CN111499628A - 2-furoylamide compound and preparation and application thereof - Google Patents
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Abstract
The invention discloses a 2-furoylamide compound, a preparation method and application thereof, wherein the 2-furoylamide compound is prepared by reacting a compound shown in a formula II with 9H-pyridine [3,4-b ] in the presence of an acid-binding agent]Indole is reacted to obtain the product. The preparation method is simple, convenient and environment-friendly, and the prepared compound has a novel structure. The 2-furoylamide compound can reduce the yield of pseudomonas aeruginosa proteolytic enzyme or pyocin on the premise of not influencing the normal growth of pseudomonas aeruginosa, and has potential application prospect in the aspect of reducing the formation of pseudomonas aeruginosa virulence factors.
Description
(I) technical field
The invention relates to a 2-furoylamide compound, a preparation method thereof and application thereof in inhibiting yield of pseudomonas aeruginosa proteolytic enzyme or pyocyancin, belonging to the technical field of fine organic chemistry and biomedicine.
(II) background of the invention
Antibiotics are one of the greatest discoveries in the 20 th century, but the overuse of antibiotics enables the drug resistance rate of pathogenic bacteria to rise year by year, and brings new threats to human survival. Therefore, the development of new anti-infective drugs is imminent. The antibacterial strategy of traditional antibiotics is bactericidal or bacteriostatic, and this strong survival pressure induces resistance in bacteria (eur.j.med.chem.2019,161, 154-178). Therefore, researchers have turned their attention to the study of "anti-virulence drugs" which block the virulence of pathogenic bacteria and thus make them unable to destroy the host immune system, thus facilitating easier clearance of pathogenic bacteria from the body (Nat Rev Microbiol 2008,6, 17-27). Blocking virulence generally does not inhibit bacterial growth and is not prone to selective stress and drug resistance. It has now been demonstrated that the virulence of a variety of pathogenic bacteria is regulated by a Quorum Sensing (QS) system, and therefore the bacterial QS system is a novel breakthrough in the development of anti-infective drugs.
Pseudomonas aeruginosa is one of the common pathogenic bacteria (clin. infection. dis.2003,37, 745-. QS enables pseudomonas aeruginosa populations to timely and synergistically synthesize and release a large number of extracellular virulence factors such as pyocyanin, rhamnolipid, proteases and the like, thereby forming pathogenicity (Prorein Cell 2015,6, 26-41). Studies have shown that the capacity of virulence factor secretion and biofilm formation is significantly reduced and the virulence and invasiveness of infected hosts are significantly reduced after blocking the QS system in pseudomonas aeruginosa (NatProtoc 2010,5, 282-293). It is now recognized that virulence factors of pseudomonas aeruginosa, which are directly regulated by the QS system, include pyocins, elastase, proteolytic enzymes, rhamnolipids, etc., and that the formation and motor behavior of pseudomonas aeruginosa biofilms are also regulated by the QS system (Protein Cell,2015,6, 26-41). Pyocin is an important phenazine toxic product secreted in pseudomonas aeruginosa infection, and can play a certain role in interfering the electron transfer, cell respiration, energy metabolism, gene expression of host cells and the immune mechanism of the host per se, thereby achieving the pathogenic effect (trends microbiol 2013,21, 73-81).
Disclosure of the invention
The invention aims to provide a 2-furoylamide compound, a preparation method thereof and application thereof in inhibiting yield of pseudomonas aeruginosa proteolytic enzyme or pyocin, reduces expression level of pseudomonas aeruginosa pathogenic virulence factors, and has potential 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 2-furoylamide compound 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 2-furoylamide compound represented by the formula (I) is one of the following:
in a second aspect, the invention provides a method for preparing a 2-furoylamide compound represented by formula (I), wherein the reaction formula of the method is as follows:
(1) reacting a compound of formula (II) with thionyl chloride (SOCl) in the presence of a diluent2) After the reaction is completed at 40-45 ℃, removing the reaction solvent to obtain the compound shown in the formula (III); the diluent is an inert organic solvent, is selected from one of toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran or ethyl acetate, and is most preferably dichloromethane;
(2) in the presence of a diluent and an acid-binding agent, completely reacting the compound shown in the formula (III) with 9H-pyridine [3,4-b ] indole at 25-30 ℃, removing the diluent by using a rotary evaporator, extracting by using an ethyl acetate aqueous solution with the volume concentration of 50%, extracting a water phase by using ethyl acetate (10m L× 3), combining ethyl acetate phases, drying by using anhydrous sodium sulfate, concentrating until no liquid is evaporated, finally performing silica gel column chromatography by using petroleum ether/ethyl acetate as an eluent in a volume ratio of 3:1, and collecting a component with the Rf value of 0.2-0.3 to obtain the 2-furoylamide compound shown in the formula (I), wherein the diluent is the same as the step (1), the acid-binding agent is selected from one of triethylamine, pyridine and N-methylmorpholine, and most preferably triethylamine;
in the formula (II), R is one or more, and R is hydrogen, halogen, nitro, C1-C4 alkyl or C1-C4 alkoxy; preferably, 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;
r in the formula (I) and the formula (III) is the same as the formula (II).
Further, the compound shown in the formula (II) in the step (1) is mixed with a diluent and SOCl2The amount ratio of the component (A) to the component (B) is 1:60 to 120:10 to 15, and more preferably 1:100: 13.
Furthermore, the amount of the compound shown in the formula (II) in the step (2) and 9H-pyridine [3,4-b ] indole is 1: 1-1.5, more preferably 1:1, the volume dosage of the diluent is 1-10m L/mmol, preferably 8m L/mmol based on the amount of the 9H-pyridine [3,4-b ] indole, and the volume dosage of the acid binding agent is 0.01-0.5m L/mmol, preferably 0.1m L/mmol based on the amount of the 9H-pyridine [3,4-b ] indole.
Further, the specific method in the step (1) comprises the following steps: dissolving the compound shown in the formula (II) by using a diluent a, adding thionyl chloride, carrying out reflux reaction at 45 ℃ for 1.5-2h, after the reaction is finished, concentrating the reaction liquid under reduced pressure to remove the solvent (preferably removing the diluent and the residual thionyl chloride by using a rotary evaporator), adding a diluent b, dissolving, concentrating under reduced pressure again to remove the solvent, and blowing nitrogen to remove the thionyl chloride to obtain brown oil or solid, namely the compound shown in the formula (III); the amount ratio of the compound shown in the formula (II) to the diluent a is 1: 100; the diluent b may be soluble, and the ratio of the amount of the compound represented by the formula (II) to the amount of the diluent b is preferably 1: 156; the diluent a and the diluent b are both diluents and are named for the purpose of expressing different amounts of the different steps, and the letters themselves have no meaning.
Further, the specific method of the step (2) comprises the steps of adding a diluent c into the compound shown in the formula (III) in the step (1) for dissolving, slowly dropwise adding 9H-pyridine [3,4-b ] indole dissolved by an acid-binding agent, after the dropwise adding is finished, completely reacting at 25 ℃, concentrating under reduced pressure to remove a solvent (preferably removing the diluent by using a rotary evaporator), extracting by using an ethyl acetate aqueous solution with the volume concentration of 50%, extracting the water phase by using ethyl acetate (preferably extracting for 3 times), combining the ethyl acetate phases, drying by using anhydrous sodium sulfate, concentrating until no liquid is distilled out, finally performing silica gel column chromatography by using petroleum ether/ethyl acetate as an eluent with the volume ratio of 3:1, collecting components with the Rf value of 0.2-0.3, obtaining the 2-furoylamide compound shown in the formula (I), wherein the ratio of the 9H-pyridine [3,4-b ] indole to the compound shown in the formula (II) is 1:1, the diluent d and the acid-binding agent are expressed by the volume ratio of 9H-pyridine [3,4-b ] indole to the compound shown in the formula (II) is L, and the diluent d and the diluent is not used in the volume ratio of 3, wherein the diluent c is different from the diluent c, and the diluent d and the diluent c, the diluent is expressed by the letter of 0.3-pyridine [ 3-3, and the.
Further, the compound represented by the formula (II) is prepared by the following method:
stirring a compound shown as a formula (IV) and a hydrochloric acid aqueous solution with the mass concentration of 15% in an ice water mixture until the compound shown as the formula (IV) is dissolved, adding a sodium nitrite aqueous solution with the mass concentration of 30%, reacting at 0-5 ℃ for 15-30 min, then adding an acetone solution of 2-furancarboxylic acid and a copper chloride dihydrate aqueous solution, reacting at 0-5 ℃ for 6h, transferring to room temperature (25 ℃) to react for 16h, performing suction filtration, washing a filter cake with water, dissolving the filter cake with a sodium bicarbonate aqueous solution with the mass concentration of 10% to be neutral or weakly alkaline (preferably pH of 7-8), then adding 2M hydrochloric acid until no solid precipitates, filtering, and drying the filter cake to obtain a compound shown as a formula (II), wherein the volume usage of the hydrochloric acid aqueous solution is 600M L/mol based on the compound shown as the formula (IV), the volume usage of the sodium nitrite aqueous solution is 500M L/mol based on the compound shown as the formula (IV), the volume usage of the compound shown as the formula (IV) and the furan carboxylic acid aqueous solution is L g/mol, and the acetone aqueous solution is 2-furancarboxylic acid substance as 600M L g/mol based on the copper chloride dihydrate (R) and 3652 g/mol).
In a third aspect, the invention also provides an application of the 2-furoylamide compound shown in the formula (I) in inhibiting the yield of the Pseudomonas aeruginosa proteolytic enzyme or the Pseudomonas aeruginosa, wherein the Pseudomonas aeruginosa is Pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO 1.
Compared with the prior art, the invention has the following beneficial effects: 9H-pyridine [3,4-b ] indole is introduced into a 2-furan carboxamide structure for the first time, and the synthesis operation of the 2-furan carboxamide compound is simple and convenient, and the reaction condition is mild. More importantly, the compounds have the function of inhibiting the yield of pseudomonas aeruginosa proteolytic enzyme and pyocin, and provide potential choices for solving the drug resistance of pseudomonas aeruginosa.
(IV) description of the drawings
FIG. 1 is a graph showing the effect of 2-furancarboxamide compounds on the growth of Pseudomonas aeruginosa.
FIG. 2 shows the inhibition of the production of Pseudomonas aeruginosa proteolytic enzyme by 2-furancarboxamide compounds.
FIG. 3 shows the inhibition of P.aeruginosa pyocin production by 2-furancarboxamide compounds.
FIG. 4 is a NMR spectrum of Compound I-3.
FIG. 5 is a NMR spectrum of Compound I-4.
FIG. 6 is a NMR spectrum of Compound I-8.
FIG. 7 is a NMR spectrum of Compound I-12.
(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 (5- (4-fluorophenyl) furan-2-yl) (9H-pyrido [3,4-b ] indol-9-yl) methanone (I-4)
(1) Preparation of Compound II-4
Adding 5.6g of para-fluoroaniline (IV-4, 0.05mol) and 30M of 15% hydrochloric acid aqueous solution with mass concentration of L into a 250M L single-neck flask, placing the mixture into an ice water mixture, fully stirring the mixture until the para-fluoroaniline is completely dissolved, then dropwise adding 25M of L of 30% sodium nitrite aqueous solution with mass concentration, controlling the temperature of a reaction system between 0 and 5 ℃, stirring the mixture for 15 minutes after the dropwise adding is finished, adding 5.6g (0.05mol) of 30ml of acetone solution of 2-furancarboxylic acid and 3g of 20M of L aqueous solution of copper chloride dihydrate into the reaction system, reacting the mixture for 6 hours at 0 to 5 ℃, then reacting the mixture at room temperature (25 ℃) for 16 hours, filtering and separating out suspended solid after the reaction is finished, washing a filter cake with water, dissolving the filter cake with 10% sodium bicarbonate aqueous solution with mass concentration to pH of 7 to 8, then adding 2M hydrochloric acid for acidification until no solid is separated out, finally filtering, drying to obtain a brown yellow solid compound II-4(5.34g), obtaining the mass yield of 51.6%, and directly purifying the product without further reaction.
(2) Preparation of Compound (I-4)
1) 206.17mg of 5- (4-fluorophenyl) furan-2-carboxylic acid (II-4, 1mmol) and 6.4m L (100mmol) of dichloromethane are added into a 100m L two-neck flask, one of the two necks is plugged by a rubber stopper, the other neck is connected with a spherical condenser tube, the uppermost end of the spherical condenser tube is connected with a nitrogen balloon, the mixture is magnetically stirred at room temperature for 15min, then condensed water is opened, 1m L (13mmol) of thionyl chloride is added by a syringe, the condenser tube is removed after reflux reaction is carried out for 2 hours at 45 ℃, a rotary evaporator is used for removing a reaction solvent, 10m L (0.156mol) of dichloromethane is added for rotary evaporation to remove the solvent, nitrogen is used for blowing out, and brown oily matter III-4 is obtained after the thionyl chloride gas is blown out, and the compound III-4 is sensitive to water without further separation and purification;
2) 6.4m L (100mmol) of dichloromethane is added to dissolve all the compound III-4 of step 1), 168.2mg (1mmol) of 9H-pyridine [3,4-b ] indole is dissolved with 2ml of dichloromethane and 0.1m L of triethylamine, then the solution is slowly added dropwise to the compound III-4, stirring is carried out at room temperature (25 ℃), T L C monitors the reaction progress (developing agent: petroleum ether/ethyl acetate volume ratio is 1/1), after the reaction is finished, a rotary evaporator is used to remove the reaction solvent, 10m L water and 10m L ethyl acetate are added for extraction, the water phase is extracted with ethyl acetate (10m L) for 3 times, the ethyl acetate phase is combined, washed with saturated brine, dried with anhydrous sodium sulfate and concentrated to no liquid, finally silica gel column chromatography (eluent is 3:1 petroleum ether/ethyl acetate volume ratio) is carried out), components with Rf value of 0.3 are collected, finally 160mg of yellow solid compound I-4 is obtained, and the mass yield is 44.9%.
Respectively replacing IV-4 in the step (1) with IV-1 to IV-13 under the same conditions; in the step (2), II-4 is replaced by II-1 to II-13 to prepare products I-1 to I-13 respectively, and the details are shown in Table 1.
Table 1 Compound numbers
TABLE 2 physicochemical constants and elemental analysis data for compounds of formula I
TABLE 3 NMR hydrogen spectra data for compounds of formula I
EXAMPLE 2 Effect of 2-Furan carboxamides of formula (I) on the growth of Pseudomonas aeruginosa
1. Experimental strains: pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1
2. The experimental method comprises the steps of picking a small amount of pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1 thallus into a fresh L B solid culture medium plate in an aseptic super clean bench by using an aseptic inoculating loop, placing the pseudomonas aeruginosa PAO1 thallus into a biochemical incubator at 37 ℃ for culturing for 24 hours, picking a single colony from the plate after the culture is finished, inoculating the single colony into a fresh L B liquid culture medium, carrying out shaking culture at 37 ℃ and 200rpm to a logarithmic phase, sucking 1m L bacterial liquid into a fresh L B liquid culture medium of 100m L after the culture is finished, uniformly mixing, firstly adding a 20mM methanol solution of the compound shown in the formula (I) 2 mu L into a 96-well plate, adding a 200 mu L uniform bacterial liquid after all methanol in a solvent is volatilized, ensuring that the final concentration of the compound shown in the formula (I) is 200 mu M, placing the plate into the biochemical incubator at 37 ℃ for culturing for 24 hours, testing the absorbance at 600nm (Angew. chem. int. Ed. 51. Ed. 5251. 26. 2012, 19. the formula):
TABLE 4 Effect of Compounds of formula I on the growth of Pseudomonas aeruginosa
From Table 4, it can be seen that the compounds other than compound I-13 have a growth inhibition rate of-30.63% on Pseudomonas aeruginosa, and the effects of the other compounds on the growth of Pseudomonas aeruginosa are within + -20%, which fall into the normal range of effects and are considered to have no significant effect on the growth of Pseudomonas aeruginosa.
EXAMPLE 3 Activity test of 2-Furancarboxamides of formula (I) on the inhibition of the production of Pseudomonas aeruginosa proteolytic enzyme
1. Experimental strains: pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1
2. The experimental method comprises the steps of picking a small amount of pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1 thallus into a fresh L B solid culture medium plate by using an aseptic inoculating loop in an aseptic super-clean bench, placing the pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1 thallus into a biochemical incubator for culturing for 24 hours at 37 ℃, picking a single colony from the plate after the culture is finished, inoculating the single colony into a fresh L B liquid culture medium, carrying out shaking culture at 37 ℃ and 200rpm until the logarithmic phase is reached, and sucking 1m L bacterial liquid into a 100m L fresh L B liquid culture medium and uniformly mixing the bacterial liquid and the liquid culture medium.
The mixed bacterial liquid is divided into 25ml triangular conical flasks, mixed bacterial liquid of DMSO solution 30 mu L and 2970 mu L of the compound shown in the formula (I) with the concentration of 20mM is sequentially added, the final concentration of the compound is 200 mu M, three groups of compounds are arranged in parallel, mixed bacterial liquid of DMSO with the concentration of 30 mu L and 2970 mu L is added into a negative control group, the triangular conical flasks are subjected to shaking culture at 37 ℃ and 200rpm until the logarithmic growth period, 1M L bacterial liquid is taken out of a centrifugal tube and centrifuged at 10000rpm for 10 minutes, 150 mu L sterile supernatant is sucked, 0.5M L azocasein solution with the mass concentration of 0.3 percent and prepared by Tris-HCl buffer solution with the pH of 7.5 and 0.05M is added into the centrifugal tube, the solution is placed into the biochemical culture box at 37 ℃ for 15 minutes, then trichloroacetic acid aqueous solution with the volume concentration of 10 percent (0.5M L) is added for stopping reaction, finally, 200 mu L supernatant is centrifuged at 10000rpm for 5 minutes, the absorbance of the mixed bacterial liquid is tested in a 96 pore plate, the absorbance of 400nm, the RSC inhibition rate is calculated according to the following formula 5513:
TABLE 5 inhibition of Pseudomonas aeruginosa proteolytic enzyme production by compounds of formula I
As can be seen from Table 5, the compounds I-3, I-4 and I-8 have better inhibition effect on the yield of the Pseudomonas aeruginosa proteolytic enzyme, and the inhibition rate exceeds 45 percent. Wherein, the inhibition rates of the compounds I-4 and I-8 reach 47.04 percent and 46.59 percent, and the compounds have better inhibition activity.
Example 4 Activity test of 2-Furan carboxamides of formula (I) on the inhibition of Pseudomonas aeruginosa production
1. Experimental strains: pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1
2. The experimental method comprises the steps of picking a small amount of pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1 thallus into a fresh L B solid culture medium plate by using an aseptic inoculating loop in an aseptic super-clean bench, placing the pseudomonas aeruginosa (Pseudomonas aeruginosa) PAO1 thallus into a biochemical incubator for culturing for 24 hours at 37 ℃, picking a single colony from the plate after the culture is finished, inoculating the single colony into a fresh L B liquid culture medium, carrying out shaking culture at 37 ℃ and 200rpm until the logarithmic phase is reached, and sucking 1m L bacterial liquid into a 100m L fresh L B liquid culture medium and uniformly mixing the bacterial liquid and the liquid culture medium.
The mixed bacterial liquid is divided into 25ml conical flasks, mixed bacterial liquid of DMSO solution 30 mu L and 2970 mu L of the compound of the formula (I) with the concentration of 20mM is sequentially added, the final concentration of the compound is 200 mu M, three groups of compounds are arranged in parallel, mixed bacterial liquid of DMSO with the concentration of 30 mu L and 2970 mu L is added into a negative control group, the conical flasks are subjected to shaking culture at 37 ℃ and 200rpm until the logarithmic growth period, 1M of the bacterial liquid L is taken out of a centrifugal tube and centrifuged at 10000rpm for 10 minutes, and finally 200 mu L supernatant is sucked into a 96-well plate, the absorbance (PNAS,2013,110,17981 and 17986) at 695nm is tested, and the inhibition rate is calculated according to the following formula:
TABLE 6 inhibition of pyocin production by compounds of formula I
As can be seen from Table 6, the compounds I-1, I-4, I-5, I-6, I-7, I-12 and I-13 have better inhibition effects on the yield of pyocins, and the inhibition rates are all over 50%, wherein the inhibition rates of the compounds I-4, I-5, I-6, I-12 and I-13 are over 55%, and the inhibition rate of the compound I-4 is even up to 60%.
The invention discloses a 2-furoylamide compound which has novel structure, simple preparation method and good biological activity, can be used as an inhibitor for yield of pseudomonas aeruginosa proteolytic enzyme and pyocyanin, and expands the application prospect of the furoylamide structure in quorum sensing inhibition.
Claims (10)
1. A2-furoylamide compound of the 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 2-furoylamide of 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. 2-furoylamide compounds according to claim 1, wherein the 2-furoylamide compound of the formula (I) is one of the following:
4. a process for the preparation of 2-furoylamides of formula (I) as claimed in claim 1, characterized in that it comprises:
(1) in the presence of a diluent, completely reacting the compound shown in the formula (II) with thionyl chloride at 40-45 ℃, and removing a reaction solvent to obtain a compound shown in the formula (III); the diluent is selected from one of toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran or ethyl acetate;
(2) in the presence of a diluent and an acid-binding agent, completely reacting a compound shown in a formula (III) with 9H-pyridine [3,4-b ] indole at 25-30 ℃, removing the diluent by using a rotary evaporator, extracting by using an ethyl acetate aqueous solution with the volume concentration of 50%, extracting a water phase by using ethyl acetate, combining ethyl acetate phases, drying by using anhydrous sodium sulfate, concentrating until no liquid is evaporated, finally performing silica gel column chromatography by using petroleum ether/ethyl acetate as an eluent in a volume ratio of 3:1, and collecting a component with the Rf value of 0.2-0.3 to obtain a 2-furoylamide compound shown in the formula (I); the diluent is the same as the diluent in the step (1); the acid-binding agent is selected from one of potassium carbonate, triethylamine, pyridine and N-methylmorpholine;
in the formula (II), R is one or more, and R is hydrogen, halogen, nitro, C1-C4 alkyl or C1-C4 alkoxy;
r in the formula (I) and the formula (III) is the same as the formula (II).
5. The process for producing 2-furoylamides according to claim 4, wherein the ratio of the amount of the compound represented by the formula (II) in the step (1) to the amount of the diluent and the thionyl chloride is: 1: 60-120: 10-15.
6. The preparation method of the 2-furoylamide compound as claimed in claim 4, wherein the amount of the compound represented by the formula (II) in the step (2) and 9H-pyrido [3,4-b ] indole is 1: 1-1.5, the volume of the diluent is 1-10m L/mmol based on the amount of the 9H-pyrido [3,4-b ] indole, and the volume of the acid-binding agent is 0.01-0.5m L/mmol based on the amount of the 9H-pyrido [3,4-b ] indole.
7. The process for producing a 2-furoylamide compound according to claim 4, wherein the process of the step (1) is: dissolving the compound shown in the formula (II) by using a diluent a, adding thionyl chloride, carrying out reflux reaction at 45 ℃ for 1.5-2h, after the reaction is finished, carrying out reduced pressure concentration on the reaction liquid to remove the solvent, adding a diluent b to dissolve, then carrying out reduced pressure concentration again to remove the solvent, and purging nitrogen to remove the thionyl chloride to obtain brown oil or solid, namely the compound shown in the formula (III); the amount ratio of the compound shown in the formula (II) to the diluent a is 1: 100.
8. The preparation method of the 2-furoylamide compound as claimed in claim 4, wherein the step (2) is carried out by adding diluent c into the compound represented by the formula (III) in the step (1) to dissolve, slowly adding 9H-pyridine [3,4-b ] indole dissolved by diluent d and acid-binding agent dropwise, after the dropwise addition, reacting at 25 ℃, concentrating under reduced pressure to remove the solvent, extracting with 50% by volume of ethyl acetate aqueous solution, extracting the aqueous phase with ethyl acetate, drying the ethyl acetate phase with anhydrous sodium sulfate, concentrating until no liquid is evaporated, finally carrying out silica gel column chromatography with petroleum ether/ethyl acetate as eluent in a volume ratio of 3:1, collecting the component with Rf value of 0.2-0.3 to obtain the 2-furoylamide compound represented by the formula (I), wherein the ratio of the compound represented by the formula (II) to the substance of 9H-pyridine [3,4-b ] indole is 1:1, the volume ratio of the diluent d and the acid-binding agent is 2.83-pyridine [3,4-b ] indole, and the diluent d is 353.84 mmol to 2.3 mmol.
9. The process for preparing 2-furoylamides according to claim 4, wherein the compound of formula (II) is prepared by:
stirring a compound shown as a formula (IV) and a hydrochloric acid aqueous solution with the mass concentration of 15% in an ice water mixture until the compound shown as the formula (IV) is dissolved, adding a sodium nitrite aqueous solution with the mass concentration of 30%, reacting at 0-5 ℃ for 15-30 min, then adding an acetone solution of 2-furancarboxylic acid and a copper chloride dihydrate aqueous solution, reacting at 0-5 ℃ for 6h, transferring to room temperature to react for 16h, filtering, washing a filter cake with water, dissolving the filter cake with a sodium bicarbonate aqueous solution with the mass concentration of 10% until the pH value is neutral or weakly alkaline, then adding 2M hydrochloric acid until a solid does not precipitate, filtering, and drying the filter cake to obtain a compound shown as a formula (II), wherein the volume usage of the hydrochloric acid aqueous solution is 600M L/mol based on the substance shown as the formula (IV), the volume usage of the sodium nitrite aqueous solution is 500M L/mol based on the substance shown as the formula (IV), the ratio of the compound shown as the formula (IV) to the 2-furancarboxylic acid substance is 1:1, the volume usage of the acetone is 600M/mol based on the substance, and the copper chloride aqueous solution is 363 g/3 g/mol based on the concentration of the copper chloride dihydrate shown as the formula (II).
10. Use of a 2-furoylamide compound of formula (I) as defined in claim 1 for inhibiting the production of pseudomonas aeruginosa proteolytic enzyme or pyocin.
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