CN114524792A - Diaryl derivative with antibacterial sensitization activity and application thereof in antibiosis - Google Patents

Diaryl derivative with antibacterial sensitization activity and application thereof in antibiosis Download PDF

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CN114524792A
CN114524792A CN202210223119.XA CN202210223119A CN114524792A CN 114524792 A CN114524792 A CN 114524792A CN 202210223119 A CN202210223119 A CN 202210223119A CN 114524792 A CN114524792 A CN 114524792A
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CN114524792B (en
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王印虎
陈军节
刘方全
薛洁
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Liaocheng University
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Abstract

The invention belongs to the field of medicinal chemistry, and relates to a diaryl derivative with antibacterial sensitization activity and application thereof in antibiosis, wherein the compound has a structure shown in a formula I:
Figure DDA0003534482520000011
the compound can be used as an inhibitor of an AcrB efflux pump, has broad-spectrum antibacterial sensitization activity, and Ar in the formula1、Ar2、R3、R4、R5And X is defined in the specification.

Description

Diaryl derivative with antibacterial sensitization activity and application thereof in antibiosis
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a diaryl derivative with antibacterial sensitization activity and application thereof as an AcrB efflux pump inhibitor in antibiosis.
Background
The information disclosed in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
In recent years, the problem of bacterial resistance has become increasingly serious due to the widespread use and even abuse of antibacterial drugs worldwide. Among them, infection by multi-drug resistant gram-negative bacteria has become one of the major factors threatening human health. Clinically, there are several most common multidrug-resistant gram-negative bacteria, such as escherichia coli, pseudomonas aeruginosa, acinetobacter baumannii and the like which spread and prevail worldwide, and the currently commonly used antibacterial drugs cannot provide effective treatment for infectious diseases caused by these drug-resistant bacteria, so that the death rate of patients is increased year by year. Among them, the multiple drug resistance rate of escherichia coli in ICU ward is as high as 44%, which often causes severe infection of various parts of human respiratory tract, digestive tract, urinary tract and skin, and has become the most serious conditional pathogen in current bacterial infection. Therefore, in the next few years or even decades, the development of new effective antibacterial drugs or drugs (antibacterial sensitizers) with improved efficacy of existing antibacterial drugs has become a research focus in the field of new drug development today.
The efflux pump is a protein widely existing on bacterial cell membranes, and can discharge harmful substances to the body under normal physiological conditions to play a self-protection role. The overexpression of the efflux pump causes the antibacterial drugs in the bacterial cells to be excreted out of the body, so that the concentration of the drugs reaching the action part is reduced and the effective antibacterial action cannot be achieved.
The AcrAB-TolC efflux pump is a protein widely existing on the cell membrane of gram-negative bacteria, and is a compound consisting of three parts, namely fusion protein (AcrA) existing in the cytoplasmic space of bacteria, inner membrane transporter (AcrB) and outer membrane channel protein (TolC). Wherein, the AcrA mainly plays an auxiliary role in the transfer process by connecting AcrB and TolC; the AcrB is responsible for capturing substrates existing in bacterial inner membranes or cytoplasm, so that the specificity of an efflux substrate is determined, and the AcrB plays a key role in the recognition and energy transduction of the efflux substrate; TolC is responsible for providing access to the environment outside the cell, expelling the substrate outside the cell. The AcrAB-TolC efflux system generally expels the antibacterial drug extracellularly by capturing the intracytoplasmic drug molecules directly through the phospholipid bilayer to pump them out, e.g., for the development of resistance to tetracycline and chloramphenicol; secondly, the drug captured in the periplasmic space is transported to the outside of the cell through TolC, and the efflux of some beta-lactam antibiotics is represented by the mechanism. Since the AcrB protein plays a decisive role in three-component excretion systems, the crystal structure and function of the AcrB protein have been the focus of research, and thus inhibiting the related functions of the AcrB protein seems to be an effective method for restoring the functions of existing antibacterial drugs.
Efflux Pump Inhibitors (EPIs) are emerging alternative therapies that can restore or enhance the activity of existing antibiotics and control the spread of antibiotic resistance, which provides a new concept for the treatment of infections with multidrug-resistant bacteria. Because the overexpression of the AcrB efflux pump is closely related to the multidrug resistance and cross resistance of various antibacterial drugs, the combined use of the novel AcrB efflux pump inhibitor and the antibacterial drugs can be an effective method for reducing the inherent drug resistance level of bacteria and recovering or enhancing the efficacy of the existing antibacterial drugs. Researches prove that the AcrB efflux pump inhibitor can weaken the efflux action of drug-resistant bacteria on antibacterial drugs, thereby reversing acquired drug resistance to a certain extent and improving the clinical curative effect of drug-resistant bacteria infection. Meanwhile, the efflux pump inhibitor also has a certain effect on improving the pharmacokinetic parameters (such as oral absorption degree and liver and kidney clearance rate) of certain medicines. Therefore, the search for new AcrB efflux pump inhibitors is of great significance for solving gram-negative bacterial infections.
Disclosure of Invention
In order to solve the problems, the invention provides a diaryl derivative with antibacterial sensitization activity and a preparation method thereof. Meanwhile, the diaryl derivative used as an AcrB efflux pump inhibitor performs in-vitro antibacterial sensitization activity research on gram-negative bacteria over expressing AcrB, and finds that a target compound shows better antibacterial sensitization activity.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
in a first aspect of the present invention, there is provided a bisaryl derivative or a pharmaceutically acceptable salt thereof having an antibacterial sensitizing activity, comprising:
the compound has the structure shown in formula I:
Figure BDA0003534482500000021
in the formula Ar1Selected from phenyl, benzopyranyl;
Ar2is selected from aryl and heteroaryl, wherein the aryl is selected from phenyl, naphthyl and biphenyl, and the heteroaryl is selected from quineAn oxazolin-4-onyl group;
R3selected from gem-dimethyl, isopropyl, tert-butyl;
R4each independently selected from hydrogen, morpholine formyl and oxadiazole base;
x is selected from-NHCO-, -NHCOCH2-、-OCH2-、-OCH2CH2-、-OCH2CO-；
R5Selected from hydrogen, methyl, halogen, trifluoromethyl, nitro, ester group,
Figure BDA0003534482500000022
Wherein R is6Is selected from
Figure BDA0003534482500000023
Figure BDA0003534482500000024
In a second aspect of the present invention, there is provided a process for preparing a biaryl derivative or a pharmaceutically acceptable salt thereof having antibacterial sensitization activity, comprising:
scheme 1 proceeds:
Figure BDA0003534482500000031
scheme 2 proceeds:
Figure BDA0003534482500000032
scheme 3 proceeds:
Figure BDA0003534482500000033
scheme 4 proceeds:
Figure BDA0003534482500000041
in a third aspect of the invention, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a gram-negative bacterial infection carrying an AcrB efflux pump; the compound of formula (I) may be a compound having a structure of formula (II), (III), (IV) or (V).
The invention has the beneficial effects that:
(1) the diaryl derivative used as an external efflux pump inhibitor of AcrB performs in-vitro antibacterial sensitization activity research on gram-negative bacteria over expressing AcrB, and finds that a target compound shows better antibacterial sensitization activity.
(2) The diaryl compound has good antibacterial sensitization activity when being used in combination with the existing antibacterial drugs. Especially has obvious effect on gram negative bacteria over expressing AcrB, and can be used for preparing medicines for treating bacterial infection.
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The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a hydrogen spectrum of Compound A9.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
A compound of formula (I) or a pharmaceutically acceptable salt thereof:
Figure BDA0003534482500000042
wherein in the compound of formula (I), Ar1Selected from phenyl, benzopyranyl;
Ar2is selected from aryl and heteroaryl, wherein the aryl is selected from phenyl and naphthylBiphenyl, the heteroaryl group being selected from the group consisting of quinazolin-4-onyl;
R3selected from gem-dimethyl, isopropyl, tert-butyl;
R4each independently selected from hydrogen, morpholine formyl and oxadiazole base;
x is selected from-NHCO-, -NHCOCH2-、-OCH2-、-OCH2CH2-、-OCH2CO-；
R5Selected from hydrogen, methyl, halogen, trifluoromethyl, nitro, ester group,
Figure BDA0003534482500000051
Wherein R is6Is selected from
Figure BDA0003534482500000052
Figure BDA0003534482500000053
In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, has the structure of formula (II):
Figure BDA0003534482500000054
wherein Ar is2Selected from phenyl, naphthyl, biphenyl;
m is selected from-CH2-、-CH2CO-；
R5Selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, nitro, methyl and carbomethoxy;
in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, has the structure of formula (III):
Figure BDA0003534482500000055
wherein Ar is2Selected from phenyl, naphthyl, biphenyl;
x is selectedfrom-CH2-、-CH2CH2-、-CH2CO-；
R5Selected from hydrogen, fluorine, chlorine, bromine, methyl, tert-butyloxycarboxamide;
in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, has the structure of formula (IV):
Figure BDA0003534482500000056
wherein R is6Is selected from
Figure BDA0003534482500000057
Figure BDA0003534482500000061
In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, has the structure of formula (V):
Figure BDA0003534482500000062
wherein R is6Is selected from
Figure BDA0003534482500000063
Figure BDA0003534482500000064
In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the following structures:
Figure BDA0003534482500000065
Figure BDA0003534482500000071
in another aspect, the invention provides methods for preparing compounds of formula (I).
In some embodiments, the compound of formula (I) has the structure shown in formula (II); further, the process proceeds as in scheme 1 below:
Figure BDA0003534482500000072
reaction conditions are as follows: (a) isoprene, xylene, orthophosphoric acid, room temperature; (b) benzyl chloride, N-dimethylformamide, 80 ℃; (c) sodium hydroxide, methanol/water, reflux; (d) morpholine, TBTU, N-diisopropylethylamine, acetonitrile, room temperature; (e) Pd/C, hydrogen, methanol/ethyl acetate, room temperature; (f) potassium carbonate, acetonitrile, Br-M-Ar2-R5,70℃。
Wherein Ar is2、R5M is as defined above in scheme (II);
in some embodiments, the method comprises starting with compound 1, which undergoes a cycloaddition reaction with isoprene to give compound 2; reacting the compound 2 with benzyl chloride to obtain a compound 3; hydrolyzing the compound 3 under alkaline conditions to obtain a compound 4; carrying out amide condensation reaction on the compound 4 and morpholine to obtain a compound 5; deprotection of compound 5 to obtain compound 6; compound 6 with Br-M-Ar2-R5The compound of formula (II) is obtained by reaction.
In some embodiments, the compound of formula (I) has the structure shown in formula (III); further, the process proceeds as in scheme 2 below:
Figure BDA0003534482500000081
reaction conditions are as follows: (a) hydrazine hydrate and refluxing; (b) refluxing triethyl orthoformate; (c) Pd/C, hydrogen, methanol/ethyl acetate, room temperature; (d) potassium carbonate, acetonitrile, Br-M-Ar2-R5,70℃。
Wherein Ar is2、R5M is as defined above in mode (III);
in some embodiments, the method comprises starting with compound 3, which is reacted with hydrazine hydrate at reflux to give compound 7; cyclizing the compound 7 and triethyl orthoformate to obtain a compound 8; removing a protecting group of the compound 8 under the hydrogen condition to obtain a compound 9; compound 9 with Br-M-Ar2-R5The compound of formula (III) is obtained by reaction.
In some embodiments, the compound of formula (I) has the structure shown in formula (IV); further, the process proceeds as in scheme 3 below:
Figure BDA0003534482500000082
reaction conditions are as follows: (a) di-tert-butyl dicarbonate, sodium carbonate, water/1, 4-dioxane, room temperature; (b) 4-isopropylaniline, PyBop, N-diisopropylethylamine, acetonitrile, room temperature; (c) trifluoroacetic acid, dichloromethane, 0 ℃; (d) r6COOH, TBTU, N-diisopropylethylamine, acetonitrile, room temperature; (e) triphosgene, triethylamine, dichloromethane, 60 ℃; (f) triphosgene, dichloromethane, R6H, room temperature.
Wherein R is6The definition of (IV) is as described in the above mode (IV);
in some embodiments, the method comprises starting with p-aminophenylacetic acid 10, protecting its amino group with Boc to produce compound 11; carrying out amide condensation reaction on the compound 11 and p-isopropylaniline to obtain a compound 12; removing Boc protecting group from the compound 12 under acidic condition to obtain a compound 13; compound 13 with fatty acid R6Amide condensation of COOH to obtain C1-C3; reacting the compound 13 with triphosgene under the condition of weak base to prepare isocyanate 14; compound 14 with fatty amine R6H carries out nucleophilic attack on isocyanate to obtain the corresponding urea compound C4-C11.
In some embodiments, the compound of formula (I) has the structure of formula (V); further, the process proceeds as in scheme 3 below:
Figure BDA0003534482500000091
reaction conditions are as follows: (a) refluxing; (b) nitric acid, sulfuric acid, 98 ℃; (c) potassium hydroxide, methanol/water, 70 ℃; (d) p-tert-butylaniline, TBTU, N, N-diisopropylethylamine, acetonitrile, room temperature; (e) Pd/C, hydrogen, methanol/ethyl acetate, room temperature; (f) r6COOH, TBTU, N-diisopropylethylamine, acetonitrile, room temperature; (g) bromoacetyl bromide, triethylamine, tetrahydrofuran, 0 ℃; (h) r6H, potassium carbonate, N-dimethylformamide, 60 ℃.
Wherein R is6Is as defined in the above mode (V);
in some embodiments, the process comprises reacting 2-aminobenzamide as a starting material with compound 16 under reflux to give compound 17; carrying out nitration reaction on the compound 17 to obtain a compound 18; hydrolyzing the compound 18 under alkaline conditions to obtain a compound 19; carrying out amide condensation reaction on the compound 19 and p-tert-butyl aniline to obtain a compound 20; carrying out reduction reaction on the compound 20 to obtain a compound 21; carrying out amide condensation on the compound 21 and different fatty acids to obtain a target product D1-D2; meanwhile, the compound 21 reacts with bromoacetyl bromide under the weak base condition of triethylamine to prepare a compound 22; and carrying out an affinity substitution reaction on the compound 22 and corresponding amine to obtain a target compound D3-D8.
In another aspect, the present application also provides a pharmaceutical composition comprising a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof. The compound of formula (I) may be a compound having a structure of formula (II), (III), (IV) or (V).
In a further aspect, the present application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, in the manufacture of a medicament for the treatment of an infection by a gram-negative bacterium harboring an AcrB efflux pump; the compound of formula (I) may be a compound having a structure of formula (II), (III), (IV) or (V).
In some embodiments, the present application further provides a combination for treating a bacterial infection harboring an AcrB efflux pump.
The present invention is described in further detail below with reference to specific examples, which are intended to be illustrative of the invention and not limiting.
Example 1.
Preparation of Compound 2
Dissolving the compound 1(2.18g,13.00mmol) and orthophosphoric acid (85%, 4mL) in xylene (12mL), slowly dropwise adding isoprene (1.36g,20.00mmol), reacting at room temperature for 6h, monitoring the reaction by TLC, evaporating the solvent under reduced pressure, adding 60mL of water, extracting with ethyl acetate (40 mL. times.3), combining organic phases, filtering, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography to obtain a colorless oily substance 1.32g, wherein the yield is as follows: and 43 percent.
Example 2.
Preparation of Compound 3
Weighing the compound 2(7.08g,30.00mmol), benzyl chloride (5.67,45.00mmol) and potassium carbonate (6.22,45.00mmol) and dissolving in 50mL of DMF, reacting at 70 ℃ for 5h, after the reaction is completed, adding 100mL of water, extracting with ethyl acetate (50mL multiplied by 3), combining organic phases, filtering, decompressing and evaporating to dryness to obtain a crude product, and purifying by silica gel column chromatography to obtain 8.31g of a white solid, wherein the yield is as follows: 89 percent.
Example 3.
Preparation of Compound 4
Weighing compound 3(8.00g,24.51mmol), dissolving in 60mL mixed solution of methanol and water (1:1), adding sodium hydroxide (4.90g,122.59mmol), reacting at 70 ℃ for 6h, monitoring the reaction by TLC, evaporating methanol solvent under reduced pressure, adjusting pH to be less than 2 by concentrated hydrochloric acid, precipitating a large amount of solid, filtering, washing twice, drying to obtain 7.04g yellow solid, yield: 92 percent.
Example 4.
Preparation of Compound 5
Weighing compound 4(5.98g,19.14mmol) and TBTU (7.37g,19.14mmol) to dissolve in 60mL acetonitrile, stirring at room temperature for 30min, adding morpholine (1.67g,19.14mmol) and N, N-diisopropylethylamine (4.91g,38.28mmol), reacting at room temperature for 4h, evaporating the solvent under reduced pressure, adding 60mL of water, extracting with ethyl acetate (40mL multiplied by 3), combining organic phases, washing with 1N hydrochloric acid, 5% sodium bicarbonate and saturated saline in sequence, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography to obtain 5.91g of a yellow solid with a yield of 81%.
Example 5.
Preparation of Compound 6
Dissolving a compound 5(4.00g,10.48mmol) in 100mL of a mixed solution (1:1) of methanol and ethyl acetate, adding 150mg of Pd/C, adding hydrogen balloon, reacting at room temperature for 12h, filtering after complete reaction, performing reduced pressure spin-drying on the filtrate to obtain a white crude product, and recrystallizing with petroleum ether/ethyl acetate to obtain a white solid 2.62g, wherein the yield is as follows: 90 percent.
Example 6.
Preparation of the Compound of formula (II)
Weighing Compound 6(500mg,1.72mmol), Br-M-Ar2-R5Dissolving (3.43mmol) and potassium carbonate (474mg,3.43mmol) in 15mL acetonitrile, reacting at 65 ℃ for 6h, adding 30mL water after the reaction is completed, extracting with ethyl acetate (10mL multiplied by 3), combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography to obtain the compound of the formula (II).
A1 light yellow solid, wherein the solid is white,1H NMR(500MHz,CDCl3)δ7.52–7.47(m,4H),7.40–7.32(m,4H),7.28–7.22(m,1H),6.39(d,J＝2.5Hz,1H),6.32(d,J＝2.5Hz,1H),4.95(s,2H),3.70(d,J＝57.3Hz,4H),3.43(t,J＝4.6Hz,2H),3.17(s,2H),2.69(dt,J＝34.4,7.7Hz,1H),2.41–2.28(m,1H),1.70(q,J＝7.0Hz,2H),1.24(s,6H).
a2 light yellow solid, wherein the solid is white,1H NMR(500MHz,CDCl3)δ7.63(d,J＝8.1Hz,2H),7.51(d,J＝8.1Hz,2H),6.43(d,J＝2.5Hz,1H),6.38(d,J＝2.5Hz,1H),5.06(s,2H),3.78(d,J＝43.4Hz,4H),3.54(t,J＝4.6Hz,2H),3.31–3.19(m,2H),2.87–2.76(m,1H),2.50–2.37(m,1H),1.79(dt,J＝13.6,6.8Hz,2H),1.32(s,6H).
a3 light yellow solid, wherein the solid is white,1H NMR(500MHz,CDCl3)δ8.23(d,J＝8.7Hz,2H),7.57(d,J＝8.7Hz,2H),6.42–6.38(m,2H),5.11(s,2H),3.79(d,J＝38.5Hz,4H),3.56(t,J＝4.6Hz,2H),3.33–3.21(m,2H),2.79(dd,J＝18.2,10.8Hz,1H),2.50–2.39(m,1H),1.80(dq,J＝13.3,6.8Hz,2H),1.32(s,6H).
a4 light yellow solid, wherein the solid is white,1H NMR(500MHz,CDCl3)δ7.27(d,J＝8.4Hz,2H),7.16(d,J＝7.9Hz,2H),6.44(d,J＝2.5Hz,1H),6.37(d,J＝2.5Hz,1H),4.95(s,2H),3.90–3.67(m,4H),3.52(t,J＝4.6Hz,2H),3.30–3.16(m,2H),2.87–2.74(m,1H),2.50–2.37(m,1H),2.34(s,3H),1.77(q,J＝6.7Hz,2H),1.32(s,6H).
a5 light yellow solid, wherein the solid is white,1H NMR(500MHz,CDCl3)δ8.07–8.01(m,2H),7.46(d,J＝6.9Hz,2H),6.40(dd,J＝17.7,2.2Hz,2H),5.07(s,2H),3.92(d,J＝2.0Hz,3H),3.79(d,J＝43.4Hz,4H),3.54(s,2H),3.34–3.15(m,2H),2.88–2.74(m,1H),2.50–2.33(m,1H),1.79(q,J＝6.8,6.4Hz,2H),1.32(s,6H).
a6 light yellow solid, wherein the solid is white,1H NMR(500MHz,CDCl3)δ8.05(d,J＝8.3Hz,2H),7.71(d,J＝8.2Hz,2H),7.67–7.59(m,2H),7.48(t,J＝7.5Hz,2H),7.41(t,J＝7.3Hz,1H),6.40(dd,J＝13.0,2.3Hz,2H),5.24(s,2H),3.83(s,4H),3.63–3.51(m,2H),3.28(d,J＝24.7Hz,2H),2.89–2.73(m,1H),2.42(d,J＝15.5Hz,1H),1.82–1.75(m,2H),1.32(s,6H).
a7 light yellow solid, wherein the solid is white,1H NMR(500MHz,CDCl3)δ7.92(d,J＝8.4Hz,2H),7.46(d,J＝8.3Hz,2H),6.43–6.32(m,2H),5.16(s,2H),3.78(d,J＝40.6Hz,4H),3.56(s,2H),3.26(d,J＝20.4Hz,2H),2.87–2.72(m,1H),2.42(d,J＝15.4Hz,1H),1.77(d,J＝6.5Hz,2H),1.31(s,6H).
A8A is yellow solid, and the yellow solid,1H NMR(500MHz,CDCl3)δ8.06–7.97(m,2H),7.17(t,J＝7.6Hz,2H),6.37(d,J＝18.2Hz,2H),5.17(s,2H),3.79(d,J＝48.8Hz,4H),3.57(s,2H),3.27(d,J＝21.3Hz,2H),2.88–2.73(m,1H),2.49–2.33(m,1H),1.88–1.70(m,2H),1.31(s,6H).
a9: a yellow solid, which is a solid,1H NMR(500MHz,CDCl3)δ7.84(dd,J＝8.5,1.8Hz,2H),7.64(dd,J＝8.5,1.8Hz,2H),6.40–6.32(m,2H),5.15(d,J＝1.6Hz,2H),3.78(d,J＝41.0Hz,4H),3.57(s,2H),3.26(d,J＝21.1Hz,2H),2.80–2.71(m,1H),2.51–2.34(m,1H),1.81–1.74(m,2H),1.31(s,6H).
example 7.
Preparation of Compound 7
Compound 3(4.00g,12.25mmol) was dissolved in 30mL of hydrazine hydrate, the reaction was refluxed for 8h, and after completion of the reaction, the solvent was removed under reduced pressure to give 2.72g of a yellow oil, yield: 68 percent.
Example 8.
Preparation of Compound 8
Compound 3(2.00g,6.13mmol) was dissolved in triethyl orthoformate (4.54g,30.65mmol), reacted for 12h under reflux, after completion of the reaction, the solvent was removed under reduced pressure and purified by silica gel column chromatography to give 1.69g of yellow oil, yield: 82 percent.
Example 9.
Preparation of Compound 9
The starting material used was compound 8, prepared in the same manner as in example 5.
Example 10.
Preparation of formula (III)
The starting material used was compound 9, prepared in the same manner as in example 6.
B1 preparation of a white solid,1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.65–7.57(m,4H),7.50(d,J＝8.1Hz,2H),7.44(t,J＝7.6Hz,2H),7.35(t,J＝7.4Hz,1H),7.22(d,J＝2.6Hz,1H),6.67(d,J＝2.6Hz,1H),5.11(s,2H),3.15(t,J＝6.8Hz,2H),1.85(t,J＝6.8Hz,2H),1.36(s,6H).
b2: a yellow solid, which is a solid,1H NMR(500MHz,CDCl3) δ 8.38(s,1H), 8.04-7.97 (m,2H), 7.69-7.62 (m,2H), 7.59-7.52 (m,2H), 7.44-7.38 (m,2H),7.34(td, J ═ 7.0,3.2Hz,1H),7.13(d, J ═ 2.7Hz,1H),6.51(d, J ═ 2.7Hz,1H),5.24(s,2H),3.07(t, J ═ 6.8Hz,2H),1.76(t, J ═ 6.8Hz,2H),1.27(s,6H), B3: pale yellow solid,1H NMR(500MHz,CDCl3)δ8.47(s,1H),7.94(d,J＝8.6Hz,2H),7.48(d,J＝8.6Hz,2H),7.17(d,J＝2.7Hz,1H),6.55(d,J＝2.6Hz,1H),5.24(s,2H),3.14(t,J＝6.8Hz,2H),1.84(t,J＝6.8Hz,2H),1.34(s,6H).
b4 of light yellow solid, namely,1H NMR(500MHz,CDCl3)δ8.54(d,J＝7.1Hz,1H),8.46(s,1H),8.04(d,J＝8.5Hz,1H),7.99(d,J＝8.2Hz,1H),7.94(d,J＝8.6Hz,1H),7.90(d,J＝8.1Hz,1H),7.64(t,J＝7.4Hz,1H),7.59(t,J＝7.4Hz,1H),7.23(s,1H),6.62(s,1H),5.44(s,2H),3.15(t,J＝6.7Hz,2H),1.84(t,J＝6.7Hz,2H),1.35(s,6H).
b5 preparation of a white solid,1H NMR(500MHz,CDCl3)δ8.46(d,J＝2.2Hz,1H),7.89(d,J＝6.2Hz,2H),7.30(d,J＝6.7Hz,2H),7.19(t,J＝2.2Hz,1H),6.56(s,1H),5.28(d,J＝2.1Hz,2H),3.14(dd,J＝6.6,4.9Hz,2H),2.44(d,J＝1.5Hz,3H),1.84(dd,J＝6.6,5.0Hz,2H),1.34(s,6H).
b6, namely, the yellow solid,1H NMR(500MHz,CDCl3)δ8.47(d,J＝1.5Hz,1H),8.04(dd,J＝7.2,5.4Hz,2H),7.18(t,J＝7.8Hz,3H),6.55(s,1H),5.25(d,J＝1.1Hz,2H),3.14(t,J＝6.6Hz,2H),1.84(t,J＝6.6Hz,2H),1.35(s,6H).
b7 (B) a yellow solid,1H NMR(500MHz,CDCl3)δ8.47(s,1H),7.91–7.84(m,2H),7.68–7.62(m,2H),7.17(d,J＝2.4Hz,1H),6.54(s,1H),5.24(s,2H),3.14(t,J＝6.7Hz,2H),1.84(t,J＝6.7Hz,2H),1.35(s,6H).
b8 preparation of a white solid,1H NMR(500MHz,CDCl3)δ8.45(s,1H),7.26–7.21(m,2H),7.09(d,J＝2.6Hz,1H),7.02–6.95(m,2H),6.55(d,J＝2.6Hz,1H),4.15(t,J＝6.8Hz,2H),3.13(t,J＝6.8Hz,2H),3.06(t,J＝6.8Hz,2H),1.84(t,J＝6.8Hz,2H),1.35(s,6H).
b9 preparation of a white solid,1H NMR(500MHz,CDCl3)δ8.45(s,1H),7.32–7.25(m,5H),7.10(s,1H),6.57(s,1H),4.18(dd,J＝7.6,6.3Hz,2H),3.15–3.08(m,4H),1.84(t,J＝6.3Hz,2H),1.35(s,6H).
b10 of light yellow solid, namely,1H NMR(500MHz,CDCl3)δ8.46(s,1H),7.30(d,J＝7.3Hz,2H),7.19(d,J＝6.8Hz,2H),7.08(s,1H),6.55(s,1H),6.44(s,1H),4.18–4.11(m,2H),3.13(t,J＝6.0Hz,2H),3.03(t,J＝6.3Hz,2H),2.05(d,J＝1.9Hz,1H),1.84(dd,J＝6.7,5.3Hz,2H),1.51(s,9H),1.35(d,J＝1.7Hz,6H).
example 11.
Preparation of Compound 11
Weighing compound 10(2.00g,13.23mmol) and sodium carbonate (1.55g,14.56mmol), dissolving in a mixed solution of water and 1, 4-dioxane (1:1,50mL), stirring under ice bath, slowly dropwise adding di-tert-butyl dicarbonate (3.18g,14.56mmol), reacting at 0 ℃ for 1h, heating to room temperature for 4h, monitoring by TLC (thin-layer chromatography), after the reaction is completed, spin-drying dioxane solvent under reduced pressure, adjusting pH to 4 with 1N HCl, extracting with ethyl acetate (30mL × 3), combining organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure to obtain a crude product, recrystallizing with ethanol to obtain a white solid 2.50g, yield: and 76 percent.
Example 12.
Preparation of Compound 12
Dissolving compound 11(2.40g,9.60mmol) and PyBop (5.25g,10.08mmol) in 40mL acetonitrile, stirring at room temperature for 0.5h, adding 4-isopropylaniline (1.36g,10.08mmol) and N, N-diisopropylethylamine (2.48g,19.20mmol), reacting at room temperature for 4h, evaporating the solvent under reduced pressure, adding 40mL of water, extracting with ethyl acetate (20mL × 3), combining the organic phases, washing with 1N hydrochloric acid, 5% sodium bicarbonate and saturated brine in sequence, drying over anhydrous sodium sulfate, filtering, evaporating under reduced pressure to obtain a crude product, and purifying by silica gel column chromatography (dichloromethane/methanol ═ 60:1) to obtain a yellow solid 3.21g, yield: 91 percent.
Example 13.
Preparation of Compound 13
Weighing compound 12(3.00g,8.14mmol), dissolving in a mixed solution (1:1,20mL) of trifluoroacetic acid and dichloromethane, reacting at room temperature for 12h, decompressing and spin-drying the solvent after the reaction is completed, adding 30mL of water, adding sodium hydroxide (0.40g,10.00mmol), stirring at room temperature for 0.5h, extracting with ethyl acetate (25mL multiplied by 3), combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to dryness to obtain a crude product, recrystallizing with petroleum ether/ethyl acetate to obtain 1.88g of a yellow solid, wherein the yield is as follows: 86 percent.
Example 14.
Preparation of Compounds C1-C3
Weighing corresponding fatty acid (0.75mmol) and TBTU (250mg,0.78mmol) and dissolving in 20mL of acetonitrile, stirring at room temperature for 0.5h, adding compound 13(200mg,0.75mmol) and N, N-diisopropylethylamine (200mg,1.50mmol), reacting at room temperature for 3h, evaporating the solvent under reduced pressure, adding 20mL of water, extracting with ethyl acetate (20mL multiplied by 3), combining organic phases, washing with 1N hydrochloric acid, 5% sodium bicarbonate and saturated salt solution in sequence, drying with anhydrous sodium sulfate, filtering, evaporating to obtain a crude product under reduced pressure, and purifying by silica gel column chromatography (dichloromethane/methanol) to obtain the corresponding target compound C1-C3.
C1, white solid, and the white solid,1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),10.05(s,1H),7.64–7.58(m,2H),7.52–7.46(m,2H),7.30–7.24(m,2H),7.18–7.12(m,2H),6.43(dd,J＝17.0,10.1Hz,1H),6.24(dd,J＝16.9,2.1Hz,1H),5.77–5.71(m,1H),3.57(s,2H),2.82(hept,J＝6.9Hz,1H),1.16(d,J＝6.9Hz,6H).
c2, white solid, and the white solid,1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.79(s,1H),7.59–7.46(m,4H),7.23(dd,J＝8.3,5.3Hz,2H),7.15(d,J＝8.5Hz,2H),5.95–5.71(m,1H),3.54(d,J＝2.0Hz,2H),3.03(s,1H),2.82(hept,J＝6.8Hz,1H),2.14(d,J＝1.2Hz,2H),1.89–1.82(m,2H),1.76(s,1H),1.16(d,J＝6.9Hz,6H).
c3, white solid, and the white solid,1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),10.03(s,1H),7.49(t,J＝8.1Hz,4H),7.23(d,J＝8.4Hz,2H),7.15(d,J＝8.5Hz,2H),3.54(s,2H),2.81(h,J＝6.9Hz,1H),2.57(d,J＝7.9Hz,2H),2.48–2.29(m,6H),1.50(p,J＝5.6Hz,4H),1.38(d,J＝6.7Hz,2H),1.16(d,J＝6.9Hz,6H).
example 15.
Preparation of Compound 14
Weighing compound 13(500mg,1.86mmol) and triphosgene (586mg,1.86mmol) and dissolving in 10mL dichloromethane, slowly adding triethylamine (566mg,5.59mmol) solution dropwise, reacting at 60 deg.C for 10h, monitoring reaction completion by TLC, and reducing pressure
The solvent was evaporated to dryness to give 550mg of off-white solid which was used in the next step without further purification.
Example 16.
Preparation of Compounds C4-C11
Dissolving a compound 14(250mg,0.85mmol) in 10mL dichloromethane, slowly dropwise adding fatty amine (0.85mmol) with different substituents, reacting at 40 ℃ for 2h, monitoring the reaction completion by TLC, adding 20mL water, extracting with dichloromethane (20mL multiplied by 3), combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure to obtain a crude product, and recrystallizing with ethyl acetate to obtain a corresponding target compound C4-C11.
C4: a white solid, a solid which is,1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.23(s,1H),7.55–7.44(m,2H),7.35–7.26(m,2H),7.21–7.09(m,4H),5.95(d,J＝7.6Hz,1H),3.74(dq,J＝13.3,6.6Hz,1H),3.50(s,2H),2.82(hept,J＝6.9Hz,1H),1.16(d,J＝6.9Hz,6H),1.08(d,J＝6.5Hz,6H).
c5, white solid, wherein the solid is white solid,1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),8.59(s,1H),7.49(d,J＝8.5Hz,2H),7.31(d,J＝8.4Hz,2H),7.20–7.10(m,4H),6.05(t,J＝5.3Hz,1H),3.50(s,2H),3.16(q,J＝5.9Hz,2H),2.81(hept,J＝6.9Hz,1H),2.31(t,J＝6.2Hz,2H),2.16(s,6H),1.16(d,J＝6.9Hz,6H).
c6, white solid, and the white solid,1H NMR(400MHz,DMSO-d6)δ10.01(s,1H),9.05(s,1H),7.53–7.44(m,2H),7.33(d,J＝8.5Hz,2H),7.16(dd,J＝8.6,7.3Hz,4H),3.51(s,2H),3.39–3.31(m,2H),2.91(s,3H),2.81(hept,J＝6.9Hz,1H),2.43(t,J＝5.9Hz,2H),2.23(s,6H),1.16(d,J＝6.9Hz,6H).
c7, white solid, and the white solid,1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.33(s,1H),7.51–7.45(m,2H),7.31(d,J＝8.5Hz,2H),7.19–7.11(m,4H),6.18(d,J＝7.7Hz,1H),3.80(d,J＝13.3Hz,2H),3.62(d,J＝7.4Hz,1H),3.50(s,2H),2.98–2.75(m,3H),1.85–1.72(m,2H),1.40(s,9H),1.25(ddd,J＝14.4,7.4,3.0Hz,2H),1.16(d,J＝6.9Hz,6H).
c8, white solid, and the white solid,1H NMR(400MHz,DMSO-d6)δ12.09(s,1H),10.00(s,1H),8.38(s,1H),7.49(d,J＝8.5Hz,2H),7.36–7.28(m,2H),7.21–7.11(m,4H),6.17(t,J＝5.7Hz,1H),3.50(s,2H),3.08(q,J＝6.6Hz,2H),2.81(h,J＝6.9Hz,1H),2.23(t,J＝7.4Hz,2H),1.65(q,J＝7.1Hz,2H),1.16(d,J＝6.9Hz,6H).
c9, white solid, and the white solid,1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.37(s,1H),7.54–7.45(m,2H),7.35–7.28(m,2H),7.21–7.12(m,4H),6.09(t,J＝5.7Hz,1H),3.57(t,J＝4.6Hz,4H),3.50(s,2H),3.09(q,J＝6.6Hz,2H),2.82(hept,J＝6.9Hz,1H),2.30(dd,J＝15.9,8.8Hz,6H),1.58(q,J＝7.0Hz,2H),1.16(d,J＝6.9Hz,6H).
c10, white solid, and the white solid,1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.37(s,1H),7.54–7.44(m,2H),7.34–7.28(m,2H),7.20–7.11(m,4H),6.09(t,J＝5.7Hz,1H),3.50(s,2H),3.07(q,J＝6.5Hz,2H),2.81(h,J＝6.9Hz,1H),2.26(dd,J＝16.5,9.4Hz,6H),1.56(q,J＝7.0Hz,2H),1.48(p,J＝5.5Hz,4H),1.37(d,J＝6.2Hz,2H),1.16(d,J＝6.9Hz,6H).
c11, white solid, and the white solid,1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),9.89(s,1H),7.50(t,J＝8.0Hz,4H),7.23(d,J＝8.5Hz,2H),7.15(d,J＝8.5Hz,2H),3.54(s,2H),2.82((hept,J＝6.9Hz,1H),2.02(s,3H),1.16(d,J＝6.9Hz,6H).
example 17.
Preparation of Compound 17
Weighing anthranilamide 15(5.00g,32.72mmol) and diethyl oxalate (11.88g,80.78mmol) under nitrogen protection, heating to 185 ℃ for reaction for 5h, after the reaction is completed, evaporating the solvent under reduced pressure, and recrystallizing with ethanol to obtain a white solid 6.12g, wherein the yield is as follows: and 76 percent.
Example 18.
Preparation of Compound 18
Compound 17(6.00g,27.50mmol) was dissolved in 20mL of concentrated sulfuric acid, stirred in ice bath, 10mL of fuming nitric acid was slowly added dropwise, and after dropping, the temperature was raised to 98 ℃ for reaction for 3 h. Pouring the reaction solution into ice water, stirring, separating out a large amount of white solid, performing suction filtration, and drying to obtain 6.12g of white solid, wherein the yield is as follows: 81 percent.
Example 19.
Preparation of Compound 19
Weighing intermediate IIF-4(5.50g,20.90mmol), dissolving in 60mL mixed solution of methanol and water (1:1), adding potassium hydroxide (5.86g,104.48mmol), reacting at 70 deg.C for 6h, monitoring reaction completion by TLC, evaporating methanol solvent under reduced pressure, concentrating with concentrated solution
Adjusting the pH value to be less than 2 by hydrochloric acid, separating out a large amount of solid, filtering, washing twice, drying to obtain 4.85g of yellow solid, wherein the yield is as follows: 99 percent.
Example 20.
Preparation of Compound 20
Compound 19(4.50g,19.14mmol) and TBTU (7.37g,19.14mmol) were weighed and dissolved in 60mL acetonitrile, stirred at room temperature for 30min, added with 4-tert-butylaniline (3.43g,19.14mmol) and N, N-diisopropylethylamine (4.91g,38.28mmol), reacted at room temperature for 4h, the solvent was evaporated to dryness under reduced pressure, 60mL of water was added, extracted with ethyl acetate (40mL × 3), the organic phases were combined, washed successively with 1N hydrochloric acid, 5% sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure to give a crude product, and purified by silica gel column chromatography (dichloromethane/methanol ═ 100:1) to give 6.14g of a yellow solid, yield: 87%.
Example 21.
Preparation of Compound 21
Dissolving the compound 20(6.14g,16.73mmol) in 100mL of a mixed solution (1:1) of methanol and ethyl acetate, adding Pd/C150 mg, adding hydrogen balloon, reacting at room temperature for 12h, filtering after complete reaction, performing reduced pressure spin drying on the filtrate to obtain a white crude product, and recrystallizing by petroleum ether/ethyl acetate to obtain a yellow solid 5.03g, wherein the yield is as follows: 89 percent.
Example 22.
Preparation of Compounds D1-D2
The starting material used was compound 21, prepared in the same manner as in example 14.
D1 preparation of a white solid,1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),10.67(s,1H),10.41(s,1H),8.52(d,J＝2.4Hz,1H),8.05(dd,J＝8.9,2.5Hz,1H),7.85(d,J＝8.8Hz,1H),7.79(d,J＝2.0Hz,1H),7.78(d,J＝2.2Hz,1H),7.42(d,J＝2.0Hz,1H),7.40(d,J＝2.1Hz,1H),2.12(s,3H),1.29(s,9H).
d2 preparation of a white solid,1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),10.69(s,1H),10.61(s,1H),8.60(d,J＝2.5Hz,1H),8.15(dd,J＝8.8,2.5Hz,1H),7.88(d,J＝8.8Hz,1H),7.82–7.76(m,2H),7.45–7.38(m,2H),6.48(dd,J＝17.0,10.0Hz,1H),6.34(dd,J＝17.0,2.0Hz,1H),5.84(dd,J＝10.0,2.0Hz,1H),1.29(s,9H).
example 23.
Preparation of Compound 22
Weighing the compound 21(500mg,1.49mmol) and triethylamine (181mg,1.79mmol), dissolving in 20mL tetrahydrofuran, slowly dropwise adding bromoacetyl bromide solution (601mg,2.98mmol) under ice bath, reacting for 5h, after the reaction is completed, evaporating the solvent under reduced pressure, adding 30mL water, extracting with ethyl acetate (20mL multiplied by 3), combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, evaporating to dryness under reduced pressure to obtain a crude product, and purifying with silica gel column chromatography (dichloromethane/methanol ═ 35:1) to obtain 551mg of yellow solid, wherein the yield is: 75 percent.
Example 24.
Preparation of Compounds D3-D8
Weighing and dissolving compound 22(150mg,0.33mmol), fatty amine (0.66mmol) with different substituents and potassium carbonate (91mg,0.66mmol) in 10mL acetonitrile, reacting at 70 ℃ for 6h, adding 50mL of water after the reaction is completed, extracting with ethyl acetate (15mL multiplied by 3), combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, filtering, decompressing and evaporating to obtain a crude product, and purifying by silica gel column chromatography to obtain a target product D3-D8.
D3, namely, a white solid,1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.59(d,J＝2.5Hz,1H),8.11(dd,J＝8.8,2.5Hz,1H),7.85(d,J＝8.8Hz,1H),7.81–7.74(m,2H),7.45–7.36(m,2H),3.34(d,2H),2.35(s,3H),1.29(s,9H).
d4 preparation of a white solid,1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),10.68(s,1H),10.24(s,1H),8.62(d,J＝2.4Hz,1H),8.14(dd,J＝8.8,2.5Hz,1H),7.85(d,J＝8.8Hz,1H),7.78(d,J＝8.6Hz,2H),7.41(d,J＝8.6Hz,2H),3.15(s,2H),2.30(s,6H),1.29(s,9H).
d5: a white solid, a solid which is,1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),8.56(d,J＝2.6Hz,1H),8.10(dd,J＝8.8,2.5Hz,1H),7.86(d,J＝8.8Hz,1H),7.83–7.75(m,2H),7.47–7.37(m,2H),3.33(d,2H),2.77(p,J＝6.2Hz,1H),1.29(s,9H),1.03(d,J＝6.2Hz,6H).
d6: a white solid, a solid which is,1H NMR(400MHz,DMSO-d6)δ10.68(s,1H),10.26(s,1H),8.57(d,J＝2.5Hz,1H),8.11(dd,J＝8.8,2.5Hz,1H),7.86(d,J＝8.8Hz,1H),7.79(d,J＝8.6Hz,2H),7.41(d,J＝8.6Hz,2H),3.41(s,2H),2.20(tt,J＝6.7,3.6Hz,1H),1.29(s,9H),0.39(dh,J＝6.5,2.9Hz,2H),0.32(q,J＝6.8,5.1Hz,2H).
d7: a white solid, a solid which is,1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),10.68(s,1H),10.22(s,1H),8.57(d,J＝2.5Hz,1H),8.14(dd,J＝8.8,2.5Hz,1H),7.86(d,J＝8.8Hz,1H),7.81–7.76(m,2H),7.44–7.39(m,2H),3.66(t,J＝4.6Hz,4H),3.20(s,2H),2.54(t,J＝4.6Hz,4H),1.29(s,9H).
d8: a yellow solid, which is a solid,1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),10.27(s,1H),8.58(d,J＝2.5Hz,1H),8.11(dd,J＝8.9,2.5Hz,1H),7.86(d,J＝8.8Hz,1H),7.79(d,J＝8.8Hz,2H),7.41(d,J＝8.8Hz,2H),3.84(d,J＝13.3Hz,2H),3.40(s,2H),2.81(s,2H),2.61(tt,J＝9.7,3.8Hz,1H),1.79(dd,J＝12.9,3.8Hz,2H),1.39(s,9H),1.29(s,9H),1.19(d,J＝10.7Hz,2H).
example 25.
The experimental principle of in vitro antibacterial test is as follows: adding a certain amount of liquid culture medium into a 96-well plate (sterilized), sequentially adding target compounds with certain concentrations and DMSO solutions of reference substances into the 96-well plate A-H lines, diluting by adopting a continuous micropore double dilution method, then inoculating a proper amount of bacteria liquid for over-expressing AcrB, incubating at constant temperature of 37 ℃ for 24H, observing the bacterial growth condition of each hole, and reading the Minimum Inhibitory Concentration (MIC) of each target compound. The method is used for measuring the inherent antibacterial activity of the compound, thereby determining the concentration range of the target compound when the target compound and the antibacterial agent are used together, and eliminating the influence of the target compound on the antibacterial activity when the target compound and the antibacterial agent are used together.
The experimental method comprises the following steps: (1) recovery and passage of bacteria: taking out the frozen E.coli BW25113 strain from a refrigerator at the temperature of-80 ℃, inoculating the strain on an LB culture medium by adopting a plate-drawing method, culturing the strain in a constant-temperature incubator at the temperature of 37 ℃ for 18 to 24 hours, selecting a single colony with good growth condition, inoculating the single colony in 10mL of LB liquid culture medium, and performing shaking culture on a constant-temperature shaking table at the temperature of 37 ℃ for 4 hours.
(2) Diluting bacterial liquid: OD of bacterial liquid of ultraviolet spectrophotometer660At 0.3, the cells were diluted to a concentration of 1X 10 with LB liquid medium5CFU/ml。
(3) Sample adding: diluting to different concentration gradients in multiple proportion by adopting a continuous micropore dilution method, adding the diluted solutions into an LB liquid culture medium containing bacterial liquid, setting a contrast, and incubating for 24 hours at 37 ℃.
(4) Reading of Minimum Inhibitory Concentration (MIC): after the incubation is finished, the growth condition of bacteria on the 96-well plate is observed, the bacteria are read from the first hole of each row, the concentration corresponding to the first hole without turbidity in the row is taken as the MIC of the compound to be detected, and the MIC of other target compounds is determined by the same method.
The experimental results are as follows: coli BW25113, MIC values for all target compounds were greater than 512 μ g/mL, indicating that these compounds had little antibacterial effect when used alone.
Example 26.
The experimental principle of the in vitro antibacterial sensitization activity test is as follows: the antibacterial sensitization activity of the target compound is determined by measuring the MIC values of different antibacterial agents (erythromycin, chloramphenicol and tetraphenylphosphonium chloride) against the wild type E.coli BW25113 strain when used alone and in combination with a sub-concentration of the target compound, and comparing the MIC values of the antibiotics in two cases. The size of the antibacterial sensitization activity of the target compound can be judged according to the MIC reduction degree of the corresponding antibiotic. According to the result of the combined medication, a potential AcrB inhibitor with better sensitization activity can be preliminarily screened.
The experimental method comprises the following steps: (1) and (3) bacterial culture: single colonies with good growth conditions were selected on LB medium, inoculated into 10mL of LB liquid medium, and cultured at 37 ℃ for 24 hours.
(2) Diluting bacterial liquid: OD of bacterial liquid of ultraviolet spectrophotometer660At 0.3, the cells were diluted to a concentration of 1X 10 with LB liquid medium5CFU/mL。
(3) Sample adding: continuously diluting the prepared antibiotics (erythromycin, chloramphenicol, and tetraphenylphosphonium chloride) to 7 different concentrations along the ordinate by continuous microporous double dilution method, diluting the target compound to 11 concentrations along the abscissa by double decreasing, and adding 1 × 105CFU/ml of the bacterial solution was inoculated into a 96-well sterile plate and incubated at 37 ℃ for 18 hours.
(4) Reading the MIC: after incubation, the inhibition of the drug combinations on bacterial growth at various concentrations on the 96-well plate was observed and the MIC was read.
The experimental results are as follows:
TABLE 1 results of in vitro antibacterial Activity test for combinations of target Compounds with antibacterial Agents
Figure BDA0003534482500000201
Figure BDA0003534482500000211
The experimental results show that the diaryl compound has good antibacterial and synergistic activity on Escherichia coli over-expressing AcrB, and the diaryl compound is found in the compounds for the first time.
It should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and the present invention is not limited thereto, and although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications and equivalents can be made in the technical solutions described in the foregoing embodiments, or equivalents thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A bisaryl derivative or a pharmaceutically acceptable salt thereof having an antibacterial sensitizing activity, comprising:
the compound has the structure shown in formula I:
Figure FDA0003534482490000011
in the formula Ar1Selected from phenyl, benzopyranyl;
Ar2is selected from aryl and heteroaryl, wherein the aryl is selected from phenyl, naphthyl and biphenyl, and the heteroaryl is selected from quinazoline-4-keto;
R3selected from gem-dimethyl, isopropyl, tert-butyl;
R4each independently selected from hydrogen, morpholine formyl and oxadiazole base;
x is selected from-NHCO-, -NHCOCH2-、-OCH2-、-OCH2CH2-、-OCH2CO-；
R5Selected from hydrogen, methyl, halogen, trifluoromethyl, nitro, ester group,
Figure FDA0003534482490000015
Wherein R is6Is selected from
Figure FDA0003534482490000016
Figure FDA0003534482490000012
2. The bisaryl derivative or pharmaceutically acceptable salt thereof having antibacterial sensitization activity according to claim 1, wherein the compound has a structure represented by formula (II):
Figure FDA0003534482490000013
wherein Ar is2Selected from phenyl, naphthyl, biphenyl;
m is selected from-CH2-、-CH2CO-；
R5Selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, nitro, methyl and carbomethoxy.
3. The bisaryl derivative or pharmaceutically acceptable salt thereof having antibacterial sensitization activity according to claim 1 wherein the compound has a structure represented by formula (III):
Figure FDA0003534482490000014
wherein Ar is2Selected from phenyl, naphthyl, biphenyl;
x is selected from-CH2-、-CH2CH2-、-CH2CO-；
R5Selected from hydrogen, fluorine, chlorine, bromine, methyl and tert-butyloxycarboxamide.
4. The bisaryl derivative or pharmaceutically acceptable salt thereof having antibacterial sensitization activity according to claim 1 wherein the compound has a structure represented by formula (IV):
Figure FDA0003534482490000021
wherein R is6Is selected from
Figure FDA0003534482490000022
Figure FDA0003534482490000023
5. The bisaryl derivative or pharmaceutically acceptable salt thereof having antibacterial sensitization activity according to claim 1 wherein the compound has a structure represented by formula (V):
Figure FDA0003534482490000024
wherein R is6Is selected from
Figure FDA0003534482490000025
Figure FDA0003534482490000026
6. The bisaryl derivative or pharmaceutically acceptable salt thereof having antibacterial sensitization activity according to claim 1, wherein the compound is selected from the group consisting of the following structures:
Figure FDA0003534482490000027
Figure FDA0003534482490000031
7. a process for preparing the biaryl derivative or its pharmaceutically acceptable salt having antibacterial sensitization activity according to claim 2, comprising:
taking a compound 1 as a starting material, and performing cycloaddition reaction on the compound 1 and isoprene to obtain a compound 2; reacting the compound 2 with benzyl chloride to obtain a compound 3; hydrolyzing the compound 3 under alkaline conditions to obtain a compound 4; carrying out amide condensation reaction on the compound 4 and morpholine to obtain a compound 5; deprotecting the compound 5 to obtain a compound 6; compound 6 with Br-M-Ar2-R5Reacting to obtain a compound shown in a formula (II);
wherein, the structural formula of the compound 1 is as follows:
Figure FDA0003534482490000041
or, taking the compound 3 as an initial raw material, and carrying out reflux reaction on the initial raw material and hydrazine hydrate to obtain a compound 7; cyclizing the compound 7 and triethyl orthoformate to obtain a compound 8; removing a protecting group of the compound 8 under the hydrogen condition to obtain a compound 9; compound 9 with Br-M-Ar2-R5Reacting to obtain a compound shown in a formula (III);
the structural formula of the compound 3 is
Figure FDA0003534482490000042
Or, taking p-aminophenylacetic acid 10 as an initial raw material, and protecting the amino group of the p-aminophenylacetic acid by Boc to prepare a compound 11; carrying out amide condensation reaction on the compound 11 and p-isopropylaniline to obtain a compound 12; removing Boc protecting group from the compound 12 under acidic condition to obtain a compound 13; compound 13 with fatty acid R6Amide condensation of COOH to obtain C1-C3; reacting the compound 13 with triphosgene under the condition of weak base to prepare isocyanate 14; compound 14 with fatty amine R6H carries out nucleophilic attack on isocyanate to obtain a corresponding urea compound C4-C11;
or, 2-aminobenzamide is taken as a starting material to react with the compound 16 under reflux to obtain a compound 17; carrying out nitration reaction on the compound 17 to obtain a compound 18; hydrolyzing the compound 18 under alkaline conditions to obtain a compound 19; carrying out amide condensation reaction on the compound 19 and p-tert-butyl aniline to obtain a compound 20; carrying out reduction reaction on the compound 20 to obtain a compound 21; carrying out amide condensation on the compound 21 and different fatty acids to obtain a target product D1-D2; meanwhile, the compound 21 reacts with bromoacetyl bromide under the weak base condition of triethylamine to prepare a compound 22; and carrying out an affinity substitution reaction on the compound 22 and corresponding amine to obtain a target compound D3-D8.
8. A pharmaceutical composition comprising the biaryl derivative having an antibacterial sensitizing activity according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
9. Use of the biaryl derivative or a pharmaceutically acceptable salt thereof having antibacterial sensitising activity according to any one of claims 1 to 6, or the pharmaceutical composition according to claim 8, in the manufacture of a medicament for the treatment of a gram-negative bacterial infection carrying an AcrB efflux pump.
10. A combination for the treatment of a bacterial infection carrying an AcrB efflux pump, which combination comprises a compound of formula (I) as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 8 in combination with an additional antibacterial agent.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115385886A (en) * 2022-06-28 2022-11-25 山东大学 AcrB efflux pump inhibitor and preparation method and application thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008373A (en) * 2016-06-12 2016-10-12 山东大学 Disubstituted bicyclic derivative and application thereof as efflux pump inhibitor to anti-microbial
CN108822095A (en) * 2018-07-25 2018-11-16 山东大学 Benzo [h] chromene compound and its application as AcrB efflux pump inhibitor in antibacterial
CN110105291A (en) * 2019-06-12 2019-08-09 山东大学 4- substitution -2- formamide quinazoline compounds and its preparation method and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008373A (en) * 2016-06-12 2016-10-12 山东大学 Disubstituted bicyclic derivative and application thereof as efflux pump inhibitor to anti-microbial
CN108822095A (en) * 2018-07-25 2018-11-16 山东大学 Benzo [h] chromene compound and its application as AcrB efflux pump inhibitor in antibacterial
CN110105291A (en) * 2019-06-12 2019-08-09 山东大学 4- substitution -2- formamide quinazoline compounds and its preparation method and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRIDGE, WALTER ET AL.: "Synthesis of rotenone and its derivatives. XIII", 《JOURNAL OF THE CHEMICAL SOCIETY》, pages 1530 - 1535 *
LEVAI, ALBERT: "Synthesis of 2, 2-dimethylchromans by the hydrogenation of 2, 2-dimethyl-2-H-chromenes", 《MONATSHEFTE FUER CHEMIE》, vol. 123, no. 5, pages 461 - 464 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115385886A (en) * 2022-06-28 2022-11-25 山东大学 AcrB efflux pump inhibitor and preparation method and application thereof
CN115385886B (en) * 2022-06-28 2024-04-19 山东大学 AcrB efflux pump inhibitor and preparation method and application thereof

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