CN116082280A - 4-aryl-5-methylene-2 (5H) -furanone derivative and preparation method and application thereof - Google Patents
4-aryl-5-methylene-2 (5H) -furanone derivative and preparation method and application thereof Download PDFInfo
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- CN116082280A CN116082280A CN202211729636.0A CN202211729636A CN116082280A CN 116082280 A CN116082280 A CN 116082280A CN 202211729636 A CN202211729636 A CN 202211729636A CN 116082280 A CN116082280 A CN 116082280A
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- Prior art keywords
- aryl
- alkyl
- methylene
- compound
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 30
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 21
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 17
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 9
- 239000003112 inhibitor Substances 0.000 claims abstract description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 51
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 241000894006 Bacteria Species 0.000 claims description 23
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 230000001580 bacterial effect Effects 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- -1 amino compound Chemical class 0.000 claims description 14
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 14
- 125000003709 fluoroalkyl group Chemical group 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 claims description 10
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
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- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 8
- 241000588724 Escherichia coli Species 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
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- 125000004054 acenaphthylenyl group Chemical group C1(=CC2=CC=CC3=CC=CC1=C23)* 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
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- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
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- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 2
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- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000005561 phenanthryl group Chemical group 0.000 claims description 2
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 claims description 2
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 claims description 2
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- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
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- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
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Abstract
The invention discloses a 4-aryl-5-methylene-2 (5H) -furanone derivative, a preparation method and application thereof, and the derivative has a structure shown in a formula I:
wherein R is 1 Is substituent on benzene ring, R 2 Selected from substituted aryl, aryl heteroaryl, substituted aryl heteroaryl, alkyl, cycloalkyl, n is 0-2, X is O or NR 3 . The invention aims to provide a 4-aryl-5-methylene-2 (5H) -furanone derivative, a preparation method and application thereof, wherein the derivative is completely different from a reported QS inhibitor parent nucleus structure, has different physicochemical properties, and experiments show that the derivative has the effect of inhibiting pseudomonas aeruginosa QS, can be used as a novel QS inhibitor and can also be used as an antibacterial sensitizer.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to a 4-aryl-5-methylene-2 (5H) -furanone derivative, and a preparation method and application thereof.
Background
The disclosure of this background section is only intended to increase the 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 already known to those of ordinary skill in the art.
With the uncontrolled use of antibiotics, the evolution of microorganisms is accelerated, and the time for generating drug resistance of new drugs is shortened. Antimicrobial resistance poses an increasing threat to human health. Thus, there is an urgent need for novel antimicrobial therapies with low resistance.
Quorum Sensing (QS) is an intercellular communication system in which bacteria produce and sense chemical signals (autoinductors) that enable the bacteria to coordinate their behavior as a population to accommodate environmental changes. The secretion and recognition process of QS signals is a cell density dependent process. As the number of bacteria increases, the concentration of the bacterial secreted autoinducer gradually increases, which, when the lowest threshold stimulus concentration of the autoinducer is detected, results in binding of the autoinducer to its cognate receptor protein and altering gene expression to modulate population behavior. Gene expression regulated by QS includes virulence factor production, biofilm formation, colony movement, and the like. Virulence factors produced by bacterial pathogens can cause damage to the host cell or evade clearance of the host cell immune system, ultimately leading to disease. Biofilm formation is associated with 80% of bacterial infections in humans. Typically, a biofilm is an extracellular polymeric matrix composed of nucleic acids, proteins, polysaccharides, and lipids. It can make bacteria attach to host surface, protect bacteria from host immune reaction or delay permeation of antibiotics, reduce antibiotic activity and even discharge antibiotics so as to promote the occurrence of chronic infection. Thus, disrupting cellular communication by interfering with QS system-mediated signals to attenuate accumulation of virulence factors and inhibit bacterial biofilm formation is an effective and promising approach to treating chronic bacterial infections. In contrast to traditional antibiotics, quorum Sensing Inhibitors (QSIs) do not affect bacterial growth and destroy bacterial viability, and ideally they do not interfere with bacterial and host metabolism. Thus, quorum sensing inhibitors are not likely to induce the development of drug resistance
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a 4-aryl-5-methylene-2 (5H) -furanone derivative, a preparation method and application thereof, wherein the derivative is completely different from a reported QS inhibitor parent nucleus structure, has different physicochemical properties, has the effect of inhibiting pseudomonas aeruginosa QS through experiments, can be used as a novel QS inhibitor, and can also be used as an antibacterial sensitizer.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
in a first aspect, a 4-aryl-5-methylene-2 (5H) -furanone derivative has a structure according to formula I:
wherein R is 1 Hydrogen, alkoxy, halogen, fluoroalkyl, fluoroalkoxy, or phenyl; r is R 2 Selected from aryl, substituted aryl, aryl heteroaryl, substituted aryl heteroaryl, alkyl, cycloalkyl; n is 0 to 2; x is-O-or-NR 3 -；R 3 Selected from hydrogen, alkyl, substituted aryl.
Further, R 1 Wherein the carbon number of the alkoxy group is 1 to 5, the carbon number of the fluoroalkyl group is 1 to 5, and the carbon number of the fluoroalkoxy group is 1 to 5.
Further, R 1 Selected from the group consisting of hydrogen, 4-methoxy, 4-chloro, 2-fluoro, 4-bromo, 3-trifluoromethyl, 3-chloro, 2-bromo, 3-fluoro, 4-phenyl.
Further, R 2 Wherein the aryl is selected from phenyl, naphthyl, anthryl, phenanthryl, indenyl, fluorenylAnd acenaphthylenyl, said substituted aryl being selected from the group consisting of
The R is 4 Selected from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, fluoroalkoxy, alkyl, cyano, and nitro. Further, R 4 Wherein the carbon number of the alkoxy group is 1 to 5, the carbon number of the fluoroalkyl group is 1 to 5, and the carbon number of the fluoroalkoxy group is 1 to 5. Further, the R 4 Selected from hydrogen, 4-methyl, 2-fluoro, 4-chloro, 3-bromo, 2-bromo, 4-bromo, 2-chloro, 3-methoxy, 2-methoxy, 3-methyl, 4-methoxy, 2-methyl, 3-chloro, 4-fluoro or 3-fluoro.
Further, R 2 Wherein the aryl is selected from the group consisting of furyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, morpholinyl, pyrazolyl, indolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, carbazolyl, purinyl, phenothiazinyl, and phenoxazinyl; the number of the substituent groups of the substituted aryl-heteroaryl is one or more, and each substituent group is independently selected from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, fluoroalkoxy, alkyl, cyano and nitro.
Further, R 2 Wherein the alkyl is selected from straight chain alkyl with 1-12C atoms or branched alkyl with 1-12C atoms; the cycloalkyl group is selected from cycloalkyl groups having 3 to 8 carbon atoms.
Further, n is 0, R 2 The alkyl is selected from ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and undecyl.
Further, R 3 The alkyl is selected from straight chain alkyl with 1-8C atoms, branched alkyl with 1-8C atoms and cycloalkyl with 3-8C atoms.
Further, R 3 Selected from ethyl, propyl, butyl, pentyl, cyclopentyl.
Further, R 3 Wherein the substituted aryl is selected from
The R is 5 Selected from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, fluoroalkoxy, alkyl, cyano, and nitro. Further, R 4 Wherein the carbon number of the alkoxy group is 1 to 5, the carbon number of the fluoroalkyl group is 1 to 5, and the carbon number of the fluoroalkoxy group is 1 to 5. Further, the R 5 Selected from 2-chloro, 4-methyl, 3-methyl, 2-methyl, 3-chloro.
In some embodiments, the following compounds are included:
in a second aspect, a process for preparing the above 4-aryl-5-methylene-2 (5H) -furanone derivative comprises the step of obtaining a compound of formula II according to scheme 1 or the step of obtaining a compound of formula III according to scheme 2:
scheme 1:
specifically, the operation steps are as follows: condensing substituted propiophenone with pyruvic acid to obtain an intermediate 1, reacting the intermediate 1 with NBS free radicals to obtain a brominated compound 2, subjecting the intermediate 2 with sodium azide to nucleophilic substitution reaction to obtain an intermediate 3, reducing the intermediate 3 with triphenylphosphine to obtain an amino compound 4, subjecting the amino compound 4 with an acyl chloride compound to amide condensation to obtain an intermediate 5, and directly dehydrating the intermediate 5 with phosphorus pentoxide to obtain a compound (furan ring end product) shown in a formula II;
intermediate 7 is obtained after the intermediate 5 is subjected to chlorination reaction, intermediate 8 is obtained after the intermediate 7 and amine compounds are subjected to lactone lactam conversion, and the intermediate 8 is dehydrated to obtain a compound (pyrrole ring-containing end product) shown in a formula III.
More specifically, the preparation method comprises the following steps:
(1) The operation mode of the step a is as follows, the substituted propiophenone and pyruvic acid raw materials are dissolved in phosphoric acid and stirred for 5 hours at 75 ℃ to carry out condensation reaction, then cooled to room temperature and stirred overnight, then ice water is added into the reaction liquid, petroleum ether is used: extracting with dichloromethane (1:1), mixing the organic phases, spin-drying to evaporate the solvent, and purifying by column chromatography to obtain a compound 1;
(2) Step b is performed in such a way that compound 1 is dissolved in acetonitrile, azobisisobutyronitrile is added and stirred at 65℃for 0.5h to initiate the radical reaction, then NBS is added in portions and stirring is continued at 80℃for 5h. After the reaction is finished, spin-drying the solvent, adding dichloromethane for dissolution, washing, and spin-drying the organic phase to obtain a crude product 2;
(3) The operation mode of the step c is as follows, the compound 2 is dissolved by DMF and water, sodium azide is added and stirred for 24 hours at 80 ℃, after the reaction is finished, water is added into the reaction liquid, the mixture is extracted by ethyl acetate, the organic phases are combined, and the solvent is evaporated by spin drying, thus obtaining a crude product compound 3;
(4) Dissolving the compound 3 by tetrahydrofuran, adding triphenylphosphine into the reaction solution, reacting for 18 hours at room temperature under the protection of nitrogen, and purifying by column chromatography after the reaction is finished to obtain a compound 4;
(5) The operation mode of the step e is as follows, the compound 4 is dissolved by methylene dichloride, triethylamine is used as an acid binding agent, amide condensation is carried out on the compound and different acyl chlorides, and the intermediate 5 is obtained after column chromatography purification after the reaction is finished;
(6) The operation mode of the step f is that after the compound 5 is dissolved by chloroform, phosphorus pentoxide is added to carry out dehydration reaction at 75 ℃, water is added to react out unreacted phosphorus pentoxide after the reaction is finished, dichloromethane is used for extraction, organic phases are combined, solvent is evaporated by spin drying, and then the furan ring end product 6 is obtained by column chromatography purification;
(7) The operation mode of the step g is as follows, the compound 5 and thionyl chloride are subjected to reflux reaction, and after the reaction is finished, the solvent is evaporated by spin drying to obtain a compound 7;
(8) The operation mode of the step h is that the compound 7 is dissolved in dichloromethane, then an aqueous solution of amine is added dropwise at the temperature of 0 ℃, the mixture is moved to room temperature after the dripping is finished to carry out lactone lactam conversion, and after the reaction is finished, the mixture is purified by column chromatography to obtain a compound 8;
(9) The operation mode of the step i is as follows, compound 8 is dissolved by chloroform, phosphorus pentoxide is added for dehydration reaction at 75 ℃, water is added for reaction at the end of the reaction to remove unreacted phosphorus pentoxide, dichloromethane is used for extraction, organic phases are combined, solvent is evaporated by spin drying, and then the pyrrole ring end product 9 is obtained by column chromatography purification.
In the scheme of the preparation method, the intermediate and the reaction product can be separated by conventional column chromatography, recrystallization and other separation means to obtain the pure product of each step of reaction.
In a third aspect, a pharmaceutically acceptable salt is a salt formed from the 4-aryl-5-methylene-2 (5H) -furanone derivative described above with an inorganic acid (e.g. hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid) or an organic acid (e.g. methanesulfonic acid, toluenesulfonic acid or trifluoroacetic acid).
In a fourth aspect, a pharmaceutical composition comprises the above 4-aryl-5-methylene-2 (5H) -furanone derivative and/or a solvate thereof. The solvate includes organic solvate and hydrate.
In a fifth aspect, a pharmaceutical formulation comprises an active ingredient which is the above 4-aryl-5-methylene-2 (5H) -furanone derivative, the above pharmaceutically acceptable salt or the above pharmaceutical composition, and at least one pharmaceutically acceptable carrier or excipient.
The pharmaceutically acceptable carrier or excipient of the present invention is non-toxic and safe, and its combination with the compounds of the present invention is also non-toxic and safe. Pharmaceutically acceptable carriers and excipients described herein are generally well known to those skilled in the art or can be determined by those skilled in the art depending on the actual situation. Examples of suitable carriers and excipients include dextrose, water, lactose, sucrose, glycerol, ethanol, propylene glycol, mannitol, corn starch, gelatin, alginic acid, microcrystalline cellulose, kaolin, dicalcium phosphate, sodium chloride, croscarmellose sodium, sodium starch glycolate and the like; hydrophilic carriers, hydrophobic carriers, combinations thereof, or the like. Hydrophobic carriers include, for example, fat emulsions, lipids, pegylated phospholipids, biocompatible polymers, lipid globules, liposomes, vesicles, polymeric matrices, and particles, and the like. Furthermore, it will be understood by those skilled in the art that diluents are included within the terms carrier and excipient. For convenience, local anesthetics, preservatives, buffers, and the like may be directly dissolved in the carrier.
The pharmaceutical composition and the pharmaceutical preparation of the present invention can be administered in unit dosage form, and the administration forms include injection, tablet, pill, capsule, suspension, emulsion, aerosol, powder, lyophilized powder for injection, clathrate, landfill, patch, liniment, etc. These dosage forms can be prepared by adding suitable excipients or excipients according to methods conventional in the art.
In a sixth aspect, the use of a 4-aryl-5-methylene-2 (5H) -furanone derivative, a pharmaceutically acceptable salt, a pharmaceutical composition or a pharmaceutical formulation as described above for the manufacture of a medicament for inhibiting the gram-negative bacterial QS system. It has the effect of competing with QS signal molecules for binding to QS system target proteins, thereby inhibiting bacterial biofilm formation, virulence factor expression and the like.
Further, the gram negative bacteria include, but are not limited to, pseudomonas aeruginosa, acinetobacter, escherichia coli, pneumobacter, vibrio cholerae, influenza (haemophilus), parainfluenza (haemophilus), legionella pneumophila, pertussis, proteus, bacillus dysenteriae, brucella, catarrhalis, yersinia, parapertussis, shigella, basdelia and parahaemolyticus. The bacterial growth inhibition experiment shows that the 4-aryl-5-methylene-2 (5H) -furanone derivative has no inhibition effect on the growth and reproduction of gram-negative bacteria, but can effectively reduce the expression of virulence factors, such as pseudomonas aeruginosa, which can obviously reduce the expression of virulence factors such as pyocin, rhamnolipid and the like and biological membranes and limit the colony movement of bacteria. Can be used in combination with antibacterial agent to improve the sensitivity of drug-resistant bacteria to antibiotics and enhance the therapeutic effect of the drug. Therefore, the 4-aryl-5-methylene-2 (5H) -furanone derivative can effectively reduce the toxicity and drug resistance of the gram-negative bacteria, is further used for treating diseases caused by the gram-negative bacteria, and can also be used for preparing medicines for treating diseases caused by the gram-negative bacteria.
Further, the diseases caused by the gram-negative bacteria include but are not limited to pneumonia, cystic fibrosis, endocarditis, peritonitis, empyema, septicemia, cholecystitis, cystitis, diarrhea, and gastroenteritis.
Further, a method of treating, alleviating or preventing a condition suffering from gram-negative bacteria-induced pneumonia, cystic fibrosis, endocarditis, peritonitis, sepsis, cholecystitis, cystitis, diarrhea, and gastroenteritis, comprising administering a therapeutically effective amount of a compound or pharmaceutically acceptable salt of formula I or a pharmaceutical composition or formulation.
Further, it is used for preparing QS inhibitor or antibacterial sensitizer.
Compared with the prior art, the invention has the beneficial effects that:
(1) The 4-aryl-5-methylene-2 (5H) -furanone derivative has no influence on the growth of various sensitive bacteria and drug-resistant bacteria, and is not easy to induce drug resistance.
(2) The 4-aryl-5-methylene-2 (5H) -furanone derivatives of the invention can interfere with the quorum sensing system of Pseudomonas aeruginosa in a concentration-wise manner, thereby inhibiting the expression of virulence factors and the formation of biofilms.
(3) The 4-aryl-5-methylene-2 (5H) -furanone derivative has good antibacterial synergistic effect.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a graph showing the results of examining the inhibitory activity of compounds I-1 to I-13 on Pseudomonas aeruginosa PAO1 pyocin in the examples of the present invention;
FIG. 2 is a graph showing the results of examining the inhibitory activity of the compounds I-14 to I-23 on Pseudomonas aeruginosa PAO1 pyocin in the examples of the present invention;
FIG. 3 is a graph showing the results of examining the inhibitory activity of compounds I-24 to I-37 on Pseudomonas aeruginosa PAO1 pyocin in the examples of the present invention;
FIG. 4 is a graph showing the results of examining the inhibitory activity of compounds I-38 to I-45 on Pseudomonas aeruginosa PAO1 pyocin in the examples of the present invention;
FIG. 5 is a graph showing synergistic antimicrobial effects of a compound and an antimicrobial agent in examples of the present invention, A is the inhibitory activity of Pseudomonas aeruginosa 27853 in cooperation with CLA, B is the inhibitory activity of Pseudomonas aeruginosa 27853 in cooperation with CIP, C is the inhibitory activity of Pseudomonas aeruginosa PAO1 in cooperation with CLA, and D is the inhibitory activity of Pseudomonas aeruginosa PAO1 in cooperation with CIP.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. 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.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular forms also are intended to include the plural forms unless the context clearly indicates otherwise, and furthermore, it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, and/or combinations thereof.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions or under conditions recommended by the manufacturer.
Unless otherwise indicated, all materials and reagents used in the present invention may be purchased by conventional means or prepared according to methods known in the art or by routine experimentation by those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Example 14 Synthesis of- (4-fluorophenyl) -5-hydroxy-3, 5-dimethylfuran-2 (5H) -one intermediate 1
4-fluorophenylacetone (1.06, 7 mmol) and pyruvic acid (1.54 g,117.5 mmol) were weighed, dissolved in 50mL of orthophosphoric acid, heated to 75℃and reacted for 5 hours. The reaction solution was left overnight at room temperature, and then ice brine (100 ml) was added to the reaction solution, followed by using methylene chloride: petroleum ether (1:1) extraction, combining organic phases, drying with anhydrous sodium sulfate, decompressing and evaporating solvent, purifying by column chromatography (eluent is petroleum ether-ethyl acetate, 10:1-8:1) to obtain compound 1, white solid 1.37g (yield 88.96%).
Example 23 Synthesis of 4- (4-fluorophenyl) -5-hydroxy-5-methylfuran-2 (5H) -one intermediate 2
The product obtained in example 1 (1.37 g,6.17 mmol) was taken, azobisisobutyronitrile (0.1 g, 0.611 mmol) was dissolved in anhydrous acetonitrile (20 mL) and stirred at 65℃for 0.5h to initiate reaction. NBS (1.21 g,6.79 mmol) was then added in portions and the reaction was gradually warmed to 80 ℃. After the TLC detection was completed, the solvent was dried by spin-drying. Washing with water, extracting with dichloromethane, combining the organic phases, washing three times with saturated sodium chloride, drying over anhydrous sodium sulfate, and filtering. The filtrate is dried by spin to obtain crude intermediate 2.
Example 33 Synthesis of- (azidomethyl) -4- (4-fluorophenyl) -5-hydroxy-5-methylfuran-2 (5H) -one intermediate 3
The product from example 2 (1.53 g,5.1 mmol) was dissolved in 16ml DMF and 4ml water, sodium azide (0.663 g,10.2 mmol) was added and reacted at 80℃for 24h. After completion of the TLC detection reaction, the reaction mixture was cooled to room temperature, and 40ml of water was added to the reaction mixture. The aqueous phase was extracted three times with 40ml of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to give crude intermediate 3.
Example 4 6 Synthesis of Ethyl 3- (trifluoromethyl) phenoxy) hexanoate intermediate 4
The product obtained in example 3 (0.95 g,3.65 mmol) was taken and dissolved in 10mL of tetrahydrofuran. Triphenylphosphine (1.9 g,7.3 mmol) and water (131 mg,7.3 mmol) were added and reacted at room temperature under nitrogen for 18h. After the completion of the TLC monitoring reaction, the reaction mixture was dried by spin-drying. The residue was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate is evaporated to dryness under reduced pressure, and purified by column chromatography (eluent is dichloromethane-methanol, 200:1-20:1) to obtain intermediate 4.
Example 5 Synthesis of N- ((4- (4-fluorophenyl) -5-hydroxy-5-methyl-2-oxo-2, 5-dihydrofuran-3-yl) methyl) -4-methylbenzamide intermediate 5
The product obtained in example 4 (318 mg,1.34 mmol) was taken and dissolved in 8mL of dichloromethane. Triethylamine (406 mg,4.02 mmol) was then added and a solution of p-toluoyl chloride (206 mg,1.34 mmol) in methylene chloride was added dropwise, and after the addition was completed, the reaction was allowed to proceed to room temperature. After completion of the TLC monitoring reaction, the reaction was evaporated to dryness under reduced pressure. Column chromatography purification (eluent dichloromethane-methanol, 200:1-100:1) to obtain intermediate 5.
EXAMPLE 6 Synthesis of Compound X=O of formula I
The product obtained in example 5 (398 mg,1.12 mmol) was taken and dissolved in 5mL of chloroform, phosphorus pentoxide (477 mg,3.36 mmol) was added to react for 12h at 75 ℃, after TLC detection, unreacted phosphorus pentoxide was reacted with water, extracted with ethyl acetate, the organic phases were combined, the solvent was evaporated by spin-drying, and column chromatography purification (eluent petroleum ether-ethyl acetate, 8:1-6:1) was performed to obtain I-8. The compound-related structure corroboration information is shown in table 1.
The preparation processes of the compounds I-1 to I-7, I-9 to I-13 and I-24 to I-45 are the same as the process for preparing I-8, and only the raw materials need to be replaced correspondingly.
Example 7 Synthesis of N- ((5-chloro-4- (4-fluorophenyl) -5-methyl-2-oxo-2, 5-dihydrofuran-3-yl) methyl) -4-methylbenzamide intermediate 7
The product obtained in example 5 (563 mg,1.59 mmol) was taken and dissolved in 10ml of thionyl chloride, heated to 80℃and refluxed for 3h, after completion of the TLC detection the solvent was evaporated by spin-drying and used directly in the next reaction without further purification.
Example 8 Synthesis of N- ((1-cyclopentyl-4- (4-fluorophenyl) -5-hydroxy-5-methyl-2-oxo-2, 5-dihydro-1H-pyrrol-3-yl) methyl) -4-methylbenzamide intermediate 8
The product obtained in example 7 was taken and dissolved in dichloromethane, stirred at 0 ℃, aqueous cyclopentylamine (135 mg,1.59 mmol) was added dropwise, after half an hour of addition, the reaction was allowed to proceed to room temperature for 24 hours, after the reaction was completed by TLC detection, the solvent was evaporated by spin-drying, water washing, dichloromethane extraction, the organic phases were combined, washed three times with saturated sodium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate is dried by spin to obtain crude intermediate 8.
Example 9 Synthesis of Compound X=NR of formula I
Dissolving the product obtained in example 8 with chloroform, adding phosphorus pentoxide (677 mg,4.77 mmol) to react for 12h at 75 ℃, adding water to react to remove unreacted phosphorus pentoxide after TLC detection, extracting with ethyl acetate, mixing organic phases, spin-drying to evaporate solvent, and purifying by column chromatography (eluent is petroleum ether-ethyl acetate, 6:1) to obtain I-18. The compound-related structure corroboration information is shown in table 1.
The preparation process of the compounds I-14 to I-23 is the process for preparing the I-18, and only the raw materials need to be replaced correspondingly.
TABLE 1 Structure confirmation information Table of Compounds I-1 to I-45
EXAMPLE 10 determination of the antibacterial Activity of the above derivatives
This example demonstrates the strength of antimicrobial action of a compound of the invention by determining the Minimum Inhibitory Concentration (MIC) of the compound of interest (i.e., compounds I-1 to I-45 of the invention) against a variety of gram-positive bacteria including Bacillus subtilis ATCC 9372, bacillus pumilus (B.pumilus CMCC 63202), staphylococcus aureus (S.aureusATCC 25923), methicillin-resistant Staphylococcus aureus (S.aureus ATCC 43300) and gram-negative bacteria including Pseudomonas aeruginosa (P.aeromonas ATCC 27853), escherichia coli (E.coli ATCC 25922), pseudomonas aeruginosa PAO 1). The strain used is from China general microbiological culture collection center (CGMCC), china industry microbiological culture collection center (CICC) and Qilu hospital clinical separation.
The MIC of each 4-aryl-5-methylene-2 (5H) -furanone derivative (namely compounds I-1 to I-45) of the application, ciprofloxacin (CIP), clarithromycin (CLA) and Azithromycin (AZM) is determined by adopting a double release method, and the compound which does not have an antibacterial effect is screened according to the result of the MIC. The controls Ciprofloxacin (CIP), clarithromycin (CLA), azithromycin (AZM) were purchased from ampoul chemistry.
a B.subtilis ATCC9372:Bacillus subtilis ATCC9372,penicillin-susceptible strain；
b B.pumilus CMCC63202:Bacillus pumilus CMCC63202,penicillin-susceptible strain；
c S.aureus ATCC25923:Staphylococcus aureus ATCC25923,erythromycin-susceptible strain；
d S.aureus ATCC43300:Staphylococcus aureusATCC43300,methicillin-resistant strain；
e P.aeruginosa ATCC27853:Pseudomonas aeruginosa ATCC27853,penicillin-susceptible strain,not characterized；
f E.coli ATCC25922:Escherichia coli ATCC25922,penicillin-susceptible strain,not characterized；
g P.aeruginosa PAO1:Pseudomonas aeruginosa CGMCC1.12483,wild type strain；
A CIP:ciprofloxacin； B CLA:clarithromycin； C AZM:azithromycin.
As can be seen from the above experimental results, most of the 4-aryl-5-methylene-2 (5H) -furanone derivatives of the present invention hardly produced antibacterial activity against various gram-positive bacteria including Bacillus subtilis ATCC 9372, bacillus pumilus (B.pumilus CMCC 63202), staphylococcus aureus (S.aureussa ATCC 25923), methicillin-resistant Staphylococcus aureus (S.aureus ATCC 43300) and gram-negative bacteria including Pseudomonas aeruginosa (P.aeromonas ATCC 27853), escherichia coli (E.coli ATCC 25922), pseudomonas aeruginosa (P.aeromonas PAO 1), and are in line with the activity characteristics of quorum sensing inhibitors.
EXAMPLE 11 Effect of the above derivatives on Pseudomonas aeruginosa PAO1 pyocin expression
This example demonstrates the intensity of QS inhibition by a compound of the invention by measuring the effect of the compound of interest (i.e., compounds I-1 to I-45 of the invention) on the expression of Pseudomonas aeruginosa (P.aerosporaaPAO 1). The strain is derived from China general microbiological culture collection center (CGMCC).
The experimental method comprises the following steps: inoculating Pseudomonas aeruginosa PAO1 into LB culture medium, culturing in a 37 deg.C constant temperature incubator for 20 hr, and diluting the passaged Pseudomonas aeruginosa with fresh LB culture medium to OD 600 Bacterial liquid=0.05, and culture was continued for 8h to logarithmic growth phase. Re-dilute to OD 600 =0.05. The diluted bacterial liquid was dispensed into 10mL ep tubes with 5 mL. mu.L of the target compound solution (final concentration: 102.4. Mu.g/mL) was added, and negative control DMSO, a blank, were set. Each sample was run in parallel 4 times. The cells were incubated at 37℃for 18h in a shaking incubator at 200 rpm. After that, the mixture was centrifuged at 9000rpm for 5 minutes, and then the supernatant was poured out, extracted with 3mL of chloroform, and allowed to stand for delamination. Discarding the upper layer, back-extracting with 1mL hydrochloric acid (0.2M) to obtain pale red solution, centrifuging at 5000rpm for 10min, collecting 100 μl of the upper layer pale red solution in 96-well plate, and measuring OD 492 . Compared with the negative control, the pyocin inhibition rate is 1- (Abs) sample -Abs blank )/(Abs negative -Abs blank )×100％。
As can be seen from FIG. 1, in the 4-aryl-5-methylene-2 (5H) -furanone derivatives (I-1 to I-13), I-13 was a strong pyocin inhibitor, and the expression level of pyocin in the test tube to which I-13 was added was 44.5% of that of the negative control. I-1 and I-6 are intermediate pyocin inhibitors, and the expression levels of pyocin in the tubes to which these two compounds were added were 68.6% and 70.6% of the negative control, respectively.
As is clear from FIG. 2, among the 4-aryl-5-methylene-2 (5H) -furanone derivatives (I-14 to I-23), the compounds I-20, I-21, I-22 have a strong inhibitory activity against the production of Pseudomonas aeruginosa PAO1 pyocin. The expression levels of pyocin in the test tubes to which these three compounds were added were 61.7%, 64.8% and 70.0% of the negative control, respectively.
As is clear from FIG. 3, among the 4-aryl-5-methylene-2 (5H) -furanone derivatives (I-24 to I-37), compound I-35 has a strong inhibitory activity against Pseudomonas aeruginosa PAO1 pyocin. It produced only 56.0% of pyocin at the tested concentration compared to the negative control. Other compounds such as I-25, I-27, I-28, I-32, I-33 had moderate pyocin production inhibitory activity, and the amount of pyocin expressed in the test tubes added with these five compounds was 72.0%, 65.3%, 68.6%, 74.5%, 71.5% of the negative control.
As is clear from FIG. 4, among the 4-aryl-5-methylene-2 (5H) -furanone derivatives (I-38 to I-45), compound I-44 has the strongest inhibitory activity against the production of pyocin. It produced only 55.3% of pyocin at the tested concentration compared to the negative control.
Synergistic antibacterial effect of the Compound of example 12 with antibacterial Agents
The experimental method comprises the following steps: inoculating Pseudomonas aeruginosa PAO1 into LB culture medium, culturing at 37deg.C in incubator for 20 hr, and diluting Pseudomonas aeruginosa with fresh LB culture medium to OD 600 Bacterial liquid=0.05, and culture was continued until logarithmic growth phase. Re-dilute to OD 600 =0.05, and then the diluted bacterial solution was dispensed into 5mL ep tubes in 2 mL. Then 20. Mu.L of DMSO mother liquor containing the objective compound (I-8, I-20, I-21, I-22, I-25, I-27, I-28, I-33 and I-35) was added to the final concentrations of 256, 128, 64, 32, 16, 8, 4, 2 and 1. Mu.g/mL, respectively. And setting a blank group and a negative Control at the same time, wherein the concentration of positive Control Ciprofloxacin (CIP) is 0.2 mug/mL, the concentration of Clarithromycin (CLA) is 3.2 mug/mL, and the samples with different concentrations are respectively combined with the antibacterial agent. Repeated 3 times. Culturing in a 37 deg.C incubator for 20 hr, sampling, and measuring OD 600 . Bacterial mortality was 1- (Abs sample -Abs blank )/(Abs negative -Abs blank )×100％。
As can be seen from FIG. 5, the compounds I-8, I-20, I-21, I-22, I-25, I-27, I-28, I-33 and I-35 significantly improved the inhibitory effects of CIP (0.2. Mu.g/mL) and CLA (3.2. Mu.g/mL) on P.aeruginosa PAO1 and P.aeruginosa 27853 in a concentration-dependent manner, wherein the combination of the compound I-28 with CIP and CLA significantly enhanced the inhibitory effects of CIP and CLA on both bacteria, and the culture fluid showed clear and transparent appearance after the bacteria were cultured overnight with little bacterial growth. Other compounds have strong combined effect with antibiotics, and the compounds are expected to be developed into novel antibacterial sensitizers for enhancing the efficacy of the existing antibiotics and reducing the bacterial resistance.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. 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 4-aryl-5-methylene-2 (5H) -furanone derivative, characterized by having a structure according to formula I:
wherein R is 1 Hydrogen, alkoxy, halogen, fluoroalkyl, fluoroalkoxy, or phenyl; r is R 2 Selected from aryl, substituted aryl, aryl heteroaryl, substituted aryl heteroaryl, alkyl, cycloalkyl; n is 0 to 2; x is-O-or-NR 3 -；R 3 Selected from hydrogen, alkyl, substituted aryl.
2. The 4-aryl-5-methylene-2 (5H) -furanone derivative according to claim 1, wherein R 1 Wherein the carbon number of the alkoxy is 1-5, the carbon number of the fluoroalkyl is 1-5, and the carbon number of the fluoroalkoxy is 1-5;
or, R 1 Selected from hydrogen, 4-methoxy, 4-chloro, 2-fluoro, 4-bromo, 3-trifluoromethyl, 3-chloro, 2-bromo, 3-fluoro, 4-phenyl;
or, R 2 Wherein the aryl is selected from the group consisting of phenyl, naphthyl, anthracenyl, phenanthryl, indenyl, fluorenyl and acenaphthylenyl, and the substituted aryl is selected from the group consisting of
The R is 4 Selected from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, fluoroalkoxy, alkyl, cyano, nitro; preferably, R 4 Wherein the carbon number of the alkoxy is 1-5, the carbon number of the fluoroalkyl is 1-5, and the carbon number of the fluoroalkoxy is 1-5; preferably, said R 4 Selected from hydrogen, 4-methyl, 2-fluoro, 4-chloro, 3-bromo, 2-bromo, 4-bromo, 2-chloro, 3-methoxy, 2-methoxy, 3-methyl, 4-methoxy, 2-methyl, 3-chloro, 4-fluoro or 3-fluoro;
or, R 2 Wherein the aryl is selected from the group consisting of furyl, pyrrolyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, morpholinyl, pyrazolyl, indolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, carbazolyl, purinyl, phenothiazinyl, and phenoxazinyl; the number of the substituent groups of the substituted aryl-heteroaryl is one or more, and each substituent group is independently selected from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, fluoroalkoxy, alkyl, cyano and nitro;
or, R 2 Wherein the alkyl is selected from straight chain alkyl with 1-12C atoms or branched alkyl with 1-12C atoms; cycloalkyl is selected from cycloalkyl with 3-8C atoms;
or n is 0, R 2 The alkyl is selected from ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and undecyl;
or, R 3 Wherein the alkyl is selected from straight chain alkyl with 1-8C atoms, branched chain alkyl with 1-8C atoms and cycloalkyl with 3-8C atoms;
or, R 3 Selected from ethyl, propyl, butyl, pentyl, cyclopentyl;
or, R 3 Wherein the substituted aryl is selected from
The R is 5 Selected from hydrogenAlkyl, alkoxy, halogen, fluoroalkyl, fluoroalkoxy, alkyl, cyano, nitro; preferably, R 4 Wherein the carbon number of the alkoxy is 1-5, the carbon number of the fluoroalkyl is 1-5, and the carbon number of the fluoroalkoxy is 1-5; preferably, said R 5 Selected from 2-chloro, 4-methyl, 3-methyl, 2-methyl, 3-chloro.
3. The 4-aryl-5-methylene-2 (5H) -furanone derivative of claim 1, comprising the following compounds:
4. a process for the preparation of a 4-aryl-5-methylene-2 (5H) -furanone derivative according to claim 1, comprising the step of obtaining a compound of formula II according to scheme 1 or the step of obtaining a compound of formula III according to scheme 2:
scheme 1:
scheme 2:
5. the method of claim 4, wherein the steps of: the operation steps are as follows: condensing substituted propiophenone with pyruvic acid to obtain an intermediate 1, reacting the intermediate 1 with NBS free radicals to obtain a bromide 2, subjecting the intermediate 2 with sodium azide to nucleophilic substitution reaction to obtain an intermediate 3, reducing the intermediate 3 with triphenylphosphine to obtain an amino compound 4, subjecting the amino compound 4 with an acyl chloride compound to amide condensation to obtain an intermediate 5, and directly dehydrating the intermediate 5 with phosphorus pentoxide to obtain a compound shown in a formula II;
intermediate 7 is obtained after the intermediate 5 is subjected to chlorination reaction, intermediate 8 is obtained after the intermediate 7 and the amine compound are subjected to lactone lactam conversion, and the compound shown in the formula III can be obtained after the intermediate 8 is dehydrated.
6. A pharmaceutically acceptable salt, characterized in that it is a salt formed from the 4-aryl-5-methylene-2 (5H) -furanone derivative according to any one of claims 1 to 3 with an inorganic or organic acid.
7. A pharmaceutical composition comprising a 4-aryl-5-methylene-2 (5H) -furanone derivative and/or a solvate thereof according to any one of claims 1 to 5.
8. A pharmaceutical formulation comprising an active ingredient together with at least one pharmaceutically acceptable carrier or excipient, characterized in that the active ingredient is a 4-aryl-5-methylene-2 (5H) -furanone derivative according to any one of claims 1 to 3, a pharmaceutically acceptable salt according to claim 6 or a pharmaceutical composition according to claim 7.
9. Use of a 4-aryl-5-methylene-2 (5H) -furanone derivative according to any one of claims 1 to 3, a pharmaceutically acceptable salt according to claim 6, a pharmaceutical composition according to claim 7 or a pharmaceutical formulation according to claim 8 for the manufacture of a medicament for inhibiting the bacterial QS system.
10. The use of claim 9, wherein the agent that inhibits the bacterial QS system is a bacterial QS inhibitor;
or, the gram-negative bacteria is Pseudomonas aeruginosa, acinetobacter, escherichia coli, klebsiella pneumoniae, vibrio cholerae, haemophilus influenzae, haemophilus parainfluenza, legionella pneumophila, bacillus pertussis, proteus, bacillus dysenteriae, brucella, moraxella catarrhalis, yersinia, bordetella parapertussis, shigella, pasteurella or Parhaemolyticus;
or in the preparation of medicaments for treating diseases caused by gram-negative bacteria; preferably, the disease caused by gram-negative bacteria is pneumonia, cystic fibrosis, endocarditis, peritonitis, empyema, septicemia, cholecystitis, cystitis, diarrhea or gastroenteritis;
or in the preparation of antibacterial sensitizer.
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