and the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3, PDB ID: 8ETR). The NLRP3 crystal structure was first obtained from the RCSB Protein Data Bank. The receptor protein was pre-processed by removing water molecules, non-standard residues, and heterologous ligands. The protein was then optimized using the CHARMM force field for hydrogen atom addition and energy minimization. The "Prepare Ligands" module was also used to perform charge assignment, protonation state adjustment, and conformational optimization on the ligand. Subsequently, the CDOCKER molecular docking algorithm was used to evaluate the binding mode between the ligand and the receptor. Ultimately, the minimum binding energy and optimal binding site were determined, and 2D / 3D binding mode maps were generated.

[0209] The molecular docking results showed that (see Figure 4In Figures A and B, the triazole-ringed curcuminol derivative h1 exhibited strong binding affinity to the NLRP3 protein, with a binding free energy of -30.4976 kcal / mol. Further analysis of the binding mode revealed that the terminal hydroxyl group of the triazole-ringed curcuminol derivative h1 formed stable hydrogen bonds with key amino acid residues in the NLRP3 protein.

[0210] To further explore the regulatory effect of curcuminol derivative h1 with a triazole ring on the NLRP3 inflammasome pathway, Western blot analysis showed (see Figure 5 ), the expression of NLRP3 inflammasome-related proteins (NLRP3, caspase-1 and IL-1β) in the lung tissue of mice in the LPS-induced acute lung injury (ALI) model group was significantly upregulated compared with the blank control group, indicating that the NLRP3 inflammasome pathway was activated; after intervention with the curcumin derivative h1 with a triazole ring, the expression levels of the above proteins were significantly reduced, suggesting that the derivative can exert anti-ALI effects by inhibiting NLRP3 inflammasome activation.

[0211] Application Example 4: Surface plasmon resonance (SPR) verified that NLRP3 is the direct target of curcumin derivative h1.

[0212] SPR assay was performed on Berthold bScreen LB 991 (V4 instrument) to determine the binding affinity of curcumol derivative h1 to NLRP 3. Figure 6 The experimental results showed that there was a significant direct interaction between the curcuminol derivative h1 and the NLRP3 protein, with a binding constant (KD value) of 35.30 nM. This result indicates that the curcuminol derivative h1 has a high binding affinity with NLRP3.

[0213] Obviously, the above embodiments of the present invention are merely examples to more clearly illustrate the present invention, and are not limitations on the implementation methods of the present invention. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made based on the above description. It is impossible to enumerate all implementation methods here. All obvious changes or modifications derived from the technical solution of the present invention are still within the scope of protection of the present invention.

Claims

1. A curcuminol derivative containing a triazole structure, characterized in that: The curcumol derivative is selected from the compound represented by formula h1: 。 2. The method for synthesizing the curcumol derivative containing a triazole structure according to claim 1, characterized in that: The synthetic route is: The synthesis method comprises the following steps: Alkynyl acid and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide were dissolved in CH2Cl2 and stirred at room temperature for 0.5 h. Then, curcumol derivative G1 and 4-dimethylaminopyridine were added to the reaction system and stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with water, extracted with CH2Cl2, and the lower layer was recovered. After separation and purification, a yellow oily intermediate product g was obtained. The intermediate product g was dissolved in tetrahydrofuran, and the air in the reaction apparatus was evacuated and the reaction apparatus was filled with nitrogen. Ethylmagnesium bromide was added, and the reaction was refluxed at 55°C for 30 min. Then, succinic anhydride was added, and the reaction was refluxed at 75°C for 4 h. Water was added to stop the reaction, and the pH was adjusted to = 4 with hydrochloric acid.

4. After extraction with ethyl acetate, the upper layer was purified by silica gel column chromatography to obtain a yellow oily substance h. In a reaction flask, the intermediate h, benzyl azide, copper sulfate pentahydrate, and sodium ascorbate were added in sequence and dissolved in dichloromethane solvent. The mixture was stirred at room temperature to react. After the reaction was completed, the reaction was quenched with water, extracted with dichloromethane, and the lower layer was recovered and separated and purified to obtain the product h1.

3. Use of the curcumol derivative containing a triazole structure according to claim 1 in the preparation of an anti-inflammatory drug, wherein the anti-inflammatory drug can inhibit the inflammatory response of M1 macrophages.

4. Use of the curcumol derivative containing a triazole structure according to claim 1 in the preparation of a medicament for improving acute lung injury.

5. The use according to claim 4, characterized in that The curcuminol derivative h1 can significantly inhibit the expression of inflammatory factors IFN-γ and IL-17A; the curcuminol derivative h1 exerts an anti-acute lung injury effect by inhibiting the activation of NLRP3 inflammasome.

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