A thiophene-containing bisindolemethane type alpha-glucosidase inhibitor and its preparation method and application

Abstract

This invention relates to a thiophene-containing bisindolemethane-type α-glucosidase inhibitor, its preparation method, and its application, belonging to the field of glucosidase inhibitor preparation technology. Specifically, this invention discloses a thiophene-containing bisindolemethane-type α-glucosidase inhibitor, its preparation method, and its application. The method involves synthesizing a 3,3'-bisindolemethane compound through photo-oxidation and reduction of nitrohaloalkanes under blue light irradiation. Bromonitromethane participates in the reaction as a methylene precursor. The preparation process uses clean energy and yields a good yield of the 3,3'-bisindolemethane compound under mild conditions. Preliminary activity tests demonstrate that the bisindolemethane-type compound prepared by this invention has a significant inhibitory effect on α-glucosidase and can be used as a lead candidate for developing novel α-glucosidase inhibitors.

Description

A thiophene-containing bisindolemethane-type α-glucosidase inhibitor, its preparation method and application Technical Field

[0001] This invention belongs to the field of glucosidase inhibitor preparation technology, and relates to a thiophene-containing bisindolemethane type α-glucosidase inhibitor, its preparation method and application. Background Technology

[0002] Diabetes is a chronic metabolic disease. High blood sugar in diabetic patients can lead to a series of complications such as blindness, high blood pressure, kidney disease, and stroke. With the improvement of people's living standards, the incidence of diabetes has risen sharply, becoming a major challenge for global healthcare systems.

[0003] Based on different pathogenesis, diabetes is mainly divided into two categories: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM is caused by an autoimmune response, where the body's defense cells attack insulin-producing cells; it is an intrinsic form of diabetes. T2DM is the most common type of diabetes, accounting for approximately 90% of all diabetes cases. It is characterized by insulin resistance, causing the body to become insensitive to insulin; it is an extrinsic form of diabetes. Postprandial hyperglycemia is a significant factor affecting T2DM; therefore, postprandial blood glucose management is one of the methods for treating T2DM. Alpha-amylase and alpha-glucosidase are the main carbohydrate-digesting enzymes related to postprandial hyperglycemia in patients with T2DM. Alpha-amylase catalyzes the breakage of glycosidic bonds, converting polysaccharides into smaller oligosaccharide fragments. These fragments are further degraded into monosaccharides by alpha-glucosidase, which are released into the bloodstream in an absorbable form. Therefore, the key to lowering blood glucose levels is to inhibit these two carbohydrate-digesting enzymes. A few synthetic drugs, such as acarbose, metformin, and sitagliptin, have been used in clinical practice. However, the use of these drugs can also cause side effects such as bloating, diarrhea, and hypoglycemia. Therefore, further development of hypoglycemic drugs is needed.

[0004] Indole derivatives, characterized by their complex structures, significant biological activities, and high drug-likeness, have become a focus of attention in fields such as total synthesis of natural products and the discovery of new lead compounds. For example, molecules such as serine (an antihypertensive drug), vinblastine (a cerebral vasodilator), quinine (an antimalarial drug), and vincristine / vincristine (antitumor drugs) are already used clinically as important drugs. Among them, bisindole derivatives possess a variety of physiological activities, including antioxidant, anti-infective, antiepileptic, antifungal, and antitumor effects. In recent years, many bisindole derivatives have been used as antitumor drugs or are undergoing clinical trials. For instance, research has found that 3,3'-diindolymethane (DIM) can effectively induce apoptosis in thymic tumor cells and reduce the risk of breast and prostate cancer. Furthermore, DIM has a synergistic effect with the anticancer drug paclitaxel, inducing apoptosis in cancer cells. Therefore, the synthesis and transformation of bisindole compounds have received considerable attention, and the synthesis of bisindole derivatives using simple methods for subsequent research is of great significance.

[0005] Numerous studies have reported on the synthesis of 3,3'-diindolemethanes with methylene substituents in the synthesis of bisindole derivatives. However, the synthesis of DIMs with 3-indole bridged by methylene groups is more difficult, requiring the use of methylene donors or methylene precursors in the presence of a catalyst or medium. These methylene precursors generate radical or imine ion intermediates in the presence of an external oxidant, which then react with various nucleophiles to yield the corresponding products.

[0006] Therefore, it is necessary to study the use of photoredox haloalkanes as methylene precursors in the reaction, 2-arylindole as a nucleophile, and the introduction of different substituents to modify and synthesize bisindole derivatives based on the active parent skeleton of indole. At the same time, the activity can also be evaluated by combining the inhibitory effect of α-glucosidase. Summary of the Invention

[0007] In view of this, one objective of the present invention is to provide a thiophene-containing bisindolemethane-type α-glucosidase inhibitor; a second objective of the present invention is to provide a method for preparing a thiophene-containing bisindolemethane-type α-glucosidase inhibitor; and a third objective of the present invention is to provide the application of a thiophene-containing bisindolemethane-type α-glucosidase inhibitor in the preparation of α-glucosidase inhibitor drugs.

[0008] To achieve the above objectives, the present invention provides the following technical solution:

[0009] 1. A thiophene-containing bisindolemethane-type α-glucosidase inhibitor, wherein the chemical structural formula of the inhibitor is:

[0010] .

[0011] 2. The method for preparing the above inhibitor, wherein the reaction formula of the preparation method is:

[0012] ,

[0013] The structural formula of reactant I is: ;

[0014] The organic solvent is any one of 1,2-dichloroethane, dichloromethane, methanol, ethanol, or acetonitrile.

[0015] The catalyst is any one or more of the following: ruthenium chloride hexahydrate terpyridine, eosin Y, rose red, or eosin B.

[0016] Preferably, the preparation method specifically includes the following steps: reactant I, bromonitromethane and catalyst are mixed and dissolved in an organic solvent, stirred at room temperature to make them evenly mixed, irradiated with a 10 W blue light lamp, the reaction is monitored by thin-layer chromatography, after the reaction is completed, the organic solvent is removed under reduced pressure, the filtrate is dried and concentrated to obtain a crude product, and after purification, a thiophene-containing bisindolemethane type α-glucosidase inhibitor is obtained.

[0017] More preferably, the molar ratio of reactant I to bromonitromethane is 1:3 to 3:1.

[0018] More preferably, the amount of catalyst added is 0.5%-4% of the molar number of bromonitromethane.

[0019] More preferably, the molar volume ratio of reactant I to organic solvent is 1:1-5, mol:L.

[0020] More preferably, the reaction time of the irradiation reaction is 6-48 hours.

[0021] More preferably, the purification method is silica gel column chromatography, wherein the eluent used in the silica gel column chromatography purification process is a mixed solvent formed by mixing petroleum ether and ethyl acetate in a volume ratio of 10:1.

[0022] 3. The application of the above-mentioned thiophene-containing bisindolemethane-type α-glucosidase inhibitors in the preparation of α-glucosidase inhibitor drugs.

[0023] 4. A medicament for the prevention and / or treatment of diabetes, wherein the active ingredient of the medicament comprises the above-mentioned thiophene-containing bisindolemethane-type α-glucosidase inhibitor.

[0024] The beneficial effects of this invention are as follows: This invention discloses a thiophene-containing bisindolemethane-type α-glucosidase inhibitor, its preparation method, and its application. Specifically, it involves the photo-oxidation and reduction of nitrohaloalkanes via visible light to synthesize 3,3'-bisindolemethane compounds, wherein bromonitromethane participates in the reaction as a methylene precursor. Using visible light, a clean energy source, 3,3'-bisindolemethane compounds are obtained in good yields under mild conditions. Evaluation of α-glucosidase inhibitory activity shows that all bisindole derivatives exhibit significant inhibitory effects (5.45-28.06 μM), all higher than acarbose. This study identifies a series of lead candidates for the development of novel α-glucosidase inhibitors.

[0025] Other advantages, objectives, and features of the invention will be set forth in part in the description which follows, and in part will be apparent to those skilled in the art from the following examination, or may be learned from practice of the invention. The objectives and other advantages of the invention can be realized and obtained through the following description. Detailed Implementation

[0026] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0027] The models and manufacturers of the experimental instruments involved in the following examples are shown in Table 1, and the manufacturers of the relevant reagents are shown in Table 2.

[0028] Table 1. Models and Manufacturers of Experimental Instruments

[0029]

[0030] Table 2 Manufacturers of relevant reagents

[0031]

[0032] Example 1

[0033] A bis(2-phenyl-1H-indol-3-yl)methane α-glucosidase inhibitor is prepared as follows:

[0034] 0.6 mmol of 2-phenylindole, 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(2-phenyl-1H-indol-3-yl)methane).

[0035] The structural formula of the above product (Bis(2-phenyl-1H-indol-3-yl)methane) is as follows:

[0036] .

[0037] Its R f = 0.25 (PE / EtOAc, 10:1). 87% yield, pale yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 2H), 7.60 - 7.49 (m, 4H), 7.43 - 7.34 (m, 4H), 7.34- 7.28 (m, 2H), 7.33 - 7.29 (m, 2H), 7.29 - 7.25 (m, 2H), 7.21 - 7.19 (m,2H), 6.86 - 6.82 (m, 2H), 4.55 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ135.94, 134.53, 133.36, 129.41, 128.70, 128.36, 127.53, 121.98, 120.04,119.46, 112.09, 110.53, 21.32. MALDI-TOF-MS: m / z: calcd for C 29 H 22 N2(M+H) + :399.1856; found 399.1852.

[0038] Example 2

[0039] A bis(indolyl)methane-type α-glucosidase inhibitor (Bis(2-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methane) is prepared as follows:

[0040] 0.6 mmol of a 2-phenylindole derivative (2-(4-(trifluoromethyl)phenyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of a catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of an organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and then irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(2-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methane).

[0041] The structural formula of the above product (Bis(2-(4-(trifluoromethyl)phenyl)-1H-indol-3-yl)methane) is as follows:

[0042] ,

[0043] Its Rf = 0.25 (PE / EtOAc, 10:1). 54% yield, pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.37 (s, 2H), 7.86 - 7.70 (m, 8H), 7.38 - 7.29(m, 2H), 7.12 -7.08(m, 2H), 7.07 - 6.98(m, 2H), 6.84 - 6.70(m, 2H), 4.58(s, 2H). 13 C NMR (101MHz, DMSO-d6) δ 137.40, 136.81, 133.26, 129.03, 127.87, 127.55, 126.13,125.84, 125.80, 122.44, 119.81, 119.28, 112.73, 111.83, 21.57. MALDI-TOF-MS:m / z: calcd for C31 H 20 F6N2(M+H) + : 535.1531; found 534.1533.

[0044] Example 3

[0045] A bis(indolyl)methane-type α-glucosidase inhibitor (Bis(2-(4-fluorophenyl)-1H-indol-3-yl)methane) is prepared as follows:

[0046] 0.6 mmol of 2-phenylindole derivative (2-(4-fluorophenyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light lamp for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(2-(4-fluorophenyl)-1H-indol-3-yl)methane).

[0047] The structural formula of the above product (Bis(2-(4-fluorophenyl)-1H-indol-3-yl)methane) is as follows:

[0048] ,

[0049] Its Rf = 0.25 (PE / EtOAc, 10:1). 76% yield, pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 2H), 7.84 - 7.51 (m, 4H), 7.44 - 7.20 (m, 6H), 7.11 -6.90 (m, 4H), 6.76 - 6.72(m, 2H), 4.45 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ163.08, 136.46, 133.93, 130.69, 130.61, 130.02, 129.99, 129.13, 121.72,119.54, 118.98, 116.07, 115.86, 111.56, 111.15, 21.50. MALDI-TOF-MS: m / z:calcd for C 29 H 20 F2N2(M): 434.1595; found: 434.1594.

[0050] Example 4

[0051] A bis(indolyl)methane-type α-glucosidase inhibitor (Bis(2-(4-chlorophenyl)-1H-indol-3-yl)methane) is prepared as follows:

[0052] 0.6 mmol of 2-phenylindole derivative (2-(4-chlorophenyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(2-(4-chlorophenyl)-1H-indol-3-yl)methane).

[0053] The structural formula of the above product (Bis(2-(4-chlorophenyl)-1H-indol-3-yl)methane) is as follows:

[0054] ,

[0055] Its R f = 0.25 (PE / EtOAc, 10:1). 58% yield, pale yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 2H), 7.40 - 7.34 (m, 4H), 7.33 - 7.26 (m, 6H), 7.26(d, J = 1.5 Hz, 1H), 7.24 (d, J = 1.0 Hz, 1H), 7.13 - 7.09 (m, 2H), 6.93 -6.89 (m, 2H), 4.49 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 135.90, 133.47,133.38, 131.62, 129.40, 129.21, 128.76, 122.37, 119.82, 119.72, 112.32,110.65, 21.05; MALDI-TOF-MS: m / z: calcd for C 29 H 20 Cl2N2(M): 466.1004; found:466.1000.

[0056] Example 5

[0057] A bis(indolyl)methane-type α-glucosidase inhibitor (Bis(2-(4-bromophenyl)-1H-indol-3-yl)methane) is prepared as follows:

[0058] 0.6 mmol of a 2-phenylindole derivative (2-(4-bromophenyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of a catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of an organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and then irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 12:1) to obtain the product (Bis(2-(4-bromophenyl)-1H-indol-3-yl)methane).

[0059] The structural formula of the above product (Bis(2-(4-bromophenyl)-1H-indol-3-yl)methane) is as follows:

[0060] (3e)

[0061] ,

[0062] Its R f = 0.25 (PE / EtOAc, 12:1). 56% yield. Yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.90 (s, 2H), 7.46 - 7.43 (m, 4H), 7.29 - 7.28(m, 8H), 7.12 -7.08 (m, 2H), 6.92 - 6.89(m, 2H), 4.47 (s, 2H). 13 C NMR (101 MHz, Chloroform-d)δ 135.87, 133.34, 132.00, 131.66, 129.62, 129.17, 122.37, 121.60, 119.78,119.71, 112.32, 110.64, 20.99. MALDI-TOF-MS (M+H) + m / z: calcd for C 29 H 20 Br2N2(M): 555.0066; found: 555.0063.

[0063] Example 6

[0064] A bisindolylmethane-type α-glucosidase inhibitor (Bis(2-(p-tolyl)-1H-indol-3-yl)methane) is prepared as follows:

[0065] 0.6 mmol of a 2-phenylindole derivative (2-(p-tolyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of a catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of an organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and then irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(2-(p-tolyl)-1H-indol-3-yl)methane).

[0066] The structural formula of the above product (Bis(2-(p-tolyl)-1H-indol-3-yl)methane) is as follows:

[0067] ,

[0068] Its R f = 0.25 (PE / EtOAc, 10:1). 76% yield, yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.97 (s, 2H), 7.53 - 7.43 (m, 4H), 7.29 - 7.26 (m, 2H), 7.24- 7.15 (m, 6H), 7.07 - 7.03 (m, 2H), 6.84 - 6.80 (m, 2H), 4.53 (s, 2H), 2.39 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 137.34, 135.85, 134.54, 130.49, 129.46,129.43, 128.22, 121.76, 120.00, 119.35, 111.79, 110.39, 21.40, 21.29. MALDI-TOF-MS: m / z: calcd for C 30 H 26 N2(M+H) + : 427.2169; found: 427.2168.

[0069] Example 7

[0070] A bis(indolyl)methane-type α-glucosidase inhibitor (Bis(2-(4-methoxyphenyl)-1H-indol-3-yl)methane) is prepared as follows:

[0071] 0.6 mmol of a 2-phenylindole derivative (2-(4-methoxyphenyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of a catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of an organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and then irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 6:1) to obtain the product (Bis(2-(4-methoxyphenyl)-1H-indol-3-yl)methane).

[0072] The structural formula of the above product (Bis(2-(4-methoxyphenyl)-1H-indol-3-yl)methane) is as follows:

[0073] ,

[0074] Its R f = 0.25 (PE / EtOAc, 6:1). 67% yield. Yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 2H), 7.49 - 7.7.44 (m, 4H), 7.30 - 7.26 (m, 2H), 7.23 - 7.18 (m, 2H), 7.05 (ddd,J= 8.2, 7.0, 1.1 Hz, 2H), 6.95 - 6.90 (m, 4H), 6.85 (ddd,J= 8.1, 7.1, 1.1 Hz, 2H), 4.49 (s, 2H), 3.83 (s, 6H). 13 C NMR (101MHz, Chloroform-d) δ 159.07, 135.75, 134.42, 129.57, 129.48, 125.91, 121.64,119.83, 119.35, 114.13, 111.42, 110.35, 55.36, 21.24. MALDI-TOF-MS: m / z:calcd for C 31 H 26 N2O2(M): 458.1994; found: 458.1997.

[0075] Example 8

[0076] A bis(indolyl)methane-type α-glucosidase inhibitor (Bis(2-(3-fluorophenyl)-1H-indol-3-yl)methane) is prepared as follows:

[0077] 0.6 mmol of 2-phenylindole derivative (2-(3-fluorophenyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light lamp for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(2-(3-fluorophenyl)-1H-indol-3-yl)methane).

[0078] The structural formula of the above product (Bis(2-(3-fluorophenyl)-1H-indol-3-yl)methane) is as follows:

[0079] ,

[0080] Its R f = 0.25 (PE / EtOAc, 10:1). 55% yield. Yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 2H), 7.35 - 7.26 (m, 6H), 7.25 (m, 1H), 7.23 (m,1H), 7.20 - 7.14 (m, 2H), 7.13 - 7.07 (m, 2H), 7.03 - 6.97 (m, 2H), 6.90 (m, 2H), 4.54 (s, 2H). 13C NMR (101 MHz, Chloroform-d) δ 161.60, 135.95, 135.33,135.25, 133.31, 133.29, 130.21, 130.12, 129.20, 123.97, 123.94, 122.48,119.98, 119.74, 115.23, 115.00, 114.53, 114.32, 112.62, 110.69, 21.11. MALDI-TOF-MS: m / z: calcd for C 31 H 26 N2O2(M+H) + : 435.1667; found: 435.1672.

[0081] Example 9

[0082] A bis(indolyl)methane-type α-glucosidase inhibitor (Bis(2-(3-chlorophenyl)-1H-indol-3-yl)methane) is prepared as follows:

[0083] 0.6 mmol of 2-phenylindole derivative (2-(3-chlorophenyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(2-(3-chlorophenyl)-1H-indol-3-yl)methane).

[0084] The structural formula of the above product (Bis(2-(3-chlorophenyl)-1H-indol-3-yl)methane) is as follows:

[0085] ,

[0086] Rf = 0.25 (PE / EtOAc, 10:1). 54% yield. Pale yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 2H), 7.41 - 7.40 (m, 2H), 7.38 - 7.33 (m, 2H), 7.31- 7.28 (m, 2H), 7.25 - 7.21 (m, 6H), 7.13 - 7.08 (m, 2H), 6.93 - 6.89 (m, 2H), 4.52 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 135.95, 134.92, 134.46,133.13, 129.75, 129.17, 128.16, 127.56, 126.47, 122.52, 119.91, 119.77,112.67, 110.70, 21.01. MALDI-TOF-MS: m / z: calcd for C 29 H 20 Cl2N2(M): 466.1004; found: 466.1005.

[0087] Example 10

[0088] A bis(indolyl)methane-type α-glucosidase inhibitor (Bis(2-(3-bromophenyl)-1H-indol-3-yl)methane) is prepared as follows:

[0089] 0.6 mmol of a 2-phenylindole derivative (2-(3-bromophenyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of a catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of an organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and then irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 12:1) to obtain the product (Bis(2-(3-bromophenyl)-1H-indol-3-yl)methane).

[0090] The structural formula of the above product (Bis(2-(3-bromophenyl)-1H-indol-3-yl)methane) is as follows:

[0091] ,

[0092] Its Rf = 0.25 (PE / EtOAc, 12:1). 62% yield. Pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 2H), 7.76 (t,J= 1.8 Hz, 2H), 7.64 - 7.60 (m, 2H), 7.54 -7.49 (m, 2H), 7.39 - 7.30 (m, 4H), 7.11 - 7.00 (m, 4H), 6.81 - 6.73 (m, 2H), 4.51 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 136.62, 135.68, 133.15, 131.02,130.87, 130.32, 129.09, 127.53, 122.38, 122.21, 119.69, 119.19, 112.03,111.74, 21.64. MALDI-TOF-MS: m / z: calcd for C 29 H 20 Br2N2(M): 555.0066; found:555.0065.

[0093] Example 11

[0094] A bisindolylmethane-type α-glucosidase inhibitor (Bis(2-(m-tolyl)-1H-indol-3-yl)methane) is prepared as follows:

[0095] 0.6 mmol of a 2-phenylindole derivative (2-(m-tolyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of a catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of an organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and then irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (using a mixed solvent of ethyl acetate and petroleum ether in a volume ratio of 8:1) to obtain the product (Bis(2-(m-tolyl)-1H-indol-3-yl)methane).

[0096] The structural formula of the above product (Bis(2-(m-tolyl)-1H-indol-3-yl)methane) is as follows:

[0097] ,

[0098] Rf = 0.25 (PE / EtOAc, 8:1). 51% yield. Pale yellow solid. 1H NMR (400MHz, Chloroform-d) δ 7.98 (s, 2H), 7.41 - 7.31 (m, 4H), 7.30 -7.27 (m, 3H),7.25 - 7.17 (m, 3H), 7.16 - 7.10 (m, 2H), 7.09 - 7.03 (m, 2H), 6.89 - 6.80(m, 2H), 4.55 (s, 2H), 2.34 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ138.30, 135.86, 134.61, MALDI-TOF-MS: m / z:calcd for C 31 H 26 N2(M+H) + : 427.2169; found: 427.2164.

[0099] Example 12

[0100] A bis(indol-3-yl)methane α-glucosidase inhibitor (Bis(2-(3-methoxyphenyl)-1H-indol-3-yl)methane) is prepared as follows:

[0101] 0.6 mmol of a 2-phenylindole derivative (2-(3-methoxyphenyl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of a catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of an organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and then irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (using a mixture of ethyl acetate and petroleum ether in a volume ratio of 8:1) to obtain the product (Bis(2-(3-methoxyphenyl)-1H-indol-3-yl)methane).

[0102] The structural formula of the above product (Bis(2-(3-methoxyphenyl)-1H-indol-3-yl)methane) is as follows:

[0103] ,

[0104] Its Rf = 0.25 (PE / EtOAc, 8:1). 46% yield, yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.00 (s, 2H), 7.33 - 7.27 (m, 4H), 7.23 - 7.19 (m, 2H), 7.16- 7.12 (m, 2H), 7.10 - 7.04 (m, 4H), 6.89 - 6.83 (m, 4H), 4.57 (s, 2H), 3.74 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 159.74, 135.85, 134.67, 134.37, 129.71,129.39, 122.04, 120.82, 120.02, 119.48, 113.80, 113.28, 112.21, 110.51,55.26, 21.33. MALDI-TOF-MS: m / z: calcd for C 31 H 26 N2O2(M): 458.1994; found:458.1994.

[0105] Example 13

[0106] A bis(5-fluoro-2-phenyl-1H-indol-3-yl)methane α-glucosidase inhibitor is prepared as follows:

[0107] 0.6 mmol of 2-phenylindole derivative (5-fluoro-2-phenyl-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixture of ethyl acetate and petroleum ether in a volume ratio of 8:1) to obtain the product (Bis(5-fluoro-2-phenyl-1H-indol-3-yl)methane).

[0108] The structural formula of the above product (Bis(5-fluoro-2-phenyl-1H-indol-3-yl)methane) is as follows:

[0109] ,

[0110] Its Rf = 0.25 (PE / EtOAc, 8:1). 41% yield, pale yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.99 (s, 2H), 7.61 - 7.52(m, 4H), 7.48 - 7.39 (m, 4H), 7.39 -7.31 (m, 2H), 7.21 - 7.12(m, 2H), 6.86 - 6.75(m, 2H), 6.74 - 6.60(m, 2H), 4.46 (s, 2H). 13 C NMR (101 MHz, Chloroform-d) δ 158.67, 156.34, 136.43, 132.86,132.38, 128.81, 128.33, 127.91, 111.63, 111.18, 111.09, 110.43, 110.17,104.80, 104.57, 21.11. MALDI-TOF-MS: m / z: calcd for C 29 H20 F2N2(M+H) + : 435.1667; found: 435.1662.

[0111] Example 14

[0112] A bis(5-chloro-2-phenyl-1H-indol-3-yl)methane α-glucosidase inhibitor is prepared as follows:

[0113] 0.6 mmol of 2-phenylindole derivative (5-chloro-2-phenyl-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light lamp for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixture of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(5-chloro-2-phenyl-1H-indol-3-yl)methane).

[0114] The structural formula of the above product (Bis(5-chloro-2-phenyl-1H-indol-3-yl)methane) is as follows:

[0115] ,

[0116] Its Rf = 0.25 (PE / EtOAc, 10:1). 39% yield, pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.42 (s, 2H), 7.69 - 7.60 (m, 4H), 7.52- 7.43 (m, 4H), 7.43 -7.35 (m, 2H), 7.29 - 7.23 (m, 2H), 6.96- 6.88 (m, 2H), 6.78 (d,J= 2.1 Hz,2H), 4.41 (s, 2H). 13C NMR (101 MHz, DMSO) δ 136.68, 134.91, 132.96, 130.01,129.30, 128.81, 128.32, 123.44, 121.62, 118.53, 113.11, 110.78, 20.95. MALDI-TOF-MS: m / z: calcd for C 29 H 20 Cl2N2(M): 466.1004; found: 466.1002.

[0117] Example 15

[0118] A bis(5-bromo-2-phenyl-1H-indol-3-yl)methane α-glucosidase inhibitor is prepared as follows:

[0119] 0.6 mmol of 2-phenylindole derivative (5-bromo-2-phenyl-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light lamp for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixture of ethyl acetate and petroleum ether in a volume ratio of 8:1) to obtain the product (Bis(5-bromo-2-phenyl-1H-indol-3-yl)methane).

[0120] The structural formula of the above product (Bis(5-bromo-2-phenyl-1H-indol-3-yl)methane) is as follows:

[0121] ,

[0122] Its Rf = 0.25 (PE / EtOAc, 8:1). 28% yield, pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 2H), 7.75 - 7.62 (m, 4H), 7.75 - 7.62 (m, 4H), 7.47 -7.40 (m, 2H), 7.26 (d,J= 8.6 Hz, 2H), 7.08 (dd,J= 8.6, 1.9 Hz, 2H), 6.99 (d,J= 1.9 Hz, 2H), 4.45 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 136.50, 135.13,132.94, 130.70, 129.33, 128.86, 128.37, 124.15, 121.62, 113.57, 111.48,110.75, 20.85. MALDI-TOF-MS: m / z: calcd for C 29 H 20 Br2N2(M+H) + : 553.9993; found:553.9996.

[0123] Example 16

[0124] A bis(5-methyl-2-phenyl-1H-indol-3-yl)methane α-glucosidase inhibitor is prepared as follows:

[0125] 0.6 mmol of 2-phenylindole derivative (5-methyl-2-phenyl-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light lamp for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixture of ethyl acetate and petroleum ether in a volume ratio of 12:1) to obtain the product (Bis(5-methyl-2-phenyl-1H-indol-3-yl)methane).

[0126] The structural formula of the above product (Bis(5-methyl-2-phenyl-1H-indol-3-yl)methane) is as follows:

[0127] ,

[0128] Its Rf = 0.25 (PE / EtOAc, 12:1). 83% yield, pale yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.82 (s, 2H), 7.63 - 7.55 (m, 4H), 7.50 - 7.41 (m, 4H), 7.40 -7.32 (m, 2H), 7.14 (dd,J= 8.6, 1.2 Hz, 2H), 6.93 - 6.82 (m, 4H), 4.52 (s, 2H), 2.19 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 134.53, 134.21, 133.78,129.54, 128.72, 128.71, 128.47, 128.27, 127.45, 123.47, 119.80, 111.98,110.06, 21.44, 20.69. MALDI-TOF-MS: m / z: calcd for C 31 H 26 N2(M+H) + : 427.2169;found: 427.2168.

[0129] Example 17

[0130] A bis(6-fluoro-2-phenyl-1H-indol-3-yl)methan α-glucosidase inhibitor is prepared as follows:

[0131] 0.6 mmol of 2-phenylindole derivative (6-fluoro-2-phenyl-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light lamp for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixture of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(6-fluoro-2-phenyl-1H-indol-3-yl)methan).

[0132] The structural formula of the above product (Bis(6-fluoro-2-phenyl-1H-indol-3-yl)methan) is as follows:

[0133] ,

[0134] Its Rf = 0.25 (PE / EtOAc, 10:1). 48% yield, pale yellow solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.00 (s, 2H), 7.60 - 7.48 (m, 4H), 7.47 - 7.38 (m, 4H), 7.38-7.30 (m, 2H), 7.10 - 6.90 (m, 4H), 6.70 - 6.51 (m, 2H), 4.51 (s, 2H). 13 C NMR(101 MHz, Chloroform-d) δ 161.07, 135.77, 134.82, 132.97, 128.80, 128.17,127.70, 125.82, 120.66, 120.56, 111.76, 108.30, 108.06, 97.06, 96.80, 21.20.MALDI-TOF-MS: m / z: calcd for C 29 H 20 F2N2(M): 434.1595; found: 434.1595.

[0135] Example 18

[0136] A bis(6-methyl-2-phenyl-1H-indol-3-yl)methane α-glucosidase inhibitor is prepared as follows:

[0137] 0.6 mmol of 2-phenylindole derivative (6-methyl-2-phenyl-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and irradiated with a 10 W blue light lamp for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was purified by silica gel column chromatography (using a mixture of ethyl acetate and petroleum ether in a volume ratio of 10:1) to obtain the product (Bis(6-methyl-2-phenyl-1H-indol-3-yl)methane).

[0138] The structural formula of the above product (Bis(6-methyl-2-phenyl-1H-indol-3-yl)methane) is as follows:

[0139] ,

[0140] Its Rf = 0.25 (PE / EtOAc, 10:1). 84% yield, pale yellow solid. 1 H NMR (400 MHz, Chloroform-d) δ 7.87 (s, 2H), 7.62 - 7.51 (m, 4H), 7.44 - 7.36 (m, 4H), 7.34- 7.27 (m, 2H), 7.12 - 7.01 (m, 4H), 6.72 – 6.63 (m, 2H), 4.51 (s, 2H), 2.36 (s, 6H). 13 C NMR (101 MHz, Chloroform-d) δ 136.36, 133.70, 133.50, 131.70,128.66, 128.17, 127.29, 127.25, 121.21, 119.69, 112.05, 110.45, 21.68, 21.46.MALDI-TOF-MS: m / z: calcd for C 29 H 20F2N2(M): 426.2096; found: 426.2099

[0141] Example 19

[0142] A thiophene-containing bisindol-methane α-glucosidase inhibitor (Bis(2-(thiophen-2-yl)-1H-indol-3-yl)methane) is prepared as follows:

[0143] 0.6 mmol of a 2-phenylindole derivative (2-(thiophen-2-yl)-1H-indole), 0.2 mmol of bromonitromethane, and 0.004 mmol of a catalyst (ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O)) were mixed and dissolved in 1 ml of an organic solvent (1,2-dichloroethane). The mixture was stirred at room temperature until homogeneous and then irradiated with a 10 W blue light for 30 h. The reaction was monitored by thin-layer chromatography. After the reaction was completed, the organic solvent was removed under reduced pressure. The filtrate was dried and concentrated to obtain the crude product, which was then purified by silica gel column chromatography (using a mixture of ethyl acetate and petroleum ether in a volume ratio of 9:1) to obtain the product (Bis(2-(thiophen-2-yl)-1H-indol-3-yl)methane).

[0144] The structural formula of the above product (Bis(2-(thiophen-2-yl)-1H-indol-3-yl)methane) is as follows:

[0145] ,

[0146] Its R f = 0.25 (PE / EtOAc, 9:1). 58% yield, orange solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.30 (s, 2H), 7.68 - 7.47 (m, 4H), 7.34 - 7.16 (m, 4H), 7.07 - 6.88(m,4H), 6.79 - 6.60(m, 2H), 4.62 (s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 136.59,135.13, 129.27, 129.08, 128.18, 126.41, 125.76, 122.18, 119.49, 119.18,111.44, 111.06, 22.31. MALDI-TOF-MS: m / z: calcd for C 25 H 18 N2S2(M) 410.0911; found 410.0912.

[0147] Example 20

[0148] The following experiments were conducted to investigate the effect of different additive variations on the preparation results:

[0149] Basic reaction: The preparation method of Example 1 was followed, with the light conditions modified to irradiation by a 10W blue light lamp for 24 hours, while other conditions remained unchanged. The yield of the product was 28% (serial number 1 in Table 3), where 1a represents 2-phenylindole, 2a represents bromonitromethane, and the amount of catalyst added varied with the amount of bromonitromethane (2a) (still 2 mol% of the amount of bromonitromethane (2a) added). Reactions marked below were carried out under the marked conditions, while those not marked were carried out under the basic reaction conditions.

[0150] 1. Effect of reaction conditions on yield

[0151] The preparation was carried out according to the method in Example 1, with the light conditions modified to irradiation by a 10W blue light lamp for 24 hours, the molar amounts of 2-phenylindole and 0.6 mmol of bromonitromethane changed, and the amount of photosensitizer changed to 0.005 mmol, while keeping other conditions unchanged. The yield of the product was 28% (item 1 in Table 3). To study the reaction mechanism, a series of control experiments were conducted, changing the reaction conditions, removing the light irradiation, or removing the addition of the catalyst. The results are shown in Table 3. As can be seen from Table 3, without visible light irradiation, the reaction cannot occur even with the addition of the catalyst (item 2 in Table 3); the reaction cannot occur without the addition of the photosensitizer, regardless of whether it is under dark or light conditions (items 3 and 4 in Table 3). Therefore, it can be seen that the addition of the catalyst and blue light irradiation are essential conditions for the preparation method of the bisindolemethane-type α-glucosidase inhibitor of the present invention.

[0152] Table 3 Effect of different reaction conditions on yield

[0153]

[0154] a. Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Ru(bpy)3Cl2·6H2O (2 mol%), 1,2-dichloroethane (1.0 mL), 23W blue light, stirring at room temperature, reaction for 24 h;

[0155] b. The yield was obtained by separation using a silica gel column chromatography.

[0156] c. Conducted under dark conditions.

[0157] 2. Effect of catalyst type on yield

[0158] To screen suitable catalysts for the reaction substrate, the effects of different catalysts on the reaction were investigated. Considering both catalytic efficiency and environmental friendliness, common transition metal ruthenium ligand complexes and organic dyes were selected as catalysts for this reaction (Ru(bpy)3Cl2•6H2O in the basic reaction was replaced with blank, eosin Y, rose red, eosin B, fluorescein, and methylene blue, respectively). The results are shown in Table 4. The experimental results show that not all catalysts can catalyze the reaction; only one or more of terpyridine ruthenium chloride (Ru(bpy)3Cl2·6H2O), eosin Y, rose red, or eosin B can catalyze the reaction to prepare bisindolemethane-type α-glucosidase inhibitors.

[0159] Table 4 Effect of catalyst type on yield

[0160]

[0161] a. Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (2 mol%), 1,2-dichloroethane (1.0 mL), 10W blue light; stirring at room temperature, reaction for 24 h;

[0162] b. The yield was obtained by separation using a silica gel column chromatography.

[0163] 3. The effect of different solvents on the reaction

[0164] Since the solvent plays a crucial role in the reaction results, the selection of solvents was necessary. Based on factors such as polarity and solubility, the organic solvents selected from the basic reaction were acetonitrile (MeCN), anhydrous ethanol (EtOH), methanol (MeOH), 1,2-dichloroethane (1,2-Dichloroethane), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and dichloromethane (DCM). Other conditions remained constant during the experiment, and the results are shown in Table 5. The experimental results indicate that bisindolemethane-type α-glucosidase inhibitors can be successfully prepared using any one of the organic solvents: dichloroethane, methanol, ethanol, dichloromethane, or acetonitrile.

[0165] Table 5. Effects of different solvents on the reaction

[0166]

[0167] a. Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Ru(bpy)3Cl2•6H2O (2 mol%), solvent (1.0 ml), 10W blue light; constant temperature 30℃ with stirring, reaction for 24 h;

[0168] b. The yield was obtained by separation using a silica gel column chromatography.

[0169] 4. Effect of catalyst addition amount on the reaction

[0170] Next, using the basic reaction as a standard, the amount of catalyst added was varied to screen the different catalyst addition amounts in the reaction. The results are shown in Table 6. Experimental results show that when the catalyst dosage increased from 0.5 mol% to 2 mol%, the yield increased significantly (Table 6, 1-3). However, as the catalyst dosage continued to increase, the reaction yield decreased and gradually stabilized, remaining unchanged (Table 6, 4-5). Therefore, it can be seen that bisindolemethane-type α-glucosidase inhibitors can be prepared by adding catalysts in the range of 0.5-4 mol% during the preparation process of this invention.

[0171] Table 6 Effect of catalyst addition amount on the reaction a

[0172]

[0173] a. Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Ru(bpy)3Cl2•6H2O (x mol%), 1,2-dichloroethane (1.0 mL), 10W blue light; stirring at 30℃ for 24 h.

[0174] b. The yield was obtained by separation using a silica gel column chromatography.

[0175] 5. Effect of reactant addition ratio on the reaction

[0176] To further improve the reaction yield, the feed ratios were screened. The molar ratio of 2-phenylindole (1a) to bromonitromethane (2a) in the basic reaction was changed from 0.5:0.6 to 1:3 (0.3:0.9), 1:2 (0.3:0.6), 1:1 (0.3:0.3), 2:1 (0.6:0.3), and 3:1 (0.6:0.2), respectively. The results are shown in Table 7. The experimental results show that excess 2-phenylindole is beneficial to the reaction, and the yield increases from 51% to 59% (Table 7, 3 and 4). When bromonitromethane is in excess, the yield does not change significantly (Table 7, 1 and 2). However, because 2-phenylindole has a relatively large molecular weight, and the solvent 1,2-dichloroethane is only 1 mL, further increasing the amount of indole makes the reaction difficult to proceed. Therefore, when the feed ratio of indole to bromonitromethane reaches 3:1 (0.6 mmol:0.2 mmol), the highest yield of the reaction is 79%. Thus, in the preparation process of this invention, a molar ratio of reactant I to bromonitromethane of 1:3-3:1 can prepare bisindolemethane-type α-glucosidase inhibitors.

[0177] Table 7 Effect of reactant addition ratio on the reaction a

[0178]

[0179] a. Reaction conditions: 1a (x mmol), 2a (x mmol), Ru(bpy)3Cl2•6H2O (2 mol%), 10W blue light, 1,2-dichloroethane (1.0 mL), constant temperature 30℃ with stirring, reaction for 24 h;

[0180] b. The yield was obtained by separation using a silica gel column chromatography.

[0181] 6. Effect of solvent addition on the reaction

[0182] Since the amount of organic solvent used in the reaction process affects the progress of organic synthesis reactions, both insufficient and excessive amounts will affect the effective concentration of reactants. This can range from requiring longer reaction times to affecting yield and even causing side reactions. Therefore, to further improve the reaction yield, the total volume of solvent used in the reaction was further screened. The solvent volume of 1.0 ml in the basic reaction was modified to 0.5 ml, 1.5 ml, 2.0 ml, and 2.5 ml, respectively. The reaction results are shown in Table 8. Experimental results show that when the total solvent volume increases from 0.5 ml to 1 ml, the yield increases significantly (Table 8, 1 and 2). However, as the total solvent volume continues to increase, the reaction yield decreases and gradually stabilizes, remaining unchanged (Table 8, 3-5). Therefore, in the preparation method of this invention, a molar volume ratio of reactant I to pre-organic solvent of 1:1-5 can prepare bisindolemethane-type α-glucosidase inhibitors.

[0183] Table 8 Effect of solvent addition on the reaction a

[0184]

[0185] a. Reaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), Ru(bpy)3Cl2•6H2O (2 mol%), 1,2-dichloroethane (x mL), 10W blue light, constant temperature 30℃ with stirring, reaction for 24 h;

[0186] b. The yield was obtained by separation using a silica gel column chromatography.

[0187] 7. The effect of reaction time on the reaction

[0188] Reaction time is also a crucial factor affecting the reaction. Therefore, to further improve the reaction yield, the reaction time was further screened, with reaction times set at 6 h, 12 h, 18 h, 24 h, 30 h, 36 h, 42 h, and 48 h, respectively. The reaction results are shown in Table 9. Experimental results show that when the reaction time increases from 6 h to 30 h, the yield increases significantly (1-5 in Table 9). However, as the reaction time continues to increase, the yield remains essentially unchanged and gradually stabilizes (6-8 in Table 9). Therefore, the reaction time of the preparation method of this invention can be within the range of 6-48 h.

[0189] Table 9. Effect of reaction time on the reaction

[0190]

[0191] a. Reaction conditions: 1a (0.6 mmol), 2a (0.2 mmol), Ru(bpy)3Cl2•6H2O (2 mol%), 1,2-dichloroethane (1.0 mL), reaction time (x h), 10 W blue light, constant temperature 30℃ with stirring;

[0192] b. The yield was obtained by separation using a silica gel column chromatography.

[0193] Performance testing

[0194] The in vitro inhibitory effect of the bisindolemethane-type α-glucosidase inhibitor prepared in this invention on α-glucosidase was tested:

[0195] The α-glucosidase inhibitory activity was determined using a commonly used method, as follows: 140 μL of phosphate buffer (pH 6.8) was added to a 96-well plate, followed by 20 μL of α-glucosidase and 20 μL of different concentrations of bisindole compounds (using 70% DMSO as solvent). The mixture was incubated at 37°C for 10 minutes. Then, 20 μL of substrate (pNPG) was added, and the mixture was incubated again at 37°C for 20 minutes. Finally, 100 μL of Na₂CO₃ was added to terminate the reaction, and the absorbance was read at 405 nm using a microplate reader. The control group was treated with 20 μL of 70% DMSO. The inhibition rate was calculated as follows:

[0196] ,

[0197] Where Asample is the absorbance of the sample; Bbackground is the absorbance of the sample control group; and Cblank is the absorbance of the blank control without the sample.

[0198] The IC50 value of the compound (the inhibitor concentration at which 50% of the enzyme activity is inhibited) is calculated based on the inhibition curve.

[0199] The inhibitory effects of the bisindolemethane-type α-glucosidase inhibitors prepared in Examples 1-19 and acarbose on α-glucosidase activity were tested. The inhibition rates of α-glucosidase are shown in Table 10. The structure-activity relationship showed that the position and nature of different substituents on the benzene ring of the indole skeleton had different effects on the inhibition of α-glucosidase activity. All compounds showed good activity against α-glucosidase, with IC50 values ​​of [missing value]. 50 The values ​​ranged from 5.45 to 28.06 μM, all lower than those of the control group acarbose. Specifically, when the substituent was Br, the IC50 value was significantly higher. 50 The lowest value was 5.45 ± 0.64 μM.

[0200] Table 10. Inhibitory effects of the compounds prepared in Examples 1-19 on α-glucosidase

[0201]

[0202] In summary, this invention discloses a thiophene-containing bisindolemethane-type α-glucosidase inhibitor, its preparation method, and its applications. Specifically, it involves the photo-oxidation and reduction of nitrohaloalkanes via visible light to synthesize 3,3'-bisindolemethane compounds, wherein bromonitromethane participates in the reaction as a methylene precursor. Using visible light, a clean energy source, 3,3'-bisindolemethane compounds were obtained in good yields under mild conditions. Evaluation of α-glucosidase inhibitory activity showed that all bisindole derivatives exhibited significant inhibitory effects (5.45-28.06 μM), all exceeding those of acarbose. This study identifies a series of lead candidates for the development of novel α-glucosidase inhibitors.

[0203] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A thiophene-containing bisindolemethane-type α-glucosidase inhibitor, characterized in that, The chemical structural formula of the inhibitor is: 。 2. The method for preparing the inhibitor according to claim 1, characterized in that, The reaction formula for the preparation method is: The structural formula of reactant I is The organic solvent is any one of 1,2-dichloroethane, methanol, ethanol, or acetonitrile; the catalyst is any one or more of ruthenium hexahydrate terpyridine chloride (Ru(bpy)3Cl2·6H2O), eosin Y, rose red, or eosin B.

3. The preparation method according to claim 2, characterized in that, The preparation method specifically includes the following steps: reactant I, bromonitromethane and catalyst are mixed and dissolved in an organic solvent, stirred at room temperature to make them evenly mixed, irradiated with a blue lamp, and the reaction is monitored by thin-layer chromatography. After the reaction is completed, the organic solvent is removed under reduced pressure, the filtrate is dried and concentrated to obtain a crude product, which is then purified to obtain a thiophene-containing bisindolemethane-type α-glucosidase inhibitor.

4. The preparation method according to claim 3, characterized in that, The molar ratio of reactant I to bromonitromethane is 1:3 to 3:

1.

5. The preparation method according to claim 3, characterized in that, The catalyst is added at a rate of 0.5%-4% of the molar number of bromonitromethane.

6. The preparation method according to claim 3, characterized in that, The molar volume ratio of reactant I to organic solvent is 1:1-5, mol:L.

7. The preparation method according to claim 3, characterized in that, The reaction time for the irradiation reaction is 6-48 hours.

8. The preparation method according to claim 3, characterized in that, The purification method is silica gel column chromatography, wherein the eluent used in the silica gel column chromatography purification process is a mixed solvent formed by mixing petroleum ether and ethyl acetate in a volume ratio of 10:

1.

9. The use of the thiophene-containing bisindolemethane-type α-glucosidase inhibitor of claim 1 in the preparation of α-glucosidase inhibitor drugs.

10. A medicament for the prevention and / or treatment of diabetes, characterized in that, The active ingredient of the drug includes the thiophene-containing bisindolemethane-type α-glucosidase inhibitor as described in claim 1.

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