Antibacterial bisindolyl methane derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of synthetic drugs, and particularly relates to an antibacterial bis (indolyl) methane derivative, or a pharmaceutically acceptable salt thereof, and a chemical structural formula of the antibacterial bis (indolyl) methane derivative or the pharmaceutically acceptable salt thereof is as shown in the specification. The invention also provides a preparation method and application of the antibacterial bis (indolyl) methane derivative or the pharmaceutically acceptable salt thereof. The method disclosed by the invention is green, environment-friendly and pollution-free in preparation, and the prepared bisindolyl methane derivative has a very strong antibacterial effect.

Description

Technical Field

[0001] The invention belongs to the technical field of synthetic drugs, and specifically relates to antibacterial bisindolylmethane derivatives and preparation methods and applications thereof. Background Art

[0002] In recent years, the widespread use of antibiotics has led to a serious social problem - the abuse of antibiotics. The consequence of the abuse of antibiotics is bacterial resistance, such as drug-resistant bacteria "super bacteria". Most antibacterial drugs on the market are ineffective or have little effect on such drug-resistant bacteria, and cannot achieve the purpose of treatment. According to statistics, among Gram-positive bacteria, infections caused by methicillin-resistant Staphylococcus aureus (MRSA) have caused 750,000 deaths worldwide. Therefore, it is particularly urgent to find and develop new antibacterial drug molecules that are highly efficient and low in toxicity.

[0003] There are more and more reports that in addition to the drugs that have been approved for clinical use, there are also many natural products from a wide range of sources that have good antibacterial activity. Among the natural plants of the Cruciferae family, there is a class of natural alkaloids with excellent antibacterial activity - bisindolylmethane and its derivatives (BIMs). Due to their important biological and pharmacological activities, they are widely used in medicine and health care products. The bisindolylmethane skeleton has attracted people's attention because of its simple structure, high flexibility, and good antibacterial effect. Many natural products also have small molecule compounds containing the bisindolylmethane skeleton, as shown in the following structure:

[0004]

[0005] There are many research reports on the antibacterial properties of bisindolylmethane. The following are some examples of foreign research reports: Saima Tauseef's team synthesized some new bisindolylmethane derivatives containing Schiff bases for selected Gram-positive and Gram-negative bacterial strains. When evaluating bisindolylmethane Schiff base derivatives, it was found that bisindolylmethane derivatives containing halogen and nitro substituents showed weak to moderate antibacterial activity against Salmonella typhi, Salmonella paratyphi A and Salmonella paratyphi B. Debaraj Mukherjee's team designed and synthesized N,N'-glycoside derivatives of BIMs, and then found that N,N'-glycoside derivatives had good inhibitory effects on Staphylococcus aureus, MRSA and VRE. Majid M. Heravi's team used benzylaminosulfonic acid as a new heterogeneous acid catalyst to catalyze the synthesis of new bis(indolyl)methane derivatives, and found that they had excellent inhibitory effects on Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa (Gram-negative bacteria).

[0006] There are also abundant reports on domestic research on bisindolylmethane: Mao Zewei's team synthesized bisindolylmethane derivatives containing phenol derivatives, and evaluated the in vitro fungal activity of Candida albicans. It was found that most bisindolylmethane derivatives showed good antibacterial activity against sensitive and resistant Candida albicans. Luo Jinyue's team used indole and benzaldehyde as raw materials to synthesize the compound 3,3'-(benzylidene)bisindole, which can effectively inhibit rapeseed sclerotinia and cucumber gray mold. Deng Guiying's team found that bisindole alkaloids have anti-tumor activity; Weng Jiang's team successfully used chiral phosphoric acid catalysts to catalyze the asymmetric synthesis of bisindolylmethane, and randomly tested the antibacterial activity of these compounds. These enantiomer-enriched BIMs showed impressive preliminary antibacterial activity.

[0007] Although there are many reports on the synthesis of bisindolylmethane skeletons, most of them are non-chiral symmetrical structures. There are few reports on bisindolylmethane skeletons with chiral quaternary carbon centers containing CF3 groups. Even if there are reports of asymmetric synthesis of bisindolylmethane skeletons with quaternary carbon chiral centers containing CF3 groups, there are still many shortcomings in the synthetic strategies reported, such as high cost and easy environmental pollution, which leads to slow progress in the research on their antibacterial activity. In order to construct BIMs derivatives with richer skeleton types to meet the structural diversity requirements of preclinical research of new antibacterial drugs, it is very necessary to study and develop derivatives of bisindolylmethane skeletons containing CF3 quaternary carbon centers. Summary of the invention

[0008] The present invention aims to solve the above technical problems and provide an antibacterial bisindolylmethane derivative to solve the problems of high cost and easy environmental pollution in the asymmetric synthesis of the bisindolylmethane skeleton containing a quaternary carbon chiral center of a CF3 group.

[0009] The technical solution of the present invention is:

[0010] The chemical structural formula of the antibacterial bisindolylmethane derivative or its pharmaceutically acceptable salt is as follows:

[0011]

[0012] Among them, R 1 is one of -CH3, -H, -F, -OCH3; R 2 It is one of -CH3, -OCH3, -Cl, -Br, -NO2, and -H.

[0013] Preferably, the reaction formula of the method for preparing the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof of the present invention is:

[0014]

[0015] Wherein, the DPP is diphenyl phosphate, which is used as catalyst A; the DCE is trichloroethane, which is used as organic solvent; and the heating temperature is 30°C.

[0016] The method for preparing the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof of the present invention comprises the following specific steps: mixing compound 1, compound 2 and catalyst A for reaction, adding an organic solvent, stirring at 30°C, obtaining a crude product after the reaction is completed, and obtaining compound 3 after purification by silica gel column chromatography.

[0017] Preferably, the molar ratio of compound 1 to compound 2 is 1:1.2; preferably, the added amount of catalyst A is 30% of the molar amount of compound 1.

[0018] Preferably, the reaction formula for preparing compound 1 of the present invention is:

[0019]

[0020] Wherein, the THF is tetrahydrofuran, which serves as catalyst B.

[0021] Preferably, the preparation method of compound 1 is: at -78°C, under nitrogen conditions, compound 7 and catalyst B tetrahydrofuran are mixed, compound 6 is added, the temperature is raised to room temperature, stirred for 3 hours, and stirred at room temperature for 8 hours, the reaction mixture is cooled to 0°C and 7 mL of NH4Cl solution is added dropwise, the organic phase is separated, the aqueous layer is extracted with ethyl acetate, the volume ratio of ethyl acetate to water is 5:1, the organic phase is collected, washed with saturated brine, and then dried over anhydrous Na2SO4, spin-dried, and purified by silica gel column chromatography to obtain compound 1.

[0022] Preferably, the molar mass ratio of the compound 6 to the compound 7 is 1:1; and the volume ratio of the catalyst B to the compound 7 is 6:1.

[0023] Preferably, the reaction formula for preparing compound 6 is:

[0024]

[0025] Wherein, the DMF is dimethylformamide, which serves as catalyst C.

[0026] Preferably, the preparation method of compound 6 is: add catalyst C to compound 6, stir evenly at 0°C, then dropwise add compound 5 at 0°C, and then stir at room temperature for 3 hours. After the reaction is complete, add ethyl acetate, and then add water for extraction, collect the organic phase, wash with saturated brine, and then dry with anhydrous Na2SO4, and spin dry to obtain compound 6.

[0027] Preferably, the molar mass ratio of the compound 4 to the compound 5 is 2:1; and the volume ratio of the catalyst C to the compound 5 is 6:1.

[0028] The present invention also provides the use of the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof in the preparation of antibacterial drugs.

[0029] The present invention uses α-indolyl-α-trifluoromethyl n-butanol as a substrate, reacts with a monosubstituted indole under the action of a catalyst DPP, and obtains a series of derivatives containing a quaternary carbon center diindolylmethane skeleton with a good yield (17 new compounds, with a yield of up to 99%), establishes a green and mild synthetic route for constructing asymmetric 3,3'-BIMs, provides a new asymmetric synthesis method, and screens the antibacterial activity of the synthesized 17 new compounds. Most of the new compounds have excellent antibacterial activity against Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa (Gram-negative bacteria), providing more possibilities for the research of antibacterial drugs and constructing a compound library with structural diversity.

[0030] Due to the adoption of the above technical solution, the beneficial effects of the present invention are:

[0031] 1. The antibacterial bisindolylmethane derivatives of the present invention have excellent antibacterial biological activity, especially against methicillin-resistant Staphylococcus aureus, common Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, Bacillus amyloliquefaciens, and Streptomyces polymorpha, showing strong antibacterial activity.

[0032] 2. The method of the present invention has mild reaction conditions, is green, environmentally friendly and pollution-free. DETAILED DESCRIPTION

[0033] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] In the following embodiments:

[0035] Nuclear magnetic resonance (NMR) 1 H, 13 C and 19 F NMR) was measured by Bruker Avance-400 MHz or Bruker Avance-500 MHz NMR instrument. 1 H NMR chemical shift solvent residual peak: CDCl3δ7.26ppm, DMSO-d6δ2.50ppm; 13C NMR chemical shift solvent residual peak: CDCl3δ77.16, DMSO-d6δ39.51ppm. The characteristic peak splitting conditions in NMR are represented by the following abbreviations: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), dt (doublet of triplets).

[0036] All commercial chemical reagents were purchased from chemical reagent companies such as Anaiji, Aladdin, and Bailingwei. The reaction solvents tetrahydrofuran and dichloromethane were redispersed and dried before use. Unless otherwise specified, commercial reagents and solvents were not pretreated. The thin layer chromatography silica gel plate GF254 was used to monitor the reaction process, and the detection method included ultraviolet light. Column chromatography used 200-300 mesh silica gel purchased from Qingdao Ocean Chemical Plant Branch.

[0037] Example 1

[0038] The preparation method of compound 3 is as follows:

[0039] (1) The synthesis reaction formula of intermediate compound 6 is as follows:

[0040]

[0041] The specific steps are as follows: indole (compound 4) (10 mmol, 1.0 equiv) was weighed into a 100 ml round-bottom flask with a stirrer, 15 ml of DMF solution was added, the reaction system was moved to 0°C for stirring, and trifluoroacetic anhydride (compound 5) (20 mmol, 2.0 equiv) was slowly added dropwise with a syringe at 0°C, and after the addition was complete, the reaction system was moved to room temperature for stirring for 3 hours, and the reaction was monitored by thin layer chromatography (PE / EA=5:1). After the reaction was complete, 50 ml of ethyl acetate was slowly added, and then water (50 ml×5 times) was used for extraction, the organic phase was collected, and washed with saturated brine (50 ml×3 times), the organic phase was continued to be collected, dried with anhydrous sodium sulfate for 5 minutes, and spin-dried to obtain a pink solid, which was compound 6;

[0042] (2) The synthetic reaction formula of raw material compound 1 is as follows:

[0043]

[0044] The specific steps are as follows: at -78°C, N2, compound 7 (6 mmol, 3.75 mL) is charged into a 100 mL round-bottom flask of redistilled THF (15 mL) with a stirrer using a syringe, and stirred at the same temperature for 10 min, then compound 6 (2 mmol, 1.0 equiv) is added to THF (5 mL), the reaction mixture is slowly heated to room temperature and stirred for 8 h, TLC spot plate detection, and then post-treatment is performed, the reaction mixture is cooled to 0°C and a saturated NH4Cl solution (7 mL) at room temperature is added dropwise, the organic layer is separated, the aqueous layer is extracted with (3×10 mL) ethyl acetate, all organic layers are collected, washed with saturated brine (30 mL), dried over anhydrous Na2SO4, and spin-dried, and the crude product is purified by silica gel column chromatography (PE / EA=10:1-5:1) to obtain an α-indolyl-α-trifluoromethyl n-butanol intermediate, i.e., compound 1;

[0045] (3) The synthetic reaction formula of compound 3 is as follows:

[0046]

[0047] The specific steps are as follows: compound 1 (0.3 mmol, 1.0 equiv), compound 2 (0.36 mmol, 1.2 equiv) and catalyst diphenyl phosphate (30 mol%) are weighed into a reaction tube, solvent DCE (2 mL) is added, the mixture is stirred at 30° C. until the reaction is completed (TLC detection), and the crude product is purified by silica gel column chromatography (PE / EA=10:1~5:1) to obtain compound 3.

[0048] Example 2: 5-methyl-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexane-2-yl)-1H-indole (Compound 3a)

[0049]

[0050] The difference from Example 1 is that: R 1 is -H, compound 2 is 5-methylindole, the amount of compound 2 added is 47.22 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3a with a yield of 85%, a time of 24 h, and a molecular mass of 384.44. 1HNMR (400MHz, CDCl3) δ7.93(s,1H),7.86(s,1H),7.34(d,J=8.2Hz,1H),7.30(d,J=8.2Hz,1H),7.24(d,J=8.3Hz,1H),7.21-7.11(m,3H ),7.09(s,1H),7.01(d,J=8.2Hz,1H),6.94(t,J=7.6Hz,1H),2.92-2.65(m,2H),2.31(s,3H),1.39-1.25(m,4H),0.88(t,J=6.5Hz,3H). 19 FNMR (376MHz,CDCl3)δ-68.82. 13 C NMR(101MHz,CDCl3)δ136.46,134.82,128.88(q,J=285.4Hz),128.49,126.84,126 .66,124.44(d,J=9.1Hz),124.28,123.58,123.48,121.75(d,J=5.4Hz),121.20(d ,J=10.7Hz),119.40(d,J=9.3Hz),114.47,113.76,111.23,110.87(d,J=5.2Hz),5 0.11 (q, J = 25.4Hz), 35.14, 27.03, 23.37, 21.67 (d, J = 9.4Hz), 13.94 (d, J = 7.5Hz).

[0051] Example 3: 5-methoxy-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexane-2-yl)-1H-indole (Compound 3b)

[0052]

[0053] The difference from Example 1 is that: R 1 is -H, compound 2 is 5-methoxyindole, the amount of compound 2 added is 52.98 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3b with a yield of 62%, a time of 24 h, and a molecular weight of 400.44. 1H NMR (400MHz, CDCl3) δ8.07(s,1H),7.97(s,1H),7.25(d,J=8.2Hz,1H),7.19(dd,J=8.4,2.7Hz,3H),7.13(d,J=8.8Hz,1H),7.01(dt,J=8.1,4.6Hz, 2H),6.74(ddd,J=8.1,7.1,1.0Hz,1H),6.66(dd,J=8.8,2.4Hz,1H),3.42 (s,3H),2.56(t,J=8.0Hz,2H),1.21-1.16(m,4H),0.72(t,J=7.0Hz,3H). 19 F NMR (376MHz, CDCl3) δ-69.24. 13 C NMR(101MHz, CDCl3)δ153.53,136.48,131.67,128.82(q,J=285.4Hz),127.35,126.82,124.78,123.97,121.92,121.6 3,119.49,114.30,114.21,111.87,111.57,111.07,104.02,55.73,49.89(q,J=25.6Hz),35.34,27.02,23.43,14.00.

[0054] Example 4: 5-methoxy-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexane-2-yl)-1H-indole (Compound 3c)

[0055]

[0056] The difference from Example 1 is that: R 1 is -H, compound 2 is 5-chloroindole, the amount of compound 2 added is 54.57 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3c with a yield of 99%, a time of 24 h, and a molecular weight of 404.86. 1 HNMR (400MHz, CDCl3) δ7.98(s,1H),7.94(s,1H),7.36(d,J=8.1Hz,1H),7.25(d,J=9.1Hz,4H),7.20(t,1H),7. 14(t,J=6.5Hz,2H), 6.99(t,J=7.5Hz,1H), 2.80(d,J=4.7Hz,2H), 1.40(d,J=3.1Hz,4H), 0.93(d,J=5.2Hz,3H). 19 F NMR (376MHz, CDCl3) δ-68.79. 13C NMR (101MHz, CDCl3) δ136.39, 134.72, 128.77 (q, J = 268.4Hz), 127.64, 126.4 4,125.50(d,J=8.6Hz),125.03(d,J=2.9Hz),124.08(d,J=8.8Hz),122.22,12 1.95,121.16,120.59(d,J=8.8Hz),119.47(d,J=7.2Hz),114.11,113.68,11 2.29, 111.43, 49.71 (q, J = 25.5Hz), 35.19, 26.91, 23.27, 13.87 (d, J = 7.1Hz).

[0057] Example 5: 5-Bromo-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3d)

[0058]

[0059] The difference from Example 1 is that: R 1 is -H, compound 2 is 5-bromoindole, the amount of compound 2 added is 70.57 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3d with a yield of 58%, a time of 24 h, and a molecular weight of 449.31. 1 HNMR(400MHz, CDCl3)δ8.00(d,J=4.9Hz,2H),7.25(d,J=8.1Hz,1H),7.15(t,3H),7.08(d,J=10.2Hz,2H), 7.05-7.00(m,2H),6.77(t,J=7.6Hz,1H),2.57(d,J=9.1Hz,2H),1.23-1.12(m,4H),0.72(t,J=6.9Hz,3H). 19 F NMR (376MHz, CDCl3) δ-69.06. 13 C NMR (101MHz, CDCl3) δ136.46,135.05,128.63(q,J=285.5Hz),128.36,126.47,125.34(d,J=8.2Hz),124.84,124.05(d,J=7.5Hz),123 .83(d,J=6.6Hz),122.00,121.26,119.48,114.25,113.82,112.86,112.67,111.37,49.81(q,J=25.6Hz),35.20,26.95,23.32,13.91.

[0060] Example 6: 5-nitro-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3e)

[0061]

[0062] The difference from Example 1 is that: R 1 is -H, compound 2 is 5-nitroindole, the amount of compound 2 added is 58.37 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3e with a yield of 99%, a time of 24 h, and a molecular weight of 415.41. 1 HNMR (400MHz, DMSO) δ11.96(s,1H),11.28(s,1H),7.82(d,J=9.3Hz,2H),7.65(s,1H),7.59-7.48(m,2H),7.36(d,J=8.0Hz ,1H),6.92(t,J=7.3Hz,1H),6.72(d,J=7.9Hz,1H),6.61(t,J=7.4Hz,1H),2.60(s,2H),1.20(s,4H),0.72(d,J=6.7Hz,3H). 19 FNMR (376MHz, DMSO) δ-68.39. 13 C NMR(101MHz,DMSO)δ140.46,139.98,136.82,126.70(q,J=409.3Hz),126.30,126.06,121.37,121.32,118.92,11 8.88,117.57,116.62,115.79,112.51,112.12,112.08,111.61,49.15(q,J=25.1Hz),35.16,26.89,22.96,14.13.

[0063] Example 7: 6-methyl-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexane-2-yl)-1H-indole (Compound 3f)

[0064]

[0065] The difference from Example 1 is that: R 1 is -H, compound 2 is 6-methylindole, the amount of compound 2 added is 47.22 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3f with a yield of 54%, a time of 24 h, and a molecular mass of 384.44. 1HNMR (400MHz, CDCl3) δ8.03(s,1H),7.91(s,1H),7.25(d,J=8.2Hz,1H),7.19-7.15(m,2H),7.08(d,J=7.6Hz,2H),7.05(d,J=4.5 Hz,2H),7.00(t,J=7.6Hz,1H),6.91(d,J=8.3Hz,1H),2.60-2.54(m,2H),2.28(s,3H),1.18-1.14(m,4H),0.70(t,J=6.7Hz,3H). 19 F NMR (376MHz,CDCl3)δ-69.25. 13 C NMR (101MHz, CDCl3) δ136.85, 136.39, 131.55, 128.84 (q, J = 285.3Hz), 126.72, 124.56, 124.18, 123.54, 121.77, 121.6 0,121.28,121.17,119.40,114.41,114.20,111.18,111.14,49.97(q,J=25.3Hz),35.32,27.01,23.39,21.55,13.95.

[0066] Example 8: 6-methoxy-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexane-2-yl)-1H-indole (Compound 3g)

[0067]

[0068] The difference from Example 1 is that: R 1 is -H, compound 2 is 6-methoxyindole, the amount of compound 2 added is 52.98 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3g with a yield of 59%, a time of 48 hours, and a molecular weight of 400.44. 1 H NMR(400MHz, CDCl3)δ8.02(s,1H),7.88(s,1H),7.29-7.23(m,1H),7.21(d ,J=8.1Hz,1H),7.15(s,1H),7.02(d,J=8.0Hz,2H),6.97(t,J=7.6Hz,1H),6 .83(d,J=8.9Hz,1H),6.73(d,J=7.8Hz,1H),6.70-6.67(m,1H),3.65(d,J=4 .6Hz,3H),2.52(d,J=7.4Hz,2H),1.17-1.12(m,4H),0.68(t,J=6.6Hz,3H). 19F NMR (376MHz, CDCl3) δ-69.32. 13 C NMR (101MHz, CDCl3) δ156.08, 137.19, 136.43, 128.25 (q, J = 390.4Hz), 126.78, 124.07, 122.78, 122.14, 121.87, 121. 58,121.19,119.42,114.51,111.15,109.46,94.44,94.33,55.55(q,J=12.2Hz),50.03,35.41,27.02,23.41,13.96.

[0069] Example 9: 6-Chloro-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3h)

[0070]

[0071] The difference from Example 1 is that: R 1 is -H, compound 2 is 6-chloroindole, the amount of compound 2 added is 54.57 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3h with a yield of 88% and a time of 24 h. The molecular weight is 404.86. 1 HNMR (400MHz, CDCl3) δ8.02(d,J=20.5Hz,2H),7.25(d,J=8.2Hz,1H),7.20(dd,J=11.6,4.8Hz,3H),7.00(t,J=7.6Hz,1H),6.95(d,J=8.2Hz,1H),6 .85(d,J=8.7Hz,1H),6.73(t,J=7.6Hz,1H),6.67(dd,J=8.7,1.8Hz,1H),2.55(d,J=8.0Hz,2H),1.17(dd,J=9.7,5.7Hz,4H),0.71(t,J=6.7Hz,3H). 19 F NMR (376MHz,CDCl3)δ-69.36. 13 C NMR (101MHz, CDCl3) δ136.76, 136.41, 128.63 (q, J = 285.3Hz), 127.82, 126.65, 125.45, 124.52, 123.91, 122.36, 12 1.99, 121.38, 120.29, 119.57, 114.81, 114.13, 111.21, 111.03, 49.77 (q, J = 25.7Hz), 35.45, 26.97, 23.38, 13.97.

[0072] Example 10: 6-bromo-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3i)

[0073]

[0074] The difference from Example 1 is that: R 1 is -H, compound 2 is 6-bromoindole, the amount of compound 2 added is 70.57 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3i with a yield of 89%, a time of 24 h, and a molecular weight of 449.31. 1 HNMR (400MHz, CDCl3) δ8.12(d,J=15.6Hz,2H),7.47(s,1H),7.34(d,J=8.2Hz,1H),7.27(d,J=6.9Hz,2H),7.09(t,J=7.6Hz,1H ),7.03(d,J=8.2Hz,1H),6.88(s,2H),6.81(t,J=7.3Hz,1H),2.62(d,J=8.8Hz,2H),1.27-1.21(m,4H),0.79(t,J=6.8Hz,3H). 19 F NMR (376MHz,CDCl3)δ-69.15. 13 C NMR (101MHz, CDCl3) δ137.12, 136.35, 128.64 (q, J = 285.3Hz), 126.59, 125.68, 124.48, 123.95, 122.77, 121.98, 121.29, 119.51,115.45,114.65,114.09,114.05,113.99,111.29,49.72(q,J=25.5Hz),35.40,26.94,23.33,13.93(d,J=6.0Hz).

[0075] Example 11: 2-methyl-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3j)

[0076]

[0077] The difference from Example 1 is that: R 1 is -H, compound 2 is 2-methylindole, the amount of compound 2 added is 47.22 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3j with a yield of 89%, a time of 3d, and a molecular weight of 384.44. 1HNMR(400MHz,DMSO)δ11.11(s,1H),10.94(s,1H),7.40-7.34(m,2H),7.25(d,J=7.8Hz,1H),7.01-6.91(m,3H),6 .77(d,J=8.0Hz,2H),6.69-6.63(m,1H),3.37(s,3H),2.76(s,2H),1.22(d,J=6.2Hz,4H),0.73(t,J=6.6Hz,3H). 19 F NMR (376MHz,CDCl3)δ-70.15. 13 CNMR(101MHz,DMSO)δ136.38,136.10,134.82,129.33(q,J=324.7Hz),128.09,126.43,122.50,120.92,120.23,119.8 3,119.63,118.46,118.28,113.43,112.33,111.54,110.50,107.51,50.03(q,J=24.9Hz),35.65,27.21,22.61,13.81.

[0078] Example 12: 4-methyl-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3k)

[0079]

[0080] The difference from Example 1 is that: R 1 is -H, compound 2 is 4-methylindole, the amount of compound 2 added is 47.22 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3k with a yield of 31%, a time of 24 h, and a molecular mass of 384.44. 1 HNMR (400MHz, CDCl3) δ7.94(s,1H),7.64(s,1H),7.26(s,1H),7.12(d,J=7.9Hz,1H),7.08(d,J=2.5Hz,1H),7.06(s,1H),7.00(t, 1H),6.93-6.87(m,1H),6.83-6.77(m,1H),6.55(t,2H),2.84-2.40(m,2H),1.64(s,3H),1.28-1.02(m,4H),0.66(t,J=7.2Hz,3H). 19 F NMR (376MHz, CDCl3) δ-69.20. 13C NMR (101MHz, CDCl3) δ137.41, 136.43, 128.80 (q, J = 285.3Hz), 126.75, 125.92, 124.15, 124.08, 121.86, 121.83, 121.6 3,121.58,119.49,119.42,114.47,111.50,111.16,109.19,50.01(q,J=25.4Hz),35.37,27.02,23.49,23.40,13.95.

[0081] Example 13: 7-methyl-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexane-2-yl)-1H-indole (Compound 31)

[0082]

[0083] The difference from Example 1 is that: R 1 is -H, compound 2 is 7-methylindole, the amount of compound 2 added is 47.22 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 31 with a yield of 80%, a time of 7 days, and a molecular mass of 384.44. 1 HNMR (400MHz, CDCl3) δ8.01(d,J=21.5Hz,2H),7.34(d,J=8.1Hz,1H),7.20(dd,J=15.5,7.9Hz,3H),7.16-7.11(m,1H),7.11-7.05(m,1H),6.95(d,J= 6.8Hz,1H),6.92-6.87(m,1H),6.83(dd,J=14.5,6.9Hz,1H),2.76(d,J=7. 3Hz, 2H), 2.49 (s, 3H), 1.33 (dd, J = 7.1, 2.7Hz, 4H), 0.85 (t, J = 6.6Hz, 3H). 19 F NMR (376MHz,CDCl3)δ-69.15. 13C NMR (101MHz, CDCl3) δ136.42, 136.00, 128.83 (q, J = 285.3Hz), 126.73, 126.25, 124.13 (d,J=7.9Hz),123.95(d,J=9.6Hz),122.35(d,J=11.9Hz),121.66(d,J=10.0Hz),120.1 5,119.49(d,J=28.2Hz),119.49(d,J=7.1Hz),114.93,114.87,114.44,114.37,111.1 8, 50.08 (q, J = 25.4Hz), 35.32, 27.04, 23.39, 16.60 (d, J = 12.1Hz), 13.95 (d, J = 7.4Hz).

[0084] Example 14: 7-Chloro-3-(1,1,1-trifluoro-2-(1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3m)

[0085]

[0086] The difference from Example 1 is that: R 1 is -H, compound 2 is 7-chloroindole, the amount of compound 2 added is 52.98 mg, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3m with a yield of 29%, a time of 2 days, and a molecular weight of 404.86. 1 HNMR (400MHz, CDCl3) δ8.38(s,1H),8.15(s,1H),7.33(d,J=7.2Hz,2H),7.27(d,J=6.4Hz,1H),7.08(dd,J=16.0,8.3Hz,3H),6. 96(d,J=8.2Hz,1H),6.82(t,J=7.6Hz,1H),6.73(t,J=7.9Hz,1H),2.68-2.62(m,2H),1.27-1.22(m,4H),0.80(t,J=6.5Hz,3H). 19 FNMR (376MHz,CDCl3)δ-80.38. 13C NMR (101MHz, CDCl3) δ136.41, 133.68, 128.61 (q, J = 285.3Hz), 128.25, 126.64, 124.61, 123.95, 122.00, 121.47, 12 1.31, 120.28, 120.25, 119.61, 116.49, 115.84, 114.11, 111.18, 49.96 (q, J = 25.5Hz), 35.44, 26.99, 23.38, 14.00.

[0087] Example 15: 5-Chloro-3-(1,1,1-trifluoro-2-(5-fluoro-1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3n)

[0088]

[0089] The difference from Example 1 is that: R 1 The compound 2 is 5-F, the compound 2 is 5-chloroindole, and the remaining steps and parameters are the same as those in Example 1 to obtain the compound 3n with a yield of 69%, a time of 24 h, and a molecular weight of 422.85. 1 H NMR (400MHz, CDCl3) δ8.20(d,J=6.0Hz,2H),7.34(t,J=9.5Hz,2H),7.24(dd,J=8.8,4.5Hz,2H),7.11-7.01(m,2 H),6.87(td,J=9.0,2.4Hz,1H),6.72-6.67(m,1H),2.66-2.60(m,2H),1.35-1.24(m,4H),0.85(t,J=6.7Hz,3H). 19 F NMR (376MHz, CDCl3) δ-69.15,-124.15. 13C NMR (101MHz, CDCl3) δ158.61, 156.29, 134.81, 132.95, 128.54 (q, J = 285.3Hz), 127.63, 126.95 (d, J = 10 .3Hz),125.56(d,J=6.6Hz),125.16,122.46,122.40,120.47(d,J=10.5Hz),114.15(d,J=4.6Hz),113.7 7,112.32,111.90(d,J=3.1Hz),111.89(d,J=16.1Hz),110.71(d,J=9.9Hz),110.45(d,J=9.7Hz),106. 16 (d, J = 11.1Hz), 105.92 (d, J = 11.2Hz), 49.50 (q, J = 25.6Hz), 35.17, 26.90, 23.31, 13.93 (d, J = 5.8Hz).

[0090] Example 16: 5-Chloro-3-(1,1,1-trifluoro-2-(5-methyl-1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3o)

[0091]

[0092] The difference from Example 1 is that: R 1 is 5-CH3, compound 2 is 5-chloroindole, and the remaining steps and parameters are the same as those in Example 1 to obtain compound 3o with a yield of 92% and a molecular weight of 418.88. 1 H NMR (400MHz, CDCl3) δ8.08(s,1H),8.01(s,1H),7.26(s,1H),7.23(t,1H),7.22(s,1H),7.20(s,1H),7.16(d,J=5.9Hz,2H),7 .05(dd,J=8.6,1.8Hz,1H),6.95(d,J=6.8Hz,2H),2.71-2.63(m,2H),2.24(s,3H),1.30-1.21(m,4H),0.81(t,J=7.0Hz,3H). 19 F NMR (376MHz, CDCl3) δ-68.94. 13C NMR (101MHz, CDCl3) δ134.88 (d, J = 3.8Hz), 128.69 (q, J = 285.4Hz), 128.61, 127.74 ,126.69,125.56(d,J=10.3Hz),125.19,124.31(d,J=11.0Hz),123.78,123.67,122 .33,122.26,120.96(d,J=11.9Hz),114.57,113.36,112.14,110.96(d,J=6.8Hz), 49.91 (q, J=25.5Hz), 35.05, 26.99, 23.35, 21.72 (d, J=8.9Hz), 13.97 (d, J=7.4Hz).

[0093] Example 17: 5-Chloro-3-(1,1,1-trifluoro-2-(5-methoxy-1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3p)

[0094]

[0095] The difference from Example 1 is that: R 1 The compound 2 is 5-OCH3, the compound 2 is 5-chloroindole, and the remaining steps and parameters are the same as those in Example 1 to obtain the compound 3p with a yield of 75%, a time of 24 h, and a molecular weight of 434.89. 1 H NMR (400MHz, CDCl3) δ8.17 (d, J = 37.7Hz, 2H), 7.35-7.23 (m, 4H), 7.08-7.03 (m, 2H), 6.78 (dd, J = 8. 8,2.3Hz,1H),6.49(s,1H),3.55(s,3H),2.63(d,J=8.9Hz,2H),1.28(s,4H),0.83(t,J=6.7Hz,3H). 19 FNMR (376MHz,CDCl3)δ-69.20. 13 C NMR(101MHz, CDCl3)δ153.43,134.82,131.78,128.68(q,J=285.4Hz),127.77,127.12,125.34,125.11,124.78,122.33,120 .72,114.09,113.50,112.15,111.83,111.64,103.98,55.78(d,J=2.1Hz),49.63(q,J=25.6Hz),35.18,26.94,23.35,13.96.

[0096] Example 18: 5-Chloro-3-(1,1,1-trifluoro-2-(6-methyl-1H-indol-3-yl)hexan-2-yl)-1H-indole (Compound 3q)

[0097]

[0098] The difference from Example 1 is that: R 1 is 6-CH3, compound 2 is 5-chloroindole, and the remaining steps and parameters are the same as in Example 1 to obtain compound 3q with a yield of 75%, a time of 24 h, and a molecular weight of 418.89. 1 H NMR(400MHz, CDCl3)δ8.00(d,J=33.4Hz,2H),7.27(t,J=4.7Hz,1H),7.18(dd,J=22.6,8.4Hz,4H),7.10-7.01 (m,2H),6.73(d,J=8.2Hz,1H),2.71-2.66(m,2H),2.42(s,3H),1.31(d,J=3.9Hz,4H),0.86(t,J=6.8Hz,3H). 19 F NMR (376MHz,CDCl3)δ-69.01. 13 C NMR (101MHz, CDCl3) δ136.93,134.78,131.77,130.08,127.74,127.25,125.45(d, J=9.7Hz),125.12,124.35,123.39(d,J=10.8Hz),122.23,121.39(d,J=11.2Hz),1 20.86(t,J=8.9Hz),114.42,113.71,112.15(d,J=3.7Hz),111.29(d,J=9.7Hz),49 .77(q,J=25.5Hz),35.19,26.96,23.35,21.55(d,J=10.9Hz),13.95(d,J=7.0Hz).

[0099] Experimental Example 1: Effects of different reaction conditions on the rate and yield of compound 3

[0100] (1) Effect of different reaction temperatures on the rate and yield of compound 3. In the following table, except for the different reaction temperatures, the rest is the same as Example 4. The rate and yield results of compound 3 at different reaction temperatures are shown in Table 1.

[0101] Table 1 Effect of different reaction temperatures on the rate and yield of compound 3

[0102] Reaction temperature / ℃ Yield of compound 3 / (%) Compound 3 generation rate / (% / h) RT / / 30℃ 99 4.125 35℃ 99 4.125

[0103] From Table 1, it can be seen that when the reaction temperature is RT, no new compound is produced; when the reaction temperature is 30°C and 35°C, the yield is 99%. According to the above data, the optimal reaction temperature is 30°C.

[0104] (2) Effect of different catalyst addition amounts on the rate and yield of compound 3. In the following table, except for the different addition amounts of the reaction catalyst, the rest is the same as Example 4. The rate and yield results of compound 3 under different catalyst addition amounts are shown in Table 2.

[0105] Table 2 Effect of different catalyst addition amounts on the rate and yield of compound 3

[0106] Catalyst addition amount / mol% Yield of compound 3 / (%) Compound 3 generation rate / (% / h) 10 49 2.04 20 69 2.875 30 99 4.125 50 99 4.125 100 99 4.125

[0107] As can be seen from Table 2, when the amount of catalyst added is 10 mol% and 20 mol%, the yield of compound 3 is low and the reaction conversion is incomplete; when the amount of catalyst added is 30 mol% and above, the yield of compound 3 reaches 99%. According to the above data, the optimal amount of catalyst added is 30 mol%.

[0108] (3) Effect of different catalyst types on the rate and yield of compound 3. In the following table, except for the different reaction solvents, the rest is the same as Example 4. The rate and yield results of compound 3 under different catalyst types are shown in Table 3.

[0109] Table 3 Effect of different catalyst types on the rate and yield of compound 3

[0110] Types of catalysts Yield of compound 3 / (%) Compound 3 generation rate / (% / h) DPP 99 4.125 <![CDATA[TsOH·H2O]]> 99 2.75

[0111] From Table 3, it can be seen that when the catalyst type is DPP or TsOH·H2O, the yield of compound 3 reaches 99%, but DPP can make the generation rate of compound 3 higher. According to the above data, it can be seen that the best catalyst type is DPP.

[0112] (4) Effect of different solvents on the rate and yield of compound 3. In the following table, except for the different reaction solvents, the rest is the same as Example 4. The rate and yield results of compound 3 in different solvents are shown in Table 3.

[0113] Table 4 Effect of different solvents on the rate and yield of compound 3

[0114] Solvents Yield of compound 3 / (%) Compound 3 generation rate / (% / h) DCM / / DCE 99 4.125

[0115] As shown in Table 4, when DCM is selected, it is only suitable for RT conditions due to its low boiling point, but no new compounds are produced under RT conditions. When the solvent is DCE, the yield of compound 3 is 99%. According to the above data, the best solvent is DCE.

[0116] Test Example 2: Antibacterial effect test of the antibacterial bisindolylmethane derivatives of the present invention

[0117] 1. Test method: Use a sterile inoculation loop to take a single colony from the plate and add it to 1 mL of freshly prepared sterile LB liquid culture medium. Incubate at 37°C and 200 rpm for 4 h until the bacterial concentration is about 1×10 8 CFU / mL, diluted with LB liquid culture medium, the dilution ratio is 1:1000. Different compounds of Examples 2-18 are prepared into DMSO solutions with a concentration of 1 mg / mL, and 10 μL is added to the first well of a 96-well plate; 190 μL of bacterial suspension diluted with LB liquid culture medium is added to the first well, and 100 μL is added to the second to tenth wells. After the drug solution and bacterial suspension in the first well are fully blown and mixed, 100 μL is drawn and added to the second well, and diluted to the tenth well in this way. After the liquid in the tenth well is blown and mixed, 100 μL is discarded. Three parallel experiments are set for each example. Ampicillin is used as a positive control drug and DMSO is used as a negative control. Place it in an incubator at 37°C and culture it for 18 hours. After the culture is completed, place it in an enzyme reader and read the absorbance at 600nm. At the same time, observe it with the naked eye, and the lowest concentration that completely inhibits the growth of the bacteria to be tested is the MIC of the compound.

[0118] 2. The test results are shown in Table 5.

[0119] Table 5 Antibacterial effects of different antibacterial bisindolylmethane derivatives of the present invention

[0120]

[0121] As can be seen from Table 5, most of the bisindolyl derivatives have excellent antibacterial activity against Staphylococcus aureus, Bacillus subtilis, and Pseudomonas aeruginosa (Gram-negative bacteria), which provides more possibilities for the research of antibacterial drugs and the construction of a compound library with structural diversity.

[0122] The above description is a detailed description of the preferred feasible embodiments of the present invention, but the embodiments are not intended to limit the scope of the patent application of the present invention. All equivalent changes or modified changes completed under the technical spirit suggested by the present invention should fall within the patent scope covered by the present invention.

Claims

1. An antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof, characterized in that: Its chemical structure is shown below: Among them, R 1 is one of -CH3, -H, -F, -OCH3; R 2 It is one of -CH3, -OCH3, -Cl, -Br, -NO2, and -H.

2. The method for preparing the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1, characterized in that: The reaction formula of the preparation method is: Wherein, the DPP is diphenyl phosphate, which is used as catalyst A; the DCE is dichloroethane, which is used as organic solvent; and the heating temperature is 30°C.

3. The antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that: The method comprises the following specific steps: compound 1, compound 2 and catalyst A are mixed for reaction, an organic solvent is added, and the mixture is stirred at 30° C. After the reaction is completed, a crude product is obtained, and compound 3 is obtained after purification by silica gel column chromatography.

4. The antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that: The molar ratio of compound 1 to compound 2 is 1:1.

2.

5. The method for preparing the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof as claimed in claim 3, characterized in that: The added amount of the catalyst A is 30% of the mole of the compound 1.

6. The method for preparing the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof as claimed in claim 2, characterized in that: The reaction formula for preparing compound 1 is: Wherein, the THF is tetrahydrofuran, which serves as catalyst B; The preparation method of compound 1 is as follows: at -78°C and nitrogen conditions, compound 7 and catalyst B are mixed, compound 6 is added, the mixture is heated to room temperature, and stirred at room temperature for 8 hours. The reaction mixture is cooled to 0°C and a saturated NH4Cl solution at room temperature is added dropwise, wherein the volume ratio of the NH4Cl solution to compound 7 is 2:

1. The organic phase is separated, the aqueous layer is extracted with ethyl acetate, and the volume ratio of ethyl acetate to water is 5:

1. The organic phase is collected, washed with saturated brine, and then dried over anhydrous Na2SO4, spin-dried, and purified by silica gel column chromatography to obtain compound 1.

7. The method for preparing the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof as claimed in claim 6, characterized in that: The molar mass ratio of the compound 6 to the compound 7 is 1:1; the volume ratio of the catalyst B to the compound 7 is 6:

1.

8. The method for preparing the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof as claimed in claim 6, characterized in that: The reaction formula for preparing compound 6 is: Wherein, the DMF is dimethylformamide, serving as catalyst C; The preparation method of compound 6 is as follows: add catalyst C to compound 6, stir evenly at 0°C, then drop compound 5 at 0°C, warm to room temperature, stir for 3 hours, add ethyl acetate after the reaction is complete, then add water for extraction, collect the organic phase, wash with saturated brine, and then dry with anhydrous Na2SO4, and spin dry to obtain compound 6.

9. The method for preparing the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof as claimed in claim 8, characterized in that: The molar mass ratio of the compound 4 to the compound 5 is 2:1; the volume ratio of the catalyst C to the compound 5 is 6:

1.

10. Use of the antibacterial bisindolylmethane derivative or a pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of antibacterial drugs.

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