Benzylidene paeonol thiazolidone compound as well as synthesis method and application thereof

Abstract

The invention discloses a benzylidene paeonol thiazolidone compound as well as a synthesis method and application thereof. The synthesis method comprises the following steps: condensing paeonol serving as a raw material with thiosemicarbazone by utilizing a pharmaceutical chemical heterozygosis principle to obtain an intermediate paeonol thiosemicarbazone; then, the paeonol thiosemicarbazone and bromoacetic acid are subjected to cyclization, and paeonol thiazolidone is obtained; finally, the paeonol thiazolidone reacts with benzaldehyde with various substituent groups on a benzene ring to generate a series of benzylidene paeonol thiazolidone compounds, the structure of the product is represented through FTIR, 1H-NMR, 13C-NMR and MS (ESI), and the anti-tumor activity of the benzylidene paeonol thiazolidone compounds is tested. Results show that most of the target compounds show good anti-tumor activity, have significant inhibitory activity on various tumor cells (such as HepG2, SK-OV-3, T-24 and A549), are superior to positive control drug cis-platinum, and especially show outstanding performance in liver cancer and ovarian cancer models.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a class of benzylidene paeonol thiazolidinone compounds, their preparation methods, and their application in antitumor drugs. Background Technology

[0002] Paeonol, also known as moutanol, with the chemical name 2-hydroxy-4-methoxyacetophenone, is the main active ingredient of the traditional Chinese medicines peony bark and cynanchum paniculatum. Pharmacological studies have shown that paeonol possesses various pharmacological activities, including antioxidant, antibacterial and anti-inflammatory, sedative-hypnotic, antipyretic and analgesic, immunomodulatory, anti-atherosclerotic, and anticoagulant effects. In recent years, research has found that paeonol has inhibitory effects on the proliferation of various tumor cells and induces apoptosis.

[0003] Thiazoles are a special type of five-membered heterocyclic compound. Most compounds containing this ring exhibit diverse pharmacological activities in organisms, leading to their applications in chemistry, pharmacy, and pesticides. Thiazole compounds can bind to various enzymes and receptors in the body, so they are now widely used in clinical treatment, such as cefdinir (antibacterial drug), thiazolidinedione (antitumor drug), ritonavir (anti-HIV drug), and pioglitazone (insulin sensitizer). Thiazole heterocyclic compounds have attracted considerable attention in drug design due to their broad biological activities (such as antitumor, antibacterial, and antiviral activity).

[0004] Derivatives of paeonol combined with a thiazole ring have been reported in the prior art (e.g., CN109970679B), but their structures differ from the thiazole one compounds of this invention. Currently, there are no reports on the synthesis and antitumor activity studies of benzylidene paeonol thiazole one compounds. Summary of the Invention

[0005] The purpose of this invention is to provide a novel class of benzylidene paeonol thiazolidinone compounds, their preparation method, and their application in antitumor drugs.

[0006] The benzyl paeonol thiazolidinone compound of the present invention has the structure shown in formula (I): ;

[0007] Formula (I);

[0008] Wherein, R is selected from hydrogen, halogen, hydroxyl, C4 alkyl, and C2 alkoxy.

[0009] Furthermore, the halogen is fluorine, chlorine, or bromine; the C4 alkyl group is methyl; and the C2 alkoxy group is methoxy.

[0010] This invention also provides a method for synthesizing the aforementioned benzylidene paeonol thiazolidinone compounds, comprising the following steps:

[0011] Step A: Paeonol and aminothiourea undergo a condensation reaction in an organic solvent in the presence of a catalyst to produce paeonol aminothiourea.

[0012] Step B: The paeonol thiourea reacts with bromoacetic acid in an organic solvent in the presence of a base to generate paeonol thiazolidinone;

[0013] Step C: The paeonol thiazolidinone reacts with substituted benzaldehyde in an organic solvent in the presence of a base to generate a compound of formula (I) benzylpaeonol thiazolidinone.

[0014] Further, in step A, the catalyst is concentrated sulfuric acid, the organic solvent is anhydrous ethanol, and the reaction temperature is 40-80℃;

[0015] In step B, the alkali is sodium acetate, the organic solvent is methanol or anhydrous ethanol, and the reaction temperature is 60-80℃.

[0016] In step C, the base is sodium acetate, the organic solvent is N,N-dimethylformamide or dimethyl sulfoxide, and the reaction temperature is 60-100℃.

[0017] Further, in step B, the molar ratio of paeonol thiourea, bromoacetic acid and sodium acetate is 1:1-2:2;

[0018] The ratio of paeonol thiourea to organic solvent is 0.1 g: 30-60 ml;

[0019] In step C, the molar ratio of paeonol thiazolidinone, sodium acetate, and benzaldehyde with different substituents is 1:3:1-2.

[0020] The ratio of paeonol thiazolidinone to organic solvent is 0.1 g: 5-10 ml.

[0021] The benzyl paeonol thiazolidinone compounds of this invention, as tested by the MTT assay, have shown significant inhibitory activity against a variety of tumor cells (such as HepG2, SK-OV-3, T-24, and A549), which is superior to the positive control drug cisplatin, especially in liver cancer and ovarian cancer models.

[0022] This invention provides a class of benzyl paeonol thiazolidinone compounds with significant antitumor activity. The preparation method is simple, low-cost, and produces little pollution, and has good prospects for drug development.

[0023] The specific implementation methods are described below with reference to the embodiments, but the present invention is not limited thereto.

[0024] Example 1: Synthesis of benzylidene paeonol thiazolidinone compounds

[0025] Synthetic reagents: Paeonol (CP, Shanghai Baoman Biotechnology Co., Ltd.); Thioaminourea (CP, Sinopharm Chemical Reagent Co., Ltd.); Anhydrous ethanol (AR, Chengdu Kelong Chemical Reagent Factory); Concentrated sulfuric acid (AR, Xilong Chemical Co., Ltd.); Chloroform (AR, Xilong Chemical Co., Ltd.); Petroleum ether (AR, Xilong Chemical Co., Ltd.); Ethyl acetate (AR, Xilong Chemical Co., Ltd.); Methanol (AR, Xilong Chemical Co., Ltd.); N,N-Dimethylformamide (DMF, AR, Xilong Chemical Co., Ltd.); Bromoacetic acid (Saen Chemical Technology Shanghai Co., Ltd.); Sodium acetate (Saen Chemical Technology Shanghai Co., Ltd.); 4-CH3 benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 2-F benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 3-F benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 4-F benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 2-Cl benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 3-Cl benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.) (Shanghai Co., Ltd.); 4-Cl benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 2-Br benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 3-Br benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 4-Br benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 2-OH benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 3-OH benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 4-OH benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.); 2-OCH3 benzaldehyde (Saen Chemical Technology Shanghai Co., Ltd.).

[0026] Synthesis instruments: DF-101S magnetic stirrer with heat collection; rotary evaporator; ZF-2 type three-in-one UV spectrometer; electric heating mantle; SHB-III circulating water multi-purpose vacuum pump; Yanaco micro melting point apparatus; Prestige 21 Fourier transform infrared spectrometer; airflow dryer for glass instruments; SHIMAZU LIQUID CHROMATOGRAPH MASS SPECTROMETRE (LC-MS-8030).

[0027] The synthesis route is as follows:

[0028] .

[0029] Synthetic method: Synthesis of paeonol thiourea (2), i.e., paeonol Schiff base:

[0030] Weigh 35 mmol / L of thioaminourea and place it in a 250 mL round-bottom flask. Add 60 mL of anhydrous ethanol and heat and stir under reflux at 80 °C to dissolve it. Then, slowly add 40 mL of hot anhydrous ethanol solution of paeonol (30 mmol / L) to the round-bottom flask, followed by 15 drops of concentrated sulfuric acid. Continue heating and stirring the reaction. Monitor the reaction progress by TLC (chloroform:methanol = 10:1). Stop the reaction after 20 h, add 80 mL of ice water, filter, and wash to obtain a pale yellow solid.

[0031] Synthesis of paeonol thiazolidinone (3):

[0032] Weigh out 1 mmol of paeonol Schiff base, 1.1 mmol of bromoacetic acid, and 2 mmol of sodium acetate, place them in a 250 mL round-bottom flask, add 150 mL of anhydrous ethanol, stir and reflux at 80 °C, and monitor the reaction progress by TLC (petroleum ether: ethyl acetate = 1:1). After 10 h of reaction, stop the reaction, remove a large amount of ethanol by rotary evaporation, add 80 mL of ice water, filter, wash, recrystallize with 95% ethanol, filter, and dry to obtain a pale yellow solid.

[0033] Synthesis of benzylidene paeonol thiazolidinone compounds (5a-o):

[0034] Weigh 1 mmol of paeonol thiazolidinone, 3 mmol of sodium acetate, and 1.1 mmol of compound 4a-4o (different substituted benzaldehydes) and place them in a 100 mL round-bottom flask. Add 15 mL of DMF and stir under a heating mantle until the mixture is refluxed. Monitor the reaction progress by TLC (petroleum ether: ethyl acetate = 1:1). After the reaction is complete, cool the mixture, dissolve the ethyl acetate, wash with distilled water, and pass the solution through a column (petroleum ether: ethyl acetate = 4:1) to obtain the solid product 5a-o.

[0035] Product 5a-o 1 H-NMR, 13 The C-NMR characterization and structural formula are as follows:

[0036] 5-(benzylidene)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5a): yellow solid, yield: 29.5%; mp 224.9-226.7 ℃; IR (KBr, cm⁻¹) -1 ): 1711(-C=O), 1608(C=N), 1524(-NH-), 1434, 1366, 1347, (-CH3); 1H NMR (600 MHz, DMSO-d6) δ 12.72 (s, 1H),7.65 (s, 1H), 7.63-7.52 (m, 5H), 7.47 (t, J=7.3 Hz, 1H), 6.52 (q, J=2.5 Hz,2H), 3.78 (s, 3H), 2.51 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.44, 167.39,162.92, 161.64, 156.14, 133.90, 131.14, 130.46, 130.17, 130.12, 129.75,122.61, 112.87, 106.81, 101.79, 55.79, 15.11, 14.55. MS-ESI m / z:366.09 ([MH] - );

[0037] The structural formula is:

[0038] .

[0039] 5-(2-Fluorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5b): Yellow solid, mp 243.5-243.8 ℃; yield: 32.54%; IR (KBr, cm⁻¹) -1 ): 1625(C=N), 3117(NH), 1696(C=O); 1 H NMR (600 MHz, DMSO-d6) δ 12.65 (s, 1H), 7.63 (s, 1H), 7.62-7.49 (m, 3H), 7.45-7.33 (m, 2H), 6.53-6.45 (m, 2H), 3.77 (s, 3H), 2.50(s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 167.49, 167.35, 162.90, 161.62, 160.00,156.08, 132.64, 132.58, 131.12, 128.98, 125.76, 125.74, 125.57, 121.89,121.81, 120.78, 120.74, 116.70, 116.56, 112.85, 106.79, 101.75, 55.77, 15.12.MS-ESI m / z: 384.10 ([MH] - );

[0040] The structural formula is:

[0041] .

[0042] 5-(3-Fluorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5c): Yellow solid, mp 246.5-246.8 ℃; yield: 35.26%; IR (KBr, cm⁻¹) -1 ): 1623(C=N), 3120(NH), 1696 (C=O); 1 H NMR (600 MHz, DMSO-d6 ) δ12.68 (s, 1H), 7.47 (s, 2H), 7.42 (s, 1H), 7.31 (s, 1H), 7.24 (d, J=5.0 Hz, 2H), 6.61 (s, 1H), 6.47 (s,1H), 3.84 (s, 3H), 3.54 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 169.39, 165.45,162.95, 160.73, 159.39, 153.06, 133.78, 130.21, 130.09, 129.57, 129.20,127.70, 118.51, 114.47, 112.64, 107.52, 100.45, 56.08, 15.80. MS-ESI m / z:384.10 ([MH] - );

[0043] The structural formula is:

[0044] .

[0045] 5-(4-Fluorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5d): yellow solid, mp 218.3-219.8 ℃; yield: 20.17%; IR (KBr, cm⁻¹) -1 ): 1623(C=N), 3209(NH), 1712(C=O); 1 H NMR (600 MHz, DMSO-d6) δ 12.70 (s, 1H), 7.67 (t, J=4.3Hz, 2H), 7.60 (d, J=8.9 Hz, 1H), 7.56 (d, J= 8.9 Hz, 1H), 7.42 (t, J=7.8 Hz, 2H), 6.53 (dd, J=8.8, 2.6 Hz, 1H), 6.46 (d, J=2.6 Hz, 1H), 3.78 (s, 3H), 2.52(s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 173.93, 167.55, 167.28, 166.11, 162.94,162.61, 161.62, 155.86, 132.56, 132.51, 131.18, 130.82, 130.54, 129.12,122.24, 116.87, 112.90, 106.60, 101.77, 55.76, 14.71. MS-ESI m / z: 384.10 ([MH] - );

[0046] The structural formula is:

[0047] .

[0048] 5-(2-Chlorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5e): Yellow solid, mp 218.7-219.1 ℃; yield: 21.0%; IR (KBr, cm⁻¹) -1 ): 1624(C=N), 3132(NH), 1712(C=O); 1H NMR (600 MHz, DMSO-d6) δ 12.60 (s, 1H), 7.80 (s, 1H), 7.59 (ddd, J=14.7, 11.6, 7.3 Hz, 4H), 7.48 (t, J=8.4 Hz, 1H), 6.54-6.46 (m, 2H),3.77 (s, 3H), 2.51 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.78, 166.91,162.97, 161.61, 155.62, 134.69, 131.90, 131.85, 131.19, 130.80, 129.09,128.49, 126.21, 125.17, 112.82, 106.84, 101.76, 55.79, 15.18. MS-ESI m / z:400.10 ([MH] - );

[0049] The structural formula is:

[0050] .

[0051] 5-(3-Chlorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5f): yellow solid, mp 230.9-232.2 ℃; yield: 48.5%; IR (KBr, cm⁻¹) -1 ): 1624(C=N), 3119(NH), 1695(C=O); 1 H NMR (600 MHz, DMSO-d6) δ 12.64 (s, 1H), 7.67 (s, 1H), 7.63(s, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.53 (dd, J=15.9, 7.9 Hz, 2H), 6.52 (dd, J=8.8, 2.6 Hz, 1H), 6.50 (d, J=2.5 Hz, 1H), 3.78 (s, 3H), 2.51 (s, 3H). 13C NMR(151 MHz, DMSO-d6) δ 167.70, 167.10, 162.97, 161.65, 155.64, 136.08, 134.37,131.52, 131.27, 131.17, 130.15, 130.02, 128.50, 127.92, 124.39, 112.82,106.91, 101.75, 55.81, 15.18. MS-ESI m / z: 400.10 ([MH] - );

[0052] The structural formula is:

[0053] .

[0054] 5-(4-Chlorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5 g): yellow solid, mp 247.9-248.9 ℃; yield: 28.5%; IR (KBr, cm⁻¹) -1 ): 1623(C=N), 3193(NH), 1715(C=O); 1 H NMR (600 MHz, DMSO-d6) δ 12.66 (s, 1H), 7.61 (t, J=11.9Hz, 6H), 6.52 (d, J=8.7 Hz, 1H), 6.49 (s, 1H), 3.79 (s, 3H), 2.51 (s, 3H). 13 CNMR (151 MHz, DMSO-d6) δ 167.62, 167.19, 162.94, 161.60, 155.69, 135.01,132.78, 131.74, 131.18, 129.82, 129.77, 128.83, 123.34, 112.88, 106.80,101.75, 55.80, 15.18. MS-ESI m / z: 400.10 ([MH] - );

[0055] The structural formula is:

[0056] .

[0057] 5-(2-Bromobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5h): yellow solid, yield: 23.4%; mp 241.3-243.2℃; IR (KBr, cm⁻¹) -1 ): 1695(-C=O), 1623(C=N), 1521(-NH-),1479(-CH3); 1 H NMR (600 MHz, DMSO-d6) δ 12.60 (s, 1H), 7.81(d, J=7.8 Hz, 1H), 7.76 (s, 1H), 7.63-7.57 (m, 3H), 7.42-7.38 (m, 1H), 6.52(dd, J=8.9, 2.6 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ167.79, 166.86, 162.98, 161.60, 155.66, 134.07, 133.61, 132.07, 131.21,129.23, 129.02, 127.98, 126.26, 125.56, 112.82, 106.85, 101.77, 55.81, 15.20.MS-ESI m / z: 445.9 ([M+H] + );

[0058] The structural formula is:

[0059] .

[0060] 5-(3-Bromobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5i): yellow solid, yield: 27.8%; mp 240.0-241.9 °C; IR (KBr, cm⁻¹) -1 ): 1702(-C=O), 1619(C=N),1522(-NH-), 1465(-CH3); 1H NMR (600 MHz, DMSO-d6) δ 12.68 (s, 1H), 7.82 (s,1H), 7.64 (d, J=8.8 Hz, 1H), 7.61-7.57 (m, 3H), 7.52 (t, J=7.9 Hz, 1H), 6.52(dd, J=8.8, 2.6 Hz, 1H), 6.49 (d, J=2.6 Hz, 1H), 3.78 (s, 3H), 2.51 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.75, 167.31, 162.89, 161.62, 156.45, 136.48,133.02, 132.78, 131.70, 131.11, 128.18, 128.04, 122.91, 112.89, 106.86,101.74, 55.81, 15.16, 14.56. MS-ESI m / z: 445.9 ([M+H] + );

[0061] The structural formula is:

[0062] .

[0063] 5-(4-Bromobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5j): yellow solid, yield: 26.7%; mp 251.6-252.7 ℃; IR (KBr, cm⁻¹) -1 ): 1688(-C=O), 1618(C=N), 1542(-NH-), 1454(-CH3), 1260(-OH); 1 H NMR (600 MHz, DMSO-d6) δ 12.66 (s,1H), 7.76 (d, J=8.5 Hz, 2H), 7.62 (s, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.54 (d, J=8.5 Hz, 2H), 6.53 (dd, J=8.9, 2.6 Hz, 1H), 6.49 (d, J=2.6 Hz, 1H), 3.79 (s,3H), 2.51 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 167.63, 167.22, 162.95,161.59, 155.73, 147.57, 133.13, 132.76, 131.91, 131.20, 128.93, 123.88,123.49, 118.93, 112.90, 106.81, 101.76, 55.81, 15.20. MS-ESI m / z: 445.9 ([M+H] + );

[0064] The structural formula is:

[0065] .

[0066] 5-(2-hydroxybenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5k): Yellow solid, yield: 28.9%; mp 271.0-273.1 °C; IR (KBr, cm⁻¹) -1 ): 1721(-C=O),1618(C=N), 1542(-NH-), 1454(-CH3), 1260(-OH); 1 H NMR (600 MHz, DMSO-d6) δ12.78 (s, 1H), 10.47 (s, 1H), 7.92 (s, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.41 (d,J=7.6 Hz, 1H), 7.31 (t, J=8.2 Hz, 1H), 7.00 (dd, J=12.5, 7.9 Hz, 2H), 6.54-6.52 (m, 1H), 6.51 (d, J=2.4 Hz, 1H), 3.79 (s, 3H), 2.52 (s, 3H). 13 C NMR (151MHz, DMSO-d6) δ 167.62, 167.19, 162.87, 161.63, 157.49, 156.58, 132.28,131.10, 128.60, 125.51, 121.03, 120.85, 120.08, 116.58, 112.89, 106.77,101.80, 55.80, 15.05. MS-ESI m / z: 382.0([MH] - );

[0067] The structural formula is:

[0068] .

[0069] 5-(3-hydroxybenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5l): Yellow solid, yield: 29.7%; mp 242.7-243.6 ℃; IR (KBr, cm⁻¹) -1 ): 1707(-C=O),1615(C=N), 1514(-NH-), 1443(-CH3), 1243(-OH); 1 H NMR (600 MHz, DMSO-d6) δ12.73 (s, 1H), 9.90 (s, 1H), 7.60 (d, J =9.6 Hz, 1H), 7.56 (s, 1H), 7.35 (t,J =7.9 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 7.01 (t, J=1.7 Hz, 1H), 6.89 (dd, J=8.1, 1.8 Hz, 1H), 6.53 (dt, J=6.0, 3.1 Hz, 2H), 3.79 (s, 3H), 2.52 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 167.48, 167.36, 162.93, 161.62, 158.35, 156.15,135.07, 131.16, 130.77, 130.47, 122.34, 121.44, 117.81, 116.33, 112.91,106.82, 101.81, 55.81, 15.15. MS-ESI m / z: 382.0([MH] - );

[0070] The structural formula is:

[0071] .

[0072] 5-(4-hydroxybenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5m): yellow solid, yield: 23.4%; mp 206.2-209.2℃; IR (KBr, cm⁻¹) -1 ):1705(-C=O), 1605(C=N),1514(-NH-), 1438, 1365(-CH3); 1H NMR (600 MHz, DMSO-d6) δ12.69 (s, 1H), 10.02(s, 1H), 7.74 (s, 2H), 7.42 (s, 1H), 7.31 (s, 1H), 6.80 (s, 2H), 6.61 (s,1H), 6.47 (s, 1H), 3.84 (s, 3H), 3.54 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ169.39, 165.45, 160.85, 160.73, 159.39, 153.06, 132.61, 132.23, 131.83,129.20, 124.72, 116.04, 112.64, 107.52, 100.45, 56.08, 15.80. MS-ESI m / z:382.0([MH] - );

[0073] The structural formula is:

[0074] .

[0075] 5-(4-methylbenzylidene)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5n): yellow solid, mp 207.8-208.8℃; yield: 23.4%; mp IR (KBr, cm⁻¹) -1 ): 1607(C=N), 3126(NH), 1705(C=O); 1 H NMR (600 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.60 (dd, J=17.9,9.6 Hz, 2H), 7.38 (d, J=3.0 Hz, 1H), 7.31 (d, J=7.9 Hz, 1H), 7.17 (d, J=7.8Hz, 2H), 6.50 (dd, J=8.9, 2.6 Hz, 1H), 6.42 (d, J=2.6 Hz, 1H), 3.76 (s, 3H), 2.43 (s, 3H), 2.37 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 175.31, 166.22,162.89, 162.62, 161.62, 161.56, 160.29, 136.54, 134.42, 130.83, 130.37,130.35, 129.53, 128.45, 128.13, 122.43, 112.94, 112.84, 106.78, 106.54,101.82, 101.73, 55.82, 55.75, 40.54, 40.42, 40.28, 40.14, 40.00, 39.86,39.72, 39.58, 21.13, 14.68. MS-ESI m / z: 380.03([MH] - );

[0076] The structural formula is:

[0077] .

[0078] 5-(2-Methoxybenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5o): yellow solid, mp 207.8-208.8 ℃; yield: 24.8%; IR (KBr, cm⁻¹) -1 ): 1617(C=N),3205(NH), 1697(C=O); 1 H NMR (600 MHz, DMSO-d6) δ 12.89 (s, 1H), 7.86 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.57 (d, J=8.9 Hz, 1H), 7.49 (d, J=7.6 Hz, 1H), 7.15(t, J=8.6 Hz, 2H), 6.55-6.52 (m, 1H), 6.46 (d, J=2.5 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3H), 2.47 (s, 3H). 13C NMR (151 MHz, DMSO-d6) δ 173.95, 166.11,162.88, 162.61, 162.16, 161.63, 158.29, 132.44, 131.12, 130.83, 128.87,122.40, 121.38, 112.90, 112.33, 106.82, 106.61, 101.79, 101.73, 56.19, 55.77,40.54, 40.42, 40.28, 40.14, 40.00, 39.86, 39.72, 39.58, 14.72. MS-ESI m / z: 396.10 ([MH]) - );

[0079] The structural formula is:

[0080] .

[0081] Example 2: Antitumor activity of the target compound

[0082] T-24 (human bladder cancer cells), HepG2 (human liver cancer cells), SK-OV-3 (human ovarian cancer cells), and A549 (human lung cancer cells) were cultured in DEME medium: fetal bovine serum: penicillin-streptomycin antibiotic = 100:10:1 in a complete culture medium and incubated at 37 ℃ in a 5% CO2 incubator at a density of 1 × 10⁶ cells per well. 5 Cells were seeded at a density of [insert density here] in 96-well plates. An equal volume of PBS was added around each well, and the plates were gently tapped to ensure even cell distribution. Different concentrations of cisplatin, paeonol, and a synthetic paeonol pyrimidine compound were added and incubated for 44 hours. Then, 20 μl of MTT (5 mg / ml) was added to each well for 4 hours. Finally, 150 μl of DMSO was added to each well, and the plates were shaken for 10 minutes to dissolve the crystals. The absorbance (OD) value of each well was measured at 490 nm using an ELISA reader. The results were calculated, and the cell growth inhibition rate was calculated using the formula: Growth inhibition rate (%) = (OD value of control group - OD value of experimental group) / OD value of control group × 100%. All experiments were repeated three times, and the average value was taken. IC50 50 Calculated using SPSS 23.0.

[0083] Bioactivity analysis:

[0084] The in vitro antitumor activity of benzylidene paeonol thiazolidinone compounds 5a-5o against T-24 (human bladder cancer cells), HepG2 (human liver cancer cells), SK-OV-3 (human ovarian cancer cells), and A549 (human lung cancer cells) was determined using a tetramethylazoazole salt microenzymatic reaction colorimetric method. The positive control was the antitumor drug cisplatin. The test results are shown in Table 1. Most of the target compounds showed good antitumor activity, among which compound 5d showed the highest IC50 against HepG2 liver cancer cells. 50 The value was (0.66±0.08) μg / mL. Compound 5o had an IC50 value of (0.66±0.08) μg / mL against human hepatocellular carcinoma cells HepG2 and human ovarian carcinoma cells SK-OV-3. 50 The values ​​were (2.13±0.16) μg / mL and (5.67±0.36) μg / mL, respectively, both of which were superior to the positive control drug cisplatin.

[0085] Table 1. In vitro antitumor activity of the compounds: .

[0086] In this embodiment, 15 benzyl paeonol thiazolidinone compounds were synthesized from paeonol, thioaminourea, bromoacetic acid and substituted benzaldehyde through condensation and cyclization reactions. This method is convenient to operate, with low consumption and little pollution, and the target products have certain research value.

[0087] The examples utilize FTIR, 1 H NMR, 13 The structures of the target compounds were characterized by C10 NMR and ESI-MS, and preliminary antitumor activity tests were performed. The results showed that some compounds exhibited certain antitumor activity against T-24, HepG2, SK-OV-3, and A549 tumor cells. Compound 5o showed significant IC50 activity against human hepatocellular carcinoma HepG2 and human ovarian cancer cells SK-OV-3. 50 The values ​​reached (2.13±0.16) μg / mL and (5.67±0.36) μg / mL, respectively. In particular, compound 5d showed a significant IC50 effect on HepG2 human liver cancer cells. 50 The value of (0.66±0.08) μg / mL significantly exceeded the antitumor activity of cisplatin against this cancer cell line, indicating good research value.

Claims

1. A benzylidene paeonol thiazolidinone compound, characterized in that, It has the structure shown in equation (I): ； Formula (I); Wherein, R is selected from hydrogen, halogen, hydroxyl, C4 alkyl, and C2 alkoxy.

2. The benzylidene paeonol thiazolidinone compound according to claim 1, characterized in that, The halogen is fluorine, chlorine, or bromine; the C4 alkyl group is methyl; and the C2 alkoxy group is methoxy.

3. The benzylidene paeonol thiazolidinone compound according to claim 1 or 2, characterized in that, The compound is selected from any of the following structures: 5-(benzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5a), with the following structural formula: ; 5-(2-fluorobenzylidene)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5b), with the following structural formula: ; 5-(3-fluorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5c), with the following structural formula: ; 5-(4-fluorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5d), with the following structural formula: ; 5-(2-chlorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5e), ​​with the following structural formula: ; 5-(3-chlorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5f), with the following structural formula: ; 5-(4-chlorobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5g), with the following structural formula: ; 5-(2-bromobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5h), with the following structural formula: ; 5-(3-bromobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5i), with the following structural formula: ; 5-(4-bromobenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5j), with the following structural formula: ; 5-(2-hydroxybenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5k), with the following structural formula: ; 5-(3-hydroxybenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5l), with the following structural formula: ; 5-(4-hydroxybenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5m), with the following structural formula: ; 5-(4-methylbenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5n), with the following structural formula: ; 5-(2-methoxybenzyl)-2-((1-(2-hydroxy-4-methoxyphenyl)ethylene)hydrazone)thiazolidin-4-one (5o), with the following structural formula: .

4. A method for preparing the benzylidene paeonol thiazolidinone compound as described in claim 1, characterized in that, The synthesis method includes the following steps: Step A: Paeonol and aminothiourea undergo a condensation reaction in an organic solvent in the presence of a catalyst to produce paeonol aminothiourea. Step B: The paeonol thiourea reacts with bromoacetic acid in an organic solvent in the presence of a base to generate paeonol thiazolidinone; Step C: The paeonol thiazolidinone reacts with substituted benzaldehyde in an organic solvent in the presence of a base to generate a compound of formula (I) benzylpaeonol thiazolidinone.

5. The synthesis method according to claim 4, characterized in that: In step A, the catalyst is concentrated sulfuric acid, the organic solvent is anhydrous ethanol, and the reaction temperature is 40-80℃; In step B, the alkali is sodium acetate, the organic solvent is methanol or anhydrous ethanol, and the reaction temperature is 60-80℃. In step C, the base is sodium acetate, the organic solvent is N,N-dimethylformamide or dimethyl sulfoxide, and the reaction temperature is 60-100℃.

6. The synthesis method according to claim 5, characterized in that: In step B, the molar ratio of paeonol thiourea, bromoacetic acid and sodium acetate is 1:1-2:2; The ratio of paeonol thiourea to organic solvent is 0.1 g: 30-60 ml; In step C, the molar ratio of paeonol thiazolidinone, sodium acetate, and benzaldehyde with different substituents is 1:3:1-2. The ratio of paeonol thiazolidinone to organic solvent is 0.1 g: 5-10 ml.

7. The use of the benzylidene paeonol thiazolidinone compound as described in any one of claims 1-3 in the preparation of antitumor drugs.

8. The application according to claim 7, characterized in that, The antitumor drugs are used to treat liver cancer, ovarian cancer, bladder cancer, or lung cancer.

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