A benzimidazole-substituted cyclopentenone compound, a preparation method and application thereof

Abstract

The application discloses a benzimidazole substituted cyclopentenone compound and a preparation method and application thereof, and the compound comprises a structural formula shown in formula I or a medicinal salt, an isomer, a medicinal derivative thereof; wherein R1 is a hydrogen atom, a chlorine atom or a fluorine atom; R2 is a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group or a methoxy group; R3 is a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group or a methoxy group; R4 is a hydrogen atom, a chlorine atom or a fluorine atom; R5 is a methyl group, an ethyl group or a propyl group; and R6 is a methyl group, an ethyl group or a propyl group. The compound has good antibacterial activity, and has strong antibacterial activity on various pathogenic microorganisms including gram-positive bacteria and fungi. The application has the advantages of rich raw materials, simple operation, mild conditions, simple post-treatment, good thermal stability and good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, and relates to a benzimidazole-substituted cyclopentenone compound, its preparation method, and its application. Background Technology

[0002] The development of natural antibiotics and synthetic antibacterial agents began with penicillin in the 1930s and experienced a period of rapid growth, with various structural types of antibiotics emerging, mainly including β-lactams, sulfonamides, tetracyclines, macrolides, aminoglycosides, chloramphenicol, polypeptides, streptomycin, and quinolones. However, since the 1970s, antibiotic development has slowed down, with only three new structural antibiotics appearing around 2000: oxazolidinones, melitrizides, and lipopeptides. In the last two decades, few new structural antibiotics have been approved for marketing. With the continuous mutation of bacteria and the widespread dissemination of drug-resistant genes, the problem of drug resistance is becoming increasingly serious. Some superbugs have developed resistance to various antibiotics and can even breach humanity's last line of antibiotic defense. Therefore, the development of novel antibacterial compounds that can overcome drug resistance is urgently needed.

[0003] Cyclopentenone derivatives are a class of organic compounds containing cyclopentenone structures. They play an important role in medicinal chemistry, particularly due to the ubiquitous presence of cyclopentenones and their derivatives in bioactive natural compounds and their crucial role in drug development and synthesis. These compounds possess a five-membered ring structure, incorporating a ketone group and an unsaturated carbon-carbon double bond, endowing them with unique electrophilic and nucleophilic reactivity properties, making them highly versatile building blocks in organic chemistry. Benzimidazole derivatives are widely used in antibacterial and insecticidal agents. Benzimidazole derivatives include albendazole (ABZ), mebendazole (MZ), and flubendazole, with ABZ and MZ being the most commonly used clinically. They possess broad-spectrum antiparasitic activity, significant efficacy, and high safety, and have therefore been used since 1975.

[0004] Both benzimidazole and cyclopentenone possess significant biological activities, but currently, no compound containing both active groups has been extracted from food-derived natural products. Furthermore, there are no precedents for combining cyclopentenone and benzimidazole, both exhibiting good biological activity, in synthetic research. Combining the excellent antibacterial and potential antitumor activities of both, the resulting compound shows great promise for application. This patent also focuses on improving traditional methods for synthesizing cyclopentenone and designing a more environmentally friendly synthetic method. Summary of the Invention

[0005] In view of the above problems, the present invention provides a benzimidazole-substituted cyclopentenone compound, its preparation method and application.

[0006] To solve the above-mentioned technical problems, the present invention provides a benzimidazole-substituted cyclopentenone compound, characterized in that the structure of the compound is shown in Formula I:

[0007]

[0008] Wherein, R1 is hydrogen atom, chlorine atom, fluorine atom; R2 is hydrogen atom, chlorine atom, fluorine atom, methyl, methoxy; R3 is hydrogen atom, chlorine atom, fluorine atom, methyl, methoxy; R4 is hydrogen atom, chlorine atom, fluorine atom; R5 is methyl, ethyl, propyl; R6 is methyl, ethyl, propyl.

[0009] This invention also discloses a method for preparing benzimidazole-substituted cyclopentenone compounds. The method involves a tandem cyclization reaction of a benzimidazole-substituted acetonitrile compound as shown in Formula II with a ketone compound as shown in Formula III and acetone to obtain a benzoindole intermediate as shown in Formula IV. The intermediate IV is then subjected to a ring-opening oxidation reaction under oxidizing conditions to obtain a benzimidazole-substituted cyclopentenone compound as shown in Formula I.

[0010]

[0011] In Formula II, R1 is a hydrogen atom, a chlorine atom, or a fluorine atom; R2 is a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, or a methoxy group; R3 is a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, or a methoxy group; R4 is a hydrogen atom, a chlorine atom, or a fluorine atom; in Formula III, R5 is a methyl group, an ethyl group, or a propyl group; and R6 is a methyl group, an ethyl group, or a propyl group.

[0012] Further preferred methods include the following steps:

[0013] Step (1): After dissolving the benzimidazole acetonitrile compound shown in Formula II in a solvent, add the ketone compound shown in Formula III and acetone, and add an organic base. The reaction is carried out at 0℃~55℃ and the reaction is monitored by TLC until the reaction substrate is completely reacted to obtain the benzoindole intermediate shown in Formula IV. Then, an oxidant and an inorganic base are added to the reaction solution to carry out the reaction and the reaction is monitored by TLC. After the reaction is complete, ice water is immediately added to quench the reaction solution to obtain the reaction solution. The molar ratio of benzimidazole acetonitrile compound II to ketone compound III is 1:1~1:1.2, and the molar ratio of benzimidazole acetonitrile compound II to acetone is 1:2~1:3. The volume of the solvent and the molar ratio of benzimidazole acetonitrile compound II are 10~15mL / 1mmol.

[0014] Step (2): Extract the reaction solution with ethyl acetate, take the organic layer, and then dry it with anhydrous Na2SO4. Concentrate and evaporate the dried liquid to dryness, and then perform column chromatography to separate the concentrated and evaporated product to obtain the benzimidazole-substituted cyclopentenone compound as shown in Formula I.

[0015] More preferably, the solvent is any one of N,N-dimethylformamide, 1,4-dioxane, acetonitrile, tetrahydrofuran, or acetone; the organic base is any one of triethylamine, piperidine, pyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene; the oxidant is any one of tert-butyl hydroperoxide, di-tert-butyl hydroperoxide, or hydroperoxide; and the inorganic base is any one of cesium carbonate, potassium carbonate, potassium hydroxide, or sodium hydroxide.

[0016] A further preferred option is a reaction time of 12–36 hours.

[0017] More preferably, the mobile phase used in the column chromatography is petroleum ether and ethyl acetate in a volume ratio of 10:1 to 6:1.

[0018] More preferably, the amount of ice water used is 3 to 5 times the amount of solvent used; during the ethyl acetate extraction, the extraction is performed 3 times, and the volume of ethyl acetate used in each extraction is the same as the volume of ice water used.

[0019] This invention also discloses the use of the above-mentioned benzimidazole-substituted cyclopentenone compounds and their pharmaceutically acceptable salts and solvates in the preparation of antibacterial or antifungal drugs.

[0020] More preferably, the bacteria is Staphylococcus aureus; the fungus is Candida albicans.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] This invention utilizes readily available raw materials, including a polysubstituted benzimidazole acetonitrile compound of Formula II, a ketone compound of Formula III, and acetone, to prepare a benzoindole intermediate of Formula IV via a tandem cyclization reaction. Further ring-opening oxidation under oxidative conditions yields the target compound I with antibacterial activity. The synthetic process of this invention is simple, yields high output, and produces stable products. It provides a novel class of potential antibacterial and antifungal compounds for the killing, treatment, and prevention of bacterial and fungal infections. Almost all of these compounds exhibit significant antifungal activity, with some compounds showing a lower minimum inhibitory concentration (MIC) against Gram-positive Staphylococcus aureus than the reference control norfloxacin, and some compounds showing a MIC against the fungus Candida albicans than the reference control fluconazole. Attached Figure Description

[0023] Figure 1The reaction formula for preparing benzimidazole-substituted cyclopentenone compounds according to the present invention is shown.

[0024] Figure 2 The image shows the proton NMR spectrum of the product obtained in Example 1 of this invention.

[0025] Figure 3 The image shows the proton NMR spectrum of the product obtained in Example 2 of this invention.

[0026] Figure 4 The image shows the proton NMR spectrum of the product obtained in Example 3 of this invention.

[0027] Figure 5 The image shows the proton NMR spectrum of the product obtained in Example 4 of this invention.

[0028] Figure 6 The image shows the proton NMR spectrum of the product obtained in Example 5 of this invention.

[0029] Figure 7 The image shows the proton NMR spectrum of the product obtained in Example 6 of this invention.

[0030] Figure 8 The image shows the proton NMR spectrum of the product obtained in Example 7 of this invention.

[0031] Figure 9 The image shows the proton NMR spectrum of the product obtained in Example 8 of this invention. Detailed Implementation

[0032] The following detailed description, in conjunction with the accompanying drawings and specific embodiments, provides a benzimidazole-substituted cyclopentenone compound, its preparation method, and its applications. The advantages and features of the present invention will become clearer from the following description. It should be noted that the drawings are all in a very simplified form and use non-precise proportions, used only to facilitate and clarify the illustration of the embodiments of the present invention. The same or similar reference numerals in the drawings represent the same or similar parts.

[0033] The method for synthesizing the benzimidazole-substituted cyclopentenone compounds of the present invention is as follows:

[0034] After dissolving the polysubstituted benzimidazole acetonitrile compound of formula II in a suitable solvent, a ketone compound of formula III and acetone were added, and the reaction was carried out under organic base catalysis at a certain temperature. The reaction was monitored by TLC until the substrate was completely reacted, yielding the benzoindole intermediate shown in formula IV. Subsequently, an oxidant and an inorganic base were added to the reaction solution, and the reaction was monitored by TLC again. After the reaction was complete, ice water was immediately added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic layer was collected. The extract was dried with anhydrous Na2SO4, and the dried liquid was concentrated and evaporated to dryness. The concentrated and evaporated liquid was then separated by column chromatography to obtain the pure target product of formula I. The specific reaction formula is as follows. Figure 1 As shown.

[0035] In Formula I, R1 represents hydrogen, chlorine, and fluorine atoms; R2 represents hydrogen, chlorine, fluorine, methyl, and methoxy atoms; R3 represents hydrogen, chlorine, fluorine, methyl, and methoxy atoms; and R4 represents hydrogen, chlorine, and fluorine atoms.

[0036] In Formula II, R1 is a hydrogen atom, a chlorine atom, and a fluorine atom; R2 is a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, and a methoxy group; R3 is a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, and a methoxy group; and R4 is a hydrogen atom, a chlorine atom, and a fluorine atom.

[0037] In Formula III, R1 is a hydrogen atom, a chlorine atom, or a fluorine atom; R2 is a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, or a methoxy group; R3 is a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, or a methoxy group; R4 is a hydrogen atom, a chlorine atom, or a fluorine atom; R5 is a methyl group, an ethyl group, or a propyl group; and R6 is a methyl group, an ethyl group, or a propyl group.

[0038] In the reaction, solvents such as N,N-dimethylformamide, 1,4-dioxane, acetonitrile, tetrahydrofuran, or acetone can be used; the reaction temperature is 0℃ to 55℃; the reaction time is not specifically specified, but is usually 12 to 36 hours. The reaction process is monitored by TLC. After the reaction is complete, the reaction solution is quenched with an equal volume of ice water to obtain the reaction solution. The reaction solution is then extracted with ethyl acetate, usually three times with an equal volume of solvent. The solvent used for column chromatography separation is not specifically specified, but the commonly used mobile phase is petroleum ether and ethyl acetate in a volume ratio of 10:1 to 6:1. In the reaction, the molar ratio of compound II to compound III is 1:1 to 1:1.2, and the molar ratio of compound II to acetone is 1:2 to 1:3; the reaction yield is 38% to 92%.

[0039] The compounds of Formula II are known and can be prepared by known methods or are commercially available.

[0040] The compounds of Formula III are well known, or can be prepared by well known methods, or are commercially available.

[0041] Acetone is well-known and can be prepared using well-known methods; it is also commercially available.

[0042] This invention starts from readily available raw materials, polysubstituted benzimidazole acetonitrile II and ketone compound III, and acetone, and synthesizes a series of novel benzimidazole-substituted cyclopentenone compounds I through a one-pot method.

[0043] The MIC value was determined using the microdilution method (References: Bioorganic & Medicinal Chemistry Letters, 2013, 23, 5958–5963; Bioorganic & Medicinal Chemistry Letters, 2013, 23, 2399–2403).

[0044] Step 1: Add sterilized liquid culture medium to a sterile 96-well polystyrene plate. Add 180 μL of medium to each well in the first column, and 100 μL to each of the remaining wells. Add 20 μL of the prepared antibiotic solution to each well in the first column. Only one antibiotic can be added to each well. Seven samples can be added to one well; the remaining well can contain either norfloxacin or fluconazole as a control. Similar to the standard dilution method, use a pipette to thoroughly mix the liquid in the first well. Add 100 μL to the second well, and repeat the process for the third well. Continue this process for the last 11 wells, mixing thoroughly each time, and discarding 100 μL at a time. The 12th well serves as a growth control. At this point, the drug concentrations in wells 1-11 were 1000.000, 500.000, 250.000, 125.000, 62.500, 31.250, 15.625, 7.813, 3.906, 1.953, and 0.976 μg / mL, respectively. To meet the MIC value determination requirements at even lower drug concentrations, sterilized liquid culture medium was added to a sterile 96-well polystyrene plate. 198 μL of medium was added to each well in the first column, and 100 μL to each of the remaining wells. 2 μL of the prepared drug solution was added to each well in the first column. Only one antibiotic could be added to each well. Seven samples could be added to one plate, with the remaining well containing either norfloxacin or fluconazole as a control. Similar to the constant dilution method, the liquid in the first well was mixed thoroughly with a pipette, and 100 μL was added to the second well. This process was repeated, and 100 μL was added to the third well, and so on, until all 11 wells were filled. After mixing thoroughly, 100 μL was removed from each well. The 12th well served as a growth control. The drug concentrations in wells 1-11 were 100.000, 50.000, 25.000, 12.500, 6.250, 3.125, 1.563, 0.781, 0.391, 0.195, and 0.098 μg / mL, respectively.

[0045] Step 2: Take 15 μL of the bacterial suspension of the compound of this invention, dilute it 1000 times with culture medium, mix thoroughly, and add 100 μL of liquid culture medium to each well of a 96-well plate. At this time, the sample concentrations in wells 1-11 are 500.000, 250.000, 125.000, 62.5.000, 31.250, 15.625, 7.813, 3.906, 1.953, 0.977, and 0.488 μg / mL, respectively. When determining the MIC value at a lower drug concentration, the sample concentrations in wells 1-11 are 50.000, 25.000, 12.500, 6.250, 3.125, 1.563, 0.781, 0.391, 0.196, 0.098, and 0.049 μg / mL, respectively. Cover the container and place it in an incubator for incubation. Bacteria require 24-48 hours of incubation, while fungi require 48-72 hours. Observe and record the results afterward.

[0046] Step 3: The lowest concentration of the sample that can completely inhibit bacterial growth in the well is the MIC value of that sample. If well skipping occurs, the highest sample concentration that inhibits bacterial growth should be used as the MIC value, and the result should be recorded. Each 96-well plate can only be inoculated with one type of bacteria, not multiple types. Generally, the experiment needs to be repeated three times, and the average of the three sets of experiments is taken as the MIC value if there is no significant error.

[0047] The obtained data confirm that the compounds of the present invention have significant activity against Staphylococcus aureus, Bacillus cereus, and Candida albicans.

[0048] The present invention will now be described in detail with reference to some specific implementation schemes.

[0049] Example 1

[0050] Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 1): First, 2-(1H-benzo[d]imidazol-2-yl)acetonitrile (1.0 mmol) was added to a 25 mL round-bottom flask at 50 °C, followed by the addition of 1,4-dioxane (10 mL) and stirring. Then, acetone (4.2 mmol) was added, and subsequently piperidine (1.0 mmol) was added to the mixture and stirred for about 18 hours. The reaction was monitored by TLC until the substrate was completely consumed to obtain the intermediate. Subsequently, TBHP (2.5 mmol) and Cs2CO3 (1.0 mmol) were added to the reaction solution, and the mixture was stirred for about 3 hours. The reaction was monitored by TLC. After the reaction was complete, ice water was immediately added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic layer was collected. The extract was dried with anhydrous Na2SO4 and then filtered. The filtrate was concentrated and evaporated to dryness. The mobile phase was petroleum ether and ethyl acetate in a 6:1 ratio. The mixture was separated by column chromatography and dried to obtain a white solid product, 3-(1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 1), with a yield of 92%.

[0051] High-resolution mass spectrometry C 14 H 15 N2O[(M+H)+], theoretical value: 227.1179; measured value: 227.1175.

[0052] The obtained product was characterized by proton nuclear magnetic resonance spectroscopy, as shown in the attached figure. Figure 2 As shown, the characterization data is as follows:

[0053] 1 H NMR (500MHz, DMSO-d6): δ = 1.60 (s, 6H, CH3), 2.45 (s, 2H, CH2), 6.82 (s, 1H, CH), 7.29 (d, J = 7.2Hz, 2H, ArH), 7.68 (s, 2H, ArH), 13.02 (s, 1H, NH).

[0054] Its structural formula is as follows:

[0055]

[0056] Example 2

[0057] Synthesis of 4,4-dimethyl-3-(6-methyl-1H-benzo[d]imidazol-2-yl)cyclopent-2-en-1-one (compound 2): First, 2-(6-methyl-1H-benzo[d]imidazol-2-yl)acetonitrile (1.0 mmol) was added to a 25 mL round-bottom flask at 50 °C, followed by the addition of 1,4-dioxane (10 mL) and stirring. Then, acetone (4.2 mmol) was added, followed by piperidine (1.0 mmol) to the mixture and stirring for about 36 hours. The reaction was monitored by TLC until the substrate was completely consumed to obtain the intermediate. Subsequently, TBHP (2.5 mmol) and Cs2CO3 (1.0 mmol) were added to the reaction solution, and the mixture was stirred for about 3 hours. The reaction was monitored by TLC. After the reaction was complete, ice water was immediately added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic layer was collected. The extract was dried with anhydrous Na2SO4 and then filtered. The filtrate was concentrated and evaporated to dryness. The mobile phase was petroleum ether and ethyl acetate in a 6:1 ratio. The mixture was separated by column chromatography and dried to obtain a white solid product, 4,4-dimethyl-3-(6-methyl-1H-benzo[d]imidazol-2-yl)cyclopent-2-en-1-one (compound 2), with a yield of 90%.

[0058] High-resolution mass spectrometry C 15 H 17 N2O[(M+H)+], theoretical value: 241.1335; measured value: 241.1331.

[0059] The obtained product was characterized by proton nuclear magnetic resonance spectroscopy, as shown in the attached figure. Figure 3 As shown, the characterization data is as follows:

[0060] 1 H NMR (500MHz, DMSO-d6): δ = 1.58 (s, 6H, CH3), 2.39–2.46 (m, 5H, CH3, CH2), 6.76 (s, 1H, CH), 7.09 (s, 1H, ArH), 7.49 (d, J = 135.6Hz, 2H, ArH), 12.83 (s, 1H, NH).

[0061] Its structural formula is as follows:

[0062]

[0063] Example 3

[0064] Synthesis of 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 3): The reaction was carried out with 2-(6-chloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 1 to give a white solid product, 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 3), in yield (93%).

[0065] High-resolution mass spectrometry C 14 H 14 ClN2O[(M+H)+], theoretical value: 261.0789; measured value: 261.0784.

[0066] The obtained product was characterized by proton nuclear magnetic resonance spectroscopy, as shown in the attached figure. Figure 4 As shown, the characterization data is as follows:

[0067] 1 H NMR (500MHz, DMSO-d6): δ = 1.56 (s, 6H, CH3), 2.43 (s, 2H, CH2), 6.81 (s, 1H, CH), 7.28–7.29 (m, 1H, ArH), 7.50–7.94 (m, 2H, ArH), 13.17–13.16 (m, 1H, NH).

[0068] Its structural formula is as follows:

[0069]

[0070] Example 4

[0071] Synthesis of 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 4): The reaction was carried out with 2-(6-fluoro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile to give a white solid product, 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 4), in 92% yield.

[0072] High-resolution mass spectrometry C 14 H 14 FN2O[(M+H)+], theoretical value: 245.1085; measured value: 245.1080.

[0073] The obtained product was characterized by proton nuclear magnetic resonance spectroscopy, as shown in the attached figure. Figure 5 As shown, the characterization data is as follows:

[0074] 1 H NMR (500MHz, DMSO-d6): δ = 1.61 (s, 6H, CH3), 2.46 (s, 2H, CH2), 6.83 (s, 1H, CH), 7.28–7.37 (m, 2H, ArH), 7.58 (s, 1H, ArH), 13.20 (s, 1H, NH).

[0075] Its structural formula is as follows:

[0076]

[0077] Example 5

[0078] Synthesis of 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 5): The reaction was carried out with 2-(7-chloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile to give a white solid product, 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 5), in yield (89%).

[0079] High-resolution mass spectrometry C 14 H 14 ClN2O[(M+H)+], theoretical value: 261.0789; measured value: 261.0782.

[0080] The obtained product was characterized by proton nuclear magnetic resonance spectroscopy, as shown in the attached figure. Figure 6 As shown, the characterization data is as follows:

[0081] 1 H NMR (600MHz, DMSO-d6): δ = 1.61 (s, 6H, CH3), 2.46 (s, 2H, CH2), 6.83 (s, 1H, CH), 7.28–7.36 (m, 2H, ArH), 7.56–7.58 (m, 1H, ArH), 13.20 (s, 1H, NH).

[0082] Its structural formula is as follows:

[0083]

[0084] Example 6

[0085] Synthesis of 3-(6-methoxy-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 6): The reaction was carried out with 2-(6-methoxy-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile to give a white solid product, 3-(6-methoxy-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 6), in yield (82%).

[0086] High-resolution mass spectrometry C 15 H 17 N2O2[(M+H)+], theoretical value: 257.1285; measured value: 257.1279.

[0087] The obtained product was characterized by proton nuclear magnetic resonance spectroscopy, as shown in the attached figure. Figure 7 As shown, the characterization data is as follows:

[0088] 1 HNMR (500MHz, DMSO-d6): δ = 1.57 (d, J = 1.8Hz, 6H, CH3), 2.41 (d, J = 1.8Hz, 2H, CH2), 3.81 (s, 3H , CH3), 6.73 (s, 1H, CH), 6.89–7.27 (m, 2H, ArH), 7.56 (d, J = 72.5Hz, 1H, ArH), 12.84 (s, 1H, NH).

[0089] Its structural formula is as follows:

[0090]

[0091] Example 7

[0092] Synthesis of 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 7): The reaction was carried out with 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 2 to give a white solid product, 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (compound 7), in yield (72%).

[0093] High-resolution mass spectrometry C 14 H 13 C l2 N2O[(M+H)+], theoretical value: 295.0399; measured value: 295.0393.

[0094] The obtained product was characterized by proton nuclear magnetic resonance spectroscopy, as shown in the attached figure. Figure 8 As shown, the characterization data is as follows:

[0095] 1H NMR (600MHz, DMSO-d6): δ = 1.67 (d, J = 6.8Hz, 6H, CH3), 2.47 (d, J = 4.0Hz, 2H, CH2), 6.74 (d, J = 8.8Hz, 1H, CH), 7.29–7.86 (m, 2H, ArH), 12.23 (s, 1H, NH).

[0096] Its structural formula is as follows:

[0097]

[0098] Example 8

[0099] Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 8): First, 2-(1H-benzo[d]imidazol-2-yl)acetonitrile (2.0 mmol) was added to a 25 mL round-bottom flask at 50 °C, followed by the addition of 1,4-dioxane (10 mL) and stirring. Then, pentanedione (1.2 mmol) and acetone (3.0 mmol) were added separately, and piperidine (1.0 mmol) was added to the mixture and stirred for about 24 hours. The reaction was monitored by TLC until the substrate was completely consumed to obtain the intermediate. Next, TBHP (2.5 mmol) and Cs₂CO₃ (1.0 mmol) were added to the reaction solution, and the mixture was stirred for approximately 3 hours. The reaction was monitored by TLC. After completion, ice water was immediately added to quench the reaction. The mixture was extracted three times with ethyl acetate, and the organic layer was collected. The extract was dried over anhydrous Na₂SO₄ and then filtered. The filtrate was concentrated and evaporated to dryness. Column chromatography was performed using petroleum ether and ethyl acetate in a 6:1 ratio as the mobile phase. The product was dried to obtain a white solid, 3-(1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 8), yield (55%).

[0100] High-resolution mass spectrometry C 16 H 19 N2O[(M+H)+], theoretical value: 255.1492; measured value: 255.1492.

[0101] The obtained product was characterized by proton nuclear magnetic resonance spectroscopy, as shown in the attached figure. Figure 9 As shown, the characterization data is as follows:

[0102] 1H NMR (600MHz, DMSO-d6): δ = 0.80 (t, J = 7.2Hz, 3H, CH3), 0.91–0.99 (m, 1H, CH2), 0.17–1. 24(m,1H,CH2),1.59(s,3H,CH3),1.82–1.88(m,1H,CH2),2.12–2.17(m,1H,CH2),2.30( d,J=18.6Hz,1H,CH2),2.51(d,J=2.5Hz,1H,CH2),6.85(d,J=1.7Hz,1H,CH),7.23–7.3 5(m,2H,ArH),7.58(d,J=8.1Hz,1H,ArH),7.79(d,J=8.1Hz,1H,ArH),12.99(s,1H,NH).

[0103] Its structural formula is as follows:

[0104]

[0105] Example 9

[0106] Synthesis of 4-methyl-3-(6-methyl-1H-benzo[d]imidazol-2-yl)-4-propylcyclopent-2-en-1-one (compound 9): The reaction was carried out with 2-(6-methyl-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile to give a white solid product, 4-methyl-3-(6-methyl-1H-benzo[d]imidazol-2-yl)-4-propylcyclopent-2-en-1-one (compound 9), in yield (44%).

[0107] High-resolution mass spectrometry C 17 H 21 N2O[(M+H)+], theoretical value: 269.1648; measured value: 269.1642.

[0108] Its structural formula is as follows:

[0109]

[0110] Example 10

[0111] Synthesis of 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 10): The reaction was carried out with 2-(6-chloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile to give a white solid product, 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 10), in yield (52%).

[0112] High-resolution mass spectrometry C 16 H 18 ClN2O[(M+H)+], theoretical value: 289.1102; measured value: 289.1092.

[0113] Its structural formula is as follows:

[0114]

[0115] Example 11

[0116] Synthesis of 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 11): The reaction was carried out with 2-(6-fluoro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile to give a white solid product, 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 11), in 50% yield.

[0117] High-resolution mass spectrometry C 16 H 18 FN2O[(M+H)+], theoretical value: 273.1398; measured value: 273.1394.

[0118] Its structural formula is as follows:

[0119]

[0120] Example 12

[0121] Synthesis of 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 12): The reaction was carried out with 2-(7-chloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile to give a white solid product, 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 12), in yield (45%).

[0122] High-resolution mass spectrometry C 16 H 18 ClN2O[(M+H)+], theoretical value: 289.1102; measured value: 289.1096.

[0123] Its structural formula is as follows:

[0124]

[0125] Example 13

[0126] Synthesis of 3-(6-methoxy-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 13): The reaction was carried out with 2-(6-methoxy-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 8 to give a white solid product, 3-(6-methoxy-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 13), in yield (40%).

[0127] High-resolution mass spectrometry C 17 H 21 N2O2[(M+H)+], theoretical value: 285.1598; measured value: 285.1591.

[0128] Its structural formula is as follows:

[0129]

[0130] Example 14

[0131] Synthesis of 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 14): The reaction was carried out with 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 8 to give a white solid product, 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-en-1-one (compound 14), in yield (32%).

[0132] High-resolution mass spectrometry C 16 H 17 C l2 N2O[(M+H)+], theoretical value: 323.0712; measured value: 323.0704.

[0133] Its structural formula is as follows:

[0134]

[0135] Example 15

[0136] Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopenta-2-en-1-one (compound 15): The reaction was carried out in place of pentanedione in Example 8 to give a white solid product, 3-(1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopenta-2-en-1-one (compound 15), in yield (45%).

[0137] High-resolution mass spectrometry C 16 H 19 N2O[(M+H)+], theoretical value: 255.1492; measured value: 255.1488.

[0138] Its structural formula is as follows:

[0139]

[0140] Example 16

[0141] Synthesis of 4,4-diethyl-3-(6-methyl-1H-benzo[d]imidazol-2-yl)cyclopent-2-en-1-one (compound 16): The reaction was carried out in place of pentanedione in Example 9 to give a white solid product, 4,4-diethyl-3-(6-methyl-1H-benzo[d]imidazol-2-yl)cyclopent-2-en-1-one (compound 16), in yield (38%).

[0142] High-resolution mass spectrometry C 17 H 21 N₂O[(M+H)+], theoretical value: 269.1648; measured value: 269.1640. Its structural formula is as follows:

[0143]

[0144] Example 17

[0145] Synthesis of 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopent-2-en-1-one (compound 17): The reaction was carried out in place of pentanedione in Example 10 with glycerol to give a white solid product, 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopent-2-en-1-one (compound 17), yield (43%).

[0146] High-resolution mass spectrometry C 16 H 18 ClN2O[(M+H)+], theoretical value: 289.1102; measured value: 289.1093.

[0147] Its structural formula is as follows:

[0148]

[0149] Example 18

[0150] Synthesis of 4,4-diethyl-3-(6-fluoro-1H-benzo[d]imidazol-2-yl)cyclopent-2-en-1-one (compound 18): The reaction was carried out in place of pentanedione in Example 11 with glycerol to give a white solid product, 4,4-diethyl-3-(6-fluoro-1H-benzo[d]imidazol-2-yl)cyclopent-2-en-1-one (compound 18), in yield (44%).

[0151] High-resolution mass spectrometry C 16 H 18 FN2O[(M+H)+], theoretical value: 273.1398; measured value: 273.1392.

[0152] Its structural formula is as follows:

[0153]

[0154] Example 19

[0155] Synthesis of 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopent-2-en-1-one (compound 19): The reaction was carried out in place of pentanedione in Example 12 with glycerol to give a white solid product, 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopent-2-en-1-one (compound 19), yield (38%).

[0156] High-resolution mass spectrometry C 16 H 18 ClN2O[(M+H)+], theoretical value: 289.1102; measured value: 289.1094.

[0157] Its structural formula is as follows:

[0158]

[0159] Example 20

[0160] The MIC value was determined using the microdilution method (References: Bioorganic & Medicinal Chemistry Letters, 2013, 23, 5958–5963; Bioorganic & Medicinal Chemistry Letters, 2013, 23, 2399–2403).

[0161] Step 1: Add sterilized liquid culture medium to a sterile 96-well polystyrene plate. Add 180 μL of medium to each well in the first column, and 100 μL to each of the remaining wells. Add 20 μL of the prepared antibiotic solution to each well in the first column. Only one antibiotic can be added to each well. Seven samples can be added to one well; the remaining well can contain either norfloxacin or fluconazole as a control. Similar to the standard dilution method, use a pipette to thoroughly mix the liquid in the first well. Add 100 μL to the second well, and repeat the process for the third well. Continue this process for the last 11 wells, mixing thoroughly each time, and discarding 100 μL at a time. The 12th well serves as a growth control. At this point, the drug concentrations in wells 1-11 were 1000.000, 500.000, 250.000, 125.000, 62.500, 31.250, 15.625, 7.813, 3.906, 1.953, and 0.976 μg / mL, respectively. To meet the MIC value determination requirements at even lower drug concentrations, sterilized liquid culture medium was added to a sterile 96-well polystyrene plate. 198 μL of medium was added to each well in the first column, and 100 μL to each of the remaining wells. 2 μL of the prepared drug solution was added to each well in the first column. Only one antibiotic could be added to each well. Seven samples could be added to one plate, with the remaining well containing either norfloxacin or fluconazole as a control. Similar to the constant dilution method, the liquid in the first well was mixed thoroughly with a pipette, and 100 μL was added to the second well. This process was repeated, and 100 μL was added to the third well, and so on, until all 11 wells were filled. After mixing thoroughly, 100 μL was removed from each well. The 12th well served as a growth control. The drug concentrations in wells 1-11 were 100.000, 50.000, 25.000, 12.500, 6.250, 3.125, 1.563, 0.781, 0.391, 0.195, and 0.098 μg / mL, respectively.

[0162] Step 2: Take 15 μL of the bacterial suspension of the compound of this invention, dilute it 1000 times with culture medium, mix thoroughly, and add 100 μL of liquid culture medium to each well of a 96-well plate. At this time, the sample concentrations in wells 1-11 are 500.000, 250.000, 125.000, 62.5.000, 31.250, 15.625, 7.813, 3.906, 1.953, 0.977, and 0.488 μg / mL, respectively. When determining the MIC value at a lower drug concentration, the sample concentrations in wells 1-11 are 50.000, 25.000, 12.500, 6.250, 3.125, 1.563, 0.781, 0.391, 0.196, 0.098, and 0.049 μg / mL, respectively. Cover the container and place it in an incubator for incubation. Bacteria require 24-48 hours of incubation, while fungi require 48-72 hours. Observe and record the results afterward.

[0163] Step 3: The lowest concentration at which the sample can completely inhibit bacterial growth within the well is the MIC value of that sample. If well skipping occurs, the highest sample concentration that inhibits bacterial growth should be used as the MIC value, and the result should be recorded.

[0164] Each 96-well plate can only be inoculated with one type of bacteria, not multiple types. Generally, the experiment needs to be repeated three times. Under conditions of minimal error, the average of the three sets of experiments is taken as the MIC value.

[0165] The measurement results are shown in Table 1.

[0166] Table 1 shows the MIC values ​​of the compounds of the present invention against bacteria and fungi.

[0167]

[0168] Note: "-" indicates no data.

[0169] Overall, this group of compounds showed some inhibitory effect on Gram-positive strain SA, and the individual products exhibited good antibacterial activity against fungal strain CA. Among them, compound 14 showed the best antibacterial activity, inhibiting the growth of both SA and CA, with MIC values ​​of 3.3 μg / mL and 1.0 μg / mL, respectively. Its activity against SA was close to that of norfloxacin (SA, 0.8 μg / mL), while its activity against CA was twice that of fluconazol (CA, 2.0 μg / mL). Furthermore, the dichloro-substituted compound 7 showed an inhibitory MIC of 0.7 μg / mL on CA, three times that of fluconazole. All these data demonstrate that this class of compounds has promising potential for antibacterial drug development.

[0170] The foregoing description illustrates and describes several preferred embodiments of the invention. However, as previously stated, it should be understood that the invention is not limited to the forms disclosed herein and should not be construed as excluding other embodiments. It can be used in various other combinations, modifications, and environments, and can be altered within the scope of the inventive concept described herein through the foregoing teachings or techniques or knowledge in related fields. Any modifications and variations made by those skilled in the art that do not depart from the spirit and scope of the invention should be within the protection scope of the appended claims.

Claims

1. A benzimidazole-substituted cyclopentenone compound, characterized in that, The structure of the compound is shown in Formula I: Its specific structural formula can be any of the following:

2. The use of the benzimidazole-substituted cyclopentenone compounds of claim 1 and their pharmaceutically acceptable salts in the preparation of antibacterial or antifungal drugs.

3. The use of the benzimidazole-substituted cyclopentenone compounds and their pharmaceutically acceptable salts according to claim 2 in the preparation of antibacterial or antifungal drugs, characterized in that, The bacteria mentioned are Staphylococcus aureus; the fungus is Candida albicans.

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