CN112480090A - Compound containing indoline and 5-aryl furan skeleton and preparation and application thereof - Google Patents
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Abstract
本发明公开了一种含有吲哚啉和5‑芳基呋喃骨架的化合物及其制备与应用，所述含有吲哚啉和5‑芳基呋喃骨架的化合物是在氯化亚砜、二氯甲烷和碱的作用下，由式Ⅱ化合物与吲哚啉通过两步反应而得。该类化合物结构创新，制备方法简便，具有良好的生物活性。所述含有吲哚啉和5‑芳基呋喃骨架的化合物具有兼顾铜绿假单胞菌的正常生长和有效抑制铜绿假单胞菌生物被膜形成的重要作用，对于解决铜绿假单胞等细菌感染及耐药性问题具有一定的应用前景。The invention discloses a compound containing indoline and 5-arylfuran skeleton and its preparation and application. The compound containing indoline and 5-arylfuran skeleton is prepared in thionyl chloride, dichloromethane Under the action of and base, it can be obtained by two-step reaction between the compound of formula II and indoline. The compound has innovative structure, simple preparation method and good biological activity. The compound containing indoline and 5-arylfuran skeleton has the important role of taking into account the normal growth of Pseudomonas aeruginosa and effectively inhibiting the formation of Pseudomonas aeruginosa biofilm, and is useful for solving bacterial infections such as Pseudomonas aeruginosa and other diseases. The problem of drug resistance has certain application prospects.
Description
(I) technical field
The invention relates to a compound containing indoline and a 5-aryl furan skeleton, a preparation method thereof and application thereof in inhibiting formation of a pseudomonas aeruginosa biofilm, belonging to the technical field of fine organic chemistry and biomedicine.
(II) background of the invention
The harm of microorganisms, infection and drug resistance are one of the major problems facing the development of human health, and the solution of the problems of bacterial infection and drug resistance thereof becomes a hotspot and difficulty of the current research. The traditional antibiotic method is sterilization or bacteriostasis, and the drug resistance of bacteria is promoted to a certain extent by the huge survival pressure (eur.j.med.chem, 2019, 161, 154-178.). Recent studies have shown that Bacterial Biofilms (BBF) are one of the important mechanisms for the development of bacterial resistance and are also the major cause of a number of iatrogenic infections.
The biofilm of pseudomonas aeruginosa is one of the important mechanisms of bacterial resistance formation, and it is composed of Extracellular Polymeric Substrates (EPS) secreted by itself. The drug resistance of the bacteria in the form of the biofilm coating is 100-1000 times stronger than that of the bacteria in the form of plankton (CurrOpinPharmacol,2013,13 (5): 699-706.). The existence of the biofilm enhances the adaptability of bacteria in various complex environments, improves the cell tolerance, and enables the bacteria to have stronger pathogenicity to cause bacterial infection. Moreover, the biofilm bacteria have strong resistance to antibiotics, so that the antibacterial action of the antibiotics is obviously reduced after the biofilm is formed, the antibacterial concentration of the drugs is obviously improved, the formation of bacterial drug resistance is promoted to a certain extent, and great challenge is brought to the solution of the bacterial drug resistance. Therefore, inhibition of biofilm formation is one of the potential strategies to address the problem of bacterial resistance and to control bacterial infections. Research and development of a target lead compound for inhibiting biofilm formation have important research significance for solving the problems of bacterial infection, drug resistance and the like.
Disclosure of the invention
The invention aims to provide a compound containing indoline and a 5-aryl furan skeleton, a preparation method thereof and application thereof in inhibiting formation of a pseudomonas aeruginosa biofilm, and the compound has a certain application prospect in the aspect of combined administration with antibiotics.
The technical scheme adopted by the invention is as follows:
in a first aspect, the present invention provides a compound having an indoline and 5-arylfuran skeleton represented by formula (I), having the following structural formula:
in the formula (I), R is one or more (preferably one), and the R is hydrogen, halogen, nitro, C1-C4 alkyl or C1-C4 alkoxy.
Further, it is preferable that R is 4-methoxy group, 2-chloro group, 3-chloro group, 4-bromo group, 2-fluoro group, 3-fluoro group, 4-fluoro group, 2, 4-difluoro group, 2, 6-difluoro group, 2-nitro group, 3-nitro group or 4-nitro group.
Further, it is preferable that the compound represented by the formula (I) is one of the following:
in a second aspect, the present invention provides a process for the preparation of a compound of formula (I), said process having the reaction formula:
r in the formula (II) and the formula (III) is the same as the formula (I);
the preparation method comprises the following steps:
(1) under the protection of nitrogen, the compound shown as the formula (II) is mixed with thionyl chloride (SOCl)2) And dichloromethane, carrying out reflux reaction at 40-45 ℃, cooling the reaction to room temperature completely, and then removing the reaction solvent by using a rotary evaporator for reduced pressure concentration to obtain the compound shown in the formula (III), wherein the compound can be directly used for the next reaction without purification;
(2) reacting the compound shown in the formula (III) with indoline and alkali at 25-30 ℃ under the action of a diluent dichloromethane, removing dichloromethane by rotary evaporation after the reaction is completed, adding water to quench the reaction, and using a water phaseExtracting with ethyl acetate (10 mL. times.3), mixing ethyl acetate phases, drying with anhydrous sodium sulfate, concentrating until no liquid is evaporated, performing silica gel column chromatography with petroleum ether/ethyl acetate (volume ratio of 3: 1) as eluent, and collecting RfA component with a value of 0.2-0.3 to obtain a compound containing indoline and 5-aryl furan skeleton shown in formula (I); the base is selected from one of triethylamine, pyridine and N-methylmorpholine, and triethylamine is most preferable.
Wherein, the compound shown in the formula (II) in the step (1) and SOCl2The amount ratio of (A) to (B) is 1:10 to 15, more preferably 1: 13. The volume of the dichloromethane added is 5-20mL/mmol based on the amount of the compound substance shown in the formula (II).
Wherein the amount of the compound represented by the formula (II) in the step (2) and indoline is 1:1 to 1.5, and more preferably 1: 1. The amount ratio of the compound represented by the formula (II) to the alkali substance is 1:0.1-1.0, preferably 1: 0.5; the volume of dichloromethane added is 1-10mL/mmol, preferably 5mL/mmol, based on the amount of the compound represented by formula (II).
Further, the specific method in the step (1) comprises the following steps: under the protection of nitrogen, dissolving the compound shown in the formula (II) by using dichloromethane a, magnetically stirring for 15min at room temperature (25 ℃), adding thionyl chloride, and carrying out reflux reaction for 1.5-4.0 hours at 40-50 ℃ (preferably for 3 hours at 50 ℃); after the reaction is finished, cooling to room temperature, concentrating the reaction liquid under reduced pressure to remove the solvent (preferably, a rotary evaporator is used for removing dichloromethane and redundant thionyl chloride), adding dichloromethane b again for dissolving, concentrating under reduced pressure to remove the solvent and redundant thionyl chloride, and repeatedly adding dichloromethane b and concentrating under reduced pressure for 2-3 times to obtain the compound shown in the formula (III) which is brown oily or solid; the dichloromethane a and the dichloromethane b are dichloromethane, the letter has no meaning per se, the volume ratio of the dichloromethane a to the dichloromethane b is 2:1, the amount of the dichloromethane a is 10mL/mmol based on the amount of the compound shown in the formula (II), and the amount of the dichloromethane b is 5mL/mmol based on the amount of the compound shown in the formula (II).
Further, the specific method in the step (2) is as follows: mixing and dissolving dichloromethane, alkali and indoline, slowly dropwise adding the mixture into a compound shown in a formula (III), stirring at room temperature (25 ℃) to react completely (monitoring the reaction process by TLC, a developing agent: petroleum ether/ethyl acetate volume ratio is 3: 1), concentrating under reduced pressure to remove a solvent, adding an ethyl acetate aqueous solution with a volume concentration of 50% to quench the reaction, extracting an aqueous phase (preferably extracting for 3 times) by using ethyl acetate until no product exists in the aqueous phase, combining the ethyl acetate phases, adding anhydrous sodium sulfate or anhydrous magnesium sulfate to dry, concentrating until no liquid is evaporated, finally performing silica gel column chromatography, collecting components with an Rf value of 0.2-0.3 by using petroleum ether/ethyl acetate (volume ratio is 3: 1) as an eluent, and obtaining a compound shown in a formula (I) and containing indoline and a 5-aryl furan skeleton; the amount ratio of the indoline to the compound shown in the formula (II) is 1: 1.
In a third aspect, the invention also provides application of the compound containing indoline and 5-aryl furan skeleton shown in the formula (I) in preparing a Pseudomonas aeruginosa biofilm formation inhibitor, wherein the Pseudomonas aeruginosa is Pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO 1.
Compared with the prior art, the invention has the following beneficial effects: the invention synthesizes compounds containing indoline and 5-aryl furan skeleton with innovative structure, and the compounds can effectively inhibit the formation of bacterial biofilm on the premise of not influencing the normal growth of pseudomonas aeruginosa so as to reduce the generation of drug resistance. The Pseudomonas aeruginosa biofilm inhibition is the para bromine atom substituted compound (I-10) with the highest inhibition rate of 50.92% at the concentration of 200 mu M. And the compound has great application potential in solving the drug resistance problem by combining with antibiotics.
(IV) description of the drawings
FIG. 1 is a NMR spectrum of Compound I-7.
FIG. 2 is a NMR spectrum of Compound I-8.
FIG. 3 is a NMR spectrum of Compound I-9.
FIG. 4 is a NMR spectrum of Compound I-10.
(V) detailed description of the preferred embodiments
The present invention will be further explained with reference to specific examples, which are not intended to limit the present invention in any way. Unless otherwise indicated, the reagents and methods referred to in the examples are those commonly used in the art.
Example 1: preparation of indolin-1-yl (5- (4-methoxyphenyl)) furan-2-yl) methanone (I-1)
1) To a 100mL two-necked flask, 218mg (1mmol) of 5- (4-methoxyphenyl) furan-2-carboxylic acid (II-1) and 10mL (0.156mol) of methylene chloride were added under nitrogen. After magnetically stirring at room temperature (25 ℃ C.) for 15min, 2mL (26mmol) of thionyl chloride was added and the reaction was refluxed at 50 ℃ for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the reaction solvent and excess dichloromethane were removed by a rotary evaporator. A further 5mL (78mmol) of dichloromethane were added and the mixture was again removed under reduced pressure. This procedure was repeated 2 to 3 times to give a brown oil III-1. Because the compound III-1 is sensitive to water, the compound can be directly used for the next reaction without further separation and purification treatment;
2) 119.2mg (1mmol) of indoline was weighed at room temperature (25 ℃), dissolved by adding 5mL (78mmol) of dichloromethane and 0.5mL of triethylamine, and the mixed solution was slowly dropped into the compound (III-1) obtained in step 1) and stirred. The progress of the reaction was monitored by TLC plates (developer: petroleum ether/ethyl acetate in a 3: 1 ratio by volume). After the reaction was completed, the reaction solvent was removed by a rotary evaporator, 10mL of water and 10mL of ethyl acetate were added to conduct extraction, and the aqueous phase was extracted 3 times with ethyl acetate (10 mL). When TLC spot plate detecting water phase has no product, discarding water phase, washing ethyl acetate phase with saturated saline solution, drying with anhydrous sodium sulfate or anhydrous magnesium sulfate, concentrating until no liquid is distilled off. Finally, silica gel column chromatography is carried out (eluent: petroleum ether/ethyl acetate volume ratio is 3: 1), and R is collectedfComponent with a value of 0.2. Compound I-1 was finally obtained as a yellow solid in 53.3% yield.
Under the same conditions, respectively replacing II-1 in the step (1) with II-1 to II-10 to respectively prepare products I-1 to I-10, the details are shown in Table 1, wherein R groups corresponding to II-1 to II-10The groups are respectively 4-OMe, 3-F, 4-F, 3-Cl and 2-NO2、3-NO2、4-NO2、2,4-di-F、2,6-di-F、4-Br。
The NMR hydrogen spectra of compounds I-7 to I-10 are shown in FIGS. 1-4, and the NMR hydrogen spectra of compounds I-1 to I-6 are shown in Table 1.
TABLE 1 physicochemical constants and NMR hydrogen spectra data for compounds of formula I
Example 2: effect of Compounds of formula (I) on the growth of Pseudomonas aeruginosa
1. Experimental strains: pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1
2. The experimental method comprises the following steps: under aseptic condition, a small amount of Pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1 cells were inoculated into a fresh LB solid medium plate by using a sterile inoculating loop, and cultured in a biochemical incubator at 37 ℃ for 24 hours. Activated single colonies were picked from LB plates and inoculated into 100mL of fresh LB liquid medium, and cultured at 37 ℃ with shaking at 200rpm to logarithmic growth phase. Subsequently, the bacterial solution was diluted 100-fold with fresh LB liquid medium for use. In order to ensure that the final concentration of the compound of the formula (I) is 200 mu M by taking LB liquid culture medium without bacteria liquid as a reference, 2 mu L of methanol solution of the compound of the formula (I) with the concentration of 20mM is added into a 96-well plate, 200 mu L of diluted bacteria liquid is added after all methanol is volatilized, and the well plate is placed in a biochemical incubator to be cultured for 24 hours at 37 ℃. Finally, the absorbance was measured at 600nm (Angew. chem. int. Ed.2012,51, 5226-. The formula for calculating the growth inhibition rate is as follows:
TABLE 2 Effect of Compounds of formula I on the growth of Pseudomonas aeruginosa PAO1
From Table 2, it can be seen that the growth inhibition rate of the compound containing indoline and 5-arylfuran skeleton on Pseudomonas aeruginosa is almost less than 20% at a concentration of 200. mu.M, and is within the normal range of influence (+/-20%). Therefore, the compounds can not generate excessive influence on the growth of the pseudomonas aeruginosa.
Example 3: activity test of compounds containing indoline and 5-arylfuran skeletons shown in formula (I) on growth of Pseudomonas aeruginosa biofilm
1. Experimental strains: pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1
2. The experimental method comprises the following steps: under aseptic condition, a small amount of Pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1 cells were inoculated into a fresh LB solid medium plate by using a sterile inoculating loop, and cultured in a biochemical incubator at 37 ℃ for 24 hours. Activated single colonies were picked from LB plates and inoculated into 100mL of fresh LB liquid medium, and cultured at 37 ℃ with shaking at 200rpm to logarithmic growth phase. Subsequently, the cell suspension was diluted 100-fold with a fresh LB liquid medium to prepare a diluted cell suspension for use.
An experimental group, a control group and a blank group are arranged, wherein each group is provided with 3 parallels, the experimental group is compounds (I-1) - (I-10), the control group is Resveratrol (Resveratrol), and the blank group is diluted bacteria liquid (namely untreated pseudomonas aeruginosa). Respectively dissolving the compounds (I-1) to (I-10) in methanol by adopting a solvent evaporation method to prepare mother liquor, adding the mother liquor into a 96-pore plate, and placing the pore plate in a super clean bench. And (3) adding the diluted bacteria liquid after the methanol is completely volatilized, and ensuring that the final concentrations of the compounds (I-1) to (I-10) in each hole and the resveratrol are all 200 mu M. Sterilizing for 30min under ultraviolet radiation, transferring the porous plate into a biochemical incubator, and standing and culturing at 37 deg.C for 24 hr.
After the culture, the bacteria suspension is aspirated by a pipette (taking care not to touch the walls and bottom of the wells). To remove the biological tissue associated with the non-biofilm in the wells, each well was washed with 225. mu.L of PBS buffer, and then the PBS buffer was aspirated and repeated 2-3 times. To fix the biofilm in the well plate, the well plate was placed in an oven to dry and dehydrate at 37 ℃. The dried biofilm was stained with 200. mu.L of 0.1% crystal violet staining solution per well, and after completion of the staining for about 15min, the crystal violet solution was removed by pouring off. The well plate was washed with 200. mu.L of PBS buffer and then with pure water until the washed liquid was purple-free. Subsequently, to fix the biofilm in the well plate again, the well plate was dried and dehydrated in an oven at 37 ℃. The dried crystal violet stained biofilm was redissolved in 200 μ L of 30% glacial acetic acid solution per well. After 15min of dissolution, the absorbance at 590nm was measured and directly reflected the amount of biofilm (Chem Biolo,2005,12(7): 789-. The calculation formula of the biofilm inhibition rate is as follows:
TABLE 3 inhibition of Pseudomonas aeruginosa PAO1 biofilm formation by compounds of formula I
As can be seen from Table 3, at a concentration of 200 μ M, the indoline compounds have a certain inhibiting effect on the formation of a Pseudomonas aeruginosa biofilm and good inhibiting activity, except that the para-fluoro-substituted compound (I-3) has a certain promoting effect on the formation of the Pseudomonas aeruginosa biofilm. Among halogen atom substituted compounds, bromine atom substituted compounds are superior to chlorine atom substituted compounds in fluorine atom substituted compounds, show the influence of different substituents on the inhibition effect, and can find that compounds containing difluoride atoms, bromine atoms and nitro groups show stronger inhibition activity. Among them, the indoline and 5-arylfuran skeleton-containing compound which is the most excellent inhibitory activity against biofilm formation is the para-bromine atom-substituted compound (I-10) having an inhibitory rate of up to 50.92% at a concentration of 200. mu.M.
The invention discloses a compound containing indoline and a 5-aryl furan skeleton, which has the advantages of innovative structure, simple and convenient preparation method and better biological activity, can effectively inhibit the formation of a pseudomonas aeruginosa biofilm, and has a certain application prospect in the aspect of solving the problems of bacterial infection and drug resistance thereof.
Claims (10)
1. A compound containing indoline and 5-arylfuran skeletons shown in formula (I):
in the formula (I), R is one or more, and R is hydrogen, halogen, nitro, C1-C4 alkyl or C1-C4 alkoxy.
2. The compound having indoline and 5-arylfuran skeleton according to claim 1, wherein R is 4-methoxy, 2-chloro, 3-chloro, 4-bromo, 2-fluoro, 3-fluoro, 4-fluoro, 2, 4-difluoro, 2, 6-difluoro, 2-nitro, 3-nitro or 4-nitro.
3. A compound having an indoline and 5-arylfuran skeleton according to claim 1, wherein the compound is one of the following:
4. a method for producing a compound having an indoline and 5-arylfuran skeleton represented by the formula (I) of claim 1, characterized by comprising:
(1) under the protection of nitrogen, carrying out reflux reaction on the compound shown in the formula (II), thionyl chloride and dichloromethane at 40-50 ℃, after the reaction is completely cooled to room temperature, carrying out reduced pressure concentration to remove a reaction solvent to obtain a compound shown in the formula (III), and directly using the compound in the next reaction without purification;
(2) under the action of a diluent dichloromethane, reacting a compound shown as a formula (III) with indoline and alkali at 25-30 ℃, after the reaction is completed, performing rotary evaporation to remove dichloromethane, adding 50% by volume of ethyl acetate aqueous solution for quenching, extracting an aqueous phase with ethyl acetate, drying an ethyl acetate phase with anhydrous sodium sulfate, concentrating until no liquid is evaporated, and finally performing reaction by using a solvent with a volume ratio of 3: 1 petroleum ether/ethyl acetate as eluent, performing silica gel column chromatography, and collecting RfA component with a value of 0.2-0.3 to obtain a compound containing indoline and 5-aryl furan skeleton shown in formula (I); the alkali is selected from one of triethylamine, pyridine and N-methylmorpholine;
in the formula (I), R is one or more, and R is hydrogen, halogen, nitro, C1-C4 alkyl or C1-C4 alkoxy; r in the formula (II) and the formula (III) is the same as the formula (I).
5. The method for producing a compound having an indoline and 5-arylfuran skeleton according to claim 4, wherein the amount ratio of the compound represented by the formula (II) in the step (1) to the substance of thionyl chloride is 1:10 to 15; the volume of the dichloromethane added is 5-20mL/mmol based on the amount of the compound substance shown in the formula (II).
6. The method for preparing a compound having indoline and 5-arylfuran skeleton according to claim 4, wherein the amount of the compound represented by the formula (II) in the step (2) and indoline is 1:1 to 1.5; the amount ratio of the compound shown in the formula (II) to the alkali substance is 1: 0.1-1.0; the volume of the dichloromethane added is 1-10mL/mmol based on the amount of the compound substance shown in the formula (II).
7. The process for producing a compound having an indoline and 5-arylfuran skeleton according to claim 4, wherein the process of the step (1) is: under the protection of nitrogen, dissolving the compound shown in the formula (II) by using dichloromethane a, magnetically stirring at room temperature for 15min, adding thionyl chloride, and carrying out reflux reaction at 40-50 ℃ for 1.5-4.0 h; and after the reaction is finished, cooling to room temperature, concentrating the reaction solution under reduced pressure to remove the solvent, adding dichloromethane b again for dissolving, concentrating under reduced pressure to remove the solvent and redundant thionyl chloride, and repeating the steps of adding dichloromethane b and concentrating under reduced pressure for 2-3 times to obtain the compound shown in the formula (III).
8. The process for producing a compound having an indoline and 5-arylfuran skeleton according to claim 4, wherein the process of the step (2) is: mixing and dissolving dichloromethane, alkali and indoline, slowly dropwise adding the mixture into a compound shown in a formula (III), stirring at room temperature to react completely, concentrating under reduced pressure to remove a solvent, adding an ethyl acetate aqueous solution with the volume concentration of 50% to quench the reaction, extracting a water phase with ethyl acetate until no product exists in the water phase, combining the ethyl acetate phases, adding anhydrous sodium sulfate or anhydrous magnesium sulfate to dry, concentrating until no liquid is evaporated, and finally performing silica gel column chromatography, wherein the volume ratio of the ethyl acetate phase to the anhydrous sodium sulfate or anhydrous magnesium sulfate is 3: 1 is used as an eluent, and components with Rf value of 0.2-0.3 are collected to obtain a compound containing indoline and 5-aryl furan skeleton shown in formula (I).
9. Use of a compound of formula (I) according to claim 1, comprising an indoline and a 5-arylfuran backbone, for the preparation of an inhibitor of pseudomonas aeruginosa biofilm formation.
10. The use according to claim 9, wherein the Pseudomonas aeruginosa is Pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115012211A (en) * | 2022-07-18 | 2022-09-06 | 南通大学 | Antibacterial ultraviolet-proof cotton fabric and preparation method thereof |
| CN115012211B (en) * | 2022-07-18 | 2023-08-08 | 南通大学 | Antibacterial anti-ultraviolet cotton fabric and preparation method thereof |
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