CN115057819A - Fluorine benzyl benzimidazole quaternary ammonium salt analogue, synthetic method and application thereof - Google Patents
Fluorine benzyl benzimidazole quaternary ammonium salt analogue, synthetic method and application thereof Download PDFInfo
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- 238000010189 synthetic method Methods 0.000 title claims description 3
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- 238000002360 preparation method Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention relates to a fluorobenzyl benzimidazole quaternary ammonium salt analogue, a synthesis method and application thereof. The structure of the compound is shown as a formula I, wherein, the fluorobenzyl is 3-fluorobenzyl or 4-fluorobenzyl; the adopted synthesis method has the advantages of easily obtained raw materials, mild conditions, simplicity, convenience, high efficiency and high product yield; the compound has certain inhibiting effect on Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis, and can be used as antibacterial lead compound for preparing antibacterial agent.
Description
Technical Field
The invention relates to a fluorobenzyl benzimidazole quaternary ammonium salt analogue, a synthesis method and application thereof, belonging to the technical field of antibacterial drugs.
Background
Currently, there are many diseases in countries around the world that are caused by bacterial infections, and the total number of people dying from infections with various bacteria each year exceeds ten million people. The advent and use of antibiotics has led to the desired effect in the treatment of many bacterial infectious diseases. However, due to the large use of antibiotics, bacteria develop resistance, resulting in a reduction in the sensitivity of some bacteria to antibiotics, and further, the lack of viable antibiotic therapy for a variety of bacterial infections. Meanwhile, under the influence of a plurality of factors, the development of novel effective antibiotics becomes harder and harder, and the development speed of the antibiotics is in a gradually decreasing trend, so that the research and development speed of the antibiotics is difficult to keep up with the speed of the bacteria for generating drug resistance. There is a continuing effort by researchers to develop new antibacterial drugs.
Benzimidazoles are a class of heteroaromatic substances having two nitrogen atoms. The structure can not only generate hydrogen bonds with receptors and proteins in organisms, but also coordinate with metal ions and generate hydrophobic effect. Benzimidazole derivatives have various biological activities, are widely used in the pharmaceutical and chemical fields, and can be used as core structural units for designing anti-cancer, antihypertensive, antibacterial, antiviral and other drugs. The study of benzimidazoles has been a focus in the fields of chemistry and medicine. The inventors' topic group have studied in this field and have achieved some results.
The research and development process of antibacterial drugs involves a plurality of methods for measuring in vitro antibacterial activity, and the methods are commonly used such as bacteriostatic ring test, minimum inhibitory concentration test, test tube dual-gradient dilution test and the like. The bacteriostatic ring test (i.e. agar diffusion method) is mainly a qualitative test, and comprises a plate punching method, a filter paper sheet method, an oxford cup method and the like. The Minimum Inhibitory Concentration (MIC) determination test, which is mainly a quantitative test, can be classified into an agar gradient dilution method (suitable for insoluble bacteriostats, which can be performed in a test tube or a plate) and a nutrient broth gradient dilution method (suitable for soluble bacteriostats, which can be performed in a test tube).
Wherein, the filter paper sheet method is divided into a filter paper sheet liquid medicine soaking method and a filter paper sheet quantitative medicine adding method.
(1) Filter paper sheet liquid medicine soaking method
Sterile gloves are worn by both hands, and after the gloves are sterilized by alcohol, sterile filter paper with sterile tweezers is placed into a sterile culture dish containing a medicine solution on a super-clean workbench for soaking for a period of time. Clamping the medicated paper with sterile forceps in sterile operation, wiping off the excessive medicinal liquid on the edge of the inner culture dish, sticking on the surface of the flat plate culture medium containing bacteria, and lightly pressing to make the tablet tightly contact with the culture medium. The filter paper sheets were 15mm from the edge of the petri dish, and 5 sheets of the filter paper soaked in sterile physiological saline were uniformly placed in each petri dish as a control. Three replicates of each tablet were run using pour-on and coating methods. After the experiment, the petri dish was placed in an incubator at 37 ℃ for 24 h. And finally, observing whether the periphery of the medicated paper has an inhibition zone, measuring the inhibition diameter (including the diameter of the paper) of the medicated paper in a cross method, and recording the inhibition diameter in millimeters.
(2) Quantitative liquid-adding method for filter paper sheet
The filter paper sheet was 15mm from the edge of the dish. 5 pieces of filter paper were placed evenly on each dish. Taking 10 μ l of the medicinal liquid with a micro-pipette, adding the medicinal liquid again after the medicinal liquid is absorbed, adding onto a filter paper for several times, and using sterilized normal saline as reference. 3 parallel experiments were performed for each tablet pour-on and coating method. After completion, the plate was incubated for 24h at 37 ℃ in a constant temperature incubator. And observing, measuring and recording.
Disclosure of Invention
The invention aims to: aiming at the problems in the prior art, the fluorine benzyl benzimidazole quaternary ammonium salt analogue has an antibacterial effect. Meanwhile, the synthesis method and the application of the compound are provided.
The technical scheme for solving the technical problems of the invention is as follows:
a fluorobenzyl benzimidazole quaternary ammonium salt analogue is characterized in that the structure is shown as formula I,
wherein, the fluorobenzyl is 3-fluorobenzyl or 4-fluorobenzyl.
Preferably, the structure of the fluorobenzyl benzimidazole quaternary ammonium salt analogue is shown as a formula II,
namely 1-benzyl-2- (3-fluorobenzyl) -1-indazole-2-bromo salt.
Preferably, the structure of the fluorobenzyl benzimidazole quaternary ammonium salt analogue is shown as a formula III,
namely 1-benzyl-2- (4-fluorobenzyl) -1-indazole-2-bromo salt.
The invention also proposes:
a synthetic method of a fluorobenzyl benzimidazole quaternary ammonium salt analogue is characterized by comprising the following steps:
dissolving benzimidazole in an organic solvent, adding NaH under ice bath, stirring, and adding benzyl bromide for reaction; after the reaction is finished, adding ice water to quench the reaction, and purifying by column chromatography to obtain a compound shown in the formula IV;
secondly, dissolving the compound shown in the formula IV in an organic solvent, adding fluorobenzyl bromide, and stirring for reaction at an ambient temperature; after the reaction is finished, purifying by column chromatography to obtain a compound shown in the formula I, namely a finished product;
wherein the fluorobenzyl bromide is 3-fluorobenzyl bromide or 4-fluorobenzyl bromide.
Preferably, in the first step, the molar ratio of benzimidazole, NaH and benzyl bromide is 1 ± 0.1: 2 ± 0.1: 1 + -0.1.
Preferably, in the second step, the molar ratio of the compound of formula IV to fluorobenzyl bromide is 1 ± 0.1: 1 + -0.1.
Preferably, the organic solvent in the first step is DMF; the organic solvent in the second step is acetonitrile; the first step and the second step respectively adopt thin layer chromatography to detect the reaction process, and respectively adopt silica gel column chromatography to purify.
Preferably, when the fluorobenzyl bromide is 3-fluorobenzyl bromide, the structure of the obtained finished product is shown as a formula II,
namely 1-benzyl-2- (3-fluorobenzyl) -1-indazole-2-bromo salt.
Preferably, when the fluorobenzyl bromide is 4-fluorobenzyl bromide, the structure of the obtained finished product is shown as a formula III,
namely 1-benzyl-2- (4-fluorobenzyl) -1-indazole-2-bromo salt.
The invention also proposes:
use of a fluorobenzyl benzimidazole quaternary ammonium salt analogue as hereinbefore described for the preparation of an antibacterial compound or an antibacterial agent.
The synthesis method of the invention introduces fluorobenzyl by performing quaternization structure modification on benzimidazole to obtain the amphiphilic quaternary ammonium salt analogue, the raw materials are easy to obtain, the conditions are mild, the method is simple and efficient, and the product yield is up to more than 90%; the obtained compound has certain inhibiting effect on Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis, and can be used as antibacterial lead compound for preparing antibacterial agent, thereby enriching candidate antibacterial drugs.
Drawings
FIG. 1 is a drawing of the product of example 1 of the invention 1 H NMR spectrum.
FIG. 2 is a HRMS spectrum of the product of example 1 of the present invention.
Fig. 3 to 6 are graphs showing bacteriostatic results of example 2 of the present invention.
FIG. 7 is a graph of the product of example 3 of the present invention 1 H NMR spectrum.
FIG. 8 is a HRMS spectrum of the product of example 3 of the present invention.
Fig. 9 to 12 are graphs showing bacteriostatic results of example 4 of the present invention.
FIGS. 13 to 14 are graphs showing the results of example 5 of the present invention.
Detailed Description
The invention is described in further detail below with reference to embodiments and with reference to the drawings. The invention is not limited to the examples given.
Example 1
This example is a preparation and characterization of a compound of formula II.
The specific preparation process of this example is:
1.2g of benzimidazole was dissolved in DMF, 0.48g of NaH was added under ice-bath, stirred for 20min, and 1.8g of benzyl bromide was added. The experimental reaction progress was checked by TLC. And (4) adding ice water to quench the reaction after the reaction is finished, and purifying by silica gel column chromatography to obtain a target product Q.
Q200 mg was dissolved in acetonitrile, 190mg of 3-fluorobenzyl bromide was added and stirred at room temperature, and the progress of the reaction was checked by TLC. After the reaction is finished, purifying by using column chromatography to obtain the target product, namely the compound (Q-2a) in the formula II.
Of the resulting product 1 The H NMR spectrum is shown in FIG. 1, and the HRMS spectrum is shown in FIG. 2.
1 H NMR(CD3OD)δ:7.90–7.86(m,2H),7.65–7.63(m,2H),7.58–7.54(m,2H),7.50–7.38(m,6H),7.18(t,J＝10Hz,2H),5.78(s,2H),5.77(s,2H)。
HRMS(ESI)m/z calcd for C21H18FN2[M-Br]+317.1449,found 377.1434。
Example 2
This example is to use the compound of formula II obtained in example 1 as an antibacterial agent to study its bacteriostatic effect.
(I) Experimental method
The bacteria used in the experiment are all preserved in the laboratory of the Pingshan institute, and are respectively as follows: gram-positive bacteria (staphylococcus aureus, No. ATCC 25923), bacillus subtilis, No. ATCC 6633). Gram-negative bacteria (pseudomonas aeruginosa, No. ATCC 27853), escherichia coli (escherichia coli), No. ATCC 25922).
Preparing an antibacterial agent: placing the antibacterial drug into a sterile operation table, starting ultraviolet light to sterilize the sterile operation table for 30 minutes, weighing 0.01024mg of the antibacterial drug, placing the weighed antibacterial drug into a 2ml centrifuge tube, transferring 100 mul of DMSO into the centrifuge tube by using a 1000 mul of pipette, shaking the centrifuge tube to completely dissolve the drug, wherein the drug concentration is 102.4mg/ml, marking the centrifuge tube as No. 1, then respectively marking the 4 centrifuge tubes as No. 2, No. 3, No. 4 and No. 5, sucking 50 mul of antibacterial liquid from the No. 1 centrifuge tube by using a double dilution method, placing the antibacterial liquid into the No. 2 centrifuge tube, sucking 50 mul of DMSO by using a 1000 mul of pipette, placing the antibacterial liquid into the No. 2 centrifuge tube, and fully dissolving the antibacterial liquid. And preparing the antibacterial solution with the concentration of 102.4mg/ml, 51.2mg/ml, 25.6mg/ml and 12.8mg/ml by analogy, sealing and then placing in a refrigerator for freezing and storing for later use.
Preparing a bacterial liquid culture medium: firstly, weighing 20g of the nutrient paste, placing the nutrient paste into a beaker, dissolving the nutrient paste by using a certain amount of distilled water, transferring the nutrient paste into a 100ml conical flask, taking a proper amount of distilled water, rotationally washing the beaker for three times, transferring the nutrient paste into the 100ml conical flask, fully dissolving the nutrient paste by using the distilled water, and finally fixing the volume to 100ml by using the distilled water.
Preparing a bacterial solid culture medium: the preparation in the previous stage is the same as the preparation method of a liquid culture medium of bacteria, and then 1.5-2.0 g of agar powder is added into every 100ml of the liquid culture medium, fully and uniformly mixed, and transferred into a conical flask. And (3) sealing the liquid culture medium and the solid culture medium of the bacteria and sticking high-temperature sterilization indicating label paper. Placing into a high-temperature sterilizing pot at 121 ℃, and sterilizing for 30 minutes.
Activation of strains: and (5) opening an ultraviolet lamp of an ultraviolet sterilization operating table, and sterilizing for 20 min. Taking out the Escherichia coli from the refrigerator storage chamber, dissolving, mixing, and placing on a sterilized ultraviolet sterilization operating table. And (3) sucking 5 mul of escherichia coli liquid by using a pipette with the range not exceeding 20 mul, putting the escherichia coli liquid into the prepared 30ml of liquid culture medium, and sealing the liquid culture medium after the operation is finished. Placing the mixture in a constant-temperature incubator at 37 ℃ and 150r/min for shake culture for 12-20 h. Multiple observations yielded a standard E.coli suspension. The preparation of the suspension of the staphylococcus aureus, the pseudomonas aeruginosa and the bacillus subtilis is the same as that of the suspension.
And (3) measuring the concentration of the bacterial liquid: and pouring the sterilized agar-added liquid culture medium into a culture dish by about 15-20 ml in an ultraviolet sterilization operation platform until the liquid culture medium is solidified, pouring the liquid culture medium to prevent the culture medium from being polluted by water vapor dripping, and standing for 15-20 min. The E.coli suspension obtained was diluted in a series of 10-fold gradients with EP tubes and labeled. 10. mu.l of the inoculum from each EP tube was pipetted into solid medium using a pipette gun, spread evenly using a spreader and labeled. Placing the mixture in a constant-temperature incubator at 37 ℃ for culturing for 16-20 h. Three parallel experiments are carried out, the average number is taken, and the concentration of the bacterial liquid is calculated. The concentration of the selected bacterial liquid is 10 8 CFU/ml of Escherichia coli solution. The concentration selection steps of the staphylococcus aureus, the pseudomonas aeruginosa and the bacillus subtilis are the same as the steps.
Susceptibility tablet test (MBC): preparing or purchasing qualitative filter paper special for a laboratory, and beating the prepared qualitative filter paper into small circular paper sheets with the diameter of 6mm by using a special punching tool. And carefully selecting after punching, and reserving the circular paper sheets with regular shapes. The round filter paper pieces are put into a glass empty bottle prepared in advance, and the bottle mouth is wrapped and sealed by special sealing paper. Placing the glass bottle filled with the paper sheets into an autoclave, sterilizing at 121 deg.C for 30min, taking out after high temperature sterilization, and oven drying at 37 deg.C to completely dry. And taking out the prepared antibacterial drugs with different concentrations. Sucking 5 mul with a pipette and beating on each sterile paper sheet, then placing in a 37 ℃ incubator to dry for 24h, placing into each sterile glass bottle respectively with a sterile forceps, and marking the drug concentration, the commodity name and the configuration time on each glass bottle with label paper. Drying, sealing, and storing in dry and cool place. And measuring the size of the bacteriostatic circle by using a ruler or a vernier caliper. The diameter of the inhibition zone is more than 7mm, and the inhibition zone has an inhibition effect; the diameter of the inhibition zone is less than or equal to 7mm, and the inhibition zone is judged to have no inhibition effect.
(II) results of experiment
The results of the bacteriostatic experiments for E.coli are shown in FIG. 3, and the data is shown in the following table, which shows: the antibacterial rate to the escherichia coli is 48.72% when the drug loading rate is 256 mug, the antibacterial rate to the escherichia coli is 41.75% when the drug loading rate is 128 mug, and no antibacterial zone appears and no antibacterial rate exists when the drug loading rate is less than 64 mug.
Note: in the bacteriostasis experiment, when the bacteriostasis rate is calculated, the data that the diameter of the bacteriostasis zone is less than or equal to 7 are discarded. The same applies below.
The results of the bacteriostatic experiments for bacillus subtilis are shown in fig. 4, and the data is shown in the following table, which shows that: when the drug loading rate is 256 mug, the inhibition rate to the bacillus subtilis is 51.22%, when the drug loading rate is 128 mug, the inhibition rate to the bacillus subtilis is 45.45%, when the drug loading rate is 64 mug, the inhibition rate to the bacillus subtilis is 41.75%, when the drug loading rate is 32 mug, the inhibition rate to the bacillus subtilis is 14.29%, and when the drug loading rate is less than 16 mug, no inhibition zone appears, and no inhibition rate exists.
The results of the bacteriostatic experiments for Staphylococcus aureus are shown in FIG. 5, and the data is shown in the following table, which shows: the antibacterial rate to staphylococcus aureus is 52.64% when the drug loading rate is 256 mug, the antibacterial rate to staphylococcus aureus is 50% when the drug loading rate is 128 mug, the antibacterial rate to staphylococcus aureus is 27.97% when the drug loading rate is 64 mug, the antibacterial rate to bacillus subtilis is 21.77% when the drug loading rate is 32 mug, and the average diameter of the antibacterial ring is less than 7mm when the drug loading rate is 16 mug, and the antibacterial rate is regarded as no antibacterial rate.
The results of the pseudomonas aeruginosa bacteriostasis experiment are shown in fig. 6, the data is shown in the following table, and the results show that: when the drug loading rate is 256 mug, the bacteriostasis rate to the pseudomonas aeruginosa is 45.45 percent, when the drug loading rate is 128 mug, the bacteriostasis rate to the pseudomonas aeruginosa is 33.33 percent, when the drug loading rate is 64 mug, the average diameter of the bacteriostasis zone is less than 7mm, and the bacteriostasis rate is considered to be no bacteriostasis rate.
In conclusion, the compound of formula II obtained in example 1 has certain inhibitory effect on Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Bacillus subtilis, and has high bacteriostatic activity on Staphylococcus aureus.
Example 3
This example is a preparation and characterization of a compound of formula III.
The specific preparation process of this example is:
1.2g of benzimidazole was dissolved in DMF, 0.48g of NaH was added under ice-bath, stirred for 20min, and 1.8g of benzyl bromide was added. The progress of the reaction was checked by TLC. And (4) adding ice water to quench the reaction after the reaction is finished, and purifying by silica gel column chromatography to obtain a target product Q.
Q200 mg was dissolved in acetonitrile, 190mg of 3-fluorobenzyl bromide was added and stirred at room temperature, and the progress of the reaction was checked by TLC. After the reaction is finished, purifying by using column chromatography to obtain the target product, namely the compound (Q-2a) in the formula II.
Of the resulting product 1 The H NMR spectrum is shown in FIG. 7, and the HRMS spectrum is shown in FIG. 8.
1 H NMR (CD3OD)δ:7.93–7.86(m,2H),7.66–7.62(m,3H),7.51–7.38(m,7H),7.28(t,J＝10Hz,1H),7.22(t,J＝10Hz,1H),5.87(s,2H),5.79(s,2H)。
HRMS(ESI)m/z calcd for C21H18FN2[M-Br]+317.1449,found 377.1435。
Example 4
This example is to use the compound of formula III obtained in example 3 as an antibacterial agent to study its bacteriostatic effect.
(I) Experimental method
The bacteria used were the same as in example 2.
The experimental procedure used is essentially the same as in example 2, with the following differences or differences:
preparing an antibacterial agent: the antibacterial drugs are prepared in a sterile operating platform, ultraviolet light of the sterile operating platform is turned on for sterilization for 30 minutes, 0.0128g of antibacterial drugs are weighed by an analysis scale, the antibacterial drugs are poured into a 2ml centrifuge tube, 1ml of DMSO is transferred into the centrifuge tube by a 1000 mul pipette gun, the centrifuge tube is shaken to enable the drugs to be completely dissolved, the label of the centrifuge tube is No. 1 to prepare 12800 mu g/ml, then 4 centrifuge tubes are respectively labeled No. 2, No. 4 and No. 5, then 500 mu l of antibacterial drugs are absorbed into the No. 2 centrifuge tube from the No. 1 centrifuge tube by a twofold dilution method, 500ml of DMSO is absorbed by the 1000 mu l pipette gun to be fully dissolved, the antibacterial drugs with different concentrations are prepared by the analogy, the concentrations are 6400 mu g/ml, 3200 mu g/ml, 1600 mu g/ml and 800 mu g/ml respectively, and the antibacterial drugs are put into a refrigerator to be frozen and stored.
In the susceptibility test (MBC): the diameter of each inhibition zone is measured by using a ruler, the average value is obtained by repeatedly measuring for three times, the size of the inhibition zone is represented by the diameter of the inhibition zone, and the inhibition rate is calculated, wherein the inhibition rate is (the diameter of the inhibition zone-the diameter of the drug sensitive tablet)/the diameter of the inhibition zone multiplied by 100%.
(II) results of the experiment
The results of the bacteriostatic experiments on E.coli are shown in FIG. 9, and the data is shown in the following table: the drug sensitive tablet has the drug content of 128 mu g/tablet, the diameter of the inhibition zone is 10.5mm, the inhibition rate is 42.86%, the diameter of the inhibition zone is 8.5mm when the drug content is 64 mu g/tablet, the inhibition rate is 29.41%, the drug content of the drug sensitive tablet is less than or equal to 16 mu g/tablet, the inhibition zone does not appear, and the inhibition rate is not high.
The results of the bacteriostatic experiments of bacillus subtilis are shown in fig. 10, and the data is shown in the following table, which shows that: when the drug sensitive tablet contains 128 mug/tablet of drug, the diameter of the inhibition zone is 7.67mm, the inhibition rate is 21.78%, the drug content is 64 mug/tablet, the diameter of the inhibition zone is 7.33mm, the inhibition rate is 18.14%, when the drug content of the drug sensitive tablet is less than or equal to 32 mug/tablet, the inhibition zone does not appear, and the inhibition rate is not existed.
The results of the staphylococcus aureus bacteriostasis experiment are shown in fig. 11, and the data is shown in the following table, which shows: when the drug sensitive tablet contains 128 mug/tablet of drug, the diameter of the inhibition zone is 9mm, the inhibition rate is 33.33%, when the drug content is 64 mug/tablet, the diameter of the inhibition zone is 7.33mm, the inhibition rate is 18.14%, when the drug content is 32 mug/tablet, the diameter of the inhibition zone is 6.33mm, the inhibition rate is 5.21%, when the drug content is less than or equal to 16 mug/tablet, the inhibition zone does not appear, and the inhibition rate is not existed.
The results of the pseudomonas aeruginosa bacteriostasis experiment are shown in fig. 12, the data is shown in the following table, and the results show that: when the drug sensitive tablet contains 128 mug of drug, the diameter of the bacteriostatic circle is 13.3mm, the bacteriostatic rate is 54.89%, when the drug content is 64 mug, the diameter of the bacteriostatic circle is 9.0mm, the bacteriostatic rate is 33.33%, the drug content is 32 mug/tablet, at the moment, the diameter of the bacteriostatic circle is 7.7mm, the bacteriostatic rate is 22.08%, when the drug content is less than or equal to 8 mug/tablet, the bacteriostatic circle does not appear, and the bacteriostatic rate is not existed.
In conclusion, the compound of the formula III obtained in example 3 has certain inhibitory effect on escherichia coli, pseudomonas aeruginosa, staphylococcus aureus and bacillus subtilis, and has higher bacteriostatic activity on pseudomonas aeruginosa.
Example 5
This example is an animal cytotoxicity test conducted on the compounds obtained in examples 1 and 3.
The cytotoxic effect of each compound on mouse macrophage RAW264.7 was detected by thiazole blue colorimetry (MTT). Digesting the adherent macrophages by pancreatin, mixing the digested macrophages uniformly, sucking 90 mu L (about 8000) of cell suspension by a row gun, adding the cell suspension into a 96-well plate, and culturing for 4h until the cells are adherent. Different concentrations (16-256 μ g/mL) of compound were added, 6 replicates per group, PBS as a control, and incubation was continued for 24h, then the medium was discarded, 0.5mg/mL MTT was added, and the incubation in the incubator was continued for 4h, the medium was discarded and 100 μ L of DMSO was added to solubilize the bluish purple formazan in the cells, and the absorbance of the solution was measured at 570nm with a microplate reader.
The results are shown in FIGS. 13 to 14, wherein FIG. 13 is the experimental result of the compound of formula II obtained in example 1, and FIG. 14 is the experimental result of the compound of formula III obtained in example 3. The results show that: the compounds obtained in examples 1 and 3 are both free from animal cytotoxicity.
In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the claims of the present invention.
Claims (10)
1. A fluorobenzyl benzimidazole quaternary ammonium salt analogue is characterized in that the structure is shown as formula I,
wherein, the fluorobenzyl is 3-fluorobenzyl or 4-fluorobenzyl.
2. The fluorobenzyl benzimidazole quaternary ammonium salt analogue as claimed in claim 1, wherein the fluorobenzyl benzimidazole quaternary ammonium salt analogue has a structure shown in formula II,
namely 1-benzyl-2- (3-fluorobenzyl) -1-indazole-2-bromo salt.
3. The fluorobenzyl benzimidazole quaternary ammonium salt analogue as claimed in claim 1, wherein the fluorobenzyl benzimidazole quaternary ammonium salt analogue has a structure shown in formula III,
namely 1-benzyl-2- (4-fluorobenzyl) -1-indazole-2-bromo salt.
4. A synthetic method of a fluorobenzyl benzimidazole quaternary ammonium salt analogue is characterized by comprising the following steps:
dissolving benzimidazole in an organic solvent, adding NaH under ice bath, stirring, and adding benzyl bromide for reaction; after the reaction is finished, adding ice water to quench the reaction, and purifying by column chromatography to obtain a compound shown in the formula IV;
secondly, dissolving the compound shown in the formula IV in an organic solvent, adding fluorobenzyl bromide, and stirring for reaction at an ambient temperature; after the reaction is finished, purifying by column chromatography to obtain a compound shown in the formula I, namely a finished product;
wherein the fluorobenzyl bromide is 3-fluorobenzyl bromide or 4-fluorobenzyl bromide.
5. The method for synthesizing fluorobenzyl benzimidazole quaternary ammonium salt analogues according to claim 4, wherein in the first step, the molar ratio of benzimidazole to NaH to benzyl bromide is 1 +/-0.1: 2 ± 0.1: 1 + -0.1.
6. The method for synthesizing fluorobenzyl benzimidazole quaternary ammonium salt analogues according to claim 4, wherein in the second step, the molar ratio of the compound shown in formula IV to fluorobenzyl bromide is 1 +/-0.1: 1 plus or minus 0.1.
7. The method for synthesizing fluorobenzyl benzimidazole quaternary ammonium salt analogues according to claim 4, wherein the organic solvent in the first step is DMF; the organic solvent in the second step is acetonitrile; the first step and the second step respectively adopt thin layer chromatography to detect the reaction process, and respectively adopt silica gel column chromatography to purify.
8. The method for synthesizing fluorobenzyl benzimidazole quaternary ammonium salt analogues according to claim 4, wherein when the fluorobenzyl bromide is 3-fluorobenzyl bromide, the structure of the obtained finished product is shown as formula II,
namely 1-benzyl-2- (3-fluorobenzyl) -1-indazole-2-bromo salt.
9. The method for synthesizing fluorobenzyl benzimidazole quaternary ammonium salt analogues according to claim 4, wherein when the fluorobenzyl bromide is 4-fluorobenzyl bromide, the structure of the obtained finished product is shown as formula III,
namely 1-benzyl-2- (4-fluorobenzyl) -1-indazole-2-bromo salt.
10. Use of fluorobenzyl benzimidazole quaternary ammonium salt analogues according to any one of claims 1 to 3 for the preparation of antibacterial compounds or agents.
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| CN105218537A (en) * | 2015-10-14 | 2016-01-06 | 西南大学 | Berberine benzimidazoles compound or its pharmacologically acceptable salt and its preparation method and application |
| CN111233839A (en) * | 2020-02-26 | 2020-06-05 | 陕西科技大学 | (E) 1-acyl-2- (2- (9-alkyl) carbazole-3-) vinyl-benzimidazole and preparation method thereof |
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