Benzimidazole-indole derivatives bridged by a benzene ring and use thereof

Abstract

The application discloses a kind of benzimidazole-indole derivatives with benzene ring bridging, with the following structure: R1 represents one or more positions of arbitrary position of benzene ring are replaced by one or several of H, C1-C6 alkyl, phenyl or pyridyl, and one or more positions of arbitrary position of the phenyl or pyridyl are replaced by one or several of H, C1-C6 alkyl, hydroxyl, C1-C6 alkoxy, R2, R3 are the same or different, selected from H or C1-C6 alkyl, and R4 represents H or C1-C6 alkyl.The application selects specific site of benzene ring to bridge benzimidazole and indole, form meta-substitution, and is replaced by selecting specific substituent group to benzene ring, and the obtained derivative has significant antibacterial effect, and is superior to commonly used broad-spectrum antibacterial drugs in clinic.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and particularly relates to a class of benzene ring-bridged benzimazole-indole derivatives, their preparation methods and applications. Background Technology

[0002] Antimicrobial drugs, as a cornerstone of modern medicine, have greatly promoted the development of infectious disease treatment. However, with the widespread use and even irrational abuse of antimicrobial drugs, bacterial resistance has evolved into a major global public health challenge. The emergence and spread of multidrug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and carbapenem-resistant Enterobacteriaceae (CRE), have led to a sharp decline in the efficacy of many traditional antimicrobial drugs, and clinical practice has even faced the severe dilemma of "no drugs available." Therefore, the development of highly effective antimicrobial drugs with novel chemical structures and unique mechanisms of action, especially drugs specifically targeting drug-resistant strains, has become a core research topic urgently needing breakthroughs in the fields of medicinal chemistry and pharmacy.

[0003] Among various biologically active heterocyclic compounds, benzimidazole and its indole skeleton have become research hotspots due to their broad-spectrum pharmacological activities. Benzimidazole compounds are the core pharmacophores of many clinical drugs, such as the antiparasitic drug albendazole and the antitumor drug bendamustine, both of which use benzimidazole as their structural core. Existing studies have confirmed that benzimidazole derivatives can exert excellent antibacterial and antifungal activities through multiple pathways, including interfering with bacterial DNA synthesis, inhibiting cell wall construction, or targeting specific enzyme molecules.

[0004] Meanwhile, the indole structure, as a widely found and advantageous backbone in nature (found in essential amino acids like tryptophan and neurotransmitters like serotonin), is also a key pharmacodynamic unit in many natural active products and synthetic drugs. Numerous studies have shown that compounds containing the indole structure exhibit significant biological activity in antibacterial, antiviral, and anti-inflammatory fields, demonstrating excellent potential for drug development.

[0005] Currently, the academic community has conducted a large number of antibacterial activity studies on derivatives of benzimidazole or indole single parent nuclei. However, such studies are mostly limited to the modification and optimization of single heterocyclic skeletons, and generally suffer from problems such as narrow activity spectrum and limited antibacterial efficacy. In particular, the inhibitory effect on Gram-negative bacteria and common clinical drug-resistant strains is often unsatisfactory.

[0006] In recent years, the "molecular hybridization" strategy, which involves the rational splicing of two or more active pharmacophores, has proven to be an effective approach for developing novel and highly effective drugs. This strategy can integrate the structural advantages and functional properties of different pharmacophores, producing synergistic effects and potentially achieving multi-target action modes, thereby significantly enhancing biological activity and overcoming drug resistance. Although a few studies have attempted to construct conjugates of benzimidazole with other heterocycles, the precise connection of benzimidazole and indole—two key antibacterial pharmacophores—through specific bridging chains (especially rigid benzene ring bridging chains), and the systematic development of structure-activity relationship analysis and antibacterial application research, remains a gap in the field. Summary of the Invention

[0007] Addressing the shortcomings of existing technologies, this invention aims to overcome technological bottlenecks by designing and synthesizing a series of novel benzene ring-bridged benzimazole-indole derivatives. By introducing a rigid benzene ring as a bridging unit, not only can the spatial conformation of the molecule be stabilized, but the interaction mode between the compound and potential bacterial targets is also expected to be optimized, providing important lead compounds and theoretical basis for the development of next-generation antibacterial drugs.

[0008] This invention bridges benzimidazole and indole at specific sites on the benzene ring to form meta-substitution, and by selectively substituting specific substituents on the benzene ring, the resulting derivative has significant antibacterial effects, which are superior to commonly used broad-spectrum antibacterial drugs in clinical practice.

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

[0010] A class of benzene ring-bridged benzimazole-indole derivatives have the following structure: R1 represents one or more positions of the benzene ring that are substituted by H, a C1-C6 alkyl group, a phenyl group, or a pyridyl group, wherein one or more positions of the phenyl or pyridyl group are substituted by H, a C1-C6 alkyl group, a hydroxyl group, or a C1-C6 alkoxy group, R2 and R3 may be the same or different and are selected from H or a C1-C6 alkyl group, and R4 is selected from H or a C1-C6 alkyl group.

[0011] The derivatives described in this invention preferably have the following structure:

[0012] .

[0013] More preferably, R2 and R3 are selected from H, and R4 is selected from H, methyl or ethyl. R1 is selected from H, methyl, ethyl, propyl, isopropyl, tolyl, phenolic, pyridyl, methylpyridyl, methoxypyridyl, hydroxypyridyl.

[0014] In a specific example of the present invention, the structure of the benzene ring-bridged benzimazole-indole derivative is as follows: , , , , , , , , , , , , , , , , .

[0015] Another object of the present invention is to provide the application of the benzene ring-bridged benzimidazole-indole derivatives described herein in the preparation of antibacterial drugs.

[0016] Another object of this invention is to provide a method for preparing the benzene ring-bridged benzimazole-indole derivatives described herein. Method 1:

[0017]

[0018] Step i. Dissolve bromoindole with different substitutions (100 mmol) and benzaldehyde 3-boronic acid with different substituents (100 mmol) in 50 mL of DMF, then add Pd(PPh3)4 and potassium carbonate (2 mmol), reflux at 50 °C, and stir for 4.2 hours. After the reaction is complete, evaporate the reaction solution to dryness under vacuum, extract with ethyl acetate and saturated brine, and evaporate the organic layer to dryness under vacuum to obtain compound 3.

[0019] Step ii. Dissolve o-phenylenediamine (50 mmol) in 20 mL of DMF, then slowly add it dropwise to 50 mL of DMF containing compound 3 (50 mmol) and sodium metabisulfite (100 mmol). Stir under reflux (110 °C) for 4 hours. Pour the reaction solution into ice water, and a large amount of yellow solid appears. Filter to obtain compound 4.

[0020] Method 2:

[0021]

[0022] Step i. Dissolve 150 mmol of 4-bromoindole and 150 mmol of 5-bromo-3-boronic acid benzaldehyde in 80 mL of DMF, then add Pd(PPh3)4 and potassium carbonate (3 mmol), reflux at 50 °C, and stir for 4.2 hours. After the reaction is complete, evaporate the reaction solution to dryness under vacuum, extract with ethyl acetate and saturated brine, and evaporate the organic layer to dryness under vacuum to obtain compound 3-bromo-5-(1H-indole-4-yl)benzaldehyde.

[0023] Step ii. Dissolve 100 mmol of 3-bromo-5-(1H-indol-4-yl)benzaldehyde and 100 mmol of boric acid with different substituents in 50 mL of DMF, then add Pd(PPh3)4 and potassium carbonate (2 mmol), reflux at 50 °C, and stir for 4.2 hours. After the reaction is complete, evaporate the reaction solution to dryness under vacuum, extract with ethyl acetate and saturated brine, and evaporate the organic layer to dryness under vacuum to obtain compound 3.

[0024] Step iii. Dissolve o-phenylenediamine (50 mmol) in 20 mL of DMF, then slowly add it dropwise to 50 mL of DMF containing compound 3 (50 mmol) and sodium metabisulfite (100 mmol). Stir under reflux (110 °C) for 4 hours. Pour the reaction solution into ice water, and a large amount of yellow solid appears. Filter to obtain compound 4.

[0025] Advantages of this invention:

[0026] This invention is based on the design concept of splicing indole and benzimidazole. The two are bridged by benzene rings to synthesize a series of benzimidazole-indole derivatives with benzene rings. During the research process of this invention, it was found that the position of indole and benzimidazole on the benzene ring and the connection site of indole and the bridging benzene ring have a certain influence on the antibacterial activity of the derivatives: (1) The compound obtained by connecting the benzene ring of benzimidazole to the carbon at the 4 position of indole has the best antibacterial effect, while the derivatives at other positions have poor antibacterial activity; (2) The antibacterial activity of indole and benzimidazole with meta-substitution on the benzene ring is better than that of para-substitution; (3) When the bridging benzene ring is further substituted by phenyl or pyridyl groups, the antibacterial activity is significantly improved, among which the substitution of pyridyl groups has the best effect.

[0027] This invention, by introducing a rigid benzene ring as a bridging unit, not only stabilizes the spatial conformation of the molecule but also promises to optimize the interaction mode between the compound and potential bacterial targets. Experimental results show that the derivatives described in this invention have a highly significant inhibitory effect on Staphylococcus aureus, Escherichia coli, and Bacillus subtilis, with effects superior to commonly used broad-spectrum antibacterial drugs in clinical practice. Detailed Implementation

[0028] The terminology used in this invention, unless otherwise specified, generally has the meanings commonly understood by those skilled in the art. The invention is further described in detail below with reference to specific embodiments and data. It should be understood that these embodiments are merely illustrative and not intended to limit the scope of the invention in any way.

[0029] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0030] In a specific embodiment, the preparation process and the structure of the related products of the present invention are described as follows:

[0031] Method 1:

[0032]

[0033] Step i. Dissolve bromoindole with different substitutions (100 mmol) and benzaldehyde 3-boronic acid with different substituents (100 mmol) in 50 mL of DMF, then add Pd(PPh3)4 and potassium carbonate (2 mmol), reflux at 50 °C, and stir for 4.2 hours. After the reaction is complete, evaporate the reaction solution to dryness under vacuum, extract with ethyl acetate and saturated brine, and evaporate the organic layer to dryness under vacuum to obtain compound 3.

[0034] Step ii. Dissolve o-phenylenediamine (50 mmol) in 20 mL of DMF, then slowly add it dropwise to 50 mL of DMF containing compound 3 (50 mmol) and sodium metabisulfite (100 mmol). Stir under reflux (110 °C) for 4 hours. Pour the reaction solution into ice water, and a large amount of yellow solid appears. Filter to obtain compound 4.

[0035] Method 2:

[0036]

[0037] Step i. Dissolve 150 mmol of 4-bromoindole and 150 mmol of 5-bromo-3-boronic acid benzaldehyde in 80 mL of DMF, then add Pd(PPh3)4 and potassium carbonate (3 mmol), reflux at 50 °C, and stir for 4.2 hours. After the reaction is complete, evaporate the reaction solution to dryness under vacuum, extract with ethyl acetate and saturated brine, and evaporate the organic layer to dryness under vacuum to obtain compound 3-bromo-5-(1H-indole-4-yl)benzaldehyde.

[0038] Step ii. Dissolve 100 mmol of 3-bromo-5-(1H-indol-4-yl)benzaldehyde and 100 mmol of boric acid with different substituents in 50 mL of DMF, then add Pd(PPh3)4 and potassium carbonate (2 mmol), reflux at 50 °C, and stir for 4.2 hours. After the reaction is complete, evaporate the reaction solution to dryness under vacuum, extract with ethyl acetate and saturated brine, and evaporate the organic layer to dryness under vacuum to obtain compound 3.

[0039] Step iii. Dissolve o-phenylenediamine (50 mmol) in 20 mL of DMF, then slowly add it dropwise to 50 mL of DMF containing compound 3 (50 mmol) and sodium metabisulfite (100 mmol). Stir under reflux (110 °C) for 4 hours. Pour the reaction solution into ice water, and a large amount of yellow solid appears. Filter to obtain compound 4.

[0040] Example 1: Preparation of 2-(3-(1H-indol-2-yl)phenyl)-1H-benzi[d]imidazole (4a)

[0041]

[0042] Following Method 1, 100 mmol of 2-bromoindole and 100 mmol of benzaldehyde 3-boronic acid were dissolved in 50 mL of DMF, followed by the addition of Pd(PPh3)4 and potassium carbonate (2 mmol). The mixture was refluxed at 50 °C and stirred for 4.2 hours. After the reaction was complete, the reaction solution was evaporated to dryness under vacuum and extracted with ethyl acetate and saturated brine. The organic layer was evaporated to dryness under vacuum to obtain compound 3. 50 mmol of o-phenylenediamine was dissolved in 20 mL of DMF and then slowly added dropwise to 50 mL of DMF containing compound 3 (50 mmol) and sodium metabisulfite (100 mmol). The mixture was stirred under reflux (110 °C) for 4 hours. The reaction solution was poured into ice water, resulting in a large amount of yellow solid. This solid was filtered to obtain compound 4a. A yellow powder was obtained, with a yield of 75.2%. mp 212 ~ 213 °C. 1 H NMR (DMSO-d6, 400MHz) δ: 6.86 (s, 1H); 7.04 - 7.05 (m, 1H); 7.11 - 7.12 (m, 1H); 7.24 (s, 2H); 7.48 - 7.51 (m, 2H); 7.70 (s, 2H); 7.76 - 7.77 (m, 1H); 7.92 (s, 2H); 8.13 -8.14 (m, 1H); 11.15 (s, 1H); 12.23 (s, 1H). MS (ESI): 309.13 ([M+H] + Anal.calc. for C 21 H 15 N3: C, 81.53; H, 4.89; N, 13.58%; Found: C, 80.93; H, 5.06; N, 14.01%.

[0043] Example 2: Preparation of 2-(3-(1H-indol-3-yl)phenyl)-1H-benzi[d]imidazole (4b)

[0044]

[0045] The preparation method is the same as in Example 1. A yellow powder was obtained, with a yield of 74.6%. mp 215 ~ 216 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 7.52 - 7.53 (m, 2H); 7.29 (s, 2H); 7.37 - 7.38 (m, 2H); 7.70 (s, 2H); 7.73 - 7.74 (m, 2H); 7.83 (s, 1H); 8.22 - 8.23 ​​(m, 2H); 12.27(s, 1H); 12.26 (s, 1H). MS (ESI): 309.13 ([M+H] + Anal. calc. for C 21 H 15 N3: C, 81.53; H, 4.89; N, 13.58%; found: C, 82.04; H, 4.76; N, 13.2%.

[0046] Example 3: Preparation of 2-(3-(1H-indol-4-yl)phenyl)-1H-benzi[d]imidazole (4c)

[0047]

[0048] Following Method 2, 150 mmol of 4-bromoindole and 150 mmol of 5-bromo-3-boronic acid benzaldehyde were dissolved in 80 mL of DMF. Pd(PPh3)4 and potassium carbonate (3 mmol) were then added, and the mixture was refluxed at 50 °C and stirred for 4.2 hours. After the reaction was complete, the reaction solution was evaporated to dryness under vacuum, extracted with ethyl acetate and saturated brine, and the organic layer was evaporated to dryness under vacuum to give compound 3-bromo-5-(1H-indol-4-yl)benzaldehyde. 100 mmol of 3-bromo-5-(1H-indol-4-yl)benzaldehyde and 100 mmol of boric acid were dissolved in 50 mL of DMF. Pd(PPh3)4 and potassium carbonate (2 mmol) were then added, and the mixture was refluxed at 50 °C and stirred for 4.2 hours. After the reaction was complete, the reaction solution was evaporated to dryness under vacuum, extracted with ethyl acetate and saturated brine, and the organic layer was evaporated to dryness under vacuum to give compound 3. 50 mmol of o-phenylenediamine was dissolved in 20 mL of DMF, and then slowly added dropwise to 50 mL of DMF containing compound 3 (50 mmol) and sodium metabisulfite (100 mmol). The mixture was stirred under reflux (110 °C) for 4 hours. The reaction solution was poured into ice water, and a large amount of yellow solid appeared. This solid was filtered to give compound 4c. A yellow powder was obtained in 72.4% yield. mp 214 ~ 216 °C. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.59 (s, 1H); 7.12 - 7.13 (m, 1H); 7.31 (s, 2H); 7.51 -7.52 (m, 1H); 7.61 - 7.62 (m, 1H); 7.71 (s, 2H); 7.74 - 7.75 (m, 2H); 7.89 -7.91 (m, 2H); 8.21 (s, 1H); 9.86 (s, 1H); 12.06 (s, 1H). MS (ESI): 309.13 ([M+H] + Anal. calc. for C 21 H 15 N3: C, 81.53; H, 4.89; N, 13.58%; found: C, 79.96; H, 5.02; N, 15.02%.

[0049] Example 4: Preparation of 2-(3-(1H-indol-5-yl)phenyl)-1H-benzi[d]imidazole (4d)

[0050]

[0051] The preparation method is the same as in Example 1. A yellow powder was obtained, with a yield of 71.9%. mp 212 ~ 213 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.53 (s, 1H); 7.10 - 7.11 (m, 1H); 7.29 (s, 2H); 7.58 -7.59 (m, 1H); 7.70 (s, 2H); 7.72 - 7.74 (m, 2H); 7.86 (s, 1H); 7.92 - 7.93(m, 2H); 8.26 (s, 1H); 9.86 (s, 1H); 12.38 (s, 1H). MS (ESI): 309.13 ([M+H] + Anal. calc. for C 21 H 15 N3: C, 81.53; H, 4.89; N, 13.58%; found: C, 78.95; H, 5.21; N, 15.84%.

[0052] Example 5: Preparation of 2-(3-(1H-indol-6-yl)phenyl)-1H-benzi[d]imidazole (4e)

[0053]

[0054] The preparation method is the same as in Example 1. A yellow powder was obtained, with a yield of 72.6%. mp 215 ~ 216 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.58 (s, 1H); 7.11 - 7.12 (m, 1H); 7.32 (s, 2H); 7.64 -7.65 (m, 1H); 7.70 (s, 2H); 7.72 - 7.73 (m, 2H); 7.96 - 7.97 (m, 2H); 8.32 -8.33 (s, 2H); 9.92 (s, 1H); 12.21 (s, 1H). MS (ESI): 309.13 ([M+H] + Anal.calc. for C 21 H 15 N3: C, 81.53; H, 4.89; N, 13.58%; found: C, 80.25; H, 5.13; N, 14.62%.

[0055] Example 6: Preparation of 2-(3-(1H-indol-7-yl)phenyl)-1H-benzi[d]imidazole (4f)

[0056]

[0057] The preparation method is the same as in Example 1. A yellow powder was obtained, with a yield of 75.1%. mp 217 ~ 218 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.55 (s, 1H); 7.16 - 7.17 (m, 1H); 7.31 (s, 2H); 7.53 -7.55 (m, 2H); 7.70 (s, 2H); 7.75 - 7.76 (m, 2H); 7.91 - 7.92 (m, 1H); 8.12(s, 1H); 8.34 - 8.35 (s, 1H); 9.95 (s, 1H); 12.28 (s, 1H). MS (ESI): 309.13([M+H] + Anal. calc. for C 21 H 15 N3: C, 81.53; H, 4.89; N, 13.58%; Found: C, 80.25; H, 5.13; N, 14.62%.

[0058] Example 7: Preparation of 2-(4-(1H-indol-4-yl)phenyl)-1H-benzi[d]imidazole (4g)

[0059]

[0060] The preparation method is the same as in Example 1. A yellow powder was obtained, with a yield of 69.3%. mp 217 ~ 218 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.61 (s, 1H); 7.13 - 7.14 (m, 1H); 7.30 (s, 2H); 7.23 -7.24 (m, 2H); 7.51 - 7.52 (m, 1H); 7.72 (s, 2H); 7.76 - 7.77 (m, 1H); 7.86 -7.87 (m, 3H); 9.89 (s, 1H); 12.05 (s, 1H). MS (ESI): 309.13 ([M+H] + Anal.calc. for C 21 H 15N3: C, 81.53; H, 4.89; N, 13.58%; found: C, 80.43; H, 4.98; N, 14.59%.

[0061] Example 8: Preparation of 2-(5-(1H-indol-4-yl)-[1,1'-biphenyl]-3-yl)-1H-benzis[d]imidazole (4h)

[0062]

[0063] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 63.2%. mp 228 ~ 229 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.48 (s, 1H); 7.14 (s, 1H); 7.21 (s, 3H); 7.45 - 7.48(m, 3H); 7.71 - 7.75 (m, 5H); 7.83 (s, 1H); 7.95 (s, 3H); 10.05 (s, 1H); 12.04 (s, 1H). MS (ESI): 385.47 ([M+H] + Anal. calc. for C 27 H 19 N3: C, 84.13; H, 4.97; N, 10.9%; found: C, 83.76; H, 5.02; N, 11.22%.

[0064] Example 9: Preparation of 2-(2'-fluoro-5-(3H-indol-4-yl)-[1,1'-biphenyl]-3-yl)-1H-benzis[d]imidazole (4i)

[0065]

[0066] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 61.9%. mp 236 ~ 237 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 3.38 (s, 2H); 7.17 (s, 1H); 7.28 - 7.29 (m, 3H); 7.51 -7.52 (m, 2H); 7.70 (s, 2H); 7.72 - 7.74 (m, 3H); 8.01 (s, 3H); 8.43 (s, 1H); 12.24 (s, 1H). MS (ESI): 403.15 ([M+H] +Anal. calc. for C 27 H 18 FN3: C, 80.38; H, 4.50; N, 10.42%; found: C, 80.24; H, 4.61; N, 10.02%.

[0067] Example 10: Preparation of 2-(3'-fluoro-5-(3H-indol-4-yl)-[1,1'-biphenyl]-3-yl)-1H-benzis[d]imidazole (4j)

[0068]

[0069] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 60.4%. mp 233 ~ 234 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 3.37 (s, 2H); 7.17 - 7.18 (m, 2H); 7.29 (s, 3H); 7.50 -7.51 (m, 2H); 7.61 - 7.62 (m, 1H); 7.70 (s, 2H); 7.71 - 7.72 (m, 1H); 8.02(s, 3H); 8.47 - 8.48 (m, 1H); 12.36 (s, 1H). MS (ESI): 403.15 ([M+H] + Anal.calc. for C 27 H 18 FN3: C, 80.38; H, 4.50; N, 10.42%; found: C, 81.21; H, 3.95; N, 10.33%.

[0070] Example 11: Preparation of 2-(4'-fluoro-5-(3H-indol-4-yl)-[1,1'-biphenyl]-3-yl)-1H-benzis[d]imidazole (4k)

[0071]

[0072] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 62.7%. mp 236 ~ 237 ℃. 1H NMR(DMSO-d6, 400 MHz) δ: 3.36 (s, 2H); 7.19 - 7.21 (m, 3H); 7.29 (s, 2H); 7.48(s, 2H); 7.70 (s, 2H); 7.73 - 7.74 (m, 2H); 8.02 (s, 3H); 8.42 (s, 1H); 12.27(s, 1H). MS (ESI): 403.15 ([M+H] + Anal. calc. for C 27 H 18 FN3: C, 80.38; H, 4.50; N, 10.42%; found: C, 80.13; H, 4.58; N, 10.37%.

[0073] Example 12: Preparation of 2-(5-(1H-indol-4-yl)-2'-methyl-[1,1'-biphenyl]-3-yl)-1H-benzis[d]imidazole (4l)

[0074]

[0075] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 61.5%. mp 230 ~ 231 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 2.21 (s, 3H); 6.52 - 6.53 (m, 1H); 7.10 - 7.11 (m, 1H); 7.31 (s, 2H); 7.36 (s, 2H); 7.43 - 7.44 (m, 1H); 7.51 - 7.52 (m, 1H); 7.70 (s, 2H); 7.74 - 7.75 (m, 2H); 7.82 - 7.83 (m, 1H); 8.02 (s, 3H); 10.02 (s, 1H); 12.38 (s, 1H). MS (ESI): 399.17 ([M+H] + Anal. calc. for C 28 H 21 N3: C, 84.18; H, 5.30; N, 10.52%; found: C, 83.44; H, 5.63; N, 10.93%.

[0076] Example 13: Preparation of 2-(5-(1H-indol-4-yl)-3'-methyl-[1,1'-biphenyl]-3-yl)-1H-benzis[d]imidazole (4m)

[0077]

[0078] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 59.8%. mp 228 ~ 229 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 2.41 (s, 3H); 6.51 - 6.52 (m, 1H); 7.15 - 7.16 (m, 2H); 7.30 (s, 2H); 7.44 - 7.46 (m, 2H); 7.61 - 7.63 (m, 2H); 7.70 (s, 2H); 7.72 -7.73 (m, 2H); 8.08 (s, 3H); 10.08 (s, 1H); 12.44 (s, 1H). MS (ESI): 399.17([M+H] + Anal. calc. for C 28 H 21 N3: C, 84.18; H, 5.30; N, 10.52%; found: C, 82.93; H, 5.44; N, 11.63%.

[0079] Example 14: Preparation of 2-(5-(1H-indol-4-yl)-4'-methyl-[1,1'-biphenyl]-3-yl)-1H-benzis[d]imidazole (4n)

[0080]

[0081] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 60.3%. mp 228 ~ 229 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 2.31 (s, 3H); 6.52 - 6.53 (m, 1H); 7.16 - 7.17 (m, 3H); 7.29 (s, 2H); 7.31 (s, 1H); 7.67 - 7.68 (m, 2H); 7.70 (s, 2H); 7.72 - 7.73(m, 2H); 8.03 (s, 3H); 10.02 (s, 1H); 12.51 (s, 1H). MS (ESI): 399.17 ([M+H] +Anal. calc. for C 28 H 21 N3: C, 84.18; H, 5.30; N, 10.52%; found: C, 82.75; H, 5.64; N, 11.61%.

[0082] Example 15: Preparation of 3'-(1H-benzo[d]imidazol-2-yl)-5'-(1H-indol-4-yl)-[1,1'-biphenyl]-2-ol (4o)

[0083]

[0084] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 58.1%. mp 238 ~ 239 ℃. 1 H NMR (DMSO-d6, 400 MHz) δ: 6.52 (s, 1H); 7.16 (s, 1H); 7.24 (s, 3H); 7.31 - 7.35(m, 3H); 7.58 (s, 1H); 1H); 7.93 (s, 3H); 8.94(s, 1H); 10.08 (s, 1H); 12.13 (s, 1H). MS (ESI): 401.47 ([M+H] + Anal. calc. for C 27 H 19 N3O: C, 80.78; H, 4.77; N, 10.47%; found: C, 81.23; H, 4.65; N, 10.69%.

[0085] Example 16: Preparation of 3'-(1H-benzo[d]imidazol-2-yl)-5'-(1H-indol-4-yl)-[1,1'-biphenyl]-3-ol (4p)

[0086]

[0087] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 58.6%. mp 237 ~ 238 ℃. 1H NMR(DMSO-d6, 400 MHz) δ: 6.53 (s, 1H); 6.78 (s, 1H); 7.08 (s, 1H); 7.13 (s, 2H); 7.27 - 7.28 (m, 3H); 7.58 (s, 1H); 7.70 (s, 2H); 7.74 (s, 1H); 7.88 (s, 1H); 8.02 (s, 3H); 9.25 (s, 1H); 10.13 (s, 1H); 12.43 (s, 1H). MS (ESI): 401.47([M+H] + Anal. calc. for C 27 H 19 N3O: C, 80.78; H, 4.77; N, 10.47%; found: C, 81.22; H, 4.65; N, 10.68%.

[0088] Example 17: Preparation of 3'-(1H-benzo[d]imidazol-2-yl)-5'-(1H-indol-4-yl)-[1,1'-biphenyl]-4-ol (4q)

[0089]

[0090] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 60.2%. mp 238 ~ 239 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.54 (s, 1H); 6.82 (s, 2H); 7.16 (s, 1H); 7.27 (s, 2H); 7.46 (s, 2H); (s, 1H); 7.92 (s, 1H); 8.03(s, 3H); 9.65 (s, 1H); 10.12 (s, 1H); 12.53 (s, 1H). MS (ESI): 401.47 ([M+H] + Anal. calc. for C 27 H 19 N3O: C, 80.78; H, 4.77; N, 10.47%; found: C, 81.22; H, 4.65; N, 10.68%.

[0091] Example 18: Preparation of 2-(3-(1H-indol-4-yl)-5-(pyridin-2-yl)phenyl)-1H-benzo[d]imidazolium (4r)

[0092]

[0093] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 58.2%. mp 221 ~ 222 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.54 (s, 1H); 6.72 - 6.78 (m, 2H); 7.12 (s, 2H); 7.29(s, 2H); (s, 1H); 8.01 (s, 1H); 8.35(s, 1H); 8.45 (s, 2H); 10.08 (s, 1H); 12.51 (s, 1H). MS (ESI): 386.15 ([M+H] + Anal. calc. for C 26 H 18 N4: C, 80.81; H, 4.69; N, 14.5%; found: C, 82.04; H, 4.12; N, 13.84%.

[0094] Example 19: Preparation of 2-(3-(1H-indol-4-yl)-5-(pyridin-3-yl)phenyl)-1H-benzo[d]imidazolium (4S)

[0095]

[0096] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 56.5%. mp 223 ~ 224 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.54 (s, 1H); 7.13 (s, 1H); 7.27 (s, 2H); 7.56 - 7.58(m, 2H); 7.70 (s, 2H); 7.72 - 7.73 (m, 1H); 7.86 (s, 1H); 8.01 (s, 3H); 8.41- 8.42 (m, 1H); 8.63 - 8.62 (m, 1H); 9.13 (s, 1H); 10.05 (s, 1H); 12.43 (s,1H). MS (ESI): 386.46 ([M+H]+ Anal. calc. for C 26 H 18 N4: C, 80.81; H, 4.69; N, 14.5%; found: C, 81.23; H, 4.36; N, 14.41%.

[0097] Example 20: Preparation of 2-(3-(1H-indol-4-yl)-5-(pyridin-4-yl)phenyl)-1H-benzo[d]imidazolium (4t)

[0098]

[0099] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 57.3%. mp 222 ~ 223 ℃. 1 7.86 (s, 1H); 7.93 (s, 2H); 8.03(s, 2H); 8.67 (s, 2H); 9.73 (s, 1H); 12.13 (s, 1H). MS (ESI): 386.15 ([M+H] + Anal. calc. for C 26 H 18 N4: C, 80.81; H, 4.69; N, 14.5%; found: C, 80.12; H, 4.97; N, 14.91%.

[0100] Example 21: Preparation of 2-(3-(1H-indol-4-yl)-5-(2-methoxypyridin-4-yl)phenyl)-1H-benzo[d]imidazolium (4u)

[0101]

[0102] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 58.6%. mp 228 ~ 229 ℃. 17.72 (s, 1H); 7.90 - 7.91 (m,2H); 8.06 (s, 3H); 8.43 (s, 1H); 8.67 (s, 1H); 9.81 (s, 1H); 12.33 (s, 1H).MS (ESI): 416.16 ([M+H] + Anal. calc. for C 27 H 20 N4O: C, 77.87; H, 4.84; N, 13.45%; found: C, 77.62; H, 4.89; N, 13.57%.

[0103] Example 22: Preparation of 2-(3-(1H-indol-4-yl)-5-(2-methoxypyridin-4-yl)phenyl)-1H-benzo[d]imidazolium (4v)

[0104]

[0105] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 56.9%. mp 230 ~ 231 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 3.78 (s, 3H); 6.17 (s, 1H); 6.50 - 6.51 (m, 1H); 7.16 (s, 1H); (m, 1H); 7.68 (s, 1H); 7.70(s, 2H); 7.72 - 7.73 (m, 1H); 7.87 (s, 1H); 8.04 (s, 3H); 416.16 ([M+H] + Anal. calc. for C 27 H 20 N4O: C, 77.87; H, 4.84; N, 13.45%; found: C, 77.73; H, 4.92; N, 13.52%.

[0106] Example 23: Preparation of 4-(3-(1H-benzo[d]imidazol-2-yl)-5-(1H-indol-4-yl)phenyl)pyridine-3-ol (4w)

[0107]

[0108] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 58.3%. mp 233 ~ 234 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 6.52 (s, 1H); 7.16 - 7.17 (m, 1H); 7.30 (s, 2H); 7.52 -7.53 (m, 1H); 7.70 (s, 2H); 7.75 (s, 1H); 7.91 - 7.92 (m, 2H); 8.07 (s, 3H); 8.52 - 8.53 (m, 1H); 8.72 - 8.73 (m, 1H); 9.52 (s, 1H); 10.10 (s, 1H); ([M+H] + Anal. calc. for C 26 H 18 N4O: C, 77.59; H, 4.51; N, 13.92%; found: C, 77.16; H, 4.86; N, 13.75%.

[0109] Example 24: Preparation of 4-(3-(1H-benzo[d]imidazol-2-yl)-5-(1H-indol-4-yl)phenyl)pyridine-2-ol (4x)

[0110]

[0111] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 60.2%. mp 233 ~ 234 ℃. 1H NMR(DMSO-d6, 400 MHz) δ: 6.13 (s, 1H); 6.53 (s, 1H); 7.12 - 7.13 (m, 1H); 7.29 (s, 2H); 7.42 - 7.43 (m, 1H); 7.57 - 7.59 (m, 2H); 7.70 (s, 2H); 7.71 (s,1H); 7.87 - 7.88 (m, 1H); 8.06 (s, 3H); 10.07 (s, 1H); 11.45 (s, 1H); 12.43(s, 1H). MS (ESI): 402.15 ([M+H] + Anal. calc. for C 26 H 18 N4O: C, 77.59; H, 4.51; N, 13.92%; found: C, 77.48; H, 4.72; N, 13.87%.

[0112] Example 25: Preparation of 2-(3-(1H-indol-4-yl)-5-(3-methylpyridin-4-yl)phenyl)-1H-benzimidazole (4y)

[0113]

[0114] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 58.4%. mp 231 ~ 232 ℃. 1 H NMR(DMSO-d6, 400 MHz) δ: 2.41 (s, 3H); 6.55 (s, 1H); 7.11 - 7.12 (m, 1H); 7.29 (s, 2H); 7.42 - 7.43 (m, 1H); 7.57 - 7.59 (m, 2H); 7.70 (s, 2H); 7.72 (s,1H); 7.82 - 7.84 (m, 3H); 8.05 (s, 3H); 8.84 (s, 1H); 8.57 (s, 1H); 400.17 ([M+H] + Anal. calc. for C 27 H 20 N4: C, 80.98; H, 5.03; N, 13.99%; Found: C, 78.62; H, 4.98; N, 16.40%.

[0115] Example 26: Preparation of 2-(3-(1H-indol-4-yl)-5-(2-methylpyridin-4-yl)phenyl)-1H-benzimidazole (4z)

[0116]

[0117] The preparation method is the same as in Example 3. A yellow powder was obtained, with a yield of 59.2%. mp 230 ~ 231 ℃. 1 7.74 - 7.75 (m, 1H); 7.86 - 7.87(m, 2H); 8.06 (s, 3H); 8.44 - 8.46 (m, 1H); 7.85 - 7.86 (m, 1H); 400.17 ([M+H] + Anal. calc. for C 27 H 20 N4: C, 80.98; H, 5.03; N, 13.99%; found: C, 78.58; H, 5.48; N, 15.94%.

[0118] Example 27: Study on the in vitro antibacterial activity of benzene ring-bridged benzimazole-indole derivatives

[0119] The MICs of compounds 4a–4z against bacteria were determined using the microbroth dilution method. Amikacin was selected as a positive control, and the antibacterial activity of indole-linked benzimidazole without benzene ring bridging was also investigated.

[0120] Different concentrations of compound solutions or control solutions, after serial dilution, were added to sterile 96-well polystyrene plates. 10 μL of sample solution was added to wells 1-11, with well 12 serving as a growth control. The plates were freeze-dried, sealed, and stored below -20°C for later use. For inoculum preparation, a bacterial suspension equivalent to 0.5 McFarland turbidity standard, prepared using the growth method or direct suspension method, was diluted 1:1000 with MH broth. 100 μL was added to each well, sealed, and incubated in a 35°C incubator for 16-20 h to determine the results.

[0121] Add the drug solution to the wells so that the concentrations from left to right are 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0 μg / mL.

[0122] The MIC values ​​of the benzene ring-bridged benzimidazole-indole derivatives listed in this invention against bacteria are shown in Table 1.

[0123] Table 1. MIC values ​​of the benzene ring-bridged benzimidazole-indole derivatives of the present invention against bacteria.

[0124]

[0125]

[0126]

[0127] The above results show that:

[0128] (1) The connection position of indole and benzene ring has an impact on antibacterial activity (compounds 4a~4f). The results show that the antibacterial activity is best when indole is substituted at the 4 position (4c), while the antibacterial activity of derivatives at other positions is poor.

[0129] (2) Comparing compounds 4c and 4g, it can be seen that the antibacterial activity of indole and benzimidazole with meta-substitution on the benzene ring is better than that with para-substitution.

[0130] (3) When the substituent on the bridged benzene ring is phenyl, the antibacterial activity does not change significantly compared with the unsubstituted case (compound 4c and compound 4h).

[0131] When the substituents on the bridged benzene ring are halophenyl groups, the antibacterial activity decreases significantly (compounds 4i~4k).

[0132] The antibacterial activity can be further enhanced when the substituents on the bridged benzene ring are alkylphenyl (4l~4n) or phenolic (4o~4q).

[0133] The antibacterial activity is significantly enhanced when the substituent on the bridged benzene ring is pyridyl, especially when the substituent is alkyl-substituted pyridyl (4y, 4z).

[0134] The above results indicate that the derivatives described in this invention have a highly significant inhibitory effect on Staphylococcus aureus, Escherichia coli, and Bacillus subtilis, and the effect is superior to commonly used broad-spectrum antibacterial drugs in clinical practice.

[0135] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present invention, various equivalent modifications can be made to the technical solutions of the present invention, and all such equivalent modifications fall within the protection scope of the present invention. Furthermore, it should be noted that the various specific technical features described in the above embodiments can be combined in any suitable manner without contradiction. To avoid unnecessary repetition, the present invention will not describe the various possible combinations separately. In addition, various different embodiments of the present invention can also be arbitrarily combined, as long as they do not violate the spirit of the present invention, and should also be considered as the content disclosed by the present invention.

Claims

1. A class of benzene ring-bridged benzimazole-indole derivatives, characterized in that... It has the following structure: R1 is selected from H, C1-C6 alkyl, phenyl substituted with one or more of H, C1-C6 alkyl, hydroxyl, and C1-C6 alkoxy, pyridyl substituted with one or more of H, C1-C6 alkyl, hydroxyl, and C1-C6 alkoxy; R2 and R3 may be the same or different and are selected from H or C1-C6 alkyl; R4 is selected from H or C1-C6 alkyl.

2. The derivative as claimed in claim 1, characterized in that... R2 and R3 are selected from H, and R4 is selected from H, methyl or ethyl.

3. The derivative as described in claim 2, characterized in that... R1 represents H, methyl, ethyl, propyl, isopropyl, tolyl, phenolic, pyridyl, methylpyridyl, methoxypyridyl, and hydroxypyridyl.

4. The derivative as described in claim 3, characterized in that... It has the following structure: , , , , , , , , , , , , , , , , .

5. The use of the benzene ring-bridged benzimidazole-indole derivative as described in any one of claims 1 to 4 in the preparation of antibacterial drugs, wherein the antibacterial drug is an anti-Staphylococcus aureus, Escherichia coli or Bacillus subtilis.

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