A curcumenol derivative, and a synthesis method and application thereof

Abstract

The application provides a zedoary alcohol derivative, a synthesis method and application thereof, and a structural general formula of the zedoary alcohol derivative is as follows: wherein R1 is selected from a naphthyl group, a dimethylamino group, a substituted benzene group, an aromatic group and a substituted aromatic group. A sulfonate compound is introduced at a hydroxyl group of zedoary alcohol to obtain the zedoary alcohol derivative with anti-influenza virus activity, the synthesis method is green and environment-friendly, the reaction condition is mild, the efficiency is high, and the drug efficacy is better than that of a parent compound zedoary alcohol.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology and relates to a curcumin alcohol derivative, its synthesis method and application. Background Technology

[0002] Curcuma phaeocaulis Valeton, a traditional Chinese medicine, is the dried rhizome of a perennial herbaceous plant belonging to the genus Curcuma in the ginger family (Zingiberaceae). It has a pungent and bitter taste, is warm in nature, and enters the liver and spleen meridians. It possesses the effects of promoting blood circulation, regulating qi, eliminating stagnation, and relieving pain. It is used to treat amenorrhea due to blood stasis, abdominal distension due to food stagnation, and abdominal masses. According to the *Compendium of Materia Medica*, "Curcuma phaeocaulis Valeton, when roasted with costus root, treats all kinds of cold-induced sharp pain in the heart, so severe that it feels like death upon onset. It is also used for those suffering from chronic, intermittent abdominal pain."

[0003] Curcuma zedoaria is rich in volatile oil, which has a complex composition, mainly consisting of sesquiterpenes and sesquiterpenes. Studies have found that the extract of Curcuma zedoaria—its volatile oil—has good antitumor, anti-inflammatory, and antiviral effects. The main antitumor active components in Curcuma zedoaria volatile oil are β-elemene, curcumol, curcumone, curcumidone, and isocurcumol. Among them, curcumol, a guaiacane-type sesquiterpene, is one of the main active components in Curcuma zedoaria volatile oil, with a high content, and is used as an important indicator for the quality evaluation of Curcuma zedoaria oil and its preparations. In our previous research, we discovered for the first time that guaiacane components, represented by curcumol, in Curcuma zedoaria possess antiviral activity. However, curcumol has poor water solubility and low bioavailability, which presents certain difficulties for its application in clinical preparations.

[0004] Currently, there is a lack of highly effective treatments for most viral pneumonias, and antiviral chemotherapy remains the primary treatment method. However, existing antiviral drugs have a narrow antiviral spectrum, are prone to drug resistance, and often cause adverse side effects such as bone marrow suppression and gastrointestinal reactions, severely limiting their application. Summary of the Invention

[0005] Based on the above, the purpose of this invention is to provide a curcuminol derivative, its synthesis method and application. By introducing a sulfonyl compound at the hydroxyl group of curcuminol, a curcuminol derivative with anti-influenza virus activity is obtained. The synthesis method is green and environmentally friendly, with mild reaction conditions, high efficiency and high yield, and the efficacy is superior to that of the parent compound curcuminol.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A curcuminol derivative has the following general structural formula:

[0008]

[0009] R1 is selected from naphthyl, dimethylamino, substituted phenyl, aromatic, substituted aromatic, etc.

[0010] This invention also provides a method for synthesizing curcumin derivatives, comprising: weighing curcumin I and 2 times the amount of a sulfonyl chloride compound, mixing them, dissolving them in DMF, stirring at room temperature, adding 6 times the amount of NaH, heating to 70°C and stirring, monitoring the reaction by TLC, and after the reaction is complete, separating and purifying to obtain curcumin derivative II. The synthetic route is as follows:

[0011]

[0012] R1 is selected from naphthyl, dimethylamino, substituted phenyl, aromatic, substituted aromatic, etc.

[0013] Preferably, thin-layer chromatography is used for separation and purification, with cyclohexane:ethyl acetate = 20:1.

[0014] Preferably, the structural formula of the curcumin alcohol derivative II is as follows:

[0015]

[0016] .

[0017] The present invention also provides the use of the above-mentioned curcumin derivatives in the preparation of drugs for treating influenza viruses.

[0018] Preferably, the drug inhibits the replication of influenza virus through a curcumin derivative.

[0019] Preferably, the drug alleviates weight loss caused by influenza virus infection through turmeric alcohol derivatives.

[0020] More preferably, the structural formula of the curcuminol derivative is:

[0021] .

[0022] The beneficial effects of this invention are as follows:

[0023] This invention develops a curcuminol derivative with anti-influenza virus activity. The synthesis method is green, safe, rapid, and yields high efficiency. In in vitro antiviral activity experiments, firefly Luciferase driven by the influenza virus promoter was inserted into the genome of 293T-IAV-Luc cells, and the viral replication level was characterized by detecting Luciferase activity. The results show that both curcuminol derivatives 1 and 2 prepared in this invention have the ability to inhibit influenza virus replication, with derivative 1 exhibiting the strongest activity, superior to the parent compound curcuminol. In in vivo experiments, derivative 1 also effectively inhibits influenza virus replication. Attached Figure Description

[0024] Figure 1 Showing derivative 1 1 H-NMR spectrum.

[0025] Figure 2 Showing derivative 1 13 C-NMR spectrum.

[0026] Figure 3 The HRMS spectrum of derivative 1 is shown.

[0027] Figure 4 Derivative 2 is shown. 1 H-NMR spectrum.

[0028] Figure 5 Derivative 2 is shown. 13 C-NMR spectrum.

[0029] Figure 6 The HRMS spectrum of derivative 2 is shown.

[0030] Figure 7 This displays the results of luciferase activity assays for different compounds.

[0031] Figure 8 The in vivo pharmacodynamic results of the antiviral activity of derivative 1 of the present invention are shown, including: A. body weight, B. survival rate, and C. viral titer. Detailed Implementation

[0032] To more clearly illustrate the present invention, the invention will be further described in detail below with reference to embodiments and accompanying drawings. Those skilled in the art should understand that the specific description below is illustrative rather than restrictive and should not be construed as limiting the scope of protection of the present invention.

[0033] The synthetic route for the curcumin alcohol derivative in this application is as follows:

[0034]

[0035] Preferably, R1 is selected from naphthyl, dimethylamino, substituted phenyl, aromatic, substituted aromatic, etc.

[0036] In the following examples, "room temperature" can be 20°C to 30°C.

[0037] Example 1: Synthesis of Curcumol Sulfonyl Ester Derivative 1

[0038] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 2-naphthalenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 1, with a yield of 80%.

[0039] 1 H NMR (600 MHz, CDCl3) δ: 8.5 (s, 1H, H-1′), 7.95 (m, 1H, H-4′), 7.93(m, 1H, H-9′), 7.92 (m, 1H, H-3′), 7.89 (m, 1H, H-7′), 7.63 (m, 1H, H-6′),7.54 (m, 1H, H-8′), 4.86 (s, 2H, H-14), 3.11(m, 1H, H-9a), 2.70 (m, 1H, H-9b), 2.12 (m, 1H, H-1), 2.06 (m, 1H, H-7), 1.99 (m, 1H, H-3a), 1.72 (m, 1H,H-11), 1.70 (m, 1H, H-6a), 1.68 (m, 1H, H-4), 1.51 (m, 1H, H-2a), 1.47 (m,1H, H-2b), 1.07 (m, 3H, H-13), 1.04 (m, 1H, H-3b), 0.94 (m, 1H, H-6b), 0.85 (m, 3H, H-12), 0.49 (m, 3H, H-15). See Figure 1 .

[0040] 13 C NMR (150 MHz, CDCl3) δ: 143.40 (C-10), 137.13 (C-2′), 134.96 (C-5′), 131.94 (C-10 ， ), 129.25 (C-4′), 129.18 (C-1′), 128.81 (C-9′), 128.70 (C-6′), 127.85 (C-7′), 127.36 (C-8′), 123.05 (C-3 V), 114.28 (C-8), 114.87 (C-14), 91.25 (C-5), 55.22 (C-1), 54.13 (C-7), 39.13 (C-4), 37.71 (C-9), 32.79 (C-3), 30.62 (C-6), 28.40 (C-11), 27.73 (C-2), 22.73 (C-12), 21.48 (C-13), 11.66 (C-15). See Figure 2 .

[0041] HR-ESI-MS m / z: 427.1936 [M+H] + (calcd for 427.1943). See Figure 3 .

[0042] Example 2: Synthesis of Curcumol Sulfonyl Ester Derivative 2

[0043] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of dimethylaminosulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 2, with a yield of 70%.

[0044] 1 H NMR (500 MHz, CDCl3) δ: 4.87 (s, 2H, H-14), 3.05 (m, 1H, H-9a), 2.91 (s, 6H, H-1′, H-2′), 2.69 (m, 1H, H-9b), 2.11 (m, 1H, H-7), 2.03 (m, 1H,H-3a), 1.86 (m, 1H, H-6a), 1.77 (m, 1H, H-4), 1.73 (m, 1H, H-11), 1.72 (m,1H, H-1), 1.60 (m, 1H, H-2a), 1.53 (m, 1H, H-2b), 1.16 (m, 1H, H-6b), 1.07(m, 1H, H-3b), 1.05 (m, 3H, H-13), 0.86 (m, 3H, H-12), 0.66 (m, 3H, H-15). See Figure 4 .

[0045] 13C NMR (125 MHz, CDCl3) δ: 143.70 (C-10), 113.71 (C-8), 112.53 (C-14), 90.92 (C-5), 54.48 (C-1), 54.36 (C-7), 39.44 (C-4), 38.41 (C-1′, C-2′), 37.15 (C-9), 33.31 (C-3), 30.98 (C-6), 28.40 (C-11), 28.09 (C-2), 22.80 (C-12), 21.49 (C-13), 12.49 (C-15). See Figure 5 .

[0046] HR-ESI-MS m / z: 344.1869 [M+H] + (calcd for 344.1896). See Figure 6 .

[0047] Example 3: Synthesis of Curcumol Sulfonyl Ester Derivative 3

[0048] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 3,5-difluorobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 3, with a yield of 62.3%.

[0049] 1H NMR (500 MHz, CDCl3) δ: 7.42 (m, 2H, H-2′, H-6′), 7.03 (m, 1H, H-4′), 4.88 (s, 2H, H-14), 3.09 (m, 1H, H-9a), 2.72 (m, 1H, H-9b), 2.13 (m, 1H,H-7), 2.06 (m, 1H, H-1), 2.02 (m, 1H, H-3a), 1.91 (m, 1H, H-6a), 1.81 (m, 1H,H-4), 1.72 (m, 1H, H-11), 1.67 (m, 1H, H-2a), 1.54 (m, 1H, H-2b), 1.22 (m,1H, H-6b), 1.09 (m, 1H, H-3b), 1.04 (m, 3H, H-13), 0.89 (m, 3H, H-12), 0.65(m, 3H, H-15).

[0050] 13 C NMR (125 MHz, CDCl3) δ: 163.37 (C-5′), 161.61 (C-3′), 142.84 (C-10), 115.37 (C-1′), 114.36 (C-4′), 111.69 (C-2′, 6′), 111.50 (C-8), 108.56(C-14), 91.89 (C-5), 55.25 (C-1), 54.08 (C-7), 39.12 (C-4), 37.63 (C-9), 32.62 (C-3), 30.71 (C-6), 28.47 (C-11), 27.90 (C-2), 22.78 (C-12), 21.56 (C-13), 11.94 (C-15).

[0051] HR-ESI-MS m / z: 413.1588 [M+H] + (calcd for 413.1598).

[0052] Example 4: Synthesis of Curcumol Sulfonyl Ester Derivative 4

[0053] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 3,5-dichlorobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 4, with a yield of 53.9%.

[0054] NMR and high-resolution mass spectrometry data of derivative 4: 1 H NMR (600 MHz, CDCl3) δ: 7.83 (m, 2H,H-2′, H-6′), 7.55 (m, 1H, H-4′), 4.89 (s, 2H, H-14), 3.07 (m, 1H, H-9a), 2.70(m, 1H, H-9b), 2.14 (m, 1H, H-7), 2.08 (m, 1H, H-1), 2.06 (m, 1H, H-3a), 1.90(m, 1H, H-6a), 1.80 (m, 1H, H-4), 1.73 (m, 1H, H-11), 1.65 (m, 1H, H-2a),1.58 (m, 1H, H-2b), 1.23 (m, 1H, H-6b), 1.09 (m, 1H, H-3b), 1.06 (m, 3H, H-13), 0.89 (m, 3H, H-12), 0.69 (m, 3H, H-15).

[0055] 13 C NMR (150 MHz, CDCl3) δ: 142.79 (C-10), 135.41 (C-1′), 132.74 (C-4′), 126.31 (C-2′, 6′), 115.24 (C-8), 114.18 (C-14), 91.87 (C-5), 55.24 (C-1), 54.06 (C-7), 39.11 (C-4), 37.61 (C-9), 32.65 (C-3), 30.69 (C-6), 28.28(C-11), 27.69 (C-2), 22.59 (C-12), 21.37 (C-13), 11.70 (C-15).

[0056] HR-ESI-MS m / z: 445.1012 [M+H] +(calcd for 445.1007).

[0057] Example 5: Synthesis of Curcumol Sulfonyl Ester Derivative 5

[0058] Preparation method: Curcumol I (0.21 mmol) and twice the amount of 2,4,6-trichlorobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 5, with a yield of 59.4%.

[0059] 1 H NMR (500 MHz, CDCl3) δ: 7.47 (s, 2H, H-3′, H-5′), 4.91 (s, 2H, H-14), 3.37 (m, 1H, H-9a), 2.69 (m, 1H, H-9b), 2.11 (m, 1H, H-7), 1.99 (m, 1H,H-1), 1.98 (m, 1H, H-3a), 1.84 (m, 1H, H-6a), 1.74 (m, 1H, H-11), 1.73 (m,1H, H-4), 1.63 (m, 2H, H-2), 1.15 (m, 1H, H-6b), 1.07 (m, 1H, H-3b), 1.06 (m,3H, H-13), 0.68 (m, 3H, H-12), 0.41 (m, 3H, H-15).

[0060] 13 C NMR (125 MHz, CDCl3) δ: 143.01 (C-10), 138.10 (C-4′), 136.14 (C-2′, 6′), 135.41 (C-1′), 115.79 (C-8), 113.96 (C-14), 92.16 (C-5), 55.23 (C-1), 54.31 (C-7), 38.94 (C-4), 37.16 (C-9), 32.67 (C-3), 30.76 (C-6), 28.30(C-11), 27.67 (C-2), 22.62 (C-12), 21.45 (C-13), 11.27 (C-15).

[0061] HR-ESI-MS m / z: 479.0612 [M+H] + (calcd for 479.0617).

[0062] Example 6: Synthesis of Curcumol Sulfonyl Ester Derivative 6

[0063] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 4-trifluoromethylbenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 6, with a yield of 60.4%.

[0064] 1 H NMR (500 MHz, CDCl3) δ: 8.06 (m, 2H, H-3′, H-5′), 7.76 (m, 2H, H-2′, H-6′), 4.88 (s, 2H, H-14), 3.09 (m, 1H, H-9a), 2.64 (m, 1H, H-9b), 2.11(m, 1H, H-7), 2.08 (m, 1H, H-1), 2.01 (m, 1H, H-3a), 1.89 (m, 1H, H-6a), 1.74(m, 1H, H-4), 1.73 (m, 1H, H-11), 1.60 (m, 1H, H-2a), 1.51 (m, 1H, H-2b), 1.07 (m, 1H, H-6b), 1.06 (m, 1H, H-3b), 1.08 (m, 3H, H-13), 0.86 (m, 3H, H-12), 0.53 (m, 3H, H-15).

[0065] 13C NMR (125 MHz, CDCl3) δ: 142.92 (C-10), 128.26 (C-5′, C-3′), 125.69 (C-2′, 6′), 114.92 (C-8), 114.16 (C-14), 91.38 (C-5), 55.19 (C-1), 54.12 (C-7), 39.16 (C-4), 37.66 (C-9), 32.76 (C-3), 30.81 (C-6), 28.36 (C-11), 27.76(C-2), 22.69 (C-12), 21.93 (C-13), 11.90 (C-15).

[0066] HR-ESI-MS m / z: 445.1653 [M+H] + (calcd for 445.1660).

[0067] Example 7: Synthesis of Curcumol Sulfonyl Ester Derivative 7

[0068] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 4-fluorobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 7, with a yield of 63.3%.

[0069] 1H NMR (600 MHz, CDCl3) δ: 7.96 (m, 2H, H-3′, H-5′), 7.16 (m, 2H, H-2′, H-6′), 4.87 (s, 2H, H-14), 3.05 (m, 1H, H-9a), 2.69 (m, 1H, H-9b), 2.11(m, 1H, H-7), 2.03 (m, 1H, H-3a), 1.86 (m, 1H, H-6a), 1.77 (m, 1H, H-4), 1.73(m, 1H, H-11), 1.72 (m, 1H, H-1), 1.60 (m, 1H, H-2a), 1.53 (m, 1H, H-2b), 1.16 (m, 1H, H-6b), 1.07 (m, 1H, H-3b), 1.05 (m, 3H, H-13), 0.86 (m, 3H, H-12), 0.66 (m, 3H, H-15).

[0070] 13 C NMR (150 MHz, CDCl3) δ: 166.04 (C-4′), 143.16 (C-10), 136.35 (C-1′), 130.50 (C-5′, C-3′), 115.83 (C-2′, 6′), 114.44 (C-8), 113.97 (C-14),91.38 (C-5), 55.19 (C-1), 54.12 (C-7), 39.16 (C-4), 37.66 (C-9), 32.76 (C-3), 30.81 (C-6), 28.36 (C-11), 27.76 (C-2), 22.69 (C-12), 21.93 (C-13), 11.90 (C-15)

[0071] HR-ESI-MS m / z: 395.1685 [M+H] + (calcd for 395.1692).

[0072] Example 8: Synthesis of Curcumol Sulfonyl Ester Derivative 8

[0073] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 4-nitro-3-chlorosulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 8, with a yield of 65.7%.

[0074] 1 H NMR (600 MHz, CDCl3) δ: 8.45 (s, 1H, H-2′), 8.06 (d, J=10.6 Hz, 1H,H-5′), 7.71 (d, J=10.4 Hz, 1H, H-6′), 4.91 (s, 2H, H-14), 3.86 (s, 3H, H-7′), 3.07 (d, J = 14.8 Hz, 1H, H-9a), 2.69 (dd, J = 14.8, 2.8 Hz, 1H, H-9b), 2.16(m, 1H, H-1), 2.14 (m, 1H, H-7), 2.14 (m, 2H, H-6a), 2.06 (m, 1H, H-3a), 1.88(m, 1H, H-3a), 1.80 (m, 1H, H-4), 1.73 (m, 1H, H-11), 1.62 (m, 2H, H-2), 1.27(m, 1H, H-3b), 1.16 (m, 2H, H-6b), 1.08 (m, 1H, H-3b), 1.05 (d, J = 6.6 Hz, 3H, H-13), 0.85 (d, J = 6.6 Hz, 3H, H-12), 0.71 (d, J = 6.6 Hz, 3H, H-15).

[0075] 13C NMR (150 MHz, CDCl3) δ: 159.51 (C-4′), 157.51 (C-3′), 142.90 (C-10), 132.34 (C-6′), 133.85 (C-2′), 125.29 (C-2′), 116.34 (C-6′), 28.30 (C-11), 27.75 (C-2), 22.61 (C-12), 21.42 (C-13), 11.79 (C-15).

[0076] HR-ESI-MS m / z: 456.1261 [M+H] + (calcd for 456.1248).

[0077] Example 9: Synthesis of Curcumol Sulfonyl Ester Derivative 9

[0078] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 2-pyridinesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 9, with a yield of 59.4%.

[0079] 1H NMR (600 MHz, CDCl3) δ: 9.11 (s, 1H, H-2′), 8.76 (d, J = 4.50 Hz, 1H, H-6′), 8.17 (d, 1H, J = 8.04 Hz, H-4′), 7.43 (dd, 1H, J = 4.50, 8.04 Hz,H-4′), 4.84 (s, 2H, H-14), 3.06 (m, 1H, H-9a), 2.68 (m, 1H, H-9b), 2.08 (m,1H, H-7), 2.00 (m, 1H, H-3a), 1.81 (m, 1H, H-6a), 1.73 (m, 1H, H-4), 1.70 (m,1H, H-11), 1.58 (m, 1H, H-2a), 1.50 (m, 1H, H-2b), 1.46 (m, 1H, H-1), 1.10(m, 1H, H-6b), 1.06 (m, 1H, H-3b), 1.05 (m, 3H, H-13), 0.83 (m, 3H, H-12), 0.52 (m, 3H, H-15).

[0080] 13 C NMR (150 MHz, CDCl3) δ: 153.27 (C-6′), 148.68 (C-2′), 142.91 (C-10), 137.19 (C-3′), 135.41 (C-4′), 123.32 (C-5′), 115.15 (C-8), 114.28 (C-14), 91.86 (C-5), 55.11 (C-1), 54.15 (C-7), 39.20 (C-4), 37.88 (C-9), 32.71(C-3), 30.82 (C-6), 28.41 (C-11), 27.79 (C-2), 22.73 (C-12), 21.52 (C-13), 11.97 (C-15).

[0081] HR-ESI-MS m / z: 378.1736 [M+H] + (calcd for 378.1739).

[0082] Example 10: Synthesis of Curcumol Sulfonyl Ester Derivative 10

[0083] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 8-quinoline sulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 10, with a yield of 57.4%.

[0084] 1 H NMR (600 MHz, CDCl3) δ: 9.16 (dd, J = 4.2, 1.6 Hz, 1H, H-2′), 8.47 (dd, J = 4.2, 1.6 Hz, 1H, H-4′), 8.21 (dd, J = 8.3, 1.5 Hz, 1H, H-7′), 8.03(dd, J = 8.2, 1.1 Hz, 1H, H-5′), 7.59 (t, J = 7.8 Hz, 1H, H-6′), 7.50 (dd, J= 8.3, 4.2 Hz, 1H, H-3′), 4.83 (dt, J = 10.6, 2.2 Hz, 2H, H-14), 2.97 (dq, J= 14.6, 2.5 Hz, 1H, H-9a), 2.71 (d, J = 14.7 Hz, 1H, H-9b), 2.16 (m, 1H, H-7), 2.14 (m, 1H, H-1), 2.08 (t, J = 12.3 Hz, 1H, H-3a), 1.92 (m, 2H, H-6a), 1.87 (m, 1H, H-3a), 1.80 (m, 1H, H-4), 1.62 (m, 2H, H-2), 1.73 (m, 1H, H-11), 1.45 (m, 1H, H-7), 1.26 (m, 1H, H-3b), 1.08 (dd, J = 33.3, 6.5 Hz, 1H, H-3b), 1.05 (d, J = 6.6 Hz, 3H, H-13), 0.98 (m, 2H, H-6b), 0.87 (d, J = 6.6 Hz, 3H,H-12), 0.79 (d, J = 6.6 Hz, 3H, H-15).

[0085] 13C NMR (150 MHz, CDCl3) δ: 171.14 (C-2′), 151.61 (C-8′), 144.06 (C-10), 143.44 (C-9′), 137.77 (C-10′), 136.20(C-7′), 133.79 (C-5′), 132.05 (C-4′), 125.09 (C-6′), 121.98 (C-3′), 114.34 (C-8), 113.65 (C-14), 90.93 (C-5), 54.20 (C-1), 53.94 (C-7), 38.93 (C-4), 37.54 (C-9), 32.62 (C-3), 30.51 (C-6), 28.45 (C-11), 27.46 (C-2), 22.74 (C-12), 21.51 (C-13), 11.56 (C-15).

[0086] HR-ESI-MS m / z: 428.1885 [M+H] + (calcd for 428.1896).

[0087] Example 11: Synthesis of Curcumol Sulfonyl Ester Derivative 11

[0088] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 5-bromothiophene sulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 11, with a yield of 57.4%.

[0089] 1H NMR (600 MHz, CDCl3) δ: 7.46 (s, 1H, H-4′), 7.03 (s, 2H, H-3′), 4.88 (s, 2H, H-14), 3.08 (dq, J = 14.4, 2.5 Hz, 1H, H-9a), 2.69 (d, J = 14.5Hz, 1H, H-9b), 2.16 (m, 1H, H-1), 2.14 (m, 1H, H-7), 2.12 (m, 2H, H-6a), 2.06(t, J = 12.3 Hz, 1H, H-3a), 1.84 (m, 1H, H-3a), 1.77 (m, 1H, H-4), 1.74 (m,1H, H-11), 1.65 (m, 2H, H-2), 1.27 (m, 1H, H-3b), 1.18 (m, 2H, H-6b), 1.08(dd, J = 33.3, 6.5 Hz, 1H, H-3b), 1.03 (d, J = 6.6 Hz, 3H, H-13), 0.88 (d, J= 6.6 Hz, 3H, H-12), 0.76 (d, J = 6.6 Hz, 3H, H-15).

[0090] 13 C NMR (150 MHz, CDCl3) δ: 166.04 (C-4′), 143.08 (C-10), 141.03 (C-5′), 136.35 (C-1′), 133.45 (C-4′), 129.58 (C-3′), 120.71 (C-2′), 28.34 (C-11), 27.89 (C-2), 22.66 (C-12), 21.41 (C-13), 11.94 (C-15).

[0091] HR-ESI-MS m / z: 461.0480 [M+H] + (calcd for 461.0456).

[0092] Example 12: Synthesis of Curcumol Sulfonyl Ester Derivative 12

[0093] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of thiophene sulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 12, with a yield of 60.6%.

[0094] 1 H NMR (600 MHz, CDCl3) δ: 7.72 (dd, J = 3.8, 1.4 Hz, 1H, H-3′), 7.61 (dd, J = 5.0, 1.4 Hz, 1H, H-5′), 7.05 (dd, J = 5.0, 3.8 Hz, 1H, H-4′), 4.88(dt, J = 10.6, 2.2 Hz, 2H, H-14), 3.07 (dq, J = 14.6, 2.5 Hz, 1H, H-9a), 2.69(d, J = 14.7 Hz, 1H, H-9b), 2.16 (m, 1H, H-1), 2.14 (m, 1H, H-7), 2.14 (m,2H, H-6a), 2.06 (t, J = 12.3 Hz, 1H, H-3a), 1.88 (m, 1H, H-3a), 1.80 (m, 1H,H-4), 1.73 (m, 1H, H-11), 1.62 (m, 2H, H-2), 1.27 (m, 1H, H-3b), 1.16 (m, 2H,H-6b), 1.08 (dd, J = 33.3, 6.5 Hz, 1H, H-3b), 1.05 (d, J = 6.6 Hz, 3H, H-13), 0.87 (d, J = 6.6 Hz, 3H, H-12), 0.79 (d, J = 6.6 Hz, 3H, H-15).

[0095] 13C NMR (150 MHz, CDCl3) δ: 166.04 (C-4′), 143.08 (C-10), 141.03 (C-5′), 136.35 (C-1′), 133.45 (C-4′), 129.58 (C-3′), 120.71 (C-2′), 28.34 (C-11), 27.89 (C-2), 22.66 (C-12),21.41 (C-13), 11.94 (C-15). HR-ESI-MS m / z: 383.1317 [M+H] + (calcd for 383.1357).

[0096] Example 13: Synthesis of Curcumol Sulfonyl Ester Derivative 13

[0097] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 4-chlorobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 13, with a yield of 57.7%.

[0098] 1H NMR (500 MHz, CDCl3) δ: 7.87 (m, 2H, H-3′, H-5′), 7.46 (m, 2H, H-2′, H-6′), 4.87 (s, 2H, H-14), 3.09 (m, 1H, H-9a), 2.69 (m, 1H, H-9b), 2.12(m, 1H, H-7), 2.08 (m, 1H, H-3a), 2.03 (m, 1H, H-1), 1.86 (m, 1H, H-6a), 1.77(m, 1H, H-4), 1.74 (m, 1H, H-11), 1.60 (m, 1H, H-2a), 1.54 (m, 1H, H-2b), 1.16 (m, 1H, H-6b), 1.07 (m, 1H, H-3b), 1.04 (m, 3H, H-13), 0.87 (m, 3H, H-12), 0.66 (m, 3H, H-15).

[0099] 13 C NMR (125 MHz, CDCl3) δ: 143.12 (C-10), 139.34 (C-1′), 138.82 (C-4′), 129.23 (C-5′, C-3′), 128.81 (C-2′, 6′), 114.55 (C-8), 114.00 (C-14),91.43 (C-5), 55.22 (C-1), 54.12 (C-7), 39.20 (C-4), 37.67 (C-9), 32.76 (C-3), 30.81 (C-6), 28.35 (C-11), 27.78 (C-2), 22.68 (C-12), 21.43 (C-13), 11.84 (C-15)

[0100] HR-ESI-MS m / z: 411.1382 [M+H] + (calcd for 411.1397).

[0101] Example 14: Synthesis of Curcumol Sulfonyl Ester Derivative 14

[0102] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 4-methylbenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the product was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 14, with a yield of 64.1%.

[0103] 1 H NMR (500 MHz, CDCl3) δ: 7.81 (d, J=8.22 Hz, 2H, H-3′, H-5′), 7.28 (d, J=8.16 Hz, 2H, H-2′, H-6′), 4.86 (s, 2H, H-14), 3.06 (m, 1H, H-9a), 2.66(m, 1H, H-9b), 2.10 (m, 1H, H-7), 2.08 (m, 1H, H-1), 1.99 (m, 1H, H-3a), 1.81(m, 1H, H-6a), 1.77 (m, 1H, H-11), 1.75 (m, 1H, H-4), 1.56 (m, 2H, H-2), 1.15(m, 1H, H-6b), 1.06 (m, 1H, H-3b), 1.04 (m, 3H, H-13), 0.85 (m, 3H, H-12), 0.66 (m, 3H, H-15).

[0104] 13 C NMR (125 MHz, CDCl3) δ: 166.04 (C-4′), 143.16 (C-10), 136.35 (C-1′), 130.50 (C-5′, C-3′), 115.83 (C-2′, 6′), 114.44 (C-8), 113.97 (C-14),91.38 (C-5), 55.19 (C-1), 54.12 (C-7), 39.16 (C-4), 37.66 (C-9), 32.76 (C-3), 30.81 (C-6), 28.36 (C-11), 27.76 (C-2), 22.69 (C-12), 21.93 (C-13), 11.90 (C-15)

[0105] HR-ESI-MS m / z: 391.1934 [M+H] +(calcd for 391.1943).

[0106] Example 15: Synthesis of Curcumol Sulfonyl Ester Derivative 15

[0107] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 4-nitrobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 15, with a yield of 58.8%.

[0108] 1 H NMR (600 MHz, CDCl3) δ: 8.35 (d, J=8.88 Hz, 2H, H-3′, H-5′), 8.13 (d, J=8.94 Hz 2H, H-2′, H-6′), 4.90 (s, 2H, H-14), 3.08 (m, 1H, H-9a), 2.71(m, 1H, H-9b), 2.11 (m, 1H, H-7), 2.03 (m, 1H, H-3a), 1.86 (m, 1H, H-6a), 1.73 (m, 1H, H-11), 1.77 (m, 1H, H-4), 1.63 (m, 1H, H-2a), 1.51 (m, 1H, H-2b), 1.26 (m, 1H, H-1), 1.11 (m, 1H, H-3b), 1.09 (m, 1H, H-6b), 1.07 (m, 3H,H-13), 0.87 (m, 3H, H-12), 0.57 (m, 3H, H-15).

[0109] 13C NMR (150 MHz, CDCl3) δ: 150.24 (C-4′), 146.10 (C-10), 142.75 (C-1′), 129.16 (C-2′, 6′), 123.94 (C-5′, C-3′), 115.54 (C-8), 114.53 (C-14),92.01 (C-5), 55.35 (C-1), 54.17 (C-7), 39.26 (C-4), 37.87 (C-9), 32.82 (C-3), 30.99 (C-6), 28.45 (C-11), 27.86 (C-2), 22.77 (C-12), 21.58 (C-13), 12.05 (C-15)

[0110] HR-ESI-MS m / z: 422.1643 [M+H] + (calcd for 422.1637).

[0111] Example 16: Synthesis of Curcumol Sulfonyl Ester Derivative 16

[0112] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of dansyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 16, with a yield of 57.2%.

[0113] 1H NMR (500 MHz, CDCl3) δ: 8.53 (d, J = 8.3 Hz, 1H, , H-8′), 8.33 (dd,J = 4.2, 1.6 Hz, 1H, H-4′), 8.26 (dd, J = 7.3, 1.3 Hz, 1H, H-2′), 7.56 (dd, J= 8.5, 7.3 Hz, 1H, H-7′), 7.50 (dd, J = 8.5, 7.3 Hz, 1H, H-3′), 7.17 (d, J =7.3 Hz, 1H, H-6′),4.83 (dt, J = 10.6, 2.2 Hz, 2H, H-14), 2.97 (dq, J = 14.6,2.5 Hz, 1H, H-9a), 2.86 (s, 6H, H-11′, H-12′ ), 2.71 (d, J = 14.7 Hz, 1H, H-9b), 2.16 (m, 1H, H-7), 2.14 (m, 1H, H-1), 2.08 (t, J = 12.3 Hz, 1H, H-3a),1.92 (m, 2H, H-6a), 1.80 (m, 1H, H-4), 1.62 (m, 2H, H-2), 1.73 (m, 1H, H-11),1.26 (m, 1H, H-6b), 1.08 (dd, J = 33.3, 6.5 Hz, 1H, H-3b), 1.05 (d, J = 6.6Hz, 3H, H-13), 0.98 (m, 2H, H-6b), 0.87 (d, J = 6.6 Hz, 3H, H-12), 0.79 (d, J= 6.6 Hz, 3H, H-15).

[0114] 13C NMR (125 MHz, CDCl3) δ:171.12 (C-5′), 143.51 (C-10), 136.26 (C-1′), 130.48 (C-8′), 130.04 (C-9′), 129.61 (C-2′), 129.15 (C-10′), 127.96 (C-7′), 123.00 (C-3′), 120.08 (C-4′), 114.99 (C-6′), 114.06 (C-8), 113.59 (C-14), 91.04 (C-5), 55.18 (C-1), 54.07 (C-7), 45.40 (C-11′, 12′), 38.98 (C-4), 37.38 (C-9), 32.58 (C-3), 30.57 (C-6), 28.37 (C-11), 27.53 (C-2), 22.70 (C-12), 21.53 (C-13), 11.40 (C-15).

[0115] HR-ESI-MS m / z: 470.2365 [M+H] + (calcd for 470.2365).

[0116] Example 17: Synthesis of Curcumol Sulfonyl Ester Derivative 17

[0117] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 4-methoxybenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the product was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 17, with a yield of 82.1%.

[0118] 1H NMR (600 MHz, CDCl3) δ: 7.87 (dd, J = 9.2, 3.3 Hz, 2H, H-2′, H-6′), 6.94 (dd, J = 9.1, 3.2 Hz, 2H, H-3′, H-5′), 4.86 (m, 2H, H-14), 3.86 (s, 3H,H-7′), 3.06 (dq, J = 14.6, 2.5 Hz, 1H, H-9a), 2.66 (d, J = 14.7 Hz, 1H, H-9b), 2.16 (m, 1H, H-1), 2.14 (m, 1H, H-7), 2.14 (m, 2H, H-3a), 2.06 (t, J =12.3 Hz, 1H, H-6a), 1.80 (m, 1H, H-4), 1.73 (m, 1H, H-11), 1.62 (m, 2H, H-2), 1.27 (m, 1H, H-3b), 1.16 (m, 1H, H-6b), 1.05 (d, J = 6.6 Hz, 3H, H-13), 0.85 (d, J = 6.6 Hz, 3H, H-12), 0.71 (d, J = 6.6 Hz, 3H, H-15).

[0119] 13 C NMR (150 MHz, CDCl3) δ: 150.24 (C-4′), 146.10 (C-10), 142.75 (C-1′), 129.16 (C-2′, 6′), 123.94 (C-5′, C-3′), 115.54 (C-8), 114.53 (C-14),92.01 (C-5), 55.35 (C-1), 54.17 (C-7), 39.26 (C-4), 37.87 (C-9), 32.82 (C-3), 30.99 (C-6), 28.45 (C-11), 27.86 (C-2), 22.77 (C-12), 21.58 (C-13), 12.05 (C-15)

[0120] HR-ESI-MS m / z: 407.1844 [M+H] + (calcd for 407.1892).

[0121] Example 18: Synthesis of Curcumol Sulfonyl Ester Derivative 18

[0122] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 4-iodobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 18, with a yield of 85.2%.

[0123] 1 H NMR (500 MHz, CDCl3) δ: 7.85 (dt, J = 8.6, 2.0 Hz, 2H, H-2′, 6′), 7.65 (dt, J = 8.5, 2.0 Hz, 2H, H-5′, H-3′), 4.88 (dt, J = 11.1, 2.2 Hz, 2H,H-14), 3.07 (d, J = 14.7 Hz, 1H, H-9a), 2.68 (dd, J = 14.9, 2.3 Hz, 1H, H-9b), 2.11 (m, 1H, H-7), 2.03 (m, 1H, H-3a), 1.86 (m, 1H, H-6a), 1.77 (m, 1H,H-4), 1.73 (m, 1H, H-11), 1.72 (m, 1H, H-1), 1.60 (m, 1H, H-2a), 1.53 (m, 1H,H-2b), 1.16 (m, 1H, H-6b), 1.07 (m, 1H, H-3b), 1.05 (m, 3H, H-13), 0.86 (m,3H, H-12), 0.66 (m, 3H, H-15).

[0124] 13C NMR (125 MHz, CDCl3) δ: 151.55 (C-4′), 143.12 (C-10), 142.75 (C-1′), 137.78 (C-2′, 6′), 129.13 (C-5′, C-3′), 114.55 (C-8), 113.97 (C-14),91.41 (C-5), 55.31 (C-1), 54.13 (C-7), 39.17 (C-4), 37.63 (C-9), 32.75 (C-3), 30.80 (C-6), 28.35 (C-11), 27.77 (C-2), 22.67 (C-12), 21.42 (C-13), 11.79 (C-15)

[0125] HR-ESI-MS m / z: 503.0732 [M+H] + (calcd for 503.0753).

[0126] Example 19: Synthesis of Curcumol Sulfonyl Ester Derivative 19

[0127] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 3-fluoro-4-bromobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 19, with a yield of 45.8%.

[0128] 1H NMR (500 MHz, CDCl3) δ: 7.70 (dt, J = 6.4, 3.2 Hz, 2H, H-2′, H-6′),6.94 (m, 1H, H-5′), 4.86 (m, 2H, H-14), 3.86 (s, 3H, H-7′), 3.07 (d, J = 14.8Hz, 1H, H-9a), 2.69 (dd, J = 14.8, 2.8 Hz, 1H, H-9b), 2.16 (m, 1H, H-1), 2.14(m, 1H, H-7), 2.14 (m, 2H, H-6a), 2.06 (t, J = 12.3 Hz, 1H, H-3a), 1.88 (m,1H, H-3a), 1.80 (m, 1H, H-4), 1.73 (m, 1H, H-11), 1.62 (m, 2H, H-2), 1.27 (m,1H, H-3b), 1.16 (m, 2H, H-6b), 1.08 (dd, J = 33.3, 6.5 Hz, 1H, H-3b), 1.05(d, J = 6.6 Hz, 3H, H-13), 0.85 (d, J = 6.6 Hz, 3H, H-12), 0.71 (d, J = 6.6Hz, 3H, H-15).

[0129] 13 C NMR (125 MHz, CDCl3) δ: 159.51 (C-4′), 157.51 (C-3′), 142.90 (C-10), 141.17 (C-1′), 133.85 (C-2′), 124.41 (C-5′), 116.34 (C-6′), 115.01 (C-8), 114.15 (C-14), 91.69 (C-5), 55.27 (C-1), 54.11 (C-7), 39.17 (C-4), 37.67(C-9), 32.75 (C-3), 30.82 (C-6), 28.33 (C-11), 27.78 (C-2), 22.64 (C-12),21.42 (C-13), 11.76 (C-15).

[0130] HR-ESI-MS m / z: 473.0801 [M+H] + (calcd for 473.0797).

[0131] Example 20: Synthesis of Curcumol Sulfonyl Ester Derivative 20

[0132] Preparation method: Curcumol I (0.21 mmol) and twice the amount of 3,4,5-trifluorobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the product was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 20, with a yield of 57.2%.

[0133] 1 H NMR (500 MHz, CDCl3) δ: 7.63 (m, 2H, H-2′, H-6′), 4.90 (m, 2H, H-14), 3.07 (d, J = 14.2 Hz, 1H, H-9a), 2.70 (dd, J = 14.1, 2.8 Hz, 1H, H-9b),2.16 (m, 1H, H-1), 2.07 (m, 1H, H-7), 2.07 (m, 1H, H-3a), 1.94 (m, 1H, H-6a),1.84 (m, 1H, H-4), 1.74 (m, 1H, H-11), 1.67 (m, 2H, H-2), 1.24 (m, 1H, H-6b), 1.10 (m, 1H, H-3b), 1.10 (d, J = 6.6 Hz, 3H, H-13), 0.86 (d, J = 6.6 Hz, 3H, H-12), 0.71 (d, J = 6.6 Hz, 3H, H-15).

[0134] 13C NMR (125 MHz, CDCl3) δ: 142.67 (C-10), 115.42 (C-8), 114.33 (C-14), 113.28 (C-4′), 113.23 (C-3′, 5′), 113.14 (C-2′, 6′), 113.09 (C-1′),91.92 (C-5), 55.25 (C-1), 54.09 (C-7), 39.16 (C-4), 37.69 (C-9), 32.73 (C-3), 30.88 (C-6), 28.31 (C-11), 27.77 (C-2), 22.61 (C-12), 21.40 (C-13), 11.86 (C-15)

[0135] HR-ESI-MS m / z: 431.1500 [M+H] + (calcd for 431.1504).

[0136] Example 21: Synthesis of Curcumol Sulfonyl Ester Derivative 21

[0137] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 3-fluorobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 21, with a yield of 57.5%.

[0138] 1H NMR (500 MHz, CDCl3) δ: 7.74 (dt, J = 6.5, 3.5 Hz, 1H, H-4′), 7.66(m, 1H, H-6′), 7.48 (m, 1H, H-2′), 7.28 (m, 1H, H-5′), 4.88 (m, 2H, 1.85 (m, 1H, H-6a), 1.77 (m, 1H,H-4), 1.73 (m, 1H, H-11), 1.60 (m, 2H, H-2), 1.16 (m, 2H, H-6b), 1.08 (m, 1H,H-3b), 1.05 (d, J = 6.6 Hz, 3H, H-13), 0.85 (d, J = 6.6 Hz, 3H, H-12), 0.63(d, J = 6.6 Hz, 3H, H-15).

[0139] 13 C NMR (125 MHz, CDCl3) δ: 143.09 (C-10), 130.26 (C-2′), 123.44 (C-4′), 120.10(C-3′), 119.93 (C-5′), 115.37 (C-1′), 115.17 (C-6′), 28.34 (C-11), 27.75 (C-2), 22.66 (C-12), 21.42 (C-13), 11.80 (C-15).

[0140] HR-ESI-MS m / z: 395.1691 [M+H]+ (calcd for 395.1692).

[0141] Example 22: Synthesis of Curcumol Sulfonyl Ester Derivative 22

[0142] Preparation method: Curcumol I (0.21 mmol) and 2 times the amount of 3-chloro-4-fluorobenzenesulfonyl chloride (0.42 mmol) were weighed and mixed, dissolved in DMF (2 mL), stirred at room temperature, and then 6 times the amount of NaH (1.2 mmol) was added. The mixture was heated to 70 °C and stirred, and the reaction was monitored by TLC. After the reaction was complete, the mixture was separated and purified by preparative thin-layer chromatography (cyclohexane:ethyl acetate = 20:1) to obtain derivative 22, with a yield of 50.1%.

[0143] 1 H NMR (500 MHz, CDCl3) δ: 8.05 (dd, J = 6.4, 3.2 Hz, 1H, H-2′), 7.85(m, 1H, H-6′), 7.27 (m, 1H, H-5′), 4.89 (m, 2H, H-14), 3.07 (d, J = 14.8 Hz,1H, H-9a), 2.68 (m, 1H, H-9b), 2.14 (m, 1H, H-1), 2.07 (m, 1H, H-7), 2.06 (m,2H, H-3a), 1.90 (m, 1H, H-6a), 1.80 (m, 1H, H-4), 1.73 (m, 1H, H-11), 1.64(m, 1H, H-2b), 1.57 (m, 1H,H-2a) 1.21 (m, 1H, H-6b), 1.09 (m, 1H, H-3b),1.07 (d, J = 6.6 Hz, 3H, H-13), 0.86 (d, J = 6.6 Hz, 3H, H-12), 0.70 (d, J =6.6 Hz, 3H, H-15).

[0144] 13C NMR (125 MHz, CDCl3) δ: 142.92 (C-10), 137.20 (C-3′), 131.07 (C-2′), 128.20 (C-6′), 121.86 (C-4′), 116.89 (C-1′), 116.71 (C-5′), 28.34 (C-11), 27.77 (C-2), 22.65 (C-12), 21.42 (C-13), 11.82 (C-15).

[0145] HR-ESI-MS m / z: 429.1294 [M+H] + (calcd for 429.1303).

[0146] Test Example 1: Evaluation of the in vitro antiviral activity of curcumin derivatives

[0147] The 293T-IAV-Luc cell genome contains Luciferase, a firefly-driven promoter of influenza virus. Luciferase can be transcribed and expressed in the presence of influenza virus polymerase. Detecting Luciferase activity reflects the activity and content of viral polymerase, thus characterizing viral replication. Laboratory-constructed 293T-IAV-Luc cells were infected with influenza virus (Mingge Wang et al. Microorganisms. 2024; DOI: 10.3390 / microorganisms12040654), and simultaneously supplemented with DMSO (control), turmeric alcohol, derivative 1 (1#), derivative 2 (2#), and hydroxyoseltamivir at a concentration of 1 μmol. Cellular Luciferase activity was detected after 24 hours to indicate the effect of the compounds on influenza virus replication.

[0148] See results Figure 7 The results showed that derivatives 1 and 2 both had good anti-influenza virus effects, and were stronger than curcuminol, with derivative 1 showing the best inhibitory effect on influenza virus.

[0149] Test Example 2: Pharmacodynamic Experiment of Derivative 1 as an Antiviral Agent

[0150] Adult C57 / BL6 mice weighing 18.5-20g were infected with influenza PR8 virus and divided into 4 groups of 16 mice each. A control group was infected with PBS (PBS) without viral load. Two hours after infection, mice were administered derivative 1 (50 mg / kg), oseltamivir (50 mg / kg), or no administration (saline only), once daily for 5 consecutive days. Mice were weighed daily thereafter to monitor survival. Lung tissue samples were collected 3 days post-infection for viral titer determination.

[0151] See results Figure 8 The results showed that derivative 1 could alleviate the decrease in body weight in mice caused by influenza virus infection (A), improve the mortality of mice caused by influenza virus infection (B), and treatment with derivative 1 could inhibit the replication of influenza virus in the lung tissue of mice (C).

[0152] Obviously, the above embodiments of the present invention are merely examples to illustrate the present invention more clearly, and are not intended to limit the implementation of the present invention. For those skilled in the art, other variations or modifications can be made based on the above description. It is impossible to exhaustively list all implementation methods here. Any obvious variations or modifications derived from the technical solutions of the present invention are still within the protection scope of the present invention.

Claims

1. The use of a curcuminol derivative in the preparation of an anti-influenza virus drug, wherein the drug inhibits influenza virus replication through the curcuminol derivative, and the structural formula of the curcuminol derivative is as follows: 。 2. The application according to claim 1, characterized in that, The drug alleviates weight loss caused by influenza virus infection through turmeric alcohol derivatives.

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