An indigo 5-arylthiazolo[2,3-b]quinazolin-6-one derivative, and a preparation method and application thereof

Abstract

The present application provides a kind of as formula (I) shown new 1-[(8,8-dimethyl-6-oxo-5-arylthiazolo [2,3 b ] quinazolin-3-yl) methyl] indoline-2,3-dione derivative, in formula (I), substituent R is H, C 1‑6 Alkyl, F, Cl, Br, I, alkoxy, hydroxyl, nitrile group, nitro group, carboxyl, amino or sulfonic acid group. The 1-[(8,8-dimethyl-6-oxo-5-arylthiazolo [2,3 b ] quinazolin-3-yl) methyl] indoline-2,3-dione derivative of the present application has certain inhibitory activity on tumor cells, and its synthesis method is simple, and the material is easy to obtain. It can be used to make antitumor drugs.

Description

Technical Field

[0001] This invention relates to the field of pharmaceuticals, and more specifically, to a 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivative, its preparation method, and its application as an anticancer drug. Background Technology

[0002] Cancer has become one of the most serious non-communicable diseases threatening human health and life. Currently, the main treatments for cancer are radiotherapy and chemotherapy. Therefore, the research and development of anticancer drugs has always been a hot topic for chemists and pharmacologists. Finding highly effective, selective, and low-toxicity anticancer drugs is one of the key directions in drug research and development.

[0003] Quinazoline derivatives are nitrogen-containing heterocyclic compounds widely found in natural products and drug molecules, attracting considerable interest due to their unique chemical, physiological, and pharmacological activities. Increasing research indicates that quinazoline compounds possess biological activities such as anticancer, antibacterial, anti-inflammatory, antiviral, and analgesic effects. For example, Jr. RR reported that erlotinib exhibits excellent antitumor activity (Pharmacol. Res. 2014, 87, 42-59), and Hong YL et al. reported a class of quinazoline derivatives with excellent anti-inflammatory activity (Eur. J. Med. Chem. 2025, 294, 117716). Given the importance of quinazoline compounds in organic and pharmaceutical synthesis, the synthesis and activity studies of these compounds have garnered significant interest.

[0004] Indigo (also known as Isatin) is an indole compound derived from marine organisms, specifically lobsters, and is a natural marine antibiotic essential for their survival. It possesses various biological activities, including antibacterial, anti-inflammatory, and antitumor effects. Examples of its clinical applications include the anticancer drugs Semaxanib (SU5416) and Sunitinib (SU11248) (Arch. Pharm. 2020, 353, 1900272). Chen R. et al. reported that isatin-oxime hybrid molecules exhibit strong antiviral activity (2019, Bioorg. Med. Chem. Lett. 29, 2635–2637). Therefore, designing and synthesizing novel indigo-containing quinazoline derivatives for use in antitumor drugs has significant theoretical and practical implications. Summary of the Invention

[0005] The purpose of this invention is to provide a novel 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivative.

[0006] The present invention also aims to provide a method for preparing a 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivative.

[0007] The purpose of this invention is also to provide the application of the above-mentioned 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivative in the preparation of antitumor drugs.

[0008] The above-mentioned objective of the present invention is achieved by the following solution:

[0009] A 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivative, the chemical structure of which is shown in Formula I:

[0010]

[0011] In formula (I), the substituent R is H or C. 1-6 Alkyl, F, Cl, Br, I, alkoxy, hydroxyl, nitrile, nitro, carboxyl, amino, or sulfonic acid groups.

[0012] A method for preparing a 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivative, wherein the general reaction formula is:

[0013]

[0014] The specific steps are as follows:

[0015] (1) Thiourea and aminosulfonic acid were dissolved in anhydrous ethanol. 5,5-Dimethyl-1,3-cyclohexanedione was slowly added to the system. After the solid in the reaction flask was completely dissolved, aromatic aldehyde was added. The reaction temperature was 80℃, and the reaction was refluxed for about 10 h. The reaction process was monitored by TLC. After the reaction was completed, a large amount of white solid precipitated in the reaction solution. The solid was filtered while hot, and the residue was recrystallized from ethanol to obtain intermediate 7,7-dimethyl-4-aryl-2-thioquinazoline-5(1H)-one 1.

[0016] (2) Weigh 1,3-dichloropropanone, then add anhydrous ethanol and tetrahydrofuran as solvents, and finally add intermediate 1. Reflux the reaction at 80°C. Solids gradually precipitate in the reaction flask, and the reaction progress is monitored by TLC. After the reaction is complete, a large amount of yellow solid appears in the reaction solution. Heating is stopped immediately, and the reaction mixture is filtered while hot. The filter cake is thoroughly washed with anhydrous ethanol until the filtrate is colorless. The obtained solid is dehydrated with concentrated sulfuric acid to obtain a cyclized liquid. Then, quenching, pH adjustment, extraction, and vacuum concentration are performed to obtain intermediate 3-(chloromethyl)-8,8-dimethyl-5-arylthiazo[2,3-b]quinazolin-6-one 2.

[0017] (3) Intermediate 2 was dissolved in tetrahydrofuran, and then potassium iodide, potassium carbonate, and indigo were added. The mixture was refluxed at 70°C, and the reaction was monitored by TLC. After the reaction was completed, heating was stopped, and the reaction solution was cooled to room temperature. The solution was then concentrated under reduced pressure, and an appropriate amount of silica gel was added for mixing. The solution was then purified by column chromatography to obtain the target compound 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione 3.

[0018] Preferably, the catalyst in step (1) is aminosulfonic acid, and the reaction temperature is 80°C.

[0019] Preferably, the reflux temperature in step (2) is 80°C.

[0020] Preferably, the alkali mentioned in step (3) is potassium carbonate, the solvent is tetrahydrofuran, and the reflux temperature is 70°C.

[0021] The application of the 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivative in the preparation of antitumor drugs.

[0022] The dosage form of the antitumor drug is tablet, pill, capsule, injection, suspension or emulsion.

[0023] The beneficial effects of this invention are as follows: Experiments have demonstrated that the 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivative of this invention exhibits good inhibitory activity against tumor cells. It can be used to prepare drugs that inhibit tumor cells. Furthermore, the synthesis method is simple, the materials are readily available, and the yield is high, providing a new development avenue for antitumor drugs. Detailed Implementation

[0024] To better understand the present invention, examples of preparing 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivatives are given, and the present invention includes, but is not limited to, this preparation method.

[0025] Example 1: Synthesis of 1-((5-(4-fluorophenyl)-8,8-dimethyl-6-oxothiazolo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione (3a).

[0026] Sulfamic acid (0.87 g, 9.0 mmol) and thiourea (1.14 g, 15 mmol) were weighed and dissolved in 10 mL of anhydrous ethanol. Then, 5,5-dimethyl-1,3-cyclohexanedione (1.68 g, 12 mmol) was slowly added at 50 °C. After all the solid in the reaction flask had dissolved, p-fluorobenzaldehyde (1.24 g, 10 mmol) was added. The reaction was refluxed at 80 °C, and the reaction was monitored by TLC. After the reaction was complete, a large amount of white solid appeared in the reaction flask. The solid was filtered while hot and recrystallized from ethanol to give intermediate 4-(4-fluorophenyl)-7,7-dimethyl-2-thio-2,3,4,6,7,8-hexahydroquinazoline-5(1H)-one.

[0027] 0.89 g (7.0 mmol) of 1,3-dichloropropanone was dissolved in 5 mL of anhydrous ethanol and 1 mL of tetrahydrofuran. Intermediate 1 (1.82 g, 6.0 mmol) was then added, and the mixture was stirred at room temperature for 10 min. The mixture was then transferred to an 80°C oil bath to continue the reaction. A solid gradually precipitated in the reaction flask, and the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was filtered while hot, and the filter cake was thoroughly washed with anhydrous ethanol until the filtrate was colorless. The resulting pale yellow solid was placed in a reaction flask, and concentrated sulfuric acid was slowly added in portions with magnetic stirring. The reaction mixture was stirred at room temperature, and the reaction solution was quenched by slowly adding it dropwise to a mixture of crushed ice and water under ice bath cooling. The pH was adjusted to neutral with saturated sodium bicarbonate solution. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The intermediate 3-(chloromethyl)-5-(4-fluorophenyl)-8,8-dimethyl-5,7,8,9-tetrahydro-6H-thiazo[2,3-b]quinazolin-6-one was finally obtained.

[0028] Intermediate 2 (0.38 g, 1.0 mmol) was dissolved in 5 mL of tetrahydrofuran, followed by the addition of potassium iodide (0.17 g, 1.0 mmol), potassium carbonate (0.17 g, 1.2 mmol), and indigo (0.22 g, 1.5 mmol). The mixture was heated to reflux at 70 °C, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, concentrated under reduced pressure, mixed with an appropriate amount of silica gel, and purified by column chromatography to obtain the orange solid target compound 1-((5-(4-fluorophenyl)-8,8-dimethyl-6-oxothiazo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione. Its chemical structure is shown in formula (3a), with a yield of 80%.

[0029]

[0030] 3a

[0031] 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 7.2 Hz, 1H), 7.41 (t, J= 8.0 Hz, 1H), 7.32 – 7.29 (m, 2H), 7.11 (t, J = 7.6 Hz, 1H), 6.98 (t, J =8.4 Hz, 2H), 6.42 (s, 1H), 6.26 – 6.22 (m, 1H), 6.06 – 6.03 (m, 1H), 4.90 (d,J = 16.8 Hz, 1H), 4.45 (d, J = 16.8 Hz, 1H), 2.38 (s, 2H), 2.24 – 2.11 (m,2H), 1.05 (s, 3H), 0.86 (s, 3H); 13 C NMR (100 MHz, Chloroform-d) δ 195.1,181.6, 168.3, 162.5 (d, J = 247.0 Hz), 158.9, 157.8, 149.2, 138.5, 137.6 (d,J = 4.0 Hz), 132.6, 128.0 (d, J = 8.0 Hz), 125.8, 124.5, 117.7, 116.2 (d, J =22.0 Hz), 110.0, 108.4, 103.6, 55.9, 50.8, 45.1, 37.5, 32.6, 29.2, 27.2; ESIMS m / z: 488 (M+H) + .

[0032] Example 2: Synthesis of 1-((5-(3-fluorophenyl)-8,8-dimethyl-6-oxothiazolo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione (3b).

[0033] The preparation method of this embodiment is the same as that of Example 1, except that 3-fluorobenzaldehyde is used instead of p-fluorobenzaldehyde. Finally, an orange solid target compound is obtained, the chemical structure of which is shown in formula (3b), and the yield is 83%.

[0034]

[0035] 3b

[0036] 1 H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 7.6 Hz, 1H), 7.42 (t, J= 8.4 Hz, 1H), 7.30 – 7.24 (m, 1H), 7.13 – 7.08 (m, 2H), 7.00 – 6.92 (m, 2H), 6.45 (s, 1H), 6.29 – 6.27 (m, 1H), 6.15 – 6.13 (m, 1H), 4.89 (d, J = 16.8 Hz, 1H), 4.48 (d, J = 16.8 Hz, 1H), 2.38 (s, 2H), 2.25 – 2.13 (m, 2H), 1.05 (s, 3H), 0.86 (s, 3H); 13 C NMR (100 MHz, Chloroform-d) δ 195.0, 181.6, 168.4,163.1 (d, J = 247.0 Hz), 159.3, 157.8, 149.3, 143.8 (d, J = 6.0 Hz), 138.5,132.6, 131.0 (d, J = 8.0 Hz), 125.7, 124.5, 121.6 (d, J = 3.0 Hz), 117.6,115.5 (d, J = 22.0 Hz), 113.1 (d, J = 22.0 Hz), 110.1, 108.0, 103.8, 55.8,50.8, 45.2, 37.5, 32.6, 29.2, 27.2; ESI MS m / z: 488 (M+H) + .

[0037] Example 3: Synthesis of 1-((5-(4-chlorophenyl)-8,8-dimethyl-6-oxothiazolo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione (3c).

[0038] The preparation method of this embodiment is the same as that of Example 1, except that p-chlorobenzaldehyde is used instead of p-fluorobenzaldehyde. Finally, an orange solid target compound is obtained, the chemical structure of which is shown in formula (3c). Yield: 67%.

[0039]

[0040] 3c

[0041] 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 7.6 Hz, 1H), 7.42 (t, J= 8.0 Hz, 1H), 7.24 (s, 4H), 7.11 (t, J = 7.6 Hz, 1H), 6.42 (s, 1H), 6.29 (s,1H), 6.04 (d, J = 7.6 Hz, 1H), 4.87 (d, J = 16.8 Hz, 1H), 4.48 (d, J = 16.8Hz, 1H), 2.38 (s, 2H), 2.25 – 2.12 (m, 2H), 1.05 (s, 3H), 0.85 (s, 3H); 13 CNMR (100 MHz, Chloroform-d) δ 195.0, 181.6, 168.3, 157.9, 149.2, 140.0,138.5, 134.4, 132.6, 129.4, 127.5, 125.8, 124.6, 117.6, 110.0, 108.2, 103.9,55.9, 50.8, 45.1, 37.5, 32.6, 29.2, 27.3; ESI MS m / z: 504 (M+H)+.

[0042] Example 4: Synthesis of 1-((5-(4-bromophenyl)-8,8-dimethyl-6-oxothiazo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione (3d).

[0043] The preparation method of this embodiment is the same as that of Example 1, except that p-bromobenzaldehyde is used instead of p-fluorobenzaldehyde. Finally, an orange solid target compound is obtained, the chemical structure of which is shown in formula (3d), and the yield is 66%.

[0044]

[0045] 3D

[0046] 1 H NMR (400 MHz, Chloroform-d) δ 7.56 (d, J = 7.2 Hz, 1H), 7.45 –7.38 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 7.12 (t, J = 7.2 Hz, 1H), 6.41 (s,1H), 1.05 (s, 3H), 0.86(s, 3H); 13 C NMR (100 MHz, Chloroform-d) δ 195.0, 181.6, 168.3, 157.9, 149.2,140.5, 138.5, 132.6, 132.4, 127.7, 125.8, 124.6, 122.5, 117.6, 110.0, 108.1,104.1, 55.9, 50.8, 45.1, 37.5, 32.6, 29.2, 27.3; ESI MS m / z: 548 (M+H) +.

[0047] Example 5: Synthesis of 1-((8,8-dimethyl-6-oxo-5-(p-tolyl)thiazo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione (3e).

[0048] The preparation method of this embodiment is the same as that of Example 1, except that p-tolualdehyde is used instead of p-fluorobenzaldehyde. Finally, an orange-red solid target compound is obtained, the chemical structure of which is shown in formula (3e), and the yield is 73%.

[0049]

[0050] 3e

[0051] 1H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 7.6 Hz, 1H), 7.32 (t, J= 7.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.11 – 7.06 (m, 3H), 6.37 (s, 1H), 6.18 (s, 1H), 5.83 (d, J = 8.0 Hz, 1H), 4.91 (d, J = 16.8 Hz, 1H), 4.45 (d, J= 16.8 Hz, 1H), 2.38 (s, 2H), 2.30 (s, 3H), 2.25 – 2.12 (m, 2H), 1.05 (s, 3H), 0.88 (s, 3H); 13 C NMR (100 MHz, Chloroform-d) δ 195.1, 181.8, 168.4,158.8, 157.9, 149.3, 138.9, 138.5, 138.4, 132.8, 129.9, 126.2, 125.6, 124.4,117.7, 110.3, 108.6, 103.1, 56.5, 50.8, 45.2, 37.5, 32.6, 29.2, 27.4, 21.2;ESI MS m / z: 484 (M+H) + .

[0052] Example 6: Synthesis of 1-((5-(2,4-difluorophenyl)-8,8-dimethyl-6-oxothiazolo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione (3f).

[0053] The preparation method of this embodiment is the same as that of Example 1, except that 2,4-difluorobenzaldehyde is used instead of p-fluorobenzaldehyde. Finally, an orange solid target compound is obtained, the chemical structure of which is shown in formula (3f), with a yield of 53%.

[0054]

[0055] 3f

[0056] 1H NMR (400 MHz, Chloroform-d) δ 7.63 (d, J = 7.6 Hz, 1H), 7.58 –7.52 (m, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 6.91 (t, J= 10.4 Hz, 1H), 6.83 (t, J = 10.8 Hz, 1H), 6.60 (s, 1H), 6.20 (d, J = 8.0 Hz,1H), 6.13 (s, 1H), 4.91 (d, J = 17.2 Hz, 1H), 4.47 (d, J = 17.2 Hz, 1H), 2.44(s, 2H), 2.26 – 2.11 (m, 2H), 1.08 (s, 3H), 0.94 (s, 3H); 13 C NMR (100 MHz, Chloroform-d) δ 194.9, 181.7, 168.3, 163.1 (d, J = 239.0 Hz), 159.5, 157.8,149.2, 138.7, 132.6, 131.0 (dd, J = 5.0, 5.0 Hz), 125.9, 124.7, 117.8, 112.6(d, J = 22.0 Hz), 110.0, 107.0, 104.6 (t, J = 26.0 Hz), 102.9, 51.9, 50.6,45.1, 37.3, 32.7, 29.3, 27.3; ESI MS m / z: 506 (M+H) + .

[0057] Example 7: Synthesis of 1-((5-(4-ethylphenyl)-8,8-dimethylthiazo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione (3g):

[0058] The preparation method of this embodiment is the same as that of Example 1, except that 4-ethylbenzaldehyde is used instead of p-fluorobenzaldehyde. Finally, an orange solid target compound is obtained, the chemical structure of which is shown in formula (3g), and the yield is 61%.

[0059]

[0060] 3g

[0061] 1H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J = 7.2 Hz, 1H), 7.31 (t, J= 8.0 Hz, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 7.13 (d, J= 4.44 (d, J = 16.8Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 2.40 (s, 2H) 2.26 – 2.13 (m, 2H), 1.21 (t,J = 7.6 Hz, 3H), 1.06 (s, 3H), 0.89 (s, 3H); 13 C NMR (100 MHz, Chloroform-d) δ195.2, 181.8, 168.3, 158.7, 157.9, 149.3, 144.8, 139.1, 138.4, 132.8, 128.7,126.3, 125.6, 124.4, 117.7, 110.2, 108.6, 103.0, 56.6, 50.8, 45.1, 37.5,32.7, 29.1, 28.5, 27.5, 15.5; ESI MS m / z: 498 (M+H) + .

[0062] Example 8: 1-((5-phenyl-8,8-dimethyl-6-oxo-thiazo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione (3h):

[0063] The preparation method of this embodiment is the same as that of Example 1, except that benzaldehyde is used instead of p-fluorobenzaldehyde. Finally, a brown solid target compound is obtained, the chemical structure of which is shown in formula (3h), and the yield is 74%.

[0064]

[0065] 3h

[0066] 1H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J = 7.6 Hz, 1H), 7.35 –7.28 (m, 6H), 7.08 (t, J = 7.6 Hz, 1H), 6.42 (s, 1H), 6.19 (s, 1H), 5.81 (d,J = 8.0 Hz, 1H), 4.94 (d, J = 16.8 Hz, 1H), 4.41 (d, J = 16.8 Hz, 1H), 2.39(s, 2H), 2.26 – 2.13 (m, 2H), 1.06 (s, 3H), 0.87 (s, 3H); 13 C NMR (100 MHz, Chloroform-d) δ 195.1, 181.8, 168.4, 158.9, 157.9, 149.3, 141.7, 138.5,132.7, 129.3, 128.6, 126.2, 125.6, 124.4, 117.6, 110.1, 108.5, 103.1, 56.7,50.8, 45.2, 37.5, 32.6, 29.2, 27.3; ESI MS m / z: 470 (M+H) + .

[0067] Example 9: Synthesis of 1-((5-(4-trifluoromethylphenyl)8,8-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-thiazo[2,3-b]quinazolin-3-yl)methyl)dihydroindole-2,3-dione (3i):

[0068] The preparation method of this embodiment is the same as that of Example 1, except that 4-trifluoromethylbenzaldehyde is used instead of p-fluorobenzaldehyde. Finally, an orange solid target compound is obtained, the chemical structure of which is shown in formula (3i), with a yield of 71%.

[0069]

[0070] 3i

[0071] 1H NMR (400 MHz, Chloroform-d) δ 7.52 – 7.50 (m, 3H), 7.40 – 7.35 (m,3H), 7.09 (t, J = 7.6 Hz, 1H), 6.52 (s, 1H), 6.36 – 6.33 (m, 1H), 6.07 – 6.03(m, 1H), 4.84 (d, J = 16.8 Hz, 1H), 4.50 (d, J = 16.8 Hz, 1H), 2.38 (s, 2H), 2.27 – 2.13 (m, 2H), 1.06 (s, 3H), 0.84 (s, 3H); 13 C NMR (100 MHz, Chloroform-d) δ 195.0, 181.5, 168.4, 159.4, 157.8, 149.1, 145.0, 138.3, 132.5, 130.6 (d,J = 32.0 Hz), 126.3, 126.2, 125.8, 124.6, 123.7 (d, J = 271.0 Hz), 117.6,109.8, 107.9, 104.5, 55.9, 50.7, 45.1, 37.5, 32.6, 29.2, 27.3; ESI MS m / z:538 (M+H) + .

[0072] The invention will be further described in detail below through examples of activity experiments.

[0073] The anticancer activity of the synthesized target product 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione was investigated using the MTT assay.

[0074] Human T24 (human bladder cancer cells), MDA-MB-231 (human breast cancer cells), SKOV3 (human ovarian cancer cells), and HUVEC (human umbilical vein endothelial cells) were used as test materials. Logarithmic growth phase cells were collected, digested with trypsin, and the cell suspension concentration was adjusted to 2 × 10⁻⁶. 4Cells / mL were dispensed into 96-well plates, 200 μL per well. The plates were incubated at 37°C with 5% CO2 for half a day until a monolayer covered the bottom of the wells. Different concentrations of sample were added, 100 μL per well, with three parallel wells. The plates were then incubated at 37°C with 5% CO2 for four days, and observed under an inverted microscope. 20 μL of MTT solution (5 mg / mL, i.e., 0.5% MTT) was added to each well, and the plates were incubated for another 4 h. If the drug reacted with MTT, the plate was centrifuged and the culture medium discarded. The plate was carefully rinsed 2-3 times with PBS, then MTT-containing culture medium was added to terminate the culture. The culture medium was carefully aspirated from the wells. 180 μL of dimethyl sulfoxide was added to each well, and the plate was shaken at low speed for 10 min to fully dissolve the crystals. The absorbance of each well was measured at 550 nm using an ELISA reader. The inhibition rate (IC50) was calculated using a control (without sample, the sample was replaced with its dissolving solvent, all other conditions were identical). 50 The test results are shown in Table 1.

[0075] Table 1. Antitumor activity of 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivatives

[0076] Note: ND indicates that IC was not measured. 50 value

[0077] As shown in Table 1, 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione derivatives exhibit antitumor activity. Among them, compound 3i shows a good inhibitory effect on T24 (human bladder cancer cells), and IC50... 50 The inhibitory effects of compound 3c on MDA-MB-231 (human breast cancer cells) and compound 3h on SKOV3 (human ovarian cancer cells) were comparable to those of the positive control 5-FU (5-fluorouracil). We also selected 3c, 3h, and 3i for normal cell toxicity assays. Table 1 shows that the tested compounds had weak effects on normal cells, exhibiting good selectivity.

Claims

1. A 5-arylthiazo[2,3-b]quinazolin-6-one derivative containing indigo, the chemical structural formula of which is shown in formula (I): In formula (I), the substituent R is H, C 1-6 alkyl, F, Cl, Br, I, alkoxy, hydroxy, nitrile, nitro, carboxyl, amino or sulfonic acid group.

2. A method for preparing the indigo-containing 5-arylthiazo[2,3-b]quinazolin-6-one derivative as described in claim 1, characterized in that... Includes the following steps: (1) Thiourea and aminosulfonic acid were dissolved in anhydrous ethanol. 5,5-Dimethyl-1,3-cyclohexanedione was slowly added to the system. After the solid in the reaction flask was completely dissolved, aromatic aldehyde was added. The reaction temperature was 80℃, and the reaction was refluxed for about 10 h. The reaction process was monitored by TLC. After the reaction was completed, a large amount of white solid precipitated in the reaction solution. The solid was filtered while hot, and the residue was recrystallized from ethanol to obtain intermediate 7,7-dimethyl-4-aryl-2-thioquinazoline-5(1H)-one 1. (2) Weigh 1,3-dichloropropanone, then add anhydrous ethanol and tetrahydrofuran as solvents, and finally add intermediate 1. Reflux the reaction at 80°C. Solids gradually precipitate in the reaction flask, and the reaction progress is monitored by TLC. After the reaction is complete, a large amount of yellow solid appears in the reaction solution. Heating is stopped immediately, and the reaction mixture is filtered while hot. The filter cake is thoroughly washed with anhydrous ethanol until the filtrate is colorless. The obtained solid is dehydrated with concentrated sulfuric acid to obtain a cyclized liquid. Then, quenching, pH adjustment, extraction, and vacuum concentration are performed to obtain intermediate 3-(chloromethyl)-8,8-dimethyl-5-arylthiazo[2,3-b]quinazolin-6-one 2. (3) Intermediate 2 was dissolved in tetrahydrofuran, and then potassium iodide, potassium carbonate, and indigo were added. The mixture was refluxed at 70°C, and the reaction was monitored by TLC. After the reaction was completed, heating was stopped, and the reaction solution was cooled to room temperature. The solution was then concentrated under reduced pressure, and an appropriate amount of silica gel was added for mixing. The solution was then purified by column chromatography to obtain the target compound 1-[(8,8-dimethyl-6-oxo-5-arylthiazo[2,3-b]quinazolin-3-yl)methyl]indoline-2,3-dione 3.

3. The use of the indigo-containing 5-arylthiazo[2,3-b]quinazolin-6-one derivative prepared by the method described in claim 2 in the preparation of antitumor drugs.

4. The use of the indigo-containing 5-arylthiazo[2,3-b]quinazolin-6-one derivative according to claim 3 in the preparation of antitumor drugs, characterized in that... The dosage form of the antitumor drug is tablet, pill, capsule, injection, suspension or emulsion.

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