A composite preparation containing indole and 3-substituted indole derivatives and its application

Abstract

The invention discloses a composite preparation containing indole and 3-substituted indole derivatives and its application, belonging to the field of biomedicine, wherein the 3-substituted indole derivatives are one or two of indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, and indole-3-methanol. The composite preparation containing indole and 3-substituted indole derivatives of the invention has a synergistic effect, has significant in vitro inhibitory activity on Helicobacter pylori, can not only inhibit the growth of Helicobacter pylori, but also can inhibit urease activity and destroy the morphology of Helicobacter pylori, and has good application prospects in developing pharmaceutical preparations with the effect of eradicating Helicobacter pylori.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine, and in particular to a composite preparation comprising indole and 3-substituted indole derivatives and application thereof. Background Art

[0002] Helicobacter pylori infection is one of the most common chronic bacterial diseases in humans, affecting about 4.4 billion people worldwide. Helicobacter pylori is spiral-shaped, has flagella, is microaerophilic, and is a Gram-negative bacterium. When it binds to gastric epithelial cells, it is highly pathogenic and can cause chronic gastritis, gastric ulcers, and in severe cases, duodenal ulcers and even gastric cancer. At present, the treatment of Helicobacter pylori is mostly quadruple therapy based on antibiotics, but this method has many limitations. First, antibiotic resistance, which is characterized by single-drug resistance, multidrug resistance, and heterogeneous resistance; second, it is easily affected by gastric acid, such as amoxicillin is easily degraded by gastric acid, so the dose needs to be increased to ensure its efficacy, which often causes other side effects that affect the eradication of Helicobacter pylori; third, the formation of Helicobacter pylori biofilms will hinder the effectiveness of antibiotics. In 2014, the World Health Organization listed antibiotic resistance as one of the three major threats to public health in the 21st century, and according to the World Health Organization's prediction, by 2050, about 10 million people will be at risk of illness due to the increase in antibiotic resistance. Based on these problems, we urgently need to find a better and safer alternative.

[0003] Indole is an important active group, also known as benzopyrrole (2,3-Benzopyrrole), which is widely used in research fields such as medicine, pesticides, spices, and dyes. Its derivatives usually have good biological and pharmacological activities, including antibacterial, anti-inflammatory, analgesic, anticancer, anti-ulcer, antioxidant, antitumor, antifungal, antidiabetic and antihypertensive. Due to its natural advantages and pharmacological activities, indole derivatives have always been compounds of great research interest in tropical regions and are one of the most popular fields of heterocyclic chemistry. Studies have shown that by introducing active small molecule groups into the indole structure, the compounds often show better antibacterial effects than before, such as 3-substituted indole derivatives: indole-3-lactic acid, indole-3-acetic acid, indole-3-ethanol, etc. At present, the indicator bacteria used in the antibacterial test of indole derivatives are Staphylococcus aureus, Escherichia coli, Salmonella enteritidis, Staphylococcus carnosus, Salmonella typhimurium, Micrococcus luteus, etc., and there are no large-scale studies on the inhibition of Helicobacter pylori. Summary of the invention

[0004] The purpose of the present invention is to provide a composite preparation containing indole and 3-substituted indole derivatives and its application. The composite preparation containing indole and 3-substituted indole derivatives provided by the present invention can directly act on Helicobacter pylori in vitro, inhibit its growth and colonization, and affect its motility by destroying its morphology.

[0005] In order to achieve the above-mentioned invention object, the present invention adopts the following technical solutions:

[0006] One of the technical solutions of the present invention is to provide a composite preparation comprising indole and 3-substituted indole derivatives, wherein the 3-substituted indole derivatives are one or two of indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, and indole-3-methanol.

[0007] The second technical solution of the present invention is to provide a composite preparation containing indole and 3-substituted indole derivatives, wherein the composite preparation includes indole and indole-3-methanol.

[0008] As a more preferred technical solution, the mass ratio of indole to indole-3-methanol is 1:1.

[0009] The third technical solution of the present invention is to provide a composite preparation containing indole and 3-substituted indole derivatives, wherein the composite preparation includes indole and indole-3-propionic acid.

[0010] As a more preferred technical solution, the mass ratio of indole to indole-3-propionic acid is 1:1.

[0011] A fourth technical solution of the present invention is to provide a composite preparation containing indole and 3-substituted indole derivatives, wherein the composite preparation includes indole and indole-3-acrylic acid.

[0012] As a more preferred technical solution, the mass ratio of indole to indole-3-acrylic acid is 1:1.

[0013] The fifth technical solution of the present invention is to provide a composite preparation containing indole and 3-substituted indole derivatives, wherein the composite preparation includes indole, indole-3-methanol and indole-3-acrylic acid.

[0014] As a more preferred technical solution, the mass ratio of indole, indole-3-methanol and indole-3-acrylic acid is 1:1:1.

[0015] The sixth technical solution of the present invention is to provide a composite preparation containing indole and 3-substituted indole derivatives, wherein the composite preparation includes indole, indole-3-methanol and indole-3-propionic acid.

[0016] As a more preferred technical solution, the mass ratio of indole, indole-3-methanol and indole-3-propionic acid is 1:1:1.

[0017] The invention relates to the use of the composite preparations described in any one to six of the technical solutions of the present invention in the preparation of drugs for inhibiting Helicobacter pylori.

[0018] Specifically, the composite preparations described in one to six of the technical solutions of the present invention include tablets, capsules, sustained-release tablets, controlled-release tablets, oral liquids, dripping pills, and injection liquid dosage forms.

[0019] Furthermore, the structural formula of the indole and 3-substituted indole derivatives is as shown in Formula I:

[0020] As a more preferred technical solution, the purity of indole, indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid and indole-3-methanol described in technical solutions 1 to 6 of the present invention is all >98%.

[0021] Specifically, the Helicobacter pylori is Helicobacter pylori SS1.

[0022] The beneficial effects of the present invention compared with the prior art are:

[0023] The present invention has been experimentally verified that the indole and 3-substituted indole derivatives (indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, indole-3-methanol) have a significant inhibitory effect on Helicobacter pylori, can inhibit the growth and colonization of Helicobacter pylori, and achieve the effect of preventing and treating Helicobacter pylori infection. Among them, the 3-substituted indole derivative can inhibit the growth and colonization of Helicobacter pylori in the stomach by inhibiting urease activity, destroy the normal morphology of Helicobacter pylori, and then achieve the effect of preventing and treating Helicobacter pylori infection. The present invention also finds that the composite preparations of indole and indole-3-methanol, indole and indole-3-acrylic acid, indole and indole-3-propionic acid, indole, indole-3-methanol and indole-propionic acid, indole, indole-3-methanol and indole-acrylic acid show a stronger anti-Helicobacter pylori effect through synergistic action, are particularly suitable for Helicobacter pylori infected people, and can become an effective drug raw material for the treatment of Helicobacter pylori infection in the future. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 It is a structural diagram of indole and 3-substituted indole derivatives;

[0025] Figure 2 This is a graph showing the inhibitory effects of single indole and 3-substituted indole derivatives on Helicobacter pylori;

[0026] Figure 3 This is a graph showing the inhibitory effect of indole and different types of 3-substituted indole derivatives on Helicobacter pylori;

[0027] Figure 4 This is a graph showing the inhibitory effect of indole + indole-3-methanol and different types of 3-substituted indole derivatives on Helicobacter pylori;

[0028] Figure 5 This is a graph showing the inhibitory effect of indole + indole-3-methanol + indole-3-acrylic acid and different types of 3-substituted indole derivatives on Helicobacter pylori;

[0029] Figure 6 It is a growth curve of Helicobacter pylori after treatment with indole, 3-substituted indole derivatives and composite preparations;

[0030] Figure 7 is a graph showing the inhibition of Helicobacter pylori urease activity by 3-substituted indole derivatives;

[0031] Figure 8 This is a scanning electron microscope image of Helicobacter pylori after being treated with the compound preparation. DETAILED DESCRIPTION

[0032] The technical solution of the present invention is further described in detail with reference to the following specific examples, but the scope of protection claimed by the present invention is not limited to the scope described in the examples.

[0033] Brain heart infusion (BHI) medium: weigh 10.0g of peptone, 12.5g of dehydrated calf brain infusion powder, 5.0g of dehydrated ox heart infusion powder, 2.0g of glucose, 5.0g of sodium chloride, and 2.5g of disodium hydrogen phosphate in a beaker, dissolve with ultrapure water, adjust pH to 7.4±0.2, and then make up to 1000mL. Dispense into Erlenmeyer flasks, sterilize at 121℃ for 15min, cool to room temperature, and set aside.

[0034] Columbia blood agar medium: weigh 10.0g of casein pancreatic digest, 5.0g of meat gastric digest, 3.0g of heart pancreatic digest, 5.0g of yeast extract powder, 1.0g of corn starch, 5.0g of sodium chloride, and 15.0g of agar in a beaker, dissolve with ultrapure water, adjust pH to 7.3±0.2, and then make up to 1000mL, stir well, and sterilize at 121℃ for 15min. Cool the sterilized medium to about 50℃, add 7.5% sterile defibrinated sheep blood, and pour into a plate.

[0035] The structural formulas of indole, indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, and indole-3-methanol are shown in the figure below. Figure 1 shown.

[0036] Example 1: Determination of the inhibitory effects of indole, 3-substituted indole derivatives and their composite preparations on the growth of Helicobacter pylori (Hp SS1)

[0037] Step 1: Determination of the inhibitory effect of single indole and 3-substituted indole derivatives on the growth of Helicobacter pylori

[0038] (1) Indole, indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, and indole-3-methanol were prepared with dimethyl sulfoxide (DMSO) into solutions with concentrations of 0.625, 1.25, 2.5, 5, and 10 mg / mL, respectively.

[0039] (2) The Oxford cup method was used to observe the inhibitory effects of the above-mentioned 3-substituted indole derivatives at different concentrations on Hp SS1 in vitro, and the diameter of the inhibition zone was measured using DMSO as a control.

[0040] The concentration of Hp SS1 suspension was adjusted to 10 8 CFU / mL, take 100 μL of bacterial solution and inoculate it onto Columbia blood agar plate and spread it evenly with a spreading rod.

[0041] Place the sterilized Oxford cups at equal distances on the evenly coated Columbia blood agar plate, and add 200 μL of 0.625, 1.25, 2.5, 5, and 10 mg / mL indole, indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, and indole-3-methanol solutions in (1) to each well. DMSO was used as a blank control. The culture dish was placed in a three-gas incubator (5% O2, 10% CO2, 85% N2) and cultured at 37°C for 48 hours before being taken out. The inhibition zone experiment was repeated 3 times. The drug sensitivity judgment standard of the reference is as follows: the inhibition zone diameter ≥ 15 mm is highly sensitive; 10 mm ≤ inhibition zone diameter < 15 mm is moderately sensitive; 6 mm ≤ inhibition zone diameter < 10 mm is lowly sensitive; the inhibition zone diameter < 5 mm or no obvious inhibition zone is insensitive.

[0042] The results are shown in Table 1 and Figure 2 As shown, within the experimental dose and limited time range, there was no inhibition zone around the blank control group; the diameter of the inhibition zone around the five 3-substituted indole derivatives increased with the increase of concentration, indicating that the antibacterial activity of indole, indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, and indole-3-methanol solutions on Hp SS1 was dose-dependent; among them, indole had the best in vitro antibacterial effect.

[0043] Table 1: Inhibition zone diameters (mm) of different concentrations of 3-substituted indole derivatives against Hp SS1

[0044]

[0045] Step 2: Determination of the inhibitory effect of indole on the growth of Helicobacter pylori after compounding with different 3-substituted indole derivatives

[0046] (1) Take the 5 mg / mL indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, and indole-3-methanol solutions prepared in step 1 (1) respectively, and mix them with the indole solution of the same concentration in a ratio of 1:1.

[0047] (2) The Oxford cup method was used to compare the changes in the diameters of the inhibition zones before and after compounding, and the antibacterial abilities of the various complexes were compared.

[0048] Place the sterilized Oxford cups at equal distances on the Columbia blood agar plate coated with Hp SS1 in step 1 (2), and add 200 μL of the solution described in step 2 (1) to each well. Incubate at 37°C in a three-gas incubator (5% O2, 10% CO2, 85% N2) for 48 hours and then take out. Repeat the inhibition zone experiment 3 times. Refer to the drug sensitivity judgment criteria in the literature: inhibition zone diameter ≥ 15mm is highly sensitive; 10mm≤ inhibition zone diameter <15mm is moderately sensitive; 6mm≤ inhibition zone diameter <10mm is lowly sensitive; inhibition zone diameter <5mm or no obvious inhibition zone is insensitive.

[0049] The results are shown in Table 2 and Figure 3 As shown in the results, within the experimental dose and time range, indole showed synergistic effects after being combined with indole-3-methanol, indole-3-acetic acid and indole-3-propionic acid in a ratio of 1:1, that is, the antibacterial effect of the complex was stronger than that of a single compound. However, the diameter of the inhibition zone did not increase significantly after indole was combined with indole-3-acrylic acid and indole-3-butyric acid. The diameter of the inhibition zone on the same Columbia blood agar plate showed that indole + indole-3-methanol had the largest inhibition zone diameter, that is, the compound had the best effect.

[0050] Table 2: Diameters of inhibition zones of Hp SS1 after different 3-substituted indole derivatives were mixed with indole in a ratio of 1:1 (mm)

[0051]

[0052] Step 3: Determination of the inhibitory effect of indole + indole-3-methanol on the growth of Helicobacter pylori after compounding with other 3-substituted indole derivatives

[0053] (1) Take 5 mg / mL indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, and indole-3-acrylic acid prepared in step 1 (1), and mix them with an indole solution and an indole-3-methanol solution of the same concentration in a ratio of 1:1:1.

[0054] (2) The Oxford cup method was used to compare the changes in the diameters of the inhibition zones before and after compounding, and the antibacterial abilities of the various complexes were compared.

[0055] Place the sterilized Oxford cups at equal distances on the Columbia blood agar plate coated with Hp SS1 in step 1 (2), and add 200 μL of the solution described in step 3 (1) to each well. Incubate at 37°C in a three-gas incubator (5% O2, 10% CO2, 85% N2) for 48 hours and then take out. Repeat the inhibition zone experiment 3 times. Refer to the drug sensitivity judgment criteria in the literature: inhibition zone diameter ≥ 15mm is highly sensitive; 10mm≤inhibition zone diameter <15mm is moderately sensitive; 6mm≤inhibition zone diameter <10mm is lowly sensitive; inhibition zone diameter <5mm or no obvious inhibition zone is insensitive.

[0056] The results are shown in Table 3 and Figure 4 As shown in the results, within the experimental dose and time range, indole and indole-3-methanol were mixed with indole-3-acrylic acid, indole-3-butyric acid, and indole-3-propionic acid in a ratio of 1:1:1, respectively, and showed a synergistic effect, that is, the antibacterial effect of the complex was stronger than that of the two-combination complex. However, the diameter of the inhibition zone did not increase significantly after indole, indole-3-acrylic acid and indole-3-acetic acid were combined. And the diameter of the inhibition zone on the same Columbia blood agar plate showed that indole + indole-3-methanol + indole-3-acrylic acid had the largest inhibition zone diameter, that is, the compounding effect was the best.

[0057] Table 3: Diameters of inhibition zones against Hp SS1 after different 3-substituted indole derivatives were mixed with indole and indole-3-methanol in a ratio of 1:1:1 (mm)

[0058]

[0059] Step 4: Determination of the inhibitory effect of indole + indole-3-methanol + indole-3-acrylic acid on the growth of Helicobacter pylori after compounding with other 3-substituted indole derivatives

[0060] (1) Indole-3-propionic acid, indole-3-acetic acid, and indole-3-butyric acid at a concentration of 5 mg / mL in step 1 (1) were respectively mixed with indole, indole-3-methanol, and indole-3-acrylic acid at the same concentration in a ratio of 1:1:1:1.

[0061] (2) The Oxford cup method was used to compare the changes in the diameters of the inhibition zones before and after compounding, and the antibacterial abilities of the various complexes were compared.

[0062] Place the sterilized Oxford cups at equal distances on the Columbia blood agar plate coated with Hp SS1 in step 1 (2), and add 200 μL of the solution described in step 4 (1) to each well. Incubate at 37°C in a three-gas incubator (5% O2, 10% CO2, 85% N2) for 48 hours and then take out. Repeat the inhibition zone experiment 3 times. Refer to the drug sensitivity judgment standard in the literature: inhibition zone diameter ≥ 15mm is highly sensitive; 10mm≤ inhibition zone diameter <15mm is moderately sensitive; 6mm≤ inhibition zone diameter <10mm is lowly sensitive; inhibition zone diameter <5mm or no obvious inhibition zone is insensitive.

[0063] The results are shown in Table 4 and Figure 5 As shown, within the experimental dosage and limited time range, indole, indole-3-methanol and indole-3-acrylic acid did not show synergistic effect when mixed with indole-3-butyric acid, indole-3-propionic acid and indole-3-acetic acid in a ratio of 1:1:1:1, that is, the antibacterial effect of the tetraindole and 3-substituted indole derivative complex was inferior to that of indole + indole-3-methanol + indole-3-acrylic acid.

[0064] Example 2: Determination of the growth curve of Helicobacter pylori after treatment with indole and 3-substituted indole derivatives

[0065] (1) Hp SS1 was diluted to 0.05 in BHI broth at an absorbance of 600 nm (OD600).

[0066] (2) Indole, indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, indole-3-methanol and the composite preparation (indole + indole-3-methanol + indole-3-acrylic acid) were prepared into mixed solutions with concentrations of 0.625, 1.25, 2.5, 5 and 10 mg / mL respectively using the brain heart infusion broth containing Hp SS1 described in step (1), and the same concentration solution prepared in BHI broth without Hp SS1 was set as a control. The mixtures were cultured at 37°C in a three-gas incubator (5% O2, 10% CO2, 85% N2), and aliquots of the samples were drawn at 6, 12, 24, 36 and 48 hours, and △OD600 was measured using an ELISA reader.

[0067] The results are as follows Figure 6 As shown in the figure, within 48 hours, as the sample concentration increased, the growth curve of Hp SS1 tended to be flat. The minimum inhibitory concentrations of indole, indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, indole-3-methanol and the composite preparation (indole + indole-3-methanol + indole-3-acrylic acid) were 1.25, 10, 10, 10, 5, 5, and 1.25 mg / mL, respectively.

[0068] Example 3: Determination of the urease activity of 3-substituted indole derivatives against Helicobacter pylori

[0069] (1) Use a loop to scrape fresh Hp SS1 of two generations of activation, wash twice with sterile PBS, centrifuge (8000 g, 5 min) to obtain bacterial sludge, and then adjust the Hp SS1 concentration to 1×10 7 CFU / mL.

[0070] (2) In a 96-well plate, 40 μL of Hp SS1 and 10 μL of different concentrations of indole, indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, indole-3-methanol, and the composite preparation (indole + indole-3-methanol + indole-3-acrylic acid) were mixed and placed in a three-gas incubator for co-culture for 48 h.

[0071] (3) Take out the 96-well plate and add 150 μL of urea-phenol red solution. After shaking evenly, use an ELISA reader to measure the absorbance at 550 nm.

[0072] The results are as follows Figure 7 As shown in the figure, since indole itself can react with urea-phenol red solution to change color, it is impossible to determine the urease activity of Hp SS1 after treatment with indole and the composite preparation (indole + indole-3-methanol + indole-3-acrylic acid). The five 3-substituted indole derivatives all have significant inhibitory activity against the urease of Hp SS1, and the inhibition rate increases with the increase of concentration. Among them, indole-3-butyric acid has the best inhibitory effect, with an inhibition rate of more than 90% when the concentration is ≥1.25mg / mL and an inhibition rate of 77.2% when the concentration is 0.625mg / mL; the inhibition rate of indole-3-propionic acid and indole-3-acetic acid is more than 90% when the concentration is ≥2.5mg / mL; the inhibition rate of indole-3-acrylic acid is more than 80% when the concentration is ≥2.5mg / mL; the inhibition rate of indole-3-methanol is more than 80% when the concentration is ≥10mg / mL. The production of urease can ensure the colonization and survival of Helicobacter pylori in the gastric acid environment. It can decompose urea in the body into NH3 and CO2, thereby increasing the pH value of the surrounding environment and allowing it to survive and proliferate stably. Therefore, 3-substituted indole derivatives can inhibit the activity of urease, depriving Helicobacter pylori of the favorable environment for survival, thereby inhibiting its colonization and growth in the stomach.

[0073] Example 4: Effect of indole + indole-3-methanol + indole-3-acrylic acid compound on the morphology of Helicobacter pylori

[0074] (1) Use a bacterial loop to scrape fresh activated two-generation Hp SS1, wash twice with sterile PBS, centrifuge (8000g, 5min) to obtain bacterial sludge, and then adjust the Hp SS1 concentration to 1×10 8 CFU / mL.

[0075] (2) Take the Hp SS1 bacterial suspension in (1) and adjust the concentration of indole, indole-3-methanol, and indole-3-acrylic acid to 5 mg / mL, and mix them in a ratio of 1:1:1. The blank control group is the Hp SS1 bacterial suspension without any treatment.

[0076] (3) The Hp SS1 treated with the composite preparation (indole + indole-3-methanol + indole-3-acrylic acid) and the untreated Hp SS1 in (2) were placed in a three-gas incubator at 37°C for 6 h.

[0077] (4) Scanning electron microscopy (SEM) was used to observe the morphological changes of Hp SS1 before and after treatment with the composite preparation (indole + indole-3-methanol + indole-3-acrylic acid).

[0078] The bacteria in (3) were collected, washed twice with PBS, mixed with 2.5% glutaraldehyde, and left to stand overnight at 4°C. The next day, they were dehydrated with ethanol (30% to 100%) gradient, cold sputtered and gold-plated after dehydration, and observed with a scanning electron microscope (ZESSI sigma300, Germany).

[0079] The results are as follows Figure 8 As shown in the figure, after treatment with the composite preparation (indole + indole-3-methanol + indole-3-acrylic acid), Hp SS1 changed from a smooth, slightly curved short rod to a rough and twisted shape, indicating that the treatment with the composite preparation (indole + indole-3-methanol + indole-3-acrylic acid) destroyed the normal morphology of Hp SS1, thereby affecting its survival and movement in gastric juice, thereby achieving the effect of preventing and treating Helicobacter pylori infection.

[0080] Finally, it should be noted that the above embodiments only illustrate the technical solutions of the present invention rather than limiting it. Although the present invention has been described in detail with reference to the aforementioned embodiments, it is still possible for a person skilled in the art to modify the technical solutions described in the aforementioned embodiments or to replace some of the technical features therein with equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions claimed to be protected by the present invention.

Claims

1. Use of a composite preparation comprising indole and a 3-substituted indole derivative in the preparation of a drug for inhibiting Helicobacter pylori, wherein the 3-substituted indole derivative is one or two of indole-3-propionic acid, indole-3-acetic acid, indole-3-butyric acid, indole-3-acrylic acid, and indole-3-methanol.

2. The use according to claim 1, characterized in that: The composite preparation comprises indole and indole-3-methanol.

3. The use according to claim 1, characterized in that: The composite preparation comprises indole and indole-3-propionic acid.

4. The use according to claim 1, characterized in that: The composite preparation comprises indole and indole-3-acrylic acid.

5. The use according to claim 1, characterized in that: The composite preparation comprises indole, indole-3-methanol and indole-3-acrylic acid.

6. The use according to claim 1, characterized in that: The composite preparation comprises indole, indole-3-methanol and indole-3-propionic acid.

7. The use according to claim 1, wherein the composite preparation comprises tablets, capsules, sustained-release tablets, controlled-release tablets, oral liquids, dripping pills, and injection liquid dosage forms.

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