Benzimidazole substituted cyclopentenone compound as well as preparation method and application thereof
Through tandem cyclization reaction and open epoxidation reaction under oxidation conditions, benzimidazole-substituted cyclopentenone compounds with antibacterial activity were successfully synthesized, which solved the problem of lack of such compounds in the prior art, and realized an environmentally friendly synthesis method.
Patent Information
- Application Number
- CN202411933602.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-26
- Publication Date
- 2025-04-04
- Estimated Expiration
- 2044-12-26
AI Technical Summary
The prior art lacks compounds that can have both benzimidazole and cyclopentenone bioactive groups, and traditional cyclopentenone synthesis methods have environmental problems.
The benzoindole intermediate was prepared by cyclizing the benzimidazole acetonitrile compound with ketone compounds and acetone, and the benzoindole intermediate was carried out under oxidation conditions to obtain benzimidazole substituted cyclopentenone compounds with antibacterial activity.
The efficient synthesis of new compounds with antibacterial activity was achieved, the environmental protection problems of traditional synthesis methods were solved, and the significant antibacterial activity against bacteria and fungi was demonstrated.
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Figure CN119751357A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of drug synthesis and relates to a benzimidazole-substituted cyclopentenone compound and a preparation method and application thereof. Background Art
[0002] The development of natural antibiotics and synthetic antimicrobial agents began with penicillin in the 1930s and has experienced a period of rapid development. Antibiotics of various structural types have emerged one after another, mainly including β-lactams, sulfonamides, tetracyclines, macrolides, aminoglycosides, chloramphenicol, peptides, streptomycins, quinolones, etc. However, since the 1970s, the development of antibiotics has slowed down. Only around 2000, three new types of antibiotics, oxazolones, mylins and lipopeptides, appeared. In the past two decades, few new structural antibiotics have been approved for marketing. With the continuous mutation of bacteria and the widespread spread of drug-resistant genes, the problem of drug resistance has become more and more serious. Some super bacteria have become resistant to various antibiotics and can even break through the last line of human antibiotic defense. Therefore, it is urgent to develop new antibacterial compounds that can overcome drug resistance.
[0003] Cyclopentenone derivatives are a class of organic compounds containing cyclopentenone structures. They play an important role in medicinal chemistry, because cyclopentenone and its derivatives are particularly important due to their ubiquitous presence in biologically active natural compounds and their key role in drug development and synthesis. This type of compound has a five-membered ring structure, in which a ketone group and an unsaturated carbon-carbon double bond are fused, which gives them unique electrophilic and nucleophilic reaction properties, making them highly plastic building blocks in organic chemistry. Benzimidazole derivatives are widely used in antibacterial insecticides. Benzimidazole BZ includes albendazole (ABZ), mebendazole (MZ) and flubendazole, of which ABZ and MZ are the most commonly used in clinical practice. They have broad-spectrum antiparasitic effects, significant efficacy and high safety, and therefore have been used since 1975.
[0004] Both benzimidazole and cyclopentenone have significant biological activity, but no compound with both active groups has been extracted from food-derived natural products, and there is no precedent for combining cyclopentenone and benzimidazole, both of which have good biologically active groups. Combined with the excellent antibacterial activity and possible anti-tumor activity of both, the new compound formed by the combination of the two has broad application prospects. At the same time, the patent is committed to improving the traditional method of synthesizing cyclopentenone and designing a more environmentally friendly method for synthesizing cyclopentenone, which is the focus of this patent. Summary of the invention
[0005] In view of this, the present invention aims at the above-mentioned problems and provides a benzimidazole-substituted cyclopentenone compound and a preparation method and application thereof.
[0006] In order to solve the above technical problems, the present invention provides a benzimidazole-substituted cyclopentenone compound, characterized in that the structure of the compound is as shown in Formula I:
[0007]
[0008] Among them, 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; R6 is a methyl group, an ethyl group, or a propyl group.
[0009] The present invention also discloses a method for preparing a benzimidazole substituted cyclopentenone compound. According to the following reaction formula, a substituted benzimidazole acetonitrile compound as shown in formula II is subjected to a tandem cyclization reaction with a ketone compound as shown in formula III and acetone to obtain a benzindole intermediate as shown in formula IV; the intermediate IV is subjected to a ring-opening oxidation reaction under oxidizing conditions to obtain a benzimidazole substituted cyclopentenone compound as shown in formula I;
[0010]
[0011] Among them, 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; R6 is a methyl group, an ethyl group, or a propyl group.
[0012] Further preferably, the method comprises the following steps:
[0013] Step (1), after dissolving the benzimidazole acetonitrile compound shown in formula II in a solvent, adding the ketone compound shown in formula III and acetone thereto, and adding an organic base, reacting at 0°C to 55°C and tracking the reaction by TLC until the reaction substrate is completely reacted, thereby obtaining a benzindole intermediate shown in formula IV; then adding an oxidant and an inorganic base to the reaction solution for reaction and tracking the reaction by TLC, and immediately adding ice water to quench after the reaction is complete to obtain a reaction solution; the molar ratio of the benzimidazole acetonitrile compound II to the ketone compound III is 1:1 to 1:1.2, and the molar ratio of the benzimidazole acetonitrile compound II to acetone is 1:2 to 1:3; the molar ratio of the volume of the solvent to the benzimidazole acetonitrile compound II is 10 to 15 mL / 1 mmol;
[0014] Step (2), extracting the reaction solution with ethyl acetate, taking the organic layer, and then drying it with anhydrous Na2SO4, concentrating and evaporating the dried liquid, and then separating the concentrated evaporated product by column chromatography to obtain a benzimidazole-substituted cyclopentenone compound as shown in Formula I.
[0015] Further 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 hydrogen peroxide; and the inorganic base is any one of cesium carbonate, potassium carbonate, potassium hydroxide or sodium hydroxide.
[0016] More preferably, the reaction time is 12 to 36 hours.
[0017] Further 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] Further preferably, the amount of ice water is 3 to 5 times the amount of solvent; when the ethyl acetate extraction is performed, the number of extractions is 3 times, and the volume of ethyl acetate used in each extraction is the same as the volume of ice water used.
[0019] The invention also discloses the use of the benzimidazole substituted cyclopentenone compounds and pharmaceutically acceptable salts and solvates thereof in preparing 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] The present invention uses the easily available raw material of formula II, a polysubstituted benzimidazole acetonitrile compound, a ketone compound of formula III and acetone, and obtains a benzindole intermediate of formula IV through a tandem cyclization reaction, and further performs a ring-opening oxidation reaction under oxidative conditions to obtain a target compound I with antibacterial activity. The invention has a simple synthesis process, high yield and stable products. A new type of potential antibacterial and antifungal compound is provided for killing, treating and preventing bacterial and fungal infections; almost all of the compounds show significant antibacterial activity against fungi, among which the minimum inhibitory concentration of some compounds against Gram-positive Staphylococcus aureus is better than that of the reference control norfloxacin, and the minimum inhibitory concentration of some compounds against the fungus Candida albicans is better than that of the reference control fluconazole. BRIEF DESCRIPTION OF THE DRAWINGS
[0023] Figure 1The reaction formula is for preparing the benzimidazole-substituted cyclopentenone compounds of the present invention.
[0024] Figure 2 The following is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 1 of the present invention.
[0025] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 2 of the present invention.
[0026] Figure 4 The following is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 3 of the present invention.
[0027] Figure 5 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 4 of the present invention.
[0028] Figure 6 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 5 of the present invention.
[0029] Figure 7 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 6 of the present invention.
[0030] Figure 8 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 7 of the present invention.
[0031] Fig. 9 This is the hydrogen nuclear magnetic resonance spectrum of the product obtained in Example 8 of the present invention. DETAILED DESCRIPTION
[0032] The following is a further detailed description of a benzimidazole-substituted cyclopentenone compound and its preparation method and application proposed by the present invention in conjunction with the accompanying drawings and specific embodiments. According to the following description, the advantages and features of the present invention will become clearer. It should be noted that the accompanying drawings are all in a very simplified form and are not in precise proportions, which are only used to conveniently and clearly assist in explaining the purpose of the embodiments of the present invention. The same or similar reference numerals in the accompanying 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 an appropriate solvent, a ketone compound of formula III and acetone are added respectively, and the reaction is carried out at a certain temperature by catalysis of an organic base, and the reaction is detected by TLC until the reaction substrate is completely reacted to obtain a benzindole intermediate as shown in formula IV; then an oxidant and an inorganic base are added to the reaction solution, and the reaction is continuously detected by TLC. After the reaction is complete, ice water is immediately added to quench; extraction is carried out with ethyl acetate, and the organic layer is taken, and the extract is dried with anhydrous Na2SO4, and the dried liquid is concentrated and evaporated to dryness, and then the concentrated evaporated product is separated by column chromatography to obtain a pure target product of formula I. The specific reaction formula is as follows: Figure 1 shown.
[0035] In formula I, 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;
[0036] 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;
[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; R6 is a methyl group, an ethyl group, or a propyl group.
[0038] In the reaction, the solvent can be N,N-dimethylformamide, 1,4-dioxane, acetonitrile, tetrahydrofuran or acetone; the reaction temperature is 0℃~55℃; the reaction time is not specified, usually 12~36 hours. The reaction process is tracked by TLC detection. After the reaction is complete, the reaction is quenched with an equal volume of ice water to obtain a reaction solution, and the reaction solution is extracted with ethyl acetate, usually with an equal volume of solvent, and extracted three times. The solvent for column chromatography separation is not specified, and the commonly used mobile phase is petroleum ether and ethyl acetate, with a volume ratio of 10:1~6:1. In the reaction, the molar ratio of the compound of formula II to the compound of formula III is 1:1~1:1.2, and the molar ratio of the compound of formula II to acetone is 1:2~1:3; the yield of the reaction is 38~92%.
[0039] The compound of formula II is known, can be prepared according to known methods, and is also commercially available.
[0040] The compounds of formula III are known, or can be prepared according to known methods, or are commercially available.
[0041] Acetone is well known and can be prepared according to known methods or purchased commercially.
[0042] The invention starts from readily available raw materials of polysubstituted benzimidazole acetonitrile II, 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 by the microdilution method (references: Bioorganic & Medicinal Chemistry Letters, 2013, 23, 5958–5963; Bioorganic & Medicinal Chemistry Letters, 2013, 23, 2399–2403):
[0044] Step 1: Add the sterilized liquid culture medium to a sterile 96-well polystyrene plate, add 180 μL of culture medium to each well in the first column of the plate, and add 100 μL to each of the remaining wells. Take 20 μL of the prepared solution and add it to the wells in the first column. Only one antibacterial drug can be added to each well. Seven samples can be added to one plate, and the remaining well can be added with the control drug norfloxacin or fluconazole. The operation is basically similar to the constant dilution method. Use a pipette to mix the liquid in the first well evenly, aspirate 100 μL and add it to the second well. Repeat the same operation. After mixing evenly, aspirate 100 μL to the third well, and then proceed to the bottom 11 wells in turn. Mix the liquid evenly, aspirate 100 μL and discard it. The 12th well is used as a growth control. At this time, the drug concentrations in wells 1-11 are 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 at a lower drug concentration, the sterilized liquid culture medium is added to the sterile 96-well polystyrene plate, 198 μL of culture medium is added to each well in the first column of the plate, and 100 μL is added to each well of the remaining wells. Take 2 μL of the prepared drug solution and add it to the first column of wells respectively. Only one antibacterial drug can be added to each well. Seven samples can be added to one plate, and the remaining one can be added with the control drug norfloxacin or fluconazole. The operation is basically similar to the constant dilution method. Use a pipette to mix the liquid in the first well, aspirate 100 μL and add it to the second well. Repeat the same operation. After mixing well, aspirate 100 μL to the third well, and then proceed to the bottom 11 wells in sequence. Mix the liquid evenly, aspirate 100 μL and discard it. The 12th well is used as a growth control. At this time, the drug concentrations in wells 1-11 are 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 15uL of the bacterial suspension of the compound of the present invention and dilute it 1000 times with the culture medium, mix well, and add 100uL of liquid culture medium to each well of the 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 0.488μg / mL, respectively. When the MIC value at a lower drug concentration is determined, 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 0.049μg / mL, respectively. Cover the lid and place in a constant temperature box for culture. Bacteria need to be cultured for 24-48 hours, and fungi need to be cultured for 48-72 hours. Then observe and record the results.
[0046] Step 3: The lowest concentration of the sample that can completely inhibit bacterial growth in the small hole is the MIC value of the sample. If the hole jump phenomenon occurs, the highest sample concentration that inhibits bacterial growth shall prevail and the result shall be recorded. Each 96-well plate can only be inoculated with one bacteria, not multiple bacteria. Generally, the test needs to be repeated three times. In the absence of large errors, the average value of the three groups of experiments is taken as the MIC value.
[0047] The obtained data confirmed that the compounds of the present invention have significant activity against Staphylococcus aureus, Bacillus cereus and Candida albicans.
[0048] The present invention is described in detail below in conjunction with some specific implementation embodiments.
[0049] Example 1
[0050] Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-en-1-one (Compound 1): First, the raw material 2-(1H-benzo[d]imidazol-2-yl)acetonitrile (1.0 mmol) was added into a 25 mL round-bottom flask at 50 °C, 1,4-dioxane (10 mL) was added to dissolve and stirred, and then acetone (4.2 mmol) was added thereto, and then piperidine (1.0 mmol) was added to the mixture and stirred for about 18 hours, and monitored by TLC until the reaction substrate was completely consumed to obtain the intermediate. Afterwards, TBHP (2.5 mmol) and Cs2CO3 (1.0 mmol) were added to the reaction solution, and stirring was continued for about 3 hours and monitored by TLC. After the reaction was complete, ice water was immediately added for quenching, and the mixture was extracted three times with ethyl acetate. The organic layer was taken, and the extract was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated and evaporated to dryness. The mobile phase used was petroleum ether and ethyl acetate in a ratio of 6:1. Column chromatography was performed for separation and drying to obtain a white solid product, 3-(1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-ene-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 hydrogen nuclear magnetic resonance spectroscopy. Figure 1 The characterization data are 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, the raw material 2-(6-methyl-1H-benzo[d]imidazol-2-yl)acetonitrile (1.0 mmol) was added into a 25 mL round-bottom flask at 50 °C, 1,4-dioxane (10 mL) was added to dissolve and stirred, and then acetone (4.2 mmol) was added thereto, and then piperidine (1.0 mmol) was added to the mixture and stirred for about 36 hours, and monitored by TLC until the reaction substrate was completely consumed to obtain the intermediate. Afterwards, TBHP (2.5 mmol) and Cs2CO3 (1.0 mmol) were added to the reaction solution, and stirring was continued for about 3 hours and monitored by TLC. After the reaction was complete, ice water was immediately added for quenching, and the mixture was extracted three times with ethyl acetate. The organic layer was taken, and the extract was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated and evaporated to dryness. The mobile phase used was petroleum ether and ethyl acetate in a ratio of 6:1. Column chromatography was performed for separation and drying to obtain a white solid product, 4,4-dimethyl-3-(6-methyl-1H-benzo[d]imidazol-2-yl)cyclopent-2-ene-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 hydrogen nuclear magnetic resonance spectroscopy. Figure 2 The characterization data are 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-ene-1-one (Compound 3): Using 2-(6-chloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 1 for the reaction can give a white solid product, 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-ene-1-one (Compound 3), with a yield of (93%).
[0065] High resolution mass spectrometry C 14 H 14 ClN2O[(M+H)+], theoretical value: 261.0789; found value: 261.0784.
[0066] The obtained product was characterized by hydrogen nuclear magnetic resonance spectroscopy. Figure 3 The characterization data are 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-ene-1-one (Compound 4): Using 2-(6-fluoro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 1 for the reaction can give a white solid product, 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-ene-1-one (Compound 4), with a yield of (92%).
[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 hydrogen nuclear magnetic resonance spectroscopy. Figure 4 The characterization data are 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-ene-1-one (Compound 5): Using 2-(7-chloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 1 for the reaction can give a white solid product, 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-ene-1-one (Compound 5), with a yield of (89%).
[0079] High resolution mass spectrometry C 14 H 14 ClN2O[(M+H)+], theoretical value: 261.0789; found value: 261.0782.
[0080] The obtained product was characterized by hydrogen nuclear magnetic resonance spectroscopy. Figure 5 The characterization data are 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-ene-1-one (Compound 6): Using 2-(6-methoxy-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 2 to carry out the reaction can obtain a white solid product, 3-(6-methoxy-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-ene-1-one (Compound 6), with a yield of (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 hydrogen nuclear magnetic resonance spectroscopy. Figure 6 The characterization data are as follows:
[0088] 1 H NMR (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-ene-1-one (Compound 7): Using 2-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 2 for the reaction can give a white solid product, 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-4,4-dimethylcyclopent-2-ene-1-one (Compound 7), with a yield of (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 hydrogen nuclear magnetic resonance spectroscopy. Figure 7 The characterization data are 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 into a 25 mL round-bottom flask at 50 °C, 1,4-dioxane (10 mL) was added to dissolve and stirred, and then pentanedione (1.2 mmol) and acetone (3.0 mmol) were added thereto respectively, and then piperidine (1.0 mmol) was added to the mixture and stirred for about 24 hours, and monitored by TLC until the reaction substrate was completely consumed to obtain the intermediate. Afterwards, TBHP (2.5 mmol) and Cs2CO3 (1.0 mmol) were added to the reaction solution, and stirring was continued for about 3 hours, and the mixture was monitored by TLC. After the reaction was complete, ice water was immediately added for quenching, and the mixture was extracted three times with ethyl acetate. The organic layer was taken, and the extract was dried over anhydrous Na2SO4 and then filtered. The filtrate was concentrated and evaporated to dryness. The mobile phase used was petroleum ether and ethyl acetate in a ratio of 6:1. Column chromatography was performed and the mixture was dried to obtain a white solid product, 3-(1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-ene-1-one (Compound 8), with a yield of (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 hydrogen nuclear magnetic resonance spectroscopy. Figure 8 The characterization data are 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-ene-1-one (Compound 9): Using 2-(6-methyl-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 8 to carry out the reaction can obtain a white solid product, 4-methyl-3-(6-methyl-1H-benzo[d]imidazol-2-yl)-4-propylcyclopent-2-ene-1-one (Compound 9), with a yield of (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-ene-1-one (Compound 10): Using 2-(6-chloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 8 to carry out the reaction can obtain a white solid product, 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-ene-1-one (Compound 10), with a yield of (52%).
[0112] High resolution mass spectrometry C 16 H 18 ClN2O[(M+H)+], theoretical value: 289.1102; found value: 289.1092.
[0113] Its structural formula is as follows:
[0114]
[0115] Embodiment 11
[0116] Synthesis of 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-ene-1-one (Compound 11): Using 2-(6-fluoro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 8 to carry out the reaction can obtain a white solid product, 3-(6-fluoro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-ene-1-one (Compound 11), with a yield of (50%).
[0117] High resolution mass spectrometry C 16 H 18 FN2O[(M+H)+], theoretical value: 273.1398; found 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-ene-1-one (Compound 12): Using 2-(7-chloro-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 8 to carry out the reaction can obtain a white solid product, 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-ene-1-one (Compound 12), with a yield of (45%).
[0122] High resolution mass spectrometry C 16 H 18 ClN2O[(M+H)+], theoretical value: 289.1102; found 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-ene-1-one (Compound 13): Using 2-(6-methoxy-1H-benzo[d]imidazol-2-yl)acetonitrile instead of 2-(1H-benzo[d]imidazol-2-yl)acetonitrile in Example 8 to carry out the reaction can obtain a white solid product, 3-(6-methoxy-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-ene-1-one (Compound 13), with a 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] Embodiment 14
[0131] Synthesis of 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-ene-1-one (Compound 14): Using 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 carry out the reaction can obtain a white solid product, 3-(5,6-dichloro-1H-benzo[d]imidazol-2-yl)-4-methyl-4-propylcyclopent-2-ene-1-one (Compound 14), with a yield of (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] Embodiment 15
[0136] Synthesis of 3-(1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopenta-2-ene-1-one (Compound 15): Using pentanedione instead of pentanedione in Example 8 to carry out the reaction can obtain a white solid product, 3-(1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopenta-2-ene-1-one (Compound 15), with a yield of (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-ene-1-one (Compound 16): Using pentanedione instead of pentanedione in Example 9 for the reaction, a white solid product, 4,4-diethyl-3-(6-methyl-1H-benzo[d]imidazol-2-yl)cyclopent-2-ene-1-one (Compound 16), was obtained in a yield of (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] Embodiment 17
[0145] Synthesis of 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopent-2-ene-1-one (Compound 17): Using pentanedione instead of pentanedione in Example 10 to carry out the reaction can obtain a white solid product, 3-(6-chloro-1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopent-2-ene-1-one (Compound 17), with a yield of (43%).
[0146] High resolution mass spectrometry C 16 H 18 ClN2O[(M+H)+], theoretical value: 289.1102; found value: 289.1093.
[0147] Its structural formula is as follows:
[0148]
[0149] Embodiment 18
[0150] Synthesis of 4,4-diethyl-3-(6-fluoro-1H-benzo[d]imidazol-2-yl)cyclopent-2-ene-1-one (Compound 18): Using pentanedione instead of pentanedione in Example 11 for the reaction, a white solid product, 4,4-diethyl-3-(6-fluoro-1H-benzo[d]imidazol-2-yl)cyclopent-2-ene-1-one (Compound 18), was obtained in a yield of (44%).
[0151] High resolution mass spectrometry C 16 H 18 FN2O[(M+H)+], theoretical value: 273.1398; found value: 273.1392.
[0152] Its structural formula is as follows:
[0153]
[0154] Embodiment 19
[0155] Synthesis of 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopent-2-ene-1-one (Compound 19): Using pentanedione instead of pentanedione in Example 12 to carry out the reaction can obtain a white solid product, 3-(7-chloro-1H-benzo[d]imidazol-2-yl)-4,4-diethylcyclopent-2-ene-1-one (Compound 19), with a yield of (38%).
[0156] High resolution mass spectrometry C 16 H 18 ClN2O[(M+H)+], theoretical value: 289.1102; found value: 289.1094.
[0157] Its structural formula is as follows:
[0158]
[0159] Embodiment 20
[0160] MIC values were 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 the sterilized liquid culture medium to a sterile 96-well polystyrene plate, add 180 μL of culture medium to each well in the first column of the plate, and add 100 μL to each of the remaining wells. Take 20 μL of the prepared solution and add it to the wells in the first column. Only one antibacterial drug can be added to each well. Seven samples can be added to one plate, and the remaining well can be added with the control drug norfloxacin or fluconazole. The operation is basically similar to the constant dilution method. Use a pipette to mix the liquid in the first well evenly, aspirate 100 μL and add it to the second well. Repeat the same operation. After mixing evenly, aspirate 100 μL to the third well, and then proceed to the bottom 11 wells in turn. Mix the liquid evenly, aspirate 100 μL and discard it. The 12th well is used as a growth control. At this time, the drug concentrations in wells 1-11 are 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 at lower drug concentrations, add the sterilized liquid culture medium to a sterile 96-well polystyrene plate, add 198 μL of culture medium to each well in the first column of the plate, and add 100 μL to each of the remaining wells. Take 2 μL of the prepared drug solution and add it to the first column of wells. Only one antibacterial drug can be added to each well. Seven samples can be added to one plate, and the remaining one can be added with the control drug norfloxacin or fluconazole. The operation is basically similar to the constant dilution method. Use a pipette to mix the liquid in the first well, aspirate 100 μL and add it to the second well. Repeat the same operation. After mixing well, aspirate 100 μL to the third well, and then proceed to the bottom 11 wells in sequence. Mix the liquid evenly, aspirate 100 μL and discard it. The 12th well is used as a growth control. At this time, the drug concentrations in wells 1-11 are 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 15uL of the bacterial suspension of the compound of the present invention and dilute it 1000 times with the culture medium, mix well, and add 100uL of liquid culture medium to each well of the 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 0.488μg / mL, respectively. When the MIC value at a lower drug concentration is determined, 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 0.049μg / mL, respectively. Cover the lid and place in a constant temperature box for culture. Bacteria need to be cultured for 24-48 hours, and fungi need to be cultured for 48-72 hours. Then observe and record the results.
[0163] Step 3: The lowest concentration of the sample that can completely inhibit bacterial growth in the small hole is the MIC value of the sample. If the hole jump phenomenon occurs, the highest sample concentration that inhibits bacterial growth shall prevail and the result shall be recorded.
[0164] Each 96-well plate can only be inoculated with one type of bacteria, not multiple bacteria. Generally, the test needs to be repeated three times. If there is no large error, the average value of the three groups of experiments is taken as the MIC value.
[0165] The measurement results are shown in Table 1.
[0166] Table 1 MIC values of the antibacterial activity test of the compounds of the present invention against bacteria and fungi
[0167]
[0168]
[0169] Note: “-” means no data.
[0170] Overall, this group of compounds has a certain inhibitory effect on the Gram-positive strain SA, and the sub-products show good antibacterial activity against the fungal strain CA. Among them, 14 has the best antibacterial activity, which can inhibit the growth of SA and CA, with MIC values of 3.3μg / mL and 1.0μg / mL, respectively. The activity of SA is close to that of the drug norfloxacin (Norfloxacin, SA, 0.8μg / mL), and the activity against CA can reach twice that of the drug fluconazole (Fluconazol, CA, 2.0μg / mL). In addition, the MIC value of dichloro compound 7 inhibiting the growth of CA reached 0.7μg / mL, which is three times that of fluconazole. The above data all prove that this type of compound has certain prospects for the development of antibacterial drugs.
[0171] The above description shows and describes several preferred embodiments of the invention, but as mentioned above, it should be understood that the invention is not limited to the form disclosed herein, and should not be regarded as excluding other embodiments, but can be used in various other combinations, modifications and environments, and can be modified within the scope of the invention concept described herein through the above teachings or the technology or knowledge of the relevant field. The changes and modifications made by those skilled in the art shall be within the scope of protection of the claims attached to the invention without departing from the spirit and scope of the invention.
Claims
1. A benzimidazole-substituted cyclopentenone compound, characterized in that: The structure of the compound is shown in Formula I: Among them, 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; R6 is a methyl group, an ethyl group, or a propyl group.
2. A method for preparing a benzimidazole-substituted cyclopentenone compound according to claim 1, characterized in that: According to the following reaction formula, a substituted benzimidazole acetonitrile compound as shown in formula II is subjected to a tandem cyclization reaction with a ketone compound as shown in formula III and acetone to obtain a benzindole intermediate as shown in formula IV; the intermediate IV is subjected to a ring-opening oxidation reaction under oxidizing conditions to obtain a benzimidazole substituted cyclopentenone compound as shown in formula I; Among them, 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; R6 is a methyl group, an ethyl group, or a propyl group.
3. The method for preparing the benzimidazole-substituted cyclopentenone compound according to claim 2, characterized in that: The steps include: Step (1), after dissolving the benzimidazole acetonitrile compound shown in formula II in a solvent, adding the ketone compound shown in formula III and acetone thereto, and adding an organic base, reacting at 0°C to 55°C and tracking the reaction by TLC until the reaction substrate is completely reacted, thereby obtaining a benzindole intermediate shown in formula IV; then adding an oxidant and an inorganic base to the reaction solution for reaction and tracking the reaction by TLC, and immediately adding ice water to quench after the reaction is complete to obtain a reaction solution; the molar ratio of the benzimidazole acetonitrile compound II to the ketone compound III is 1:1 to 1:1.2, and the molar ratio of the benzimidazole acetonitrile compound II to acetone is 1:2 to 1:3; the molar ratio of the volume of the solvent to the benzimidazole acetonitrile compound II is 10 to 15 mL / 1 mmol; Step (2), extracting the reaction solution with ethyl acetate, taking the organic layer, and then drying it with anhydrous Na2SO4, concentrating and evaporating the dried liquid, and then separating the concentrated evaporated product by column chromatography to obtain a benzimidazole-substituted cyclopentenone compound as shown in Formula I.
4. The method for preparing the benzimidazole-substituted cyclopentenone compound according to claim 3, characterized in that: 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 hydrogen peroxide; and the inorganic base is any one of cesium carbonate, potassium carbonate, potassium hydroxide or sodium hydroxide.
5. The method for preparing the benzimidazole-substituted cyclopentenone compound according to claim 3, characterized in that: The reaction time is 12 to 36 hours.
6. The method for preparing the benzimidazole-substituted cyclopentenone compound according to claim 3, characterized in that: The mobile phase used in the column chromatography is petroleum ether and ethyl acetate, and the volume ratio is 10:1 to 6:
1.
7. The method for preparing the benzimidazole-substituted cyclopentenone compound according to claim 3, characterized in that: The amount of ice water used is 3 to 5 times the amount of solvent used; when the ethyl acetate extraction is used, the extraction times are 3 times, and the volume of ethyl acetate used in each extraction is the same as the volume of ice water used.
8. The benzimidazole-substituted cyclopentenone compounds and pharmaceutically acceptable salts thereof as claimed in claim 1 and their use in the preparation of antibacterial or antifungal drugs.
9. Use of the benzimidazole-substituted cyclopentenone compounds and pharmaceutically acceptable salts thereof as claimed in claim 8 for preparing antibacterial or antifungal drugs, characterized in that: The bacteria is Staphylococcus aureus; the fungus is Candida albicans.