CN110862374B - Naphthalimide benzimidazole compound and preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of medicinal chemistry, and discloses a naphthalimide benzimidazole compound shown as a formula I, and a preparation method and application thereof, wherein the compound has strong in-vitro antimicrobial activity, particularly shows high inhibitory activity on gram-positive bacteria such as staphylococcus aureus, methicillin-resistant staphylococcus aureus, bacillus subtilis, micrococcus luteus and the like, gram-negative bacteria such as escherichia coli, proteus, pseudomonas aeruginosa, salmonella typhi and the like, and fungi such as candida utilis, aspergillus flavus, saccharomyces cerevisiae, candida albicans and the like, can be used for preparing antibacterial and/or antifungal medicaments, and is beneficial to solving clinical treatment problems of increasingly severe drug resistance, stubborn pathogenic microorganisms, newly-appearing harmful microorganisms and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a naphthalimide benzimidazole compound, and a preparation method and application thereof.
Background
Cyclic imines are of interest for their broad potential application in the antimicrobial, especially antibacterial, field. Naphthalimides are cyclic imines with strong hydrophobicity and large conjugated systems, and can interact with various active targets in a living system through noncovalent bond acting force such as pi-pi accumulation and the like, so that the naphthalimides have wide biological activity, such as anticancer, antibacterial, trypanosome resisting, pain relieving and the like. To date, many naphthalimide compounds have been used in the anti-tumor field, and some derivatives such as amonafide and edrina have been clinically tested, mainly by inserting deoxyribonucleic acid (DNA) to exert anti-tumor effect. Due to their remarkable achievements in the antitumor field, many efforts have been made to study the naphthalimide-based compounds in other medical fields. Recently, the studies on the antibacterial, antifungal and antiviral properties of naphthalimide derivatives have been actively conducted, and particularly, the antibacterial and antifungal properties have been studied most extensively, and various derivatives having potential biological activities have been under development. In view of the important role of heterocyclic compounds in drug design and synthesis, a great deal of research shows that the introduction of nitrogen-containing heterocycles on the naphthalimide skeleton is favorable for regulating physicochemical properties and improving biological activity, for example, the piperazino-containing naphthalimide compound can effectively inhibit the growth of escherichia coli and pseudomonas aeruginosa and is equivalent to that of the reference drug ciprofloxacin.
The benzimidazole ring has a structure similar to purine, and can effectively inhibit the synthesis of nucleic acid or protein in bacteria, thereby killing or inhibiting the growth of the bacteria. In recent years, there have been studies on introduction of a benzimidazole ring into a naphthalimide structure in order to obtain a drug lead molecule having a remarkable antimicrobial activity, but unfortunately, a compound excellent in antimicrobial activity has not been found. Therefore, it is necessary to continue the research on the naphthalimide benzimidazole compound.
Disclosure of Invention
The invention provides a naphthalimide benzimidazole compound with a novel structure and a preparation method thereof.
The invention also provides the application of the naphthalimide benzimidazole compound in preparing antibacterial and/or antifungal medicaments.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
a naphthalimide benzimidazole compound having a structure represented by formula (I):
wherein n is an integer of 1 to 5.
Preferably, n is 2 or 5.
A method for preparing the naphthalimide benzimidazole compound comprises the following steps:
in an organic solvent, in the presence of alkali, 4-bromine-1, 8-naphthalimide shown in a formula (V) reacts with a compound shown in a formula (III) to prepare a naphthalimide benzimidazole compound shown in a formula (I); the reaction equation is as follows:
preferably, the organic solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide, benzene and toluene.
Preferably, the alkali is one or more of potassium carbonate, sodium hydroxide and potassium hydroxide.
Preferably, the reaction temperature is 60 to 90 ℃.
Further, after the reaction is finished, removing the organic solvent, and performing column chromatography separation and drying on the residue to obtain the naphthalimide benzimidazole compound shown in the formula (I).
Preferably, the column chromatography is silica gel column chromatography, and the eluent is a mixture of dichloromethane and acetone in a volume ratio of 20.
The naphthalimide benzimidazole compound is applied to preparing antibacterial and/or antifungal medicaments.
Preferably:
the bacteria are any one or more of staphylococcus aureus, methicillin-resistant staphylococcus aureus, micrococcus luteus, bacillus subtilis, escherichia coli, pseudomonas aeruginosa and proteus vulgaris; and/or
The fungi is one or more of candida utilis, aspergillus flavus, saccharomyces cerevisiae, candida albicans and candida albicans; and/or
The medicine is any one of tablets, capsules, aerosols and ointments.
Compared with the prior art, the technical scheme of the invention has the following advantages:
the naphthalimide benzimidazole compound provided by the embodiment of the invention has a simple structure, has strong in-vitro antimicrobial activity, particularly shows high inhibitory activity on gram-positive bacteria such as staphylococcus aureus, methicillin-resistant staphylococcus aureus, bacillus subtilis, micrococcus luteus and the like, gram-negative bacteria such as escherichia coli, proteus bacillus, pseudomonas aeruginosa, salmonella typhi and the like, and fungi such as candida utilis, aspergillus flavus, saccharomyces cerevisiae, candida albicans and the like, can be used for preparing antibacterial and/or antifungal medicaments, provides more efficient and safe candidate medicaments for clinical antimicrobial treatment, and is beneficial to solving clinical treatment problems of increasingly severe drug resistance, stubborn pathogenic microorganisms, newly-appeared harmful microorganisms and the like.
Detailed Description
The technical solutions of the present invention will be described clearly and completely below, and it should be apparent that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In the description of the present invention, it should be noted that the terms "first" and "second" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance. In addition, the technical features involved in the different embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
Preparing a naphthalimide benzimidazole compound I-1, wherein the reaction formula is as follows:
the method comprises the following specific steps:
weighing 1.195g of 4-bromo-1, 8-naphthalimide, 10.912g of 2- (chloromethyl) -1-propyl-1H-benzimidazole III and 0.768g of potassium carbonate into a 100mL round-bottom flask, adding a small amount of DMF dissolution system, putting the round-bottom flask into an oil bath kettle, adding a reflux device, heating and stirring at 60 ℃, tracking to the end of the reaction by using thin-layer chromatography, cooling to room temperature, distilling under reduced pressure to remove an organic solvent DMF to obtain a residue, carrying out separation and purification by using silica gel column chromatography on the residue, and drying the separated product by using a mixed solution of dichloromethane and acetone with a volume ratio of 20 as an eluent to obtain a brown syrupy naphthalimide benzimidazole compound I-1.
The yield of the example is 76%; 1 H NMR(400MHz,DMSO-d 6 ):δ0.93(t,3H,J＝8.0Hz,CH 2 CH 2 CH 2 ),1.90-1.79(m,2H,CH 2 CH 2 CH 2 ),4.31-4.27(t,2H,J＝8.0Hz,CH 2 CH 2 CH 2 ),5.11(s,2H,BIM-2-C-CH 2 ),7.33-7.24(m,2H,BIM-5,6-H),7.66-7.64(m,2H,BIM-4,7-H),7.99(t,1H,J＝6.0Hz,NAPH-6-H),8.22(d,1H,J＝8.0Hz,NAPH-4-H),8.28(d,1H,J＝8.0Hz,NAPH-3-H),8.55-8.52(m,2H,NAPH-5,7-H)ppm。
wherein the starting material 2- (chloromethyl) -1-propyl-1H-benzo [ d ] imidazole III-1 is prepared by the literature method (Link Zhang, dinesh Addla, jeyakkumar Ponmani, ao Wang, dan Xie, ya-Nan Wang, shao-Lin Zhang, rong-Xia Geng, gui-Xin Cai, shuo Li, cheng-He Zhou. Discovery of membrane active benzene sulfonic acid of mesoporous ligands of DNA binding antisense Chemistry,2016,111, 160-182) by N-chloroethane reaction between o-phenylenediamine and bromopropane followed by cyclization with acid.
Example 2
The naphthalimide benzimidazole compound I-2 has the following reaction formula:
the method comprises the following specific steps:
weighing 1.204g of 4-bromo-1, 8-naphthalimide, 21.097g of 2- (chloromethyl) -1-hexyl-1H-benzimidazole III-21.097g and 0.837g of potassium carbonate into a 100mL round-bottom flask, adding a small amount of DMF dissolution system, putting the round-bottom flask into an oil bath, adding a reflux device, heating and stirring at 60 ℃, tracking to the end of the reaction by using thin-layer chromatography, cooling to room temperature, distilling under reduced pressure to remove an organic solvent DMF to obtain a residue, carrying out separation and purification by using silica gel column chromatography on the residue, and drying the separated product by using a mixed solution of dichloromethane and acetone with a volume ratio of 20 as an eluent to obtain a brown syrup-shaped naphthalimide benzimidazole compound I-2.
This example yield was 51%; 1 H NMR(400MHz,DMSO-d 6 ):δ0.73(t,3H,J＝6.0Hz,CH 2 (CH 2 ) 4 CH 3 ),1.35-1.09(m,4H,(CH 2 ) 3 (CH 2 ) 2 CH 3 ),1.83-1.75(m,4H,CH 2 (CH 2 ) 2 (CH 2 ) 2 CH 3 ),4.17-4.14(t,2H,J＝6.0Hz,CH 2 (CH 2 ) 4 CH 3 ),5.08(s,2H,BIM-2-C-CH 2 ),7.53-7.42(m,4H,BIM-4,5,6,7-H),7.97(t,1H,J＝6.0Hz,NAPH-6-H),8.20(d,1H,J＝8.0Hz,NAPH-4-H),8.25(d,1H,J＝8.0Hz,NAPH-3-H),8.53-8.50(m,2H,NAPH-5,7-H)ppm。
among them, the starting material 2- (chloromethyl) -1-hexyl-1H-benzimidazole III-2 is prepared by the literature reference method (Link Zhang, dinesh Addla, jeyakkumar Ponmani, ao Wang, dan Xie, ya-Nan Wang, shao-Lin Zhang, rong-Xia Geng, gui-Xin Cai, shuo Li, cheng-He Zhou. Discovery of membrane active benzene azo-compounds-base-bound topoisome inhibitors-European Journal of Medicinal Chemistry,2016, 111).
Comparative example 1
Referring to the literature, "study on the design and synthesis of novel benzimidazole compounds and their related antimicrobial activities", royunlei, the academic papers of China Master, the preparation method of compound III-5a was used to prepare comparative compound I-0:
example 3
The naphthalimide benzimidazole compounds prepared in examples 1-2 and comparative example 1 were tested for in vitro antimicrobial activity using a 96-well microdilution method in accordance with the Clinical Laboratory Standards (NCCLS) set by the National Committee of america in 1993, and the Minimum Inhibitory Concentrations (MICs) of these compounds against staphylococcus aureus, MASR, micrococcus luteus, bacillus subtilis, escherichia coli, pseudomonas aeruginosa, proteus, candida utilis, aspergillus flavus, saccharomyces cerevisiae, candida albicans, and candida albicans were determined.
The specific test method comprises the following steps: dissolving the compound to be tested with a small amount of dimethyl sulfoxide, adding water to dilute the solution to obtain a solution with the concentration of 1.28mg/mL, diluting the solution to 1024 mu g/mL with a culture solution, culturing the solution at 35 ℃ for 24-72 hours, placing a culture plate on an oscillator, fully and uniformly stirring the culture plate, and measuring the MIC value at the 490nm wavelength, wherein the results are shown in tables 1 and 2.
TABLE 1 antibacterial Activity of naphthalimide benzimidazole Compounds (MIC, μ g/mL)
| Compound (I) | Staphylococcus aureus | MASR | Micrococcus luteus | Bacillus subtilis | Escherichia coli | Pseudomonas aeruginosa | Proteobacteria |
| I-1 | 8 | 16 | 8 | 8 | 16 | 8 | 8 |
| I-2 | 16 | 16 | 4 | 8 | 16 | 4 | 16 |
| I-0 | 256 | 256 | 512 | 128 | 512 | 256 | 128 |
| Chloromycetin | 16 | 32 | 16 | 32 | 16 | 32 | 32 |
| Norfloxacin hydrochloride | 1 | 8 | 2 | 4 | 2 | 4 | 4 |
TABLE 2 antifungal Activity of naphthalimide benzimidazole Compounds (MIC, μ g/mL)
| Compound (I) | Candida utilis | Aspergillus flavus fungus | Saccharomyces cerevisiae | Candida albicans | Candida mycoderma |
| I-1 | 8 | 16 | 8 | 4 | 8 |
| I-2 | 16 | 8 | 16 | 8 | 4 |
| I-0 | 256 | 128 | 256 | 256 | 512 |
| Fluconazole | 8 | 256 | 16 | 8 | 8 |
From table 1, it can be seen that the naphthalimide benzimidazole compounds of the present invention all exhibit significant inhibitory action on tested bacteria, which is generally superior to chloramphenicol, and table 2 shows that the naphthalimide benzimidazole compounds of the present invention all exhibit equivalent or even better inhibitory action on fungi to be tested than that of fluconazole as a control drug. In addition, the inhibitory activity of the naphthalimide benzimidazole compound of the invention on tested bacteria and fungi is obviously better than that of the comparative compound I-0, so that the naphthalimide benzimidazole compound of the invention has good antimicrobial activity and can be used for preparing antibacterial and/or antifungal medicaments.
EXAMPLE 4 preparation of tablets
Prescription: naphthalimide benzimidazole compound I-1 g, starch 40g, microcrystalline cellulose 80g, magnesium stearate 3.0g and a proper amount of hydroxypropyl methyl cellulose E-30 (solution with the mass fraction of 40%) are prepared into 4000 tablets.
The preparation method comprises the following steps: preparing 4% hydroxypropyl methyl cellulose E-30 solution for later use; weighing starch 20g, and drying at 105 ℃ for 5 hours to obtain dry starch for later use; weighing 20g of starch, a prescribed amount of naphthalimide benzimidazole compound I-1 and microcrystalline cellulose, uniformly mixing, crushing, sieving with a 80-mesh sieve, preparing a soft material by using a 4% hydroxypropyl methyl cellulose E-30 solution by mass fraction, granulating with a 20-mesh sieve, drying at 50-60 ℃ until the moisture content is about 3%, sieving with a 20-mesh sieve, granulating, adding 20g of dry starch and a prescribed amount of magnesium stearate into the dry granules, uniformly mixing, and tabletting to obtain the finished product.
The application method and the dosage are as follows: according to the disease condition and individual difference of patients, the daily dosage is recommended to be 3-6 tablets, which is equivalent to 0.075-0.15g of naphthalimide bis-benzimidazole compound I-1/60kg of body weight per day, the medicine is taken after meals for 3 times, and a cup of water is drunk when the medicine is taken; or following the medical advice.
EXAMPLE 5 preparation of capsules
Prescription: 2-2 g of naphthalimide benzimidazole compound, 50g of modified starch (120 meshes), 30g of microcrystalline cellulose (100 meshes), 10g of low-substituted hydroxypropyl cellulose (100 meshes), 10g of talcum powder (100 meshes), 5g of sweetening agent, 1g of orange essence, a proper amount of pigment and a proper amount of water, and the granules are prepared into 4000 granules.
The preparation method comprises the following steps: micronizing and pulverizing the naphthalimide benzimidazole compound I-2 with prescription amount into superfine powder, mixing with the modified starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, talcum powder, sweetener, orange essence and pigment with prescription amount, making into soft material with water, granulating with 12-14 mesh sieve, drying at 40-50 deg.C, sieving, grading, and making into empty capsule.
The application method and the dosage are as follows: according to the illness condition and individual difference of patients, the daily dosage is recommended to be 3-6 granules, which is equivalent to 0.075-0.15g of naphthalimide benzimidazole compound I-2/60kg of body weight per day, the medicine is taken after meals for 3 times, and a cup of water is drunk when the medicine is taken; or following the medical advice.
EXAMPLE 6 preparation of Aerosol
Prescription: naphthalimide benzimidazole compound I-1.5g, span20 3g, talcum powder (100 meshes) 4g and trichlorofluoromethane are added to a proper amount.
The preparation method comprises the following steps: respectively placing the naphthalimide benzimidazole compound I-1, the Span20 and the talcum powder in a vacuum drying oven for drying for a plurality of hours, placing in a drier for cooling to room temperature, crushing into micro powder by using an airflow crusher, uniformly mixing according to the prescription amount, filling into a closed container, and adding trichlorofluoromethane to a specified amount.
The application method and the dosage are as follows: the medicine is recommended to be used 3-4 times per day according to the disease condition and individual difference of patients.
EXAMPLE 7 preparation of the ointments
Prescription: 2g of naphthalimide benzimidazole compound I-2 g, 12g of stearic acid, 3g of vaseline, 3g of monoglyceride, 0.5g of ethylparaben, 60mL of distilled water, 1g of borax, 0.5g of potassium hydroxide, 0.3g of potassium sorbate, 0.5g of glycerol and 0.5g of liquid paraffin, and the total weight is 85g.
The preparation method comprises the following steps: taking stearic acid, vaseline, monoglyceride and ethylparaben according to the prescription amount, heating to melt, sieving with a 100-mesh sieve, and keeping the temperature at 80 ℃ to obtain an oil phase for later use; taking distilled water, borax, potassium hydroxide, potassium sorbate, glycerol and liquid paraffin according to the prescription amount, heating and boiling to obtain a water phase; cooling the water phase to 85 ℃, adding the oil phase under continuous stirring, emulsifying, adding the formula amount of the naphthalimide benzimidazole compound I-2, cooling and stirring to obtain the naphthalimide benzimidazole compound emulsion.
The application method and the dosage are as follows: applied to the affected part, and rubbed repeatedly until the skin is hot, 2 times daily.
By applying the tablets, capsules, aerosols and ointments prepared in examples 4-7 to affected parts, the wound infection symptoms of patients can be obviously relieved, which shows that the naphthalimide benzimidazole compounds with the general formula I can obviously inhibit bacterial and/or fungal infection and accelerate wound healing after being applied to the preparation of antimicrobial drugs, so that more efficient and safe candidate drugs are provided for clinical antimicrobial therapy, and the preparation method is helpful for solving clinical treatment problems such as increasingly severe drug resistance, stubborn pathogenic microorganisms, newly-appeared harmful microorganisms and the like.
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.
Claims (10)
1. A naphthalimide benzimidazole compound having a structure represented by formula (I):
wherein n is an integer of 1 to 5.
2. The naphthalimide benzimidazole compound of claim 1, wherein n is 2 or 5.
3. A process for preparing the naphthalimide benzimidazole compound of claim 1 or 2, wherein:
in an organic solvent, in the presence of alkali, 4-bromine-1, 8-naphthalimide shown in a formula (V) reacts with a compound shown in a formula (III) to prepare a naphthalimide benzimidazole compound shown in a formula (I); the reaction equation is as follows:
4. the preparation method according to claim 3, wherein the organic solvent is one or more of N, N-dimethylformamide, dimethyl sulfoxide, benzene and toluene.
5. The preparation method of claim 3, wherein the base is one or more of potassium carbonate, sodium hydroxide and potassium hydroxide.
6. The method according to claim 3, wherein the reaction temperature is 60 to 90 ℃.
7. The production method according to any one of claims 3 to 6, characterized in that the organic solvent is removed after the reaction is completed, and the residue is separated by column chromatography and dried to obtain the naphthalimide benzimidazole compound represented by the formula (I).
8. The preparation method according to claim 7, wherein the column chromatography is silica gel column chromatography, and the eluent is a mixture of dichloromethane and acetone with a volume ratio of 20.
9. Use of the naphthalimide benzimidazole compounds according to claim 1 or 2 for the preparation of antibacterial and/or antifungal medicaments.
10. Use according to claim 9, characterized in that:
the bacteria are any one or more of staphylococcus aureus, methicillin-resistant staphylococcus aureus, micrococcus luteus, bacillus subtilis, escherichia coli, pseudomonas aeruginosa and proteus vulgaris; and/or
The fungi is one or more of candida utilis, aspergillus flavus, saccharomyces cerevisiae, candida albicans and candida albicans; and/or
The medicine is any one of tablet, capsule, aerosol and ointment.
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