CN103113285B - Indole compound and application thereof as HIV-1 reverse transcriptase inhibitor - Google Patents

Abstract

The invention belongs to the field of medical technology, and specifically discloses an indole compound and an application thereof as an HIV-1 reverse transcriptase inhibitor. The indole compound disclosed by the invention has a structural general formula: wherein the formula is described in the specification.

Description

A kind of indole compound and its application as HIV-1 reverse transcriptase inhibitor

technical field

The invention belongs to the technical field of medicine, and relates to an indole compound and its application as an HIV-1 reverse transcriptase inhibitor.

Background technique

Acquired Immunodeficiency Syndrome (AIDS) is prevalent in the world and in my country, and it is a major epidemic disease that causes death worldwide. The latest figures from World Guardian show that about 3 million people worldwide have died from AIDS, and there are still 30 million patients who are still struggling with AIDS. Therefore, the research and development of efficient and cheap therapeutic drugs is still an urgent task in the prevention and treatment of AIDS. Human immunodeficiency virus type 1 (HIV-1) is the pathogenic factor that causes acquired immunodeficiency syndrome. After the virus infects the host, it mainly uses reverse transcriptase, integrase and protease to complete its replication cycle. Because HIV is constantly mutating during the replication process, it has brought huge challenges to the development of drugs and vaccines. At present, the combination of several drugs with different mechanisms of action is mainly used clinically, that is, highly active antiretroviral therapy. The promotion and use of highly active antiretroviral therapy has effectively alleviated the condition of patients and prolonged the average life expectancy of AIDS patients. However, the cost of treatment is high, and long-term use has produced unbearable adverse reactions and drug resistance. At present, we still lack an effective anti-AIDS vaccine, and the research and development of high-efficiency and cheap therapeutic drugs is still a top priority for the prevention and treatment of AIDS.

According to different targets, AIDS drugs on the market can be divided into: reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, and entry inhibitors. Among them, reverse transcriptase inhibitors play an important role in the treatment of AIDS, and their targets are reverse transcriptase (RT) of HIV-1. According to different mechanisms of action, reverse transcriptase inhibitors can be divided into nucleoside reverse transcriptase inhibitors (NRTs) and non-nucleoside reverse transcriptase inhibitors (NNRTS). Nucleoside reverse transcriptase inhibitors are incorporated into the viral reverse transcription product by competing with the normal nucleotide substrates during viral replication, thereby stopping the elongation of the viral genome. Non-nucleoside reverse transcriptase inhibitors act by approx. The hydrophobic pocket of the reverse transcriptase regulates or affects the conformation of reverse transcriptase through isomerization, destroying its activity of synthesizing DNA.

Non-nucleoside reverse transcriptase inhibitors have been studied for more than 20 years, and at least 50 kinds of non-nucleoside reverse transcriptase inhibitors with different structures have been found. The first-generation non-nucleoside drugs are nevirapine and delavirdine, and the second-generation non-nucleoside drugs are efavirenz, etravirine, and rilpivirine . There are also multiple non-nucleoside candidate drugs in the clinical research stage. The above-mentioned non-nucleoside drugs have the advantages of strong activity and good specificity, and do not affect the DNA synthesis of cells or mitochondria, but their clinical use is limited due to the emergence of drug-resistant mutants. Therefore, there is an urgent need to develop new non-nucleoside inhibitors to broaden the options for clinical medication. Recently, it has been reported in the literature that some indole compounds have certain anti-HIV reverse transcriptase activity, but most of them have complex structures, are difficult to synthesize, and their activities are not particularly good, which limits their possibility of becoming a drug.

Contents of the invention

The technical problem to be solved by the present invention is to provide an indole compound and its application as an HIV-1 reverse transcriptase inhibitor.

The indole compound provided by the present invention has the structure shown in the following general formula:

in,

R ¹ is H, 2-Me, 4-OH, 4-NO ₂ , 4-COOMe, 5-CHO, 5-CN, 5-F, 5-Br, 5-Cl, 5-NO ₂ , 5-COOMe or 6-F;

^R is Me or Et;

R ³ is H, Boc, Me or Isopentyl (isopentyl).

Through in vitro anti-HIV-1 activity experiments, the present invention finds that the above-mentioned indole compounds can be used as HIV-1 non-nucleoside reverse transcriptase inhibitors to prepare anti-AIDS drugs. Preferred, especially the following compounds:

2-(5-nitro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionic acid ethyl ester (HX1),

2-(5-Fluoro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionic acid ethyl ester (HX2),

2-(5-Chloro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionic acid ethyl ester (HX3),

2-(6-Fluoro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionic acid ethyl ester (HX4),

2-(5-Bromo-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionic acid ethyl ester (HX5),

Ethyl 2-(5-cyano-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX7) or

Ethyl 2-(1-methyl-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX12).

The present invention also provides a preparation method of the indole compound represented by the above structural formula.

When R ¹ =H, R ³ =Isopentyl, the indole derivatives with R ¹ and R ³ can be synthesized through the reaction shown in the following formula i. The specific operation steps can be:

Dissolve indole (232 mg, 2 mmol) in 10 mL of DMF, add 8 mL of DMF solution containing 96 mg (2.4 mmol) of NaH (60% dispersed in mineral oil) at 5°C, and the mixture is at room temperature After stirring at low temperature for 30 minutes, it was cooled to 5°C, and then 5 mL of DMF solution in which 362.5 mg of isopentyl bromide (2.4 mmol) was dissolved was added dropwise, and reacted at room temperature, monitored by TLC. After 16 hours, the mixture was cooled to 5°C, and 15 mL of water was added to quench the reaction. The product was extracted with ether, and separated by column chromatography to obtain the reaction product as the raw material of reaction (iii).

When R ¹ =H, R ³ =Boc (tert-butoxycarbonyl), the indole derivatives with R ¹ and R ³ can be synthesized through the reaction shown in the following formula ii. The specific operation steps can be:

Indole (232 mg, 2 mmol) was dissolved in 10 mL of dichloromethane, (Boc) ₂ (480.15 mg, 2.2 mmol) was added dropwise at room temperature, and 1 mL of triethylamine was added to stir the reaction at room temperature. The reaction was monitored by TLC. After 5 hours, the reaction product was separated by column chromatography as the raw material of reaction (iii).

Indole derivatives with R ¹ and R ³ other than the above two can be purchased in the market.

Obtain the indole derivatives with R ¹ and R ³ by synthesizing or purchasing commercial products, and then take an equivalent amount of indole derivatives with R ¹ and R ³ and trifluoropyruvate and dissolve them in dichloromethane to fully dissolve, Then add enough _AlCl3 to catalyze the Friedel-Crafts reaction, and monitor the progress of the reaction by TLC. After the basic reaction of the raw materials is complete, the target compound is separated by column chromatography.

The reaction formula is shown in formula (iii) below.

R ¹ is H, 2-Me, 4-OH, 4-NO ₂ , 4-COOMe, 5-CHO, 5-CN, 5-F, 5-Br, 5-Cl, 5-NO ₂ , 5-COOMe or 6-F;

^R is Me or Et;

R ³ is H, Boc, Me or Isopentyl.

The specific operation process can be as follows:

Take 0.2 mmol of Reaction 1 or Reaction 2 or commercially available indole derivatives with R ¹ and R ³ and 0.2 mmol of trifluoropyruvate into a single-necked round-bottomed flask containing a magnet, add 5 mL of di Chloromethane was used to dissolve it, stirred evenly, and _0.2 mmol of AlCl was added to catalyze the Friedel-Crafts reaction, and the reaction was monitored by TLC. After the basic reaction of the raw materials is complete, the pure target compound is obtained through column chromatography separation.

The compound described in the invention can be used as an HIV-1 non-nucleoside reverse transcriptase inhibitor for the preparation of anti-AIDS drugs. Therefore, the present invention also provides an anti-AIDS pharmaceutical composition, comprising the compound described in the present invention and one or more pharmaceutically acceptable carriers or excipients, which can be prepared according to existing conventional medical techniques.

Detailed ways

Example 1: Preparation of ethyl 2-(5-nitro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX1)

Take 0.2mmol of 5-nitroindole and 0.2mmol of trifluoropyruvate into a single-necked round-bottomed flask containing a magnet, add 5mL of dichloromethane to dissolve, stir well, add 0.2mmol of AlCl ₃ The Friedel-Crafts reaction was catalyzed, and the reaction was monitored by TLC. After the raw materials were fully reacted, the pure solid compound HX1 was separated by column chromatography, and the product was a yellow solid with a yield of 88%. ¹ H NMR(400MHz,Acetone-d ₆ )δ11.09(s,1H),8.85(d,J=1.7Hz,1H),7.96(dd,J=9.0,2.2Hz,1H),7.74(s, 1H),7.53(d,J=9.0Hz,1H),4.33–4.23(m,2H),1.20(t,J=7.1Hz,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ168.69,142.80 , 140.78, 129.76, 129.60, 126.41, 125.72, 119.27, 118.07, 113.13, 112.07, 64.07, 14.20.

Example 2: Preparation of ethyl 2-(5-fluoro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX2)

The preparation method was as in Example 1, and the product was a white solid with a yield of 90%. ¹ H NMR (400MHz, CDCl ₃ )δ8.38(s,1H),7.57(d,J=10.3Hz,1H),7.42(s,1H),7.20(s,1H),6.95(t,J= 9.0Hz,1H),4.40(dq,J=20.9Hz,3H),1.33(t,J=7.1Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ169.19,159.28,132.90,126.16,125.57,125.47 , 124.93, 122.08, 112.14, 112.04, 111.38, 111.12, 108.67, 108.62, 106.40, 106.15, 64.42, 13.86.

Example 3: Preparation of ethyl 2-(5-chloro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX3)

The preparation method was as in Example 1, and the product was a white solid with a yield of 87%. ¹ H NMR (400MHz, CDCl ₃ )δ8.34(s,1H),8.00(s,1H),7.35(s,1H),7.18(d,J=10.3Hz,1H),7.11(d,J= 8.6Hz,1H),4.40–4.27(m,2H),1.28(t,J=7.1Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ169.09,135.03,126.78,125.70,125.63,124.82,123.90, 121.97, 113.91, 112.81, 108.28, 64.51, 13.89.

Example 4: Preparation of ethyl 2-(6-fluoro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX4)

The preparation method was as in Example 1, the product was a white solid, and the yield was 100%. ¹ H NMR (400MHz,Acetone-d ₆ )δ10.60(s,1H),7.90(dd,J=8.8,5.6Hz,1H),7.59(d,J=2.4Hz,1H),7.19(dd, ¹³ C NMR (101MHz, Acetone-d ₆ ) δ169.17, 161.74, 137.73, 126.52, 123.18, 123.12, 109.93, 109.19, 108.95, 98.53, 98.27, 63.71, 14.24.

Example 5: Preparation of ethyl 2-(5-bromo-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX5)

The preparation method was as in Example 1, and the product was a light yellow solid with a yield of 85%. ¹ H NMR (400MHz, CDCl ₃ )δ8.34(s,1H),8.00(s,1H),7.35(s,1H),7.18(d,J=10.3Hz,1H),7.11(d,J= 8.6Hz,1H),4.40–4.27(m,3H),1.28(t,J=7.1Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ169.09,135.03,126.78,125.70,125.63,124.82,123.90, 121.97, 113.91, 112.81, 108.28, 64.51, 13.89.

Example 6: Preparation of ethyl 2-(1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX6)

The preparation method was as in Example 1, and the product was a white solid with a yield of 99%. ¹ H NMR (400MHz, CDCl ₃ )δ8.28(s,1H),7.89(d,J=8.1Hz,1H),7.43(d,J=2.5Hz,1H),7.34(d,J=8.1Hz ,1H),7.28–7.10(m,2H),4.65–4.27(m,3H),1.33(t,J=7.1Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ )δ169.42,136.35,125.13,124.99 , 124.44, 122.70, 121.15, 121.14, 120.53, 111.39, 108.65, 64.25, 13.93.

Example 7: Preparation of ethyl 2-(5-cyano-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX7)

The preparation method was as in Example 1, and the product was a light yellow solid with a yield of 92%. ¹ H NMR (400MHz,Acetone-d ₆ )δ11.12(s,1H),8.36(s,1H),7.81(d,J=2.0Hz,1H),7.66(d,J=8.5Hz,1H) ,7.48(dd,J=8.5,1.3Hz,1H),4.40(dt,J=7.1,3.7Hz,2H),1.32(t,J=7.1Hz,3H). ¹³ C NMR(101MHz,Acetone-d ₆ ) δ168.76, 139.45, 128.61, 127.69, 126.44, 126.28, 125.37, 123.60, 121.00, 114.05, 110.58, 103.87, 63.96, 14.22.

Example 8: Preparation of methyl 2-(1-Boc-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX8)

Indole (232 mg, 2 mmol) was dissolved in 10 mL of dichloromethane, (Boc) ₂ (480.15 mg, 2.2 mmol) was added dropwise at room temperature, and 1 mL of triethylamine was added to stir the reaction at room temperature. The reaction was monitored by TLC. After 5 hours, 1-Boc indole was obtained through column chromatography separation. The subsequent preparation method was as in Example 1, and the product was a colorless oil with a yield of 95%. ¹ H NMR(400MHz,Acetone-d ₆ )δ8.19(d,J=8.4Hz,1H),7.86(d,J=6.3Hz,2H),7.37(t,J=7.7Hz,1H),7.27 (t,J=7.6Hz,1H),3.90(s,3H),1.70(s,9H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ168.86,149.92,136.46,128.56,126.51,126.20,125.65, 123.79, 122.31, 115.94, 115.16, 103.32, 85.37, 54.13, 28.15.

Example 9: Preparation of ethyl 2-(1-isopentyl-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX9)

Dissolve indole (232 mg, 2 mmol) in 10 mL of DMF, add 8 mL of DMF solution containing 96 mg (2.4 mmol) NaH (60% dispersed in mineral oil) at 5°C, and stir the mixture at room temperature for 30 min Cool to 5°C, then add dropwise 5 mL of a DMF solution in which 362.5 mg of isopentyl bromide (2.4 mmol) was dissolved, react at room temperature, and monitor by TLC. After 16 hours, the mixture was cooled to 5°C, 15mL of water was added to quench the reaction, the product was extracted with diethyl ether, separated by column chromatography to obtain 1-isoamylindole, the following preparation method was as in Example 1, and the product was light yellow oil material with a yield of 93%. ¹ H NMR (400MHz,Acetone-d ₆ )δ7.89(d,J=8.1Hz,1H),7.53(s,1H),7.45(d,J=8.3Hz,1H),7.19(t,J= 7.6Hz,1H),7.07(t,J=7.6Hz,1H),4.40–4.30(m,2H),4.29–4.21(m,2H),1.73(dd,J=14.8,7.0Hz,2H), 1.60(dt, J=13.3,6.6Hz,1H),1.28(t,J=7.1Hz,3H),0.96(d,J=6.6Hz,6H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ169 .22, 137.41, 128.87, 126.99, 125.40, 123.81, 122.61, 122.30, 120.40, 110.72, 108.61, 63.54, 45.29, 39.70, 26.50, 22.72, 22.70, 14.28.

Example 10: Preparation of methyl 2-(5-chloro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX10)

The preparation method was as in Example 1, and the product was a light yellow solid with a yield of 88%. ¹ H NMR (400MHz,Acetone-d ₆ )δ10.63(s,1H),7.78(d,J=1.3Hz,1H),7.50(d,J=2.6Hz,1H),7.33(d,J= 8.7Hz,1H),7.01(dd,J=8.7,2.0Hz,1H),3.77(s,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ169.54,136.21,127.52,126.53,125.95,123.69, 122.96, 121.22, 113.99, 109.39, 78.25, 53.95.

Example 11: Preparation of methyl 2-(5-nitro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX11)

The preparation method was as in Example 1, and the product was a yellow solid with a yield of 89%. ¹ H NMR (400MHz, Acetone-d ₆ )δ11.13(s,1H),8.82(s,1H),7.95(d,J=9.0Hz,1H),7.72(s,1H),7.53(d, J=9.0Hz, 1H), 3.80(s, 3H). ¹³ C NMR (101MHz, Acetone-d ₆ ) δ169.22, 142.83, 140.72, 129.68, 126.38, 125.77, 123.54, 119.12, 118.10, 113.14, 111.96, 54.19.

Example 12: Preparation of ethyl 2-(1-methyl-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX12)

The preparation method was as in Example 1, and the product was light yellow oil with a yield of 92%. ¹ H NMR (400MHz,Acetone-d ₆ )δ7.88(d,J=8.1Hz,1H),7.47(s,1H),7.40(d,J=8.3Hz,1H),7.20(dd,J= 11.3,4.0Hz,1H),7.08(t,J=7.4Hz,1H),4.40–4.29(m,2H),3.85(d,J=3.8Hz,3H),1.28(t,J=7.1Hz, 3H). ¹³ CNMR (101MHz, Acetone-d ₆ ) δ169.25, 138.25, 129.91, 126.86, 126.65, 123.81, 122.67, 122.11, 120.44, 110.56, 108.55, 63.58, 33.05, 14.24.

Example 13: Preparation of ethyl 2-(5-carboxymethyl-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX13)

The preparation method was as in Example 1, and the product was a white solid with a yield of 86%. ¹ H NMR (400MHz,Acetone-d ₆ )δ10.90(s,1H),8.77(s,1H),7.86(d,J=8.6Hz,1H),7.73(d,J=2.3Hz,1H) ,7.54(d,J=8.6Hz,1H),4.45–4.34(m,2H),3.89(s,3H),1.33(t,J=7.1Hz,3H). ¹³ C NMR(101MHz,Acetone-d ₆ ) δ169.07, 168.27, 140.35, 127.75, 126.56, 125.99, 125.08, 123.93, 123.72, 122.85, 112.46, 111.14, 63.87, 52.02, 14.22.

Example 14: Preparation of ethyl 2-(4-nitro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX14)

The preparation method was as in Example 1, and the product was a yellow solid with a yield of 83%. ¹ H NMR (400MHz,Acetone-d ₆ )δ11.28(s,1H),7.86(dd,J=11.2,3.0Hz,2H),7.62(d,J=7.7Hz,1H),7.31(t, J=7.9Hz,1H),4.38–4.28(m,2H),1.26(q,J=6.8Hz,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ168.56,145.00,139.52,129.62,129.58, 126.66, 123.80, 121.91, 118.09, 117.60, 108.96, 63.63, 14.17.

Example 15: Preparation of methyl 2-(4-carboxymethyl-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX15)

The preparation method was as in Example 1, and the product was a light yellow solid with a yield of 86%. ¹ H NMR (400MHz,Acetone-d ₆ )δ10.94(s,1H),7.72(dd,J=8.1,0.5Hz,1H),7.66(s,1H),7.51(d,J=7.4Hz, 1H),7.23(t,J=7.8Hz,1H),3.89(d,J=4.5Hz,3H),3.77(s,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ171.79,169.80,138.45 ,128.02,127.98,125.71,123.42,123.11,121.94,116.90,110.38,106.62,53.71,53.00.

Example 16: Preparation of methyl 2-(5-fluoro-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX16)

The preparation method was as in Example 1, the product was light yellow solid, and the yield was 91%. ¹ H NMR (400MHz,Acetone-d ₆ )δ10.54(s,1H),7.50(d,J=2.6Hz,1H),7.42(dd,J=10.6,2.1Hz,1H),7.32(dd, J=8.9,4.6Hz,1H),6.82(td,J=9.1,2.5Hz,1H),3.77(s,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ169.63,159.78,134.40,127.77, 126.71, 123.77, 113.60, 111.23, 110.97, 106.44, 78.25, 53.91.

Example 17: Preparation of methyl 2-(5-cyano-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX17)

The preparation method was as in Example 1, and the product was a white solid with a yield of 81%. ¹ H NMR (400MHz,Acetone-d ₆ )δ11.12(s,1H),8.36(s,1H),7.82(d,J=1.6Hz,1H),7.67(d,J=8.5Hz,1H) ,7.49(dd,J=8.5,1.3Hz,1H),3.94(s,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ169.34,139.44,128.62,127.57,126.41,126.28,125.45,123.57,121.06 , 114.07, 110.51, 103.94, 54.18.

Example 18: Preparation of ethyl 2-(4-hydroxy-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX18)

The preparation method was as in Example 1, the product was a yellow solid, and the yield was 100%. ¹ H NMR (400MHz,Acetone-d ₆ )δ10.60(s,1H),7.49(s,1H),7.07–6.94(m,2H),6.54(dd,J=7.4,1.0Hz,1H), 4.39(dt,J=7.1,4.2Hz,2H),1.32(t,J=7.1Hz,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ168.16,150.26,139.93,126.18,124.68,124.44,115.85 , 108.18, 106.08, 104.43, 104.38, 63.72, 14.20.

Example 19: Preparation of ethyl 2-(2-methyl-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX19)

The preparation method was as in Example 1, and the product was a light yellow solid with a yield of 96%. ¹ H NMR (400MHz, CDCl ₃ )δ8.02(s,1H),7.79(d,J=7.9Hz,1H),7.21(s,1H),7.11(dd,J=16.7,7.8Hz,2H) ,4.37(dd,J=24.4,7.2Hz,2H),4.02(s,1H),2.48(s,3H),1.32(t,J=7.1Hz,3H). ¹³ C NMR(101MHz,CDCl ₃ ) δ169.38, 135.30, 134.66, 126.83, 125.40, 122.56, 121.61, 120.45, 120.23, 110.38, 103.89, 63.58, 13.89, 13.74.

Example 20: Preparation of ethyl 2-(5-formyl-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX20)

The preparation method was as in Example 1, and the product was a light yellow solid with a yield of 92%. ¹ H NMR (400MHz,Acetone-d ₆ )δ11.04(s,1H),10.05(s,1H),8.54(s,1H),7.75(s,2H),7.62(d,J=7.9Hz, 1H),4.39(d,J=4.8Hz,2H),1.31(d,J=7.0Hz,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ191.72,166.67,140.21,130.10,128.79,127.16, 126.60, 125.40, 122.76, 121.67, 112.45, 110.67, 62.98, 13.34.

Example 21: Preparation of methyl 2-(5-formyl-1H-indol-3-yl)-2-hydroxy-3,3,3-trifluoropropionate (HX21)

The preparation method was as in Example 1, and the product was a light yellow solid with a yield of 91%. ¹ H NMR (400MHz,Acetone-d ₆ )δ11.07(s,1H),10.05(s,1H),8.51(s,1H),7.74(d,J=5.8Hz,2H),7.63(d, J=8.5Hz,1H),3.93(s,3H). ¹³ C NMR(101MHz,Acetone-d ₆ )δ191.81,168.53,140.02,130.17,127.15,127.00,126.57,125.58,125.41,121.60,112.45,99.99, 53.15.

Table 1 The chemical structure of the target compound HX1-21 synthesized by the method of the present invention

compound R ¹ R ² R ³

HX1 5-NO ₂ Et h HX2 5-F Et h HX3 5-Cl Et h HX4 6-F Et h HX5 5-Br Et h HX6 h Et h HX7 5-CN Et h HX8 h Me Boc HX9 h Et isopentyl HX10 5-Cl Me h HX11 5-NO ₂ Me h HX12 h Et Me HX13 5-COOMe Et h HX14 4-NO ₂ Et h HX15 4-COOMe Me h HX16 5-F Me h HX17 5-CN Me h HX18 4-OH Et h HX19 2-Me Et h HX20 5-CHO Et h HX21 5-CHO Me h

Experimental Example 22: Pharmacological Experiment of Indole Compounds

(1) Cytotoxicity determination of indole compounds:

Yellow thiazolan, referred to as MTT, can enter the cell through the cell membrane. The amber dehydrogenase in the mitochondria of living cells can reduce the exogenous MTT to blue-purple needle-shaped Formazan crystals that are insoluble in water and deposit in the cell. The crystals can be dissolved by 20% (mass to volume) SDS, and the light absorption value is measured at 595nm wavelength with an enzyme-linked immunosorbent detector, which can indirectly reflect the number of cells.

During the experiment, TZM-bl (provided by the National Institutes of Health) cells were transferred to a 96-well plate, and the compound was added to the cells at a certain dilution after 24 hours. After culturing at 37°C for 72 hours, 100 μl of the supernatant was sucked away, and added 20 μl of MTT was incubated at 37°C for 4 hours, 100 μl of 20% SDS was added for 18 hours, and the OD value at a wavelength of 595 nm was measured with a microplate reader. Inhibition rate of the compound (%)=[1-(EN)/(PN)]×100, where "E" represents the OD value of the administration group, "P" represents the OD value of the non-administration group, and "N" represents OD value of blank group. The half inhibitory concentration (CC ₅₀ ) of a compound was used as an indicator of the cytotoxicity of the compound.

(2) Anti-HIV-1 activity of indole compounds in vitro:

HIV-ⅢB (provided by the National Institutes of Health) is a classic HIV drug screening experimental strain, and TZM-bl (provided by the National Institutes of Health) cells are modified Hela (provided by the American Type Collection) cell line with stable cell membranes Expresses the HIV receptor and coreceptor, and stably integrates the HIV long terminal repeat-driven luciferase gene into the nucleus. After HIV-ⅢB infects TZM-b1 cells, the TAT protein expressed by the virus can activate the expression of luciferase gene in the cells, and the level of virus replication can be judged by detecting the activity of luciferase in the cells. By detecting the luciferase in the cells after drug treatment, the activity of the drug to inhibit the HIV-1 virus can be accurately quantified.

During the experiment, HIV-ⅢB virus and drug were mixed and added to TZM-bl cells (60% (area ratio) confluent). After the virus was adsorbed to the cells for 2 hours, the mixture of virus and drug was sucked off, and fresh medium was added ( DMEM, 90% (volume ratio), fetal bovine serum, 10% (volume ratio), G418, 500 μg/ml; hygromycin, 100 μg/ml; puromycin, 1 μg/ml. sub-content) to continue culturing, and do 8 replicate wells for each dilution. After incubation at 37°C for 24 hours, the luciferase activity in the cells was detected. Inhibition rate of compound (%)=[1-(EN)/(PN)]×100, where "E" represents the activity of luciferase in the experimental group, "P" represents the activity of luciferase in the positive group, "N" represents the luciferase activity in the negative group. The half inhibitory concentration (IC ₅₀ ) of the compound was used as an indicator of its antiviral activity.

The present invention uses delavirdine (DEV) and efavirenz (EFV) as a control, checks the cytotoxicity and anti-HIV-1 activity of 21 compounds synthesized, and calculates the selectivity index SI of the compound, and the results are shown in the table 2.

Table 2 Cytotoxicity and anti-HIV-1 activity results of the target compound HX1-21 synthesized by the present invention

The above experimental results show that most of the synthesized compounds have good anti-HIV-1 activity, such as compounds HX1 (IC ₅₀ =0.045μM, SI=1404.6), HX3 (IC ₅₀ =0.249μM, SI=552.6), HX4 ( IC ₅₀ =0.147μM, SI=757.8), HX12 (IC ₅₀ =0.309μM, SI=752.0), etc.

Claims (4)

1. An indole compound has a structure shown in the following general formula:

wherein,

R¹is 4-OH, 4-NO₂、4-COOMe、5-CHO；

R²Me or Et;

R³boc, Me or isoamyl.

2. An application of indole compounds in preparing anti-AIDS drugs, wherein the indole compounds have a structure shown as the following general formula:

wherein,

R¹is H, 2-Me, 4-OH, 4-NO₂、4-COOMe、5-CHO、5-CN、5-F、5-Br、5-Cl、5-NO₂5-COOMe or 6-F;

R²me or Et;

R³h, Boc, Me or isoamyl.

3. The use according to claim 2, wherein the indole is

2- (5-nitro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,

2- (5-fluoro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,

2- (5-chloro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,

2- (6-fluoro-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,

2- (5-bromo-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester,

2- (5-cyano-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester or

2- (1-methyl-1H-indol-3-yl) -2-hydroxy-3, 3, 3-trifluoropropionic acid ethyl ester.

4. An anti-aids pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carriers or excipients.