CN114524792B - Diaryl derivative with antibacterial sensitization activity and application thereof in antibacterial - Google Patents

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

Info

Publication number
CN114524792B
CN114524792B CN202210223119.XA CN202210223119A CN114524792B CN 114524792 B CN114524792 B CN 114524792B CN 202210223119 A CN202210223119 A CN 202210223119A CN 114524792 B CN114524792 B CN 114524792B
Authority
CN
China
Prior art keywords
compound
antibacterial
mmol
white solid
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN202210223119.XA
Other languages
Chinese (zh)
Other versions
CN114524792A (en
Inventor
王印虎
陈军节
刘方全
薛洁
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Liaocheng University
Original Assignee
Liaocheng University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Liaocheng University filed Critical Liaocheng University
Priority to CN202210223119.XA priority Critical patent/CN114524792B/en
Publication of CN114524792A publication Critical patent/CN114524792A/en
Application granted granted Critical
Publication of CN114524792B publication Critical patent/CN114524792B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The application belongs to the field of pharmaceutical chemistry, and relates to diaryl derivatives with antibacterial sensitization activity and application thereof in antibacterial, wherein the compounds have a structure shown in a formula I:the compound can be used as an AcrB efflux pump inhibitor, has broad-spectrum antibacterial sensitization activity, and is Ar in the formula 1 、Ar 2 、R 3 、R 4 、R 5 X is defined as the specification.

Description

Diaryl derivative with antibacterial sensitization activity and application thereof in antibacterial
Technical Field
The application relates to the field of pharmaceutical chemistry, in particular to a diaryl derivative with antibacterial sensitization activity and application thereof as an AcrB efflux pump inhibitor in antibacterial.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the application and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
In recent years, bacterial resistance has become increasingly problematic due to the widespread use and even abuse of antibacterial drugs worldwide. Among them, infections caused by multidrug-resistant gram-negative bacteria have become one of the major factors threatening human health. Clinically, there are several most common multi-drug resistant gram-negative bacteria, such as Escherichia coli, pseudomonas aeruginosa, acinetobacter baumannii, etc., which spread epidemic in the world, 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 increases year by year. The multi-drug resistance rate of the escherichia coli in the ICU ward is as high as 44%, so that serious infection of various parts of human respiratory tract, digestive tract, urinary tract, skin and the like is often caused, and the escherichia coli becomes the most serious conditional pathogenic bacteria in the current bacterial infection. Therefore, in the next few years or even decades, the development of new effective antibacterial drugs or drugs (antibacterial sensitizers) with the efficacy of improving the existing antibacterial drugs has become a research hotspot in the field of new drug development today.
The efflux pump is a kind of protein widely existing on bacterial cell membranes, and can be used for excreting harmful substances to the efflux pump to the outside of the body under normal physiological conditions, thereby playing a role in self-protection. Over-expression of the efflux pump causes the antibacterial agent in the bacterial cells to be expelled from the body, thereby reducing the concentration of the agent reaching the site of action and failing to exert an effective antibacterial effect.
The AcrAB-TolC efflux pump is a class of proteins that are widely present on the cell membrane of gram-negative bacteria and is a complex composed of three parts, the fusion protein (AcrA), the inner membrane transporter (AcrB) and the outer membrane channel protein (TolC), which are present in the bacterial cytoplasmic gap. Wherein, acrA plays an auxiliary role in the transportation process mainly by connecting AcrB and TolC; acrB is responsible for capturing substrates present in the bacterial endomembrane or cytoplasm, thus determining the specificity of the efflux substrate, playing 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, and for the efflux of substrates outside the cell. The AcrAB-TolC efflux system normally excretes antibacterial drugs outside the cell by two routes, one is to capture the drug molecules in the cytoplasm and pump them out directly through the phospholipid bilayer, such as the development of drug resistance such as tetracycline and chloramphenicol; secondly, the transport of periplasmic space captured drugs to the outside of the cell via TolC, the efflux of some β -lactam antibiotics being representative of this mechanism. Since AcrB protein plays a decisive role in the three-component efflux system, its crystal structure and function have become the focus of research, and thus inhibition of the related functions of 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 restore or enhance the activity of existing antibiotics and control the spread of antibiotic resistance, providing a new concept for the treatment of infections with multi-drug resistant bacteria. Because the overexpression of the AcrB efflux pump is closely related to multi-drug resistance and cross-drug resistance of various antibacterial drugs, the combined use of the novel AcrB efflux pump inhibitor and the antibacterial drugs is an effective method for reducing the inherent drug resistance level of bacteria and recovering or enhancing the efficacy of the existing antibacterial drugs. Research shows that the AcrB efflux pump inhibitor can weaken the efflux effect of drug-resistant bacteria on antibacterial drugs, so that acquired drug resistance is reversed to a certain extent, and the clinical curative effect of drug-resistant bacteria infection is improved. Meanwhile, the efflux pump inhibitor has a certain effect on improving the pharmacokinetic parameters (such as oral absorbability and liver and kidney clearance) of some medicines. Therefore, the search for new AcrB efflux pump inhibitors is of great importance for the resolution of gram-negative bacterial infections.
Disclosure of Invention
In order to solve the problems, the application provides a diaryl derivative with antibacterial sensitization activity and a preparation method thereof. Meanwhile, the diaryl derivative disclosed by the application is used as an AcrB efflux pump inhibitor to perform in-vitro antibacterial sensitization activity research on gram-negative bacteria over-expressing AcrB, and the target compound is found to show better antibacterial sensitization activity.
In order to achieve the technical purpose, the application adopts the following technical scheme:
in a first aspect of the present application there is provided a bisaryl derivative or a pharmaceutically acceptable salt thereof having antibacterial sensitization activity comprising:
the compound has a structure shown in a formula I:
ar in (a) 1 Selected from phenyl, benzopyranyl;
Ar 2 selected from aryl, aryl-heteroaryl, wherein the aryl is selected from phenyl, naphthyl, biphenyl, and the aryl-heteroaryl is selected from quinazolin-4-one;
R 3 selected from gem-dimethyl, isopropyl, tert-butyl;
R 4 each independently selected from hydrogen, morpholinyl, oxadiazolyl;
x is selected from-NHCO-, -NHCOCH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-OCH 2 CO-；
R 5 Selected from hydrogen, methyl, halogen, trifluoromethyl, nitro, ester group,Wherein R is 6 Selected from->
In a second aspect of the present application, there is provided a process for the preparation of a biaryl derivative having antibacterial sensitization activity or a pharmaceutically acceptable salt thereof, comprising:
scheme 1 proceeds:
scheme 2 proceeds:
scheme 3 proceeds:
scheme 4 proceeds:
in a third aspect of the application 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 the structure of formula (II), (III), (IV) or (V).
The application has the beneficial effects that:
(1) The biaryl derivative disclosed by the application is used as an AcrB efflux pump inhibitor to perform in-vitro antibacterial sensitization activity research on gram-negative bacteria over-expressing AcrB, and the target compound is found to show better antibacterial sensitization activity.
(2) The biaryl compound has good antibacterial sensitization activity when being used in combination with the existing antibacterial drugs. Particularly has remarkable effect on gram negative bacteria over-expressing AcrB, and can be used for preparing medicaments for treating bacterial infection.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application.
FIG. 1 is a hydrogen spectrum of Compound A9.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the application. 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 application belongs.
A compound of formula (I) or a pharmaceutically acceptable salt thereof:
wherein in the compound of formula (I), ar 1 Selected from phenyl, benzopyranyl;
Ar 2 selected from aryl, aryl-heteroaryl, wherein the aryl is selected from phenyl, naphthyl, biphenyl, and the aryl-heteroaryl is selected from quinazolin-4-one;
R 3 selected from gem-dimethyl, isopropyl, tert-butyl;
R 4 each independently selected from hydrogen, morpholinyl, oxadiazolyl;
x is selected from-NHCO-, -NHCOCH 2 -、-OCH 2 -、-OCH 2 CH 2 -、-OCH 2 CO-；
R 5 Selected from hydrogen, methyl, halogen, trifluoromethyl, nitro, ester group,Wherein R is 6 Selected from->
In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, has a structure of formula (II):
wherein Ar is 2 Selected from phenyl, naphthyl, biphenyl;
m is selected from-CH 2 -、-CH 2 CO-；
R 5 Selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, nitro, methyl ester groups;
in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, has a structure of formula (III):
wherein Ar is 2 Selected from phenyl, naphthyl, biphenyl;
x is selected from-CH 2 -、-CH 2 CH 2 -、-CH 2 CO-；
R 5 Selected from hydrogen, fluorine, chlorine, bromine, methyl, t-butoxycarboxamido;
in some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, has a structure of formula (IV):
wherein R is 6 Selected from the group consisting of
In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, has the structure of formula (V):
wherein R is 6 Selected from the group consisting of
In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from the following structures:
in another aspect, the present application provides various methods for preparing compounds of formula (I).
In some embodiments, the compound of formula (I) has a structure represented by formula (II); further, the process is carried out according to scheme 1 below:
reaction conditions: (a) isoprene, xylene, orthophosphoric acid, room temperature; (b) benzyl chloride, N-dimethylformamide, 80 ℃; (c) sodium hydroxide, methanol/water, reflux; (d) Morpholine, TBTU, N, N-diisopropylethylamine, acetonitrile, room temperature; (e) Pd/C, hydrogen, methanol/ethyl acetate, room temperature; (f) Potassium carbonate, acetonitrile, br-M-Ar 2- R 5 ,70℃。
Wherein Ar is 2 、R 5 M is as defined in the above-mentioned mode (II);
in some embodiments, the method comprises starting with compound 1, which is cycloaddition reacted with isoprene to give compound 2; compound 2 and benzyl chlorideReacting to obtain a compound 3; hydrolyzing the compound 3 under alkaline conditions to obtain a compound 4; the compound 4 and morpholine undergo an amide condensation reaction to obtain a compound 5; deprotection of compound no 5 to give compound 6; compound 6 and Br-M-Ar 2- R 5 The reaction produces the compound of formula (II).
In some embodiments, the compound of formula (I) has a structure represented by formula (III); further, the process proceeds as in scheme 2 below:
reaction conditions: (a) hydrazine hydrate, refluxing; (b) triethyl orthoformate, refluxing; (C) Pd/C, hydrogen, methanol/ethyl acetate, room temperature; (d) Potassium carbonate, acetonitrile, br-M-Ar 2- R 5 ,70℃。
Wherein Ar is 2 、R 5 M is as defined in the above mode (III);
in some embodiments, the method comprises starting with compound 3, which is reacted with hydrazine hydrate under reflux to give compound 7; the compound 7 is cyclized with triethyl orthoformate to prepare a compound 8; removing protecting groups from the compound 8 under the condition of hydrogen to obtain a compound 9; compound 9 and Br-M-Ar 2- R 5 The reaction produces the compound of formula (III).
In some embodiments, the compound of formula (I) has a structure represented by formula (IV); further, the process proceeds as in scheme 3 below:
reaction conditions: (a) Di-tert-butyl dicarbonate, sodium carbonate, water/1, 4-dioxane, room temperature; (b) 4-isopropylaniline, pyBop, N, N-diisopropylethylamine, acetonitrile, room temperature; (c) trifluoroacetic acid, dichloromethane, 0 ℃; (d) R is R 6 COOH, TBTU, N-diisopropylethylamine, acetonitrile, room temperature; (e) triphosgene, triethylamine, dichloromethane, 60 ℃; (f) Triphosgene, dichloromethane, R 6 H, room temperature.
Wherein R is 6 The definition of (a) is as described in the above mode (IV);
in some embodiments, the method comprises starting with para-aminophenylacetic acid 10, protected with Boc to produce compound 11; compound 11 and p-isopropylaniline undergo an amide condensation reaction to prepare compound 12; removing Boc protecting group from the compound 12 under acidic condition to obtain a compound 13; compound 13 and fatty acid R 6 The COOH is subjected to amide condensation to obtain a product C1-C3; reacting the compound 13 with triphosgene under a weak base condition to prepare isocyanate 14; compound 14 and fatty amine R 6 Nucleophilic attack of H on isocyanate to obtain corresponding urea compound C4-C11.
In some embodiments, the compound of formula (I) has a structure represented by formula (V); further, the process proceeds as in scheme 3 below:
reaction conditions: (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) R is R 6 COOH, TBTU, N-diisopropylethylamine, acetonitrile, room temperature; (g) bromoacetyl bromide, triethylamine, tetrahydrofuran, 0deg.C; (h) R is R 6 H, potassium carbonate, N, N-dimethylformamide, 60 ℃.
Wherein R is 6 The definition of (a) is as described in the above mode (V);
in some embodiments, the method comprises reflux reacting 2-aminobenzamide starting with compound 16 to provide compound 17; the compound 17 is subjected to nitration reaction to obtain a compound 18; hydrolyzing the compound 18 under alkaline conditions to obtain a compound 19; compound 19 and p-tertiary butyl aniline undergo an amide condensation reaction to prepare compound 20; the compound 20 is subjected to reduction reaction to obtain a compound 21; the compound 21 and different fatty acids undergo amide condensation to obtain target products D1-D2; meanwhile, the compound 21 reacts with bromoacetyl bromide under the weak base condition of triethylamine to prepare a compound 22; the compound 22 and corresponding amine undergo a nucleophilic substitution reaction to obtain target compounds D3-D8.
In another aspect, the present application also provides a pharmaceutical composition comprising a compound of formula (I) above or a pharmaceutically acceptable salt thereof. The compound of formula (I) may be a compound having the structure of formula (II), (III), (IV) or (V).
In a further aspect, the application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, 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 the structure of formula (II), (III), (IV) or (V).
In some embodiments, the application also provides a combination for treating bacterial infection carrying an AcrB efflux pump.
The application will now be described in further detail with reference to the following specific examples, which should be construed as illustrative rather than limiting.
Example 1.
Preparation of Compound 2
Compound 1 (2.18 g,13.00 mmol) and orthophosphoric acid (85%, 4 mL) were dissolved in xylene (12 mL), isoprene (1.36 g,20.00 mmol) was slowly added dropwise, the reaction was completed at room temperature for 6h, tlc monitored the reaction, the solvent was evaporated under reduced pressure, 60mL of water was added, extraction was performed with ethyl acetate (40 ml×3), the organic phases were combined, filtered, evaporated under reduced pressure to obtain crude product, silica gel column chromatography was performed to obtain colorless oily substance 1.32g, yield: 43%.
Example 2.
Preparation of Compound 3
Compound 2 (7.08 g,30.00 mmol), benzyl chloride (5.67, 45.00 mmol) and potassium carbonate (6.22, 45.00 mmol) were weighed and dissolved in 50mL DMF, reacted for 5h at 70 ℃ and after the reaction was complete, 100mL of water was added, extracted with ethyl acetate (50 ml×3), the organic phases were combined, filtered, evaporated to dryness under reduced pressure to give crude product, which was purified by silica gel column chromatography to give 8.31g of white solid, yield: 89%.
Example 3.
Preparation of Compound 4
Compound 3 (8.00 g,24.51 mmol) was weighed and dissolved in 60mL of a mixed solution of methanol and water (1:1), sodium hydroxide (4.90 g,122.59 mmol) was added, the reaction was carried out for 6h at 70 ℃, tlc was monitored to be complete, the methanol solvent was evaporated under reduced pressure, pH <2 was adjusted with concentrated hydrochloric acid, a large amount of solid was precipitated, filtered, washed twice with water, and dried to obtain 7.04g of yellow solid, yield: 92%.
Example 4.
Preparation of Compound 5
Compound 4 (5.98 g,19.14 mmol) and TBTU (7.37 g,19.14 mmol) were weighed and dissolved in 60mL of acetonitrile, stirred at room temperature for 30min, morpholine (1.67 g,19.14 mmol) and N, N-diisopropylethylamine (4.91 g,38.28 mmol) were added, reacted at room temperature for 4h, the solvent was evaporated under reduced pressure, 60mL of water was added, extracted with ethyl acetate (40 mL. Times.3), the organic phases were combined, washed successively with 1N hydrochloric acid, 5% sodium bicarbonate, saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to give crude product, and purified by silica gel column chromatography to give 5.91g of yellow solid with a yield of 81%.
Example 5.
Preparation of Compound 6
Compound 5 (4.00 g,10.48 mmol) was dissolved in 100mL of mixed solution of methanol and ethyl acetate (1:1), pd/C150 mg was added, the reaction was carried out with a hydrogenation balloon at room temperature for 12h, after the reaction was completed, the mixture was filtered, the filtrate was dried under reduced pressure to obtain a white crude product, and the white crude product was recrystallized from petroleum ether/ethyl acetate to obtain a white solid 2.62g, yield: 90%.
Example 6.
Preparation of Compounds of formula (II)
Compound 6 (500 mg,1.72 mmol), br-M-Ar was weighed out 2- R 5 (3.43 mmol) and potassium carbonate (470 mg,3.43 mmol) were dissolved in 15mL of acetonitrile and reacted at 65℃for 6 hours, after the reaction was completed, 30mL of water was added, ethyl acetate (10 mL. Times.3) was extracted, the organic phases were combined, washed with 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 to give the compound of formula (II).
A1 is a light yellow solid, which is prepared from the following components, 1 H NMR(500MHz,CDCl 3 )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 is a light yellow solid, which is prepared from the following components, 1 H NMR(500MHz,CDCl 3 )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 is a light yellow solid, which is prepared from the following components, 1 H NMR(500MHz,CDCl 3 )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 is a light yellow solid, which is prepared from the following components, 1 H NMR(500MHz,CDCl 3 )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 is a light yellow solid, which is prepared from the following components, 1 H NMR(500MHz,CDCl 3 )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 is a light yellow solid, and the light yellow solid, 1 H NMR(500MHz,CDCl 3 )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 is a light yellow solid, which is prepared from the following components, 1 H NMR(500MHz,CDCl 3 )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).
a8-yellow solid, 1 H NMR(500MHz,CDCl 3 )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 was used as the starting material, 1 H NMR(500MHz,CDCl 3 )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 (4.00 g,12.25 mmol) was dissolved in 30mL of hydrazine hydrate and reacted at reflux for 8h, after the reaction was complete, the solvent was removed under reduced pressure to give 2.72g of yellow oil, yield: 68%.
Example 8.
Preparation of Compound 8
Compound 3 (2.00 g,6.13 mmol) was dissolved in triethyl orthoformate (4.54 g,30.65 mmol), reacted for 12h at reflux, after the reaction was complete, the solvent was removed under reduced pressure, and purified by silica gel column chromatography to give yellow oil 1.69g, yield: 82%.
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 is a white solid, and the white solid, 1 H NMR(500MHz,CDCl 3 )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 was used as the starting material, 1 H NMR(500MHz,CDCl 3 )δ8.38(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=2.7 Hz, 1H), 6.51 (d, J=2.7 Hz, 1H), 5.24 (s, 2H), 3.07 (t, J=6.8 Hz, 2H), 1.76 (t, J=6.8 Hz, 2H), 1.27 (s, 6H) B3: pale yellow solid, 1 H NMR(500MHz,CDCl 3 )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 is a light yellow solid, and the light yellow solid, 1 H NMR(500MHz,CDCl 3 )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 is a white solid, and the white solid, 1 H NMR(500MHz,CDCl 3 )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 is a light yellow solid, and the light yellow solid, 1 H NMR(500MHz,CDCl 3 )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-yellow solid, 1 H NMR(500MHz,CDCl 3 )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-white solid, 1 H NMR(500MHz,CDCl 3 )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 is a white solid, and the white solid, 1 H NMR(500MHz,CDCl 3 )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 is a light yellow solid, and the light yellow solid, 1 H NMR(500MHz,CDCl 3 )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
Compound 10 (2.00 g,13.23 mmol) and sodium carbonate (1.55 g,14.56 mmol) were weighed and dissolved in a mixed solution of water and 1, 4-dioxane (1:1, 50 mL), stirred under ice bath, di-tert-butyl dicarbonate (3.18 g,14.56 mmol) was slowly added dropwise, the mixture was reacted for 1h at 0 ℃, the reaction was warmed to room temperature, 4h was reacted after the reaction was completed by tlc monitoring, the dioxane solvent was dried under reduced pressure, ph=4 was adjusted by 1N HCl, extracted by ethyl acetate (30 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure to obtain crude product, which was recrystallized from ethanol to obtain 2.50g of white solid, yield: 76%.
Example 12.
Preparation of Compound 12
Compound 11 (2.40 g,9.60 mmol) and PyBop (5.25 g,10.08 mmol) were dissolved in 40mL of acetonitrile, stirred at room temperature for 0.5h, 4-isopropylaniline (1.36 g,10.08 mmol) and N, N-diisopropylethylamine (2.48 g,19.20 mmol) were added, reacted at room temperature for 4h, the solvent was evaporated under reduced pressure, 40mL of water was added, extracted with ethyl acetate (20 mL. Times.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 crude product, and silica gel column chromatography (dichloromethane/methanol=60:1) was purified to give 3.21g of yellow solid, yield: 91%.
Example 13.
Preparation of Compound 13
Compound 12 (3.00 g,8.14 mmol) was weighed and dissolved in a mixture of trifluoroacetic acid and dichloromethane (1:1, 20 mL), reacted at room temperature for 12h, after the reaction was completed, the solvent was dried by spin-drying under reduced pressure, 30mL of water was added, sodium hydroxide (0.40 g,10.00 mmol) was added and stirred at room temperature for 0.5h, extracted with ethyl acetate (25 ml×3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure to give crude product, which was recrystallized from petroleum ether/ethyl acetate to give yellow solid 1.88g, yield: 86%.
Example 14.
Preparation of Compounds C1-C3
The corresponding fatty acid (0.75 mmol) and TBTU (250 mg,0.78 mmol) were weighed and dissolved in 20mL of acetonitrile, stirred at room temperature for 0.5h, compound 13 (200 mg,0.75 mmol) and N, N-diisopropylethylamine (200 mg,1.50 mmol) were added, reacted at room temperature for 3h, the solvent was evaporated to dryness under reduced pressure, 20mL of water was added, extracted with ethyl acetate (20 mL. Times.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 crude product, and purified by silica gel column chromatography (dichloromethane/methanol) to give the corresponding target compound C1-C3.
C1 is a white solid, and the white solid, 1 H NMR(400MHz,DMSO-d 6 )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 is a white solid, and the white solid, 1 H NMR(400MHz,DMSO-d 6 )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 is a white solid, and the white solid, 1 H NMR(400MHz,DMSO-d 6 )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
Compound 13 (500 mg,1.86 mmol) and triphosgene (586 mg,1.86 mmol) were weighed and dissolved in 10mL of dichloromethane, triethylamine (566 mg,5.59 mmol) solution was slowly added dropwise, reacted for 10h at 60℃and monitored by TLC for completion of the reaction, and reduced pressure
The solvent was evaporated to dryness to give 550mg of an off-white solid which was used in the next step without purification.
Example 16.
Preparation of Compounds C4-C11
Compound 14 (250 mg,0.85 mmol) was dissolved in 10mL of dichloromethane, aliphatic amines (0.85 mmol) with different substituents were slowly added dropwise, the reaction was continued for 2h at 40℃and monitored by TLC, 20mL of water was added, dichloromethane (20 mL. Times.3) was used for extraction, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure to give crude product, and recrystallized from ethyl acetate to give the corresponding target compound C4-C11.
And C4: a white solid was used as a solid, 1 H NMR(400MHz,DMSO-d 6 )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 is a white solid, and the white solid, 1 H NMR(400MHz,DMSO-d 6 )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 is a white solid, and the white solid, 1 H NMR(400MHz,DMSO-d 6 )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 is a white solid, and the white solid, 1 H NMR(400MHz,DMSO-d 6 )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 is a white solid, and the white solid, 1 H NMR(400MHz,DMSO-d 6 )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, the white solid, 1 H NMR(400MHz,DMSO-d 6 )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 is a white solid, which is a white solid, 1 H NMR(400MHz,DMSO-d 6 )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 is a white solid, which is a white solid, 1 H NMR(400MHz,DMSO-d 6 )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
Anthranilamide 15 (5.00 g,32.72 mmol) and diethyl oxalate (11.88 g,80.78 mmol) were weighed out under nitrogen protection, heated to 185 ℃ for reaction for 5h, after the reaction was completed, the solvent was evaporated under reduced pressure, and recrystallized from ethanol to obtain white solid 6.12g, yield: 76%.
Example 18.
Preparation of Compound 18
Compound 17 (6.00 g,27.50 mmol) was dissolved in 20mL of concentrated sulfuric acid, stirred in an ice bath, 10mL of fuming nitric acid was slowly added dropwise, and the mixture was heated to 98℃to react for 3h. Pouring the reaction solution into ice water for stirring, precipitating a large amount of white solid, carrying out suction filtration and drying to obtain 6.12g of white solid, and obtaining the yield: 81%.
Example 19.
Preparation of Compound 19
Intermediate IIF-4 (5.50 g,20.90 mmol) was weighed and dissolved in 60mL of a mixed solution of methanol and water (1:1), potassium hydroxide (5.86 g,104.48 mmol) was added, the reaction was completed by TLC monitoring at 70℃for 6h, the methanol solvent was evaporated under reduced pressure, and concentrated was used
The pH value is regulated to be less than 2 by hydrochloric acid, a large amount of solids are separated out, the mixture is filtered, washed twice by water, and 4.85g of yellow solid is obtained after drying, and the yield is: 99%.
Example 20.
Preparation of Compound 20
Compound 19 (4.50 g,19.14 mmol) and TBTU (7.37 g,19.14 mmol) were weighed and dissolved in 60mL of acetonitrile, stirred at room temperature for 30min, 4-tert-butylaniline (3.43 g,19.14 mmol) and N, N-diisopropylethylamine (4.91 g,38.28 mmol) were added, reacted at room temperature for 4h, the solvent was evaporated under reduced pressure, 60mL of water was added, extracted with ethyl acetate (40 mL. Times.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 crude product, and silica gel column chromatography (dichloromethane/methanol=100:1) was purified to give 6.14g of yellow solid in 87% yield.
Example 21.
Preparation of Compound 21
Compound 20 (6.14 g,16.73 mmol) was dissolved in 100mL of mixed solution of methanol and ethyl acetate (1:1), pd/C150 mg was added, the reaction was carried out with a hydrogenation balloon at room temperature for 12h, after the reaction was completed, the mixture was filtered, the filtrate was dried under reduced pressure to give a white crude product, and the crude product was recrystallized from petroleum ether/ethyl acetate to give a yellow solid, 5.03g, yield: 89%.
Example 22.
Preparation of Compounds D1-D2
The starting material used was compound 21, prepared in the same manner as in example 14.
D1 is a white solid, which is a white solid, 1 H NMR(400MHz,DMSO-d 6 )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. a white solid, which is a white solid, 1 H NMR(400MHz,DMSO-d 6 )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
Compound 21 (500 mg,1.49 mmol) and triethylamine (181 mg,1.79 mmol) were weighed and dissolved in 20mL of tetrahydrofuran, bromoacetyl bromide solution (601 mg,2.98 mmol) was slowly added dropwise under ice bath, after completion of the reaction, the reaction was completed for 5 hours, the solvent was evaporated under reduced pressure, 30mL of water was added, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure to give crude product, silica gel column chromatography (dichloromethane/methanol=35:1) was purified to give 551mg of yellow solid, yield: 75%.
Example 24.
Preparation of Compounds D3-D8
Compound 22 (150 mg,0.33 mmol), aliphatic amine with different substituents (0.66 mmol) and potassium carbonate (91 mg,0.66 mmol) were weighed and dissolved in 10mL acetonitrile, reacted for 6h at 70 ℃, after the reaction was completed, 50mL water was added, ethyl acetate (15 ml×3) was added for extraction, the organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered, evaporated to dryness under reduced pressure to obtain crude product, and the target product D3-D8 was purified by silica gel column chromatography.
D3. White solid, the white solid, 1 H NMR(400MHz,DMSO-d 6 )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. White solid, the white solid, 1 H NMR(400MHz,DMSO-d 6 )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 was used as a solid, 1 H NMR(400MHz,DMSO-d 6 )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 was used as a solid, 1 H NMR(400MHz,DMSO-d 6 )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 was used as a solid, 1 H NMR(400MHz,DMSO-d 6 )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 was used as the starting material, 1 H NMR(400MHz,DMSO-d 6 )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.
In vitro antibacterial test experimental principle: adding a certain amount of liquid culture medium into a 96-well plate (sterilized), sequentially adding DMSO solutions of a target compound and a reference substance with a certain concentration into each row of the 96-well plate A-H, diluting by adopting a continuous micropore double dilution method, inoculating a proper amount of bacteria liquid over-expressing AcrB, incubating for 24 hours at a constant temperature of 37 ℃, observing the bacterial growth condition of each well, and reading the Minimum Inhibitory Concentration (MIC) of each target compound. The method is used for determining the inherent antibacterial activity of the compound, so that the concentration range of the target compound and the antibacterial agent when the target compound and the antibacterial agent are combined is determined, and the influence of the target compound on the antibacterial activity when the target compound and the antibacterial agent are combined is eliminated.
The experimental method comprises the following steps: (1) resuscitation and passaging of bacteria: taking out frozen E.coli BW25113 strain from a refrigerator at-80 ℃, inoculating the strain to an LB culture medium by adopting a plate streaking method, culturing the strain for 18-24 hours in a constant temperature incubator at 37 ℃, and then picking single bacterial colony with good growth condition, inoculating the single bacterial colony to 10mL of LB liquid culture medium, and culturing the strain for 4 hours by shaking the strain in a constant temperature incubator at 37 ℃.
(2) Diluting bacterial liquid: OD of bacteria liquid is measured by ultraviolet spectrophotometer 660 At 0.3, the culture broth was diluted to a concentration of 1X 10 with LB 5 CFU/ml。
(3) Sample adding: diluting with continuous microporous double dilution method, respectively diluting to different concentration gradients, adding into LB liquid culture medium containing bacterial liquid, setting control, and incubating at 37deg.C for 24 hr.
(4) Minimum Inhibitory Concentration (MIC) reading: after incubation, bacterial growth on the 96-well plate is observed, the MIC of the other target compounds is determined by reading from the first well of each row and taking the concentration corresponding to the first non-turbid well of the row as the MIC of the compound to be tested.
Experimental results: for wild type e.coli BW25113, MIC values for all target compounds were greater than 512 μg/mL, indicating that these compounds have little antimicrobial effect when used alone.
Example 26.
In vitro antibacterial sensitization activity test experimental principle: the antimicrobial sensitization activity of the target compounds was determined by determining the MIC values of different classes of antimicrobial agents (erythromycin, chloramphenicol, tetraphenylphosphine chloride) alone and in combination with sub-concentrations of the target compounds against the wild-type e.coli BW25113 strain, and comparing the MIC values of the antibiotics in both cases. The magnitude of the antimicrobial sensitization activity of the target compound can be judged according to the MIC reduction degree of the corresponding antibiotics. According to the result of the combined application, potential AcrB inhibitors with better sensitization activity can be initially screened out.
The experimental method comprises the following steps: (1) bacterial culture: single colonies with good growth conditions are picked on LB culture medium and inoculated into 10mL of LB liquid culture medium for 24h at 37 ℃.
(2) Diluting bacterial liquid: OD of bacteria liquid is measured by ultraviolet spectrophotometer 660 At 0.3, the culture broth was diluted to a concentration of 1X 10 with LB 5 CFU/mL。
(3) Sample adding: the prepared antibiotics (erythromycin, chloramphenicol and tetraphenylphosphine chloride) are serially diluted to 7 different test concentrations along the ordinate by adopting a serial microporous double dilution methodThe target compound was diluted in two-fold decrease along the abscissa to 11 test concentrations, and 1X 10 was added 5 CFU/ml bacterial liquid is inoculated in a 96-well sterile culture plate and incubated for 18h at 37 ℃.
(4) MIC reading: after incubation, the inhibition of bacterial growth by drug combinations at various concentrations on 96-well plates was observed and MIC was read.
Experimental results:
TABLE 1 results of in vitro antibacterial Activity test of the combination of target Compounds and antibacterial Agents
From the experimental results, it is found that the biaryl compound of the present application has good antibacterial synergistic activity against Escherichia coli overexpressing AcrB, which is first found in such compounds.
Finally, it should be noted that the above-mentioned embodiments are only preferred embodiments of the present application, and the present application is not limited to the above-mentioned embodiments, but may be modified or substituted for some of them by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application should be included in the protection scope of the present application.

Claims (3)

1. A group of biaryl derivatives having antibacterial sensitization activity, or pharmaceutically acceptable salts thereof, said biaryl derivatives selected from the following structures:
the A3 has antibacterial synergistic activity on chloramphenicol CAM;
the A5 has antibacterial synergistic activity on erythromycin ERY;
the A8 has antibacterial synergistic activity on chloramphenicol CAM and erythromycin ERY;
the A9 has antibacterial synergistic activity on chloramphenicol CAM and erythromycin ERY;
the B5 has antibacterial synergistic activity on erythromycin ERY;
the B9 has antibacterial synergistic activity on erythromycin ERY.
2. A pharmaceutical composition comprising the biaryl derivative having antibacterial sensitization activity of claim 1 or a pharmaceutically acceptable salt thereof.
3. A combination comprising the biaryl derivative of claim 1, or a pharmaceutically acceptable salt thereof, and an additional antibacterial agent;
when the biaryl derivative is A3, the additional antibacterial agent is chloramphenicol CAM;
when the biaryl derivative is A5, the additional antibacterial agent is erythromycin eri;
when the biaryl derivative is A8, the other antibacterial drugs are chloramphenicol CAM and erythromycin ERY;
when the diaryl derivative is A9, the other antibacterial drugs are chloramphenicol CAM and erythromycin ERY;
when the biaryl derivative is B5, the additional antibacterial agent is erythromycin eri;
when the biaryl derivative is B9, the additional antibacterial agent is erythromycin eri.
CN202210223119.XA 2022-03-07 2022-03-07 Diaryl derivative with antibacterial sensitization activity and application thereof in antibacterial Active CN114524792B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202210223119.XA CN114524792B (en) 2022-03-07 2022-03-07 Diaryl derivative with antibacterial sensitization activity and application thereof in antibacterial

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202210223119.XA CN114524792B (en) 2022-03-07 2022-03-07 Diaryl derivative with antibacterial sensitization activity and application thereof in antibacterial

Publications (2)

Publication Number Publication Date
CN114524792A CN114524792A (en) 2022-05-24
CN114524792B true CN114524792B (en) 2023-11-14

Family

ID=81626064

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202210223119.XA Active CN114524792B (en) 2022-03-07 2022-03-07 Diaryl derivative with antibacterial sensitization activity and application thereof in antibacterial

Country Status (1)

Country Link
CN (1) CN114524792B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115385886B (en) * 2022-06-28 2024-04-19 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
Levai, Albert.Synthesis of 2,2-dimethylchromans by the hydrogenation of 2,2-dimethyl-2-H-chromenes.《Monatshefte fuer Chemie》.1992,第123卷(第5期),第461-464页. *
Synthesis of rotenone and its derivatives. XIII;Bridge, Walter et al.;《Journal of the Chemical Society》;第1530-1535页 *

Also Published As

Publication number Publication date
CN114524792A (en) 2022-05-24

Similar Documents

Publication Publication Date Title
US10071969B2 (en) Methods for the synthesis of activated ethylfumarates and their use as intermediates
TWI518084B (en) Process for pyrone and pyridone derivatives
JP5400032B2 (en) Benzimidazole and pharmaceutical composition thereof
CN101815718A (en) Pyridine derivate and using method thereof
US9617249B2 (en) Benzoheterocyclic anti-bacterial agents
TW200406198A (en) O-substituted hydroxyaryl derivatives
WO2019080882A1 (en) Hdac inhibitor and preparation method therefor and use thereof
CN114524792B (en) Diaryl derivative with antibacterial sensitization activity and application thereof in antibacterial
CN113912560B (en) Oxazole histone deacetylase inhibitor and preparation method and application thereof
CN114685382B (en) Quinazoline-4-amine derivative with HDACs inhibitory activity, and preparation method and application thereof
CN108822095B (en) Benzo [ h ] chromene compound and application thereof as AcrB efflux pump inhibitor in antibiosis
CN113896725B (en) Pyrazoloquinoline compound and preparation method and application thereof
CN108409608B (en) Aromatic nitrogen mustard histone deacetylase inhibitor and preparation method and application thereof
CN111187218B (en) Application of 1-substituted-1H-imidazole-2-carboxylic acid compound in preparation of metal beta-lactamase inhibitor
CN102367239B (en) 2-aryl-2,3-dihydro-4H-1,3-benzothiazine-4-ketone derivatives and uses thereof
US20140256775A1 (en) Novel transcription factor modulators
CN114957153B (en) QS (quality control system) inhibitory active compound, composition and application thereof in field of preparation of antibacterial preparations
CN113754587B (en) Phenylpyrazole compound and application thereof
CN114605348A (en) Compounds having HDAC inhibitory activity, methods of making, compositions, and uses thereof
CN111285808B (en) 4-aromatic heterocycle substituted indazole compound and application thereof as IDO/TDO dual inhibitor
KR100820039B1 (en) Alkylamino naphthalenyloxymethyl propenyl hydroxybenzamide derivatives having inhibitory activity against histone deacetylase, method for the preparation thereof, and anticancer composition comprising the same
JP2002128768A (en) Compound having medicine drainage pump-inhibiting action
CN109705057B (en) Histone deacetylase inhibitor and preparation method and application thereof
CN114907288B (en) Application of nitrobenzene compounds in preparation of pseudomonas aeruginosa quorum sensing inhibitor
CN115043891B (en) Compound and preparation method and application thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant