Synthesis and antitumor activity research of novel drug micromolecule containing phenothiazine structure

Abstract

The invention discloses synthesis and antitumor activity research of a novel drug small molecular formula (1) containing a phenothiazine structure. R is # imgabs 1 #. 10H phenothiazine is used as an initial raw material, (E)-3-(10-ethyl-10H-phenothiazin-3-yl) acrylic acid is generated through a typical Friedel-Crafts alkylation reaction, an NBS bromination reaction and the like, and then an important intermediate compound 6 is synthesized through a Wittig reaction and a hydrolysis reaction. And carrying out coupling reaction on the intermediate compound 7 and different amine compounds to obtain 11 target compounds 7a-7k: formula (1). A CCK-8 experiment is carried out on a target compound to obtain a conclusion that the target compound 7a-7k and 5-fluorouracil are tested at the concentration of 20 mu M, and the result shows that the compound 7f has the best inhibition effect on A549, Hep G2 and HeLa cells, and the compound 7c has the better inhibition effect on the A549 cells. IC50 value calculation is carried out on a target compound under various concentrations, the IC50 value of 7c to HELA cells is small, the IC50 value of 7f to Hep G2 and HeLa cells is minimum, and the inhibition effect is the best. Therefore, the compound can be used for antitumor drugs.

Description

Technical Field

[0001] The present invention relates to the synthesis and anti-tumor activity research of a novel drug small molecule containing a phenothiazine structure Background Art

[0002] Cancer refers to all malignant tumors. It is caused by the mutation of oncogenes and tumor suppressor genes in normal cells under the influence of physical, chemical, viral and other carcinogenic factors. Cancer cells are different from normal cells. They can proliferate indefinitely and destroy normal cell tissues. They can also invade normal tissues locally and even metastasize to other parts of the body through the circulatory system or lymphatic system in the body. Cancer, cardiovascular disease, accidents and incidents together constitute the three major causes of death in the world today. It is one of the main diseases that seriously affect human health and threaten human life. In addition to causing obstructive and compressive symptoms to the body, cancer may also affect the normal function of organs and cause people's death. The occurrence and development of human cancer involves multiple steps, including maintaining proliferation signal transduction, escaping inhibitors and growing, resisting cell death, making DNA replicate indefinitely, and inducing activation and invasion of angiogenesis. Among all current treatment methods, chemotherapy and drug-assisted treatment are still the most common choices for cancer treatment. However, most anticancer drugs are hindered by serious toxic side effects. Therefore, the development of new therapeutic drugs will be of great research significance.

[0003] Phenothiazine compounds have good antipsychotic and antihistamine activities. Clinically, antipsychotic drugs such as chlorpromazine and trifluoperazine and antihistamine drugs such as promethazine and dimethizine all have phenothiazine core structures. In recent years, with the continuous deepening of research, it has been found that a series of phenothiazine derivatives designed and synthesized based on the phenothiazine structure have multiple pharmacological activities such as antioxidant, antiviral, antibacterial, anti-inflammatory, and anti-tumor. Phenothiazine compounds have high application value in the development of new drugs. Summary of the invention

[0004] The invention discloses a method for preparing a small molecule drug containing a phenothiazine structure. A CCK8 method is used to perform a toxicity experiment on cells to evaluate the anti-proliferation effect of the compound on A549, HeLa, HepG2 and normal mouse fibroblast L929.

[0005] The present invention adopts the following technical scheme, containing a small molecule of a phenothiazine structure drug, the structural formula of which is

[0006] In the present invention, R is R1, R2, and R3 are each independently H, OCH3, F, HCOOCH3, or -CN.

[0007] The present invention uses 10H phenothiazine, undergoes a typical Friedel-Crafts alkylation reaction, an NBS bromination reaction, a Wittig reaction, and finally undergoes a hydrolysis reaction and other multi-step reactions to synthesize (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, and the structural formula is:

[0008] In the present invention, (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid and different amine compounds are coupled to obtain a drug small molecule containing a phenothiazine structure: formula (1).

[0009] The present invention is characterized by nuclear magnetic resonance, high-resolution mass spectrometry, infrared spectroscopy and the like, and the results fully confirm the synthesis of the compound. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 It is a synthetic route; Figure 2 It is the target product of the synthetic route; Figure 3 are the hydrogen and carbon spectra of intermediate compound 4; Figure 4 are the hydrogen and carbon spectra of the intermediate compound 5; Figure 5-15 are the hydrogen and carbon spectra of target compounds 7a-7k; Fig.16 It is the inhibition rate of target compounds 7a-7k and 5-fluorouracil on different cancer cells at a concentration of 20 μM.

[0011] Fig.17 The IC50 values ​​of target compounds 7a-7k are shown in Figure 2 DETAILED DESCRIPTION

[0012] Embodiment 1: (1) Synthesis of (E)-3-(10-ethyl-10H-phenothiazin-3-yl)methyl acrylate (Intermediate Compound 6) Take a 100ml single-mouth bottle, add 0.1g of 10-ethyl-10H-phenothiazine-3-carboxaldehyde, 0.26g of triphenylphosphine acetate, and a certain amount of dichloromethane to dissolve it at room temperature, transfer the entire reaction system to a 40-degree Celsius oil pan, connect a straight condenser, introduce nitrogen, and react for 4 hours. After the reaction is completed, cool to room temperature, concentrate, and elute with an eluent (V ethyl acetate: V petroleum ether = 1:20) through column chromatography. After elution, the solvent is rotated out with a rotary evaporator, and the residue is placed in a vacuum drying oven to dry to obtain a yellow solid. Yield: 78%. 1HNMR(400MHz,Chloroform-d)δ7.55(d,J=16.0Hz,1H),7.30–7.24(m,3H),7.12(dt,J=13.4,7.7Hz,2H),6.8 7(dt,J=36.6,7.8Hz,3H),6.27(d,J=15.9Hz,1H),3.93(q,J=6.8Hz,2H),3.78(s,3H),1.42(t,J=6.9Hz,3H). (2) Synthesis of (E)-3-(10-ethyl-10H-phenothiazin-3-yl)acrylic acid (Intermediate Compound 7) Take a 100ml single-mouth bottle, add 0.1g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) methyl acrylate, 1.47g of sodium hydroxide, 10ml of water, and a certain amount of anhydrous ethanol as a reaction solvent at room temperature, transfer the entire reaction system to an 80 degree Celsius oil pan, connect a condenser, protect with nitrogen, and reflux for 4 hours. After the reaction is completed, cool it to room temperature, remove the rotor, remove the ethanol, add diluted concentrated hydrochloric acid, make the pH value acidic, and precipitate, filter, and place the filter cake in a vacuum drying oven to dry overnight to obtain an orange solid. Yield: 80%. 1HNMR (400MHz, DMSO-d6) δ12.23(s,1H),7.55–7.39(m,3H),7.26–6.89(m,5H),6.47–6.32(m,1H),3.93(d,J=7.3Hz,2H),1.36–1.20(m,3H). Example 2: Synthesis of target compounds 7a-k

[0013] (1) Synthesis of (E)-3-(10-ethyl-10H-phenothiazine-3-yl)-N-phenylacrylamide (Compound 7a) Take a 100ml single-mouth bottle, add 0.1g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.13g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 0.09g of 1-hydroxybenzotriazole (HoBt), 120μl of N,N-Diisopropylethylamine (DIPEA) at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, protect it with nitrogen, and react at room temperature for 1 hour. After 1 hour, add 61μl of aniline and continue to react for 12 hours. After the reaction, the product was washed several times with saturated NaCl solution and dichloromethane, dried with anhydrous magnesium sulfate for one hour, filtered after drying, concentrated, and eluted by column chromatography using an eluent (V ethyl acetate: V petroleum ether = 1:7). After elution, the solvent was removed and the residue was placed in a vacuum drying oven and dried overnight to obtain a yellow solid. Yield: 28%. 1H NMR (400MHz, DMSO-d6) δ10.06(s,1H),7.64(d,J=8.0Hz,2H),7.44(s,1H),7.42–7.38(m,2H),7.32(s,1H),7.28(t,J=7.9Hz,2H),7.17(d,J= 8.2Hz,1H),7.11(s,1H),7.00(t,J=7.4Hz,3H),6.91(t,J=7.4Hz,1H),6.64(d,J=15.7Hz,1H),3.90(q,J=6.7Hz,2H),1.26(t,J=6.5Hz,4H).

[0014] (2) Synthesis of (E)-3-(10-ethyl-10H-phenothiazin-3-yl)-N-(2-methoxyphenyl)acrylamide (Compound 7b) Take a 100ml single-mouth bottle, add 0.2g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.26g of EDC, 0.18g of HOBT, 234μl of DIPEA at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, protect it with nitrogen, and react at room temperature for 1 hour. After 1 hour, add 150μl of o-aminoanisole and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, and then dry it with anhydrous magnesium sulfate for one hour. After drying, filter it with suction, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:6) to elute it through column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry overnight to obtain a yellow-orange solid. Yield: 35%. 1HNMR(400MHz,DMSO-d6)δ9.20(s,1H),8.18(d,J=7.8Hz,1H),7.47–7.38(m,3H),7.20(t,J=7.7Hz,1H),7.14(d ,J=6.5Hz,1H),7.11–7.02(m,5H),6.98–6.90(m,2H),3.94(q,J=6.7Hz,2H),3.87(s,3H),1.31(t,J=6.8Hz,3H).

[0015] (3) Synthesis of (E)-3-(10-ethyl-10H-phenothiazin-3-yl)-N-(3-methoxyphenyl)acrylamide (Compound 7c) Take a 100ml single-mouth bottle, add 0.2g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.26g of EDC, 0.18g of HoBt, 234μl of DIPEA at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, pass nitrogen, and react at room temperature for 1 hour. After 1 hour, add 151μl of m-aminoanisole and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, dry with anhydrous magnesium sulfate for one hour, filter after drying, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:4) for column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry to obtain a yellow solid. Yield: 20%. 1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),7.48(s,1H),7.47–7.42(m,2H),7.41(s,1H),7.37–7.34(m,1H),7.25–7.17(m,3H),7.16–7.12(m,1H) ,7.05(t,J=7.5Hz,2H),6.96(t,J=7.4Hz,1H),6.69(s,1H),6.64(d,J=7.4Hz,1H),3.94(q,J=6.7Hz,2H),3.74(s,3H),1.31(t,J=6.9Hz,3H).

[0016] (4) Synthesis of (E)-3-(10-ethyl-10H-phenothiazin-3-yl)-N-(4-methoxyphenyl)acrylamide (Compound 7d) Take a 100ml single-mouth bottle, add 0.16g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.21g of EDC, 0.15g of HoBt, 187μl of DIPEA at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, pass nitrogen, and react at room temperature for 1 hour. After 1 hour, add 0.13g of p-anisidine and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, dry with anhydrous magnesium sulfate for one hour, filter after drying, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:7) for column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry to obtain a yellow solid. Yield: 48%. 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),7.61(d,J=8.8Hz,2H),7.45(d,J=15.1Hz,2H),7.37(s,1H),7.22(t,J=7.6Hz,1H),7.16(d,J=7.5Hz,1H ),7.06(dd,J=8.0,5.3Hz,2H),6.95(dd,J=24.5,8.1Hz,3H),6.51(d,J=8.8Hz,1H),3.95(q,J=6.6Hz,2H),3.74(s,3H),1.32(t,J=6.8Hz,3H).

[0017] (5) Synthesis of (E)-3-(10-ethyl-10H-phenothiazin-3-yl)-N-(2-fluorophenyl)acrylamide (Compound 7e) Take a 100ml single-mouth bottle, add 0.2g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.26g of EDC, 0.18g of HoBt, 234μl of DIPEA at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, pass nitrogen, and react at room temperature for 1 hour. After 1 hour, add 130μl of 2-fluoroaniline and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, dry with anhydrous magnesium sulfate for one hour, filter after drying, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:7) for column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry to obtain a yellow solid. Yield: 30%. 1H NMR(400MHz, DMSO-d6)δ7.99(d,J=8.4Hz,1H),7.73(d,J=8.4Hz,1H),7.55–7.39(m,5H),7.19(t,J=7.7Hz,1H), 7.13(d,J=7.6Hz,1H),7.04–6.94(m,3H),6.40(d,J=16.0Hz,1H),3.93(q,J=6.8Hz,2H),1.29(t,J=6.8Hz,3H).

[0018] (6) Synthesis of (E)-3-(10-ethyl-10H-phenothiazin-3-yl)-N-(3-fluorophenyl)acrylamide (Compound 7f) Take a 100ml single-mouth bottle, add 0.2g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.26g of EDC, 0.18g of HoBt, 234μl of DIPEA at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, pass nitrogen, and react at room temperature for 1 hour. After 1 hour, add 130μl of 3-fluoroaniline and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, dry with anhydrous magnesium sulfate for one hour, filter after drying, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:7) for column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry to obtain a yellow solid. Yield: 35%. 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),7.72(d,J=12.1Hz,1H),7.51(s,1H),7.46(d,J=8.6Hz,2H),7.37(d,J=8.9Hz,3H),7.21(t,J=8.0Hz,1H),7.1 4(d,J=7.4Hz,1H),7.05(t,J=5.2Hz,2H),6.96(t,J=7.0Hz,1H),6.88(s, 1H), 6.66 (d, J = 15.7Hz, 1H), 3.95 (d, J = 6.4Hz, 2H), 1.31 (t, J = 4.7Hz, 3H).

[0019] (7) Synthesis of (E)-3-(10-ethyl-10H-phenothiazin-3-yl)-N-(4-fluorophenyl)acrylamide (Compound 7g) Take a 100ml single-mouth bottle, add 0.2g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.26g of EDC, 0.18g of HoBt, 234μl of DIPEA at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, pass nitrogen, and react at room temperature for 1 hour. After 1 hour, add 130μl of 4-fluoroaniline and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, dry with anhydrous magnesium sulfate for one hour, filter after drying, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:8) for column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry to obtain a yellow solid. Yield: 25%. 1H NMR(400MHz, DMSO-d6)δ10.18(s,1H),7.70(dd,J=8.8,5.0Hz,2H),7.49–7.42(m,2H),7.37(s,1H),7.22–7.13(m,4 H),7.06–7.01(m,2H),6.95(d,J=7.4Hz,1H),6.66(d,J=15.7Hz,1H),3.94(q,J=6.8Hz,2H),1.30(t,J=6.8Hz,3H).

[0020] (8) Synthesis of methyl (E)-2-(3-(10-ethyl-10H-phenothiazin-3-yl)acrylamide)benzoate (Compound 7h) Take a 100ml single-mouth bottle, add 0.2g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.26g of EDC, 0.18g of HoBt, 234μl of DIPEA in sequence at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, pass nitrogen, and react at room temperature for 1 hour. After 1 hour, add 0.2g of methyl anthranilate and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, dry with anhydrous magnesium sulfate for one hour, filter after drying, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:7) for column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry to obtain an orange solid. Yield: 30%. 1H NMR(400MHz, DMSO-d6)δ8.36(s,1H),7.94(d,J=8.6Hz,1H),7.65(d,J=7.7Hz,1H),7.53–7.43(m,3H),7.38(d,J=1.6Hz,1H),7.20(t,J=8.3Hz,1H), 7.16–7.12(m,1H),7.04(t,J=7.9Hz,2H),6.96(t,J=7.3Hz,1H),6.67(d, J=15.7Hz,1H),3.94(q,J=6.8Hz,2H),3.86(s,3H),1.31(t,J=6.8Hz,3H).

[0021] (9) Synthesis of Methyl (E)-3-(3-(10-ethyl-10H-phenothiazin-3-yl)acrylamide)benzoate (Compound 7i) Take a 100ml single-mouth bottle, add 0.2g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.26g of EDC, 0.18g of HoBt, 234μl of DIPEA at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, pass nitrogen, and react at room temperature for 1 hour. After 1 hour, add 0.2g of methyl 3-aminobenzoate and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, dry with anhydrous magnesium sulfate for one hour, filter after drying, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:7) for column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry to obtain a yellow solid. Yield: 50%. 1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.36(s,1H),7.94(d,J=8.2Hz,1H),7 .65(d,J=7.6Hz,1H),7.53–7.42(m,3H),7.38(s,1H),7.21(t,J=8.0Hz,1H) ,7.14(d,J=7.6Hz,1H),7.04(t,J=7.8Hz,2H),6.96(t,J=7.4Hz,1H),6.67( d,J=15.7Hz,1H),3.94(q,J=6.7Hz,2H),3.86(s,3H),1.31(t,J=6.8Hz,3H).

[0022] (10) Synthesis of methyl (E)-4-(3-(10-ethyl-10H-phenothiazin-3-yl)acrylamide)benzoate (Compound 7j) Take a 100ml single-mouth bottle, add 0.2g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.26g of EDC, 0.18g of HoBt, 234μl of DIPEA at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, pass nitrogen, and react at room temperature for 1 hour. After 1 hour, add 0.2g of methyl 4-aminobenzoate and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, dry with anhydrous magnesium sulfate for one hour, filter after drying, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:7) for column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry to obtain an orange solid. Yield: 30%. 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),7.94(d,J=8.7Hz,2H),7.82(d,J=8.7Hz,2H),7.55–7.44(m,2H),7.41–7.36(m,1H),7.21(t,J=7.3Hz,1H),7. 14(d,J=7.5Hz,1H),7.05(t,J=7.9Hz,2H),6.96(t,J=7.8Hz,1H),6.70(d, J=15.7Hz,1H),3.95(q,J=6.8Hz,2H),3.82(s,3H),1.31(t,J=6.9Hz,3H).

[0023] (11) Synthesis of (E)-N-(3-cyanophenyl)-3-(10-ethyl-10H-phenothiazin-3-yl)acrylamide (Compound 7k) Take a 100ml single-mouth bottle, add 0.2g of (E)-3-(10-ethyl-10H-phenothiazine-3-yl) acrylic acid, 0.26g of EDC, 0.18g of HoBt, 234μl of DIPEA at room temperature, add a certain amount of dichloromethane and ultra-dry tetrahydrofuran to dissolve it, transfer the entire reaction system to a magnetic stirrer, pass nitrogen, and react at room temperature for 1 hour. After 1 hour, add 0.16g of 3-aminobenzonitrile and continue to react for 12 hours. After the reaction is completed, extract with saturated NaCl solution and dichloromethane, dry with anhydrous magnesium sulfate for one hour, filter after drying, concentrate the filtrate, use eluent (V ethyl acetate: V petroleum ether = 1:6) for column chromatography, remove the solvent after elution, and place the residue in a vacuum drying oven to dry to obtain an orange solid. Yield: 25%. 1H NMR (400MHz, DMSO-d6) δ10.45(s,1H),7.86(d,J=7.9Hz,1H),7.59–7.44(m,5H),7.39(s,1H),7.21(t,J=8.4Hz,1H),7.14(d, J=6.3Hz,1H),7.05(t,J=7.6Hz,2H),6.96(t,J=7.4Hz,1H),6.66(d,J=15.6Hz,1H),3.98–3.93(m,2H),1.30(d,J=6.7Hz,3H).

[0024] The present invention conducted CCK-8 experimental tests on target compounds 7a-7k, expressed HeLa, A549, Hep G2 and L929, and tested target compounds 7a-7k and 5-fluorouracil at a concentration of 20 μM. As can be seen from the figure, 7f containing a methoxy-substituted amine compound structure grafted at the end of the benzene ring of a phenothiazine structure has the best inhibitory effect on HeLa cells, Hep G2 cells and A549 cells, with inhibition rates of 70.33%, 64.72% and 51.69% respectively, and the inhibition rates of 5-fluorouracil on HeLa cells, Hep G2 cells and A549 cells are 47.71%, 54.95% and 13.56% respectively. The inhibitory effect of structure 7c, a phenothiazine structure-containing non-grafted amine compound at the end of the benzene ring, on HeLa cells, Hep G2 cells and A549 cells was second, with inhibition rates of 61.17%, 48.44% and 55.33%, while the inhibition rates of 5-fluorouracil were 56.11%, 44.97% and 43.20%.

[0025] The present invention calculates the IC50 values ​​of compounds 7a-7k at 40 μM, 20 μM, 10 μM, and 5 μM concentrations for HeLa, A549, and Hep G2 cells, wherein compound 7c has a lower IC50 value for A549 cells, and compound 7f has a lower IC50 value for HeLa cells and Hep G2 cells. For amine compounds with different groups connected to the end of the benzene ring at position 3, the efficacy of the compound containing F atoms in Hep G2 cells and HeLa cells is significantly better than that of the compound containing methyl benzoate, while the efficacy of the compound containing methoxy groups is better than that of the compound containing methyl benzoate. The difference is that at position 3, in A549 cells, the efficacy of the compound containing F atoms is also better than that of the compound containing methyl benzoate, and the efficacy of the compound containing methoxy groups is still better than that of the compound containing methyl benzoate. Fig.12 IC50 values ​​of target compounds 7a-7f on different cells.

Claims

1. A novel small molecule drug containing a phenothiazine structure (1), characterized in that: The molecular chemical structure is as follows:

2. R is R1, R2, and R3 are H, OCH3, F, HCOOCH3, or -CN at corresponding positions.

3. The phenothiazine derivative according to claim 1, wherein: Target product:

4. The phenothiazine derivative according to claim 1, characterized in that Synthesis route:

5. As claimed in claim 1, the use of the phenothiazine derivative of formula (1) having multiple biological activities such as antiviral, antibacterial, and antitumor.

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