CN108929260A - 2,3- naphthalimide analog derivative and its preparation method and application - Google Patents
2,3- naphthalimide analog derivative and its preparation method and application Download PDFInfo
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- CN108929260A CN108929260A CN201810687817.9A CN201810687817A CN108929260A CN 108929260 A CN108929260 A CN 108929260A CN 201810687817 A CN201810687817 A CN 201810687817A CN 108929260 A CN108929260 A CN 108929260A
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- 238000002360 preparation method Methods 0.000 title abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 117
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- 239000012453 solvate Substances 0.000 claims abstract description 27
- 101100378121 Drosophila melanogaster nAChRalpha1 gene Proteins 0.000 claims abstract description 22
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 20
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 138
- 238000006243 chemical reaction Methods 0.000 claims description 123
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 55
- 238000003756 stirring Methods 0.000 claims description 55
- QWBBPBRQALCEIZ-UHFFFAOYSA-N 2,3-dimethylphenol Chemical compound CC1=CC=CC(O)=C1C QWBBPBRQALCEIZ-UHFFFAOYSA-N 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 53
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 51
- 239000012074 organic phase Substances 0.000 claims description 49
- 239000000243 solution Substances 0.000 claims description 48
- 239000007787 solid Substances 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 40
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 38
- 238000001914 filtration Methods 0.000 claims description 38
- 229940125782 compound 2 Drugs 0.000 claims description 37
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- 229940126214 compound 3 Drugs 0.000 claims description 30
- 238000002390 rotary evaporation Methods 0.000 claims description 29
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 27
- 238000010438 heat treatment Methods 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 26
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 26
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 26
- 238000010992 reflux Methods 0.000 claims description 26
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
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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 20
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 19
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 19
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
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- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 15
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- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 11
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 10
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
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- 238000004809 thin layer chromatography Methods 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- VOFUROIFQGPCGE-UHFFFAOYSA-N nile red Chemical compound C1=CC=C2C3=NC4=CC=C(N(CC)CC)C=C4OC3=CC(=O)C2=C1 VOFUROIFQGPCGE-UHFFFAOYSA-N 0.000 description 6
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- BMVXCPBXGZKUPN-UHFFFAOYSA-N 1-hexanamine Chemical compound CCCCCCN BMVXCPBXGZKUPN-UHFFFAOYSA-N 0.000 description 1
- HIDBROSJWZYGSZ-UHFFFAOYSA-N 1-phenylpyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C1=CC=CC=C1 HIDBROSJWZYGSZ-UHFFFAOYSA-N 0.000 description 1
- NWUYCZFXVRWCLA-UHFFFAOYSA-N 5-methoxybenzo[f][2]benzofuran-1,3-dione Chemical compound COC=1C2=CC3=C(C(OC3=O)=O)C=C2C=CC=1 NWUYCZFXVRWCLA-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
- C07D209/66—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles with oxygen atoms in positions 1 and 3
-
- 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
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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides compound or its isomers or solvate or officinal salt and its preparation method and application shown in a kind of Formulas I, and the compound has preferable antibacterial synergistic activity and outlet inhibitory activity to the gram negative bacterium for being overexpressed AcrB.
Description
Technical Field
The invention relates to the field of medical chemistry, in particular to a 2, 3-naphthalimide derivative and a preparation method and application thereof.
Background
The problem of bacterial resistance is becoming more and more serious due to the widespread use and even abuse of antibiotics, and has become one of the important factors seriously threatening human health. In recent years, the multidrug resistance of gram-negative bacteria to antibacterial drugs has increased, and infection with multidrug-resistant gram-negative bacteria has become a leading cause of death in clinical patients. The clinical most common multiple drug resistant gram-negative bacteria comprise escherichia coli, pseudomonas aeruginosa, enterobacter aerogenes, acinetobacter baumannii and the like, wherein the separation rate of the escherichia coli in an ICU ward is as high as 34%, and the multiple drug resistant rate is as high as 44%, so that serious infection of various parts of a human body, such as respiratory tracts, digestive tracts, genitourinary tracts, blood, skin and the like is often caused.
The efflux pump is a protein widely existing on bacterial cell membranes, and can pump harmful substances in cells out of the cells under normal physiological conditions to achieve a self-protection effect. The overexpression of the efflux pump causes the antibacterial drugs in the bacterial cells to be excreted to the outside of the cells, so that the drug concentration in the bacterial cells is reduced to be insufficient to exert the antibacterial action of the antibacterial drugs, thereby causing the generation of multi-drug resistance of the bacteria. Some efflux pumps selectively pump out certain antibiotics, such as tetracycline; however, some efflux pumps are capable of transporting a structurally diverse array of unrelated compounds, such as antibiotics (fluoroquinolones, macrolides, tetracyclines, chloramphenicol, etc.), metal ions, dyes, etc., resulting in a multidrug resistant phenotype. The research shows that the AcrAB-TolC is the most important efflux pump in the gram-negative bacteria and can mediate the high-level drug resistance of the gram-negative bacteria. Wherein, the AcrAB-TolC has the closest relation to mediating the multidrug resistance of gram-negative bacteria. In AcrAB-TolC, AcrB efflux proteins are responsible for substrate recognition and energy transduction, which makes them critical in the efflux system, and thus inhibition of AcrB efflux pumps appears to be an effective means to restore or enhance the efficacy of existing antibiotics.
The efflux pump inhibitor can reduce the inherent drug resistance level of bacteria, reverse acquired drug resistance, expand the antibacterial spectrum and reduce the incidence rate of drug-resistant mutant strains. The exocrine pump inhibitor can inhibit the efflux of drug-resistant bacteria and tumor cells to the drug, recover or improve the antibiotic efficacy, improve the clinical treatment effect of drug-resistant bacterial infection and tumor, and has wide application in improving the pharmacokinetic characteristics of certain drugs (such as improving the absorption of oral drugs and improving the clearance of liver and kidney). Meanwhile, the efflux pump inhibitor also has a certain effect on improving the infectivity and the toxicity of the bacteria. At present, research on an efflux pump inhibitor aiming at a bacterial AcrB efflux pump is a hotspot, focus and difficulty of the current domestic and foreign research, and the discovery of a novel AcrB efflux pump inhibitor is rarely reported in recent years. Therefore, the search for a new effective AcrB efflux pump inhibitor is of great significance for overcoming multidrug resistant glan negative bacterial infection.
Disclosure of Invention
In order to solve the problems, the invention provides a novel 2, 3-naphthalimide derivative and a preparation method thereof, in-vitro antibacterial activity research and efflux substrate inhibition research are carried out on gram-negative bacteria over-expressing AcrB, and the compound shows better antibacterial synergistic activity and efflux inhibition activity.
The invention is realized by the following technical scheme:
in a first aspect, the present invention provides a compound of formula I or an isomer or solvate or pharmaceutically acceptable salt thereof:
wherein R is1One or more selected from straight-chain or branched alkyl, saturated or unsaturated cycloalkyl, alkoxy, aromatic group, five-membered or six-membered aromatic heterocycle containing one or more heteroatoms or aliphatic heterocycle, which is mono-or polysubstituted on the naphthalene ring; wherein the heteroatoms, which may be the same or different, are selected from N, O, S, and the like; r2Selected from benzene ring, substituted benzene ring, aromatic group, substituted aromatic group, benzyl group, substituted benzyl group, straight chain or branched chain alkyl, saturated or unsaturated cycloalkyl.
Preferably, said R is1Is selected from C1-C22Straight or branched alkyl, C3-C22Saturated or unsaturated cycloalkyl, C1-C22Alkoxy, aryl, five-membered or six-membered aromatic heterocycle or aliphatic heterocycle containing one or more heteroatoms;
preferably, said R is2Selected from benzene ring, substituted benzene ring, aromatic group, substituted aromatic group, benzyl, substituted benzyl and C1-C22Straight or branched alkyl, C3-C22A saturated or unsaturated cycloalkyl group;
preferably, said R is1Is selected from C1-C8Straight or branched alkyl, C3-C8Saturated or unsaturated cycloalkyl, C1-C8Alkoxy, aryl, containingA five-or six-membered aromatic or aliphatic heterocyclic ring having one or more heteroatoms; preferably, said R is1Substitution, preferably mono-or disubstituted, at the 5-8 position of the naphthalene ring; preferably, said R is1Mono-substituted on the 5, 6, 7 or 8 position of the naphthalene ring; preferably, said R is1Is C1-C8An alkoxy group; preferably, said R is1Selected from methoxy, ethoxy, propoxy, isopropoxy n-butoxy, isobutoxy, tert-butoxy; preferably, said R is1Is methoxy, ethoxy or propoxy;
preferably, said R is2Selected from benzene ring, substituted phenyl, aryl, substituted aryl, benzyl, substituted benzyl, C1-C12Straight or branched alkyl of (2), C3-C6Saturated or unsaturated cycloalkyl groups of (a); wherein, the benzene ring, the aromatic group and the benzyl can be respectively and independently substituted by halogen, halogen or unsubstituted C1-C8Straight or branched alkyl, C substituted or unsubstituted by halogen1-C8Alkoxy radical, C3-C6Substituted with saturated or unsaturated cycloalkyl, phenyl;
preferably, the halogen is selected from F, Cl, Br, I, etc.;
preferably, said R is2Selected from benzene ring, substituted benzene ring, benzyl, substituted benzyl, phenethyl, substituted phenethyl, C1-C12Straight or branched alkyl of (2), C3-C6Saturated or unsaturated cycloalkyl groups of (a);
preferably, said R is2Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl ring, benzyl, phenethyl;
wherein the benzene ring, benzyl, phenethyl can be unsubstituted or each independently be selected from halogen, C which is mono-or poly-substituted or unsubstituted by the same or different halogen1-C8Straight or branched chainAlkyl, C which is mono-or polysubstituted or unsubstituted by identical or different halogens1-C8Alkoxy radical, C3-C6Substituted by a saturated or unsaturated cycloalkyl, phenyl, said substitution being mono-or polysubstituted;
preferably, the benzene ring, benzyl, phenethyl can be unsubstituted or each independently be substituted by a halogen, C mono-or poly-substituted or unsubstituted with the same halogen1-C5Straight-chain or branched alkyl, C mono-or polysubstituted or unsubstituted by the same halogen1-C5Alkoxy radical, C3-C6Substituted by a saturated or unsaturated cycloalkyl, phenyl, said substitution being mono-or polysubstituted;
preferably, the mono-or poly-substitution may be mono-, di-or tri-substitution;
preferably, the substitution on the phenyl ring, benzyl, phenethyl can occur in the para, meta or ortho position, preferably in the ortho position;
preferably, the benzene ring, benzyl, phenethyl can be unsubstituted or each independently be trisubstituted or unsubstituted by a group selected from halogen, C being the same halogen1-C4Straight or branched alkyl, C tri-substituted or unsubstituted by the same halogen1-C3Alkoxy substituted, the substitution is mono-substitution, and the halogen is F or Cl; preferably, said benzene ring, benzyl, phenethyl may be unsubstituted or C, trisubstituted or unsubstituted by F, selected from F, Cl1-C4Straight or branched alkyl, C trisubstituted or unsubstituted by F1-C2Alkoxy is monosubstituted; preferably, said benzene ring, benzyl, phenethyl may be unsubstituted or C, trisubstituted or unsubstituted by F, selected from F, Cl1-C4Linear or branched alkyl, methoxy or trifluoromethoxy monosubstituted;
preferably, said R is2Selected from methyl, isopropyl, tert-butyl, n-pentyl, n-hexyl, ortho-or para-pentylPhenyl or benzyl substituted in position by methyl, ethyl or isopropyl, phenyl or benzyl substituted in ortho or para position by F or Cl, phenyl or benzyl substituted in ortho or para position by methoxy or trifluoromethoxy.
Secondly, the invention provides a compound shown as a formula II or an isomer or solvate or a pharmaceutically acceptable salt thereof:
wherein R is2As described above.
Preferably, the compound of formula I or the compound of formula II as described above comprises the following structure:
thirdly, the invention provides a method for preparing the compound shown in the formula II, wherein the method takes 2, 3-xylenol as an initial raw material and comprises the steps of performing methylation reaction, bromination reaction, Diels-Alder reaction and amide condensation to obtain the compound shown in the formula II;
preferably, the method uses 2, 3-xylenol as a starting material, and comprises the steps of sequentially carrying out methylation reaction, bromination reaction, Diels-Alder reaction and amide condensation to obtain a compound of a formula II, namely the method obtains the compound of the formula II by a reaction route 1;
preferably, scheme 1 is as follows:
wherein,R2is as defined above;
preferably, scheme 1 comprises the steps of:
(1) 2, 3-xylenol is used as an initial raw material, and methylation reaction is carried out on the initial raw material and methyl iodide under an alkaline condition to obtain a compound 2;
(2) carrying out bromination reaction on the compound 2 and excessive N-bromosuccinimide to obtain a compound 3;
(3) carrying out Diels-Alder reaction on the compound 3 and maleic anhydride under the catalysis of solid potassium iodide to obtain a compound 4;
(4) dehydrating the compound 4 at high temperature to obtain a compound 5;
(5) compound 5 and R2-NH2Amide condensation to give compounds of formula II, wherein R2As claimed in claim 1 or 2;
preferably, scheme 1 comprises the steps of:
(1) dissolving 2, 3-xylenol in a methylation solvent, adding solid anhydrous potassium carbonate, adding methyl iodide liquid under a dark condition, heating the mixture, stirring and refluxing to react; after the reaction is finished, stopping stirring, diluting with water, extracting with ethyl acetate, combining organic phases, fully drying, filtering, and removing an ethyl acetate solvent by rotary evaporation to obtain a crude compound 2;
(2) diluting and dissolving the crude product of the compound 2 by using a solvent, adding N-bromosuccinimide and an initiator azodiisobutyronitrile into the mixed liquid, uniformly mixing, heating, stirring and refluxing for reaction; after the reaction is completed, cooling, filtering, washing the filtrate with saturated sodium bisulfite solution, standing for layering, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound 3;
(3) putting the compound 3, maleic anhydride and potassium iodide solid into N, N-dimethylformamide, uniformly stirring, and heating and stirring a reaction system; after the reaction is completed, cooling and stopping stirring, pouring the reaction solution into a dilute sodium bisulfite solution, separating out yellow solid, filtering, and drying a filter cake to obtain a crude product yellow solid of the compound 4;
(4) dissolving the crude product of the compound 4 in a solvent, and heating and refluxing; detecting that the reaction is basically complete, and removing the solvent by high-temperature rotary evaporation to obtain a dark brown solid compound 5 crude product;
(5) dissolving the crude compound 5 in solvent, and adding R dropwise into the mixed solution2-NH2Fully and uniformly stirring, and heating a reaction system to reflux for reaction; after the detection reaction is finished, removing the solvent by high-temperature rotary evaporation, dissolving the residue obtained after the rotary evaporation by dichloromethane, washing the solution by dilute hydrochloric acid, collecting an organic phase, drying the organic phase by anhydrous sodium sulfate, filtering, and taking the filtrate to perform silica gel column chromatography to obtain a compound shown in a formula II;
preferably, in step (1), the methylating solvent is selected from the group consisting of acetone, N-dimethylformamide, tetrahydrofuran, ethyl acetate and acetonitrile, preferably acetone; preferably, in the step (1), the molar ratio of the anhydrous potassium carbonate, the iodomethane and the 2, 3-dimethylphenol is 1.5-3.0: 1.5-3.0: 1.0, preferably 3: 3: 1; preferably, in the step (1), the mixture is heated to 30-60 ℃ and stirred for reaction for 12-28 h, preferably heated to 50 ℃ and stirred for reaction for 24 h;
preferably, in step (2), the solvent is selected from benzene and carbon tetrachloride, preferably carbon tetrachloride; preferably, in step (2), the molar ratio of compound 2 to N-bromosuccinimide is 1.0: 3.0-8.0, preferably 1: 6.8; preferably, in the step (2), the molar ratio of the added amount of the initiator azodiisobutyronitrile to the compound 2 is 0.05-0.10: 1; preferably, in the step (2), the reactants are heated to 77 ℃ after being uniformly mixed, stirred and refluxed for 12-48 hours, preferably 24 hours;
preferably, in step (3), the molar ratio of compound 3, maleic anhydride and potassium iodide solid is 1.0: 1.0-2.0: 5.0-7.0, preferably 1: 1: 7; preferably, in the step (3), the concentration of the dilute sodium bisulfite is 0.2-0.4 mol/L, preferably 0.25 mol/L; preferably, in the step (3), the reaction system is heated to 50-100 ℃ and stirred for 8-16 h, preferably 70 ℃ and stirred for 8 h;
preferably, in step (4), the solvent is selected from acetic anhydride, oxalyl chloride, thionyl chloride, preferably acetic anhydride; preferably, in the step (4), the crude compound 4 is dissolved in a solvent, heated to 100-140 ℃ and reacted for 2-3h, preferably heated to 100 ℃ and reacted for 2-3 h;
preferably, in step (5), the solvent is selected from pyridine, hydroxylamine hydrochloride, glacial acetic acid and N, N-dimethylformamide, preferably pyridine; preferably, in step (5), the compound 5 is reacted with R2-NH2Is 1.0: 1.0 to 1.5, preferably 1: 1.5; preferably, in the step (5), the reaction system is heated to 80-120 ℃ for reaction for 12-24 h, and preferably heated to 120 ℃ for reaction for 12 h;
or, preferably, the method uses 2, 3-xylenol as a starting material, and comprises the following steps of sequentially carrying out methylation reaction, bromination reaction, amide condensation and Diels-Alder reaction to obtain the compound of the formula II, namely, the method obtains the compound of the formula II by a reaction route 2;
preferably, scheme 2 is as follows:
wherein R is2Is as defined above;
preferably, scheme 2 comprises the steps of:
(a) 2, 3-xylenol is used as an initial raw material, and methylation reaction is carried out on the initial raw material and methyl iodide under an alkaline condition to obtain a compound 2;
(b) carrying out bromination reaction on the compound 2 and excessive N-bromosuccinimide to obtain a compound 3;
(c) get R2-NH2Amide condensation reaction with maleic anhydride to obtain a compound 7, wherein R2As claimed in claim 1 or 2;
(d) carrying out Diels-Alder reaction on the compound 3 and the compound 7 to obtain a compound shown in a formula II;
preferably, scheme 2 comprises the steps of:
(a) dissolving 2, 3-xylenol in a methylation solvent, adding solid anhydrous potassium carbonate, adding methyl iodide liquid under a dark condition, and heating, stirring and refluxing the mixture to react; after the reaction is finished, stopping stirring, diluting with water, extracting with ethyl acetate, combining organic phases, fully drying, filtering, and removing an ethyl acetate solvent by rotary evaporation to obtain a crude compound 2;
(b) diluting and dissolving the crude product of the compound 2 by using a solvent, adding N-bromosuccinimide and an initiator azodiisobutyronitrile into the mixed liquid, uniformly mixing, heating, stirring and refluxing for reaction; after the reaction is completed, cooling, filtering, washing the filtrate with saturated sodium bisulfite solution, standing for layering, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound 3;
(c) dissolving maleic anhydride in glacial acetic acid, and slowly dripping R while electromagnetically stirring2-NH2Heating, stirring and refluxing the reaction liquid to carry out reaction; stopping stirring after the reaction is detected to be basically complete, cooling to room temperature, diluting the neutralization reaction solution with dilute sodium hydroxide solution, extracting with ethyl acetate, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound 7;
(d) respectively putting the compound 3, the compound 7 and the potassium iodide solid into N, N-dimethylformamide, heating the reaction system and stirring; detecting complete reaction, cooling, stopping stirring, performing high-temperature rotary evaporation on N, N-dimethylformamide, diluting residual liquid with saturated sodium bisulfite solution, extracting with ethyl acetate, collecting organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound of formula II;
preferably, in step (a), the methylating solvent is selected from the group consisting of acetone, N-dimethylformamide, tetrahydrofuran, ethyl acetate and acetonitrile, preferably acetone; preferably, in the step (a), the molar ratio of the anhydrous potassium carbonate, the iodomethane and the 2, 3-dimethylphenol is 1.5-3.0: 1.5-3.0: 1.0, preferably 3: 3: 1; preferably, in the step (a), the mixture is heated to 30-60 ℃ and stirred for reaction for 12-48 h, preferably heated to 50 ℃ and stirred for reaction for 24 h;
preferably, in step (b), the solvent is selected from benzene and carbon tetrachloride, preferably carbon tetrachloride; preferably, in step (b), the molar ratio of compound 2 to N-bromosuccinimide is 1.0: 3.0-8.0, preferably 1: 6.8; preferably, in the step (b), the molar ratio of the added amount of the initiator azodiisobutyronitrile to the compound 2 is 0.05-0.1: 1; preferably, in the step (b), the reactants are heated to 77 ℃ after being uniformly mixed, stirred and refluxed for 12-48 hours, and preferably 24 hours;
preferably, in step (c), the maleic anhydride is reacted with R2-NH2Is 1.0: 1.0 to 1.5, preferably 1: 1.5; preferably, in the step (c), the reaction solution is heated to 80-120 ℃ and stirred for reaction for 4 hours, preferably heated to 120 ℃ and stirred for reaction for 4 hours;
preferably, in the step (d), the molar ratio of the compound 3 to the compound 7 to the potassium iodide solid is 1.0-1.5: 1.0: 5.0-7.0, preferably 1.5: 1: 7; preferably, in the step (d), the reaction system is heated to 50-100 ℃ and stirred for reaction for 6 hours, preferably heated to 70 ℃ and stirred for reaction for 6 hours;
or, preferably, the method uses 2, 3-xylenol as a starting material, and comprises the steps of sequentially carrying out methylation reaction, bromination reaction, amide condensation, cyclic amidation and Diels-Alder reaction to obtain the compound of the formula II, namely, the method obtains the compound of the formula II by a reaction route 3;
preferably, scheme 3 is as follows:
wherein R is2Is as defined above;
preferably, scheme 3 comprises the steps of:
(i) 2, 3-xylenol is used as an initial raw material, and methylation reaction is carried out on the initial raw material and methyl iodide under an alkaline condition to obtain a compound 2;
(ii) carrying out bromination reaction on the compound 2 and excessive N-bromosuccinimide to obtain a compound 3;
(iii)R2-NH2amide condensation reaction with maleic anhydride to obtain compound 8, wherein R2As claimed in claim 1 or 2;
(iv) further cycloamidating the compound 8 to give a compound 7;
(v) carrying out Diels-Alder reaction on the compound 7 and the compound 3 to obtain a target compound;
preferably, scheme 3 comprises the steps of:
(i) dissolving 2, 3-xylenol in a methylation solvent, adding solid anhydrous potassium carbonate, adding methyl iodide liquid under a dark condition, heating the mixture, stirring and refluxing to react; after the reaction is finished, stopping stirring, diluting with water, extracting with ethyl acetate, combining organic phases, fully drying, filtering, and removing an ethyl acetate solvent by rotary evaporation to obtain a crude compound 2;
(ii) diluting and dissolving the crude product of the compound 2 by using a solvent, adding N-bromosuccinimide and an initiator azodiisobutyronitrile into the mixed liquid, uniformly mixing, heating, stirring and refluxing for reaction; after the reaction is completed, cooling, filtering, washing the filtrate with saturated sodium bisulfite solution, standing for layering, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound 3;
(iii) mixing maleic anhydride and R2-NH2Each separately dissolved in dichloromethane, a solution of maleic anhydride in dichloromethane was added dropwise to R2-NH2Stirring the reaction system at normal temperature in the dichloromethane solution to find that a compound 8 is separated out;
(iv) dissolving the crude product of the compound 8 in acetic anhydride, adding a small amount of sodium acetate into a reaction solution, heating the reaction system, and stirring and refluxing to perform reaction; after the reaction is detected to be complete, stopping stirring, diluting the reaction solution with an ice-water mixture, extracting with ethyl acetate, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound 7;
(v) respectively putting the compound 3, the compound 7 and the potassium iodide solid into N, N-dimethylformamide, heating the reaction system and stirring; detecting complete reaction, cooling, stopping stirring, performing rotary evaporation on DMF at high temperature, diluting the residual liquid with saturated sodium bisulfite solution, extracting with ethyl acetate, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound of formula II;
preferably, in step (i), the methylating solvent is selected from acetone, N-dimethylformamide, tetrahydrofuran, ethyl acetate and acetonitrile, preferably acetone; preferably, in step (i), the molar ratio of the anhydrous potassium carbonate, methyl iodide and 2, 3-dimethylphenol is 1.5-3.0: 1.5-3.0: 1.0, preferably 3: 3: 1; preferably, in the step (i), the mixture is heated to 30-60 ℃ and stirred for reaction for 12-48 h, preferably heated to 50 ℃ and stirred for reaction for 24 h;
preferably, in step (ii), the solvent is selected from benzene and carbon tetrachloride, preferably carbon tetrachloride; preferably, in step (ii), the molar ratio of compound 2 to N-bromosuccinimide is 1.0: 3.0-8.0, preferably 1: 6.8; preferably, in step (ii), the molar ratio of the added amount of the initiator azodiisobutyronitrile to the compound 2 is 0.05-0.10: 1; preferably, in the step (ii), the reactants are heated to 77 ℃ after being uniformly mixed, stirred and refluxed for 12-48 hours, preferably 24 hours;
preferably, in step (iii), the maleic anhydride is reacted with R2-NH2Is 1.0: 1.0 to 1.5, preferably 1: 1.5;
preferably, in step (iv), the sodium acetate is added in a molar ratio to maleic anhydride of 1.0: 2.0: 1;
preferably, in step (v), the molar ratio of the compound 3 to the compound 7 to the potassium iodide solid is 1.0 to 1.5: 1.0: 5.0-7.0, preferably 1.5: 1: 7; preferably, in the step (v), the reaction system is heated to 80-120 ℃ and stirred for 8h, preferably heated to 70 ℃ and stirred for 8 h.
Again, the present invention also provides a pharmaceutical composition comprising a compound of formula I or formula II as described above or an isomer or solvate or pharmaceutically acceptable salt thereof.
In addition, the invention also provides the application of the compound of the formula I or the isomer or the solvate or the medicinal salt thereof in preparing the medicament for treating bacterial infection; and the use of a compound of formula II as described above, or an isomer or solvate or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a bacterial infection; and, the use of a pharmaceutical composition as described above for the manufacture of a medicament for the treatment of a bacterial infection;
preferably, the compound of formula I or formula II or its isomer or solvate or pharmaceutically acceptable salt has antibacterial sensitization activity to bacteria; preferably, the bacterium is an AcrB-bearing bacterium, preferably a gram-negative bacterium that overexpresses AcrB.
In addition, the invention also provides application of the compound shown in the formula I or the isomer or solvate or pharmaceutically acceptable salt thereof in preparing a bacterial medicament carrying an AcrB efflux pump; and the use of a compound of formula II as described above, or an isomer or solvate or pharmaceutically acceptable salt thereof, in the preparation of a bacterial medicament carrying an AcrB efflux pump; and the use of a pharmaceutical composition as described above for the preparation of a bacterial medicament carrying an AcrB efflux pump;
preferably, the compound of formula I or formula II or an isomer or solvate or pharmaceutically acceptable salt thereof has efflux inhibiting activity against bacteria; preferably, the bacterium is an AcrB-carrying bacterium, preferably a gram-negative bacterium that overexpresses AcrB
In addition, the invention also provides a combined drug combination for treating bacterial infection, the combined drug combination comprises the compound of the formula I or the isomer or the solvate or the pharmaceutically acceptable salt thereof and the antibacterial drug, or the combined drug combination comprises the compound of the formula II or the isomer or the solvate or the pharmaceutically acceptable salt thereof and the antibacterial drug; preferably, the antibacterial drug is selected from erythromycin, chloramphenicol, triphenylphosphine, and levofloxacin.
The 2, 3-naphthalimide derivative has an antibacterial synergistic effect, is combined with the existing antibacterial drugs to have an obvious antibacterial synergistic effect on gram-negative drug-resistant bacteria, and can be used for preparing drugs for treating bacterial infection.
Drawings
Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a reaction scheme 1 for the synthesis of compounds of formula II;
FIG. 2 is a reaction scheme 2 for the synthesis of compounds of formula II;
FIG. 3 is a reaction scheme 3 for the synthesis of compounds of formula II.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
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. 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 embodiments and materials described herein are intended to be exemplary only.
Example 1α preparation α of α alpha α, α alpha α' α - α tetrabromo α - α 3 α - α methoxy α - α o α - α xylene α (α Compound α 3 α) α
2, 3-xylenol (3.00g, 24.6mmol) was dissolved in acetone (30ml), solid anhydrous potassium carbonate (10.0g, 73.8mmol) was added, methyl iodide (5ml, 73.8mmol) was added in the dark, and the mixture was heated to 50 ℃ and stirred under reflux for 24 h. After completion of the reaction, the stirring was stopped by Thin Layer Chromatography (TLC), and the mixture was diluted with 100ml of water, extracted three times with ethyl acetate (50 ml. times.3), and the organic phases were combined and dried for 12 hours by adding anhydrous sodium sulfate to the organic phase. Filtering, and removing the ethyl acetate solvent by rotary evaporation to obtain 3.5g of crude 3-methoxy-o-xylene (compound 2) light yellow oily liquid with the yield of 104.7 percent.
The crude 3-methoxy-o-xylene product is diluted and dissolved by carbon tetrachloride (100ml), N-bromosuccinimide (NBS, 34.0g, 190.4mmol) and an initiator azobisisobutyronitrile (AIBN, 0.30g) are added into the mixed liquid, and after uniform mixing, the mixture is heated to 77 ℃ and stirred and refluxed for 24 hours. TLC detection reaction is almost complete, cooling and stirring are stopped, reaction liquid is filtered, filtrate is taken and washed twice by saturated sodium bisulfite solution (50ml multiplied by 2), standing and demixing are carried out, organic phase is collected and dried for 12h by anhydrous sodium sulfate. Filtering, taking the filtrate, and carrying out silica gel column chromatography, wherein an eluent is pure petroleum ether, so that 7.70g of white solid is obtained, and the yield is 69.2%.
Example 2Preparation of 5-methoxy-2, 3-naphthalic anhydride (Compound 5)
the α, α' -tetrabromo-3-methoxy-o-xylene (1.88g, 4.2mmol) prepared in example 1, maleic anhydride (0.41g, 4.2mmol) and potassium iodide solid (4.83g, 30mmol) were put into N, N-dimethylformamide (DMF, 20ml) and stirred uniformly, the reaction system was heated to 70 ℃ and stirred for 8h, the reaction was checked for substantial completion by TLC, cooling and stirring were stopped, the reaction solution was poured into a prepared dilute sodium bisulfite solution (5g/200ml), yellow solid was observed to precipitate immediately, the reaction solution was left for a while, filtered, the filter cake was washed three times with a small amount of dilute sodium bisulfite solution, and dried to obtain crude 5-methoxy-2, 3-naphthalenedicarboxylic acid (compound 4) crude yellow solid 0.63g, yield was 61%.
Weighing a 5-methoxy-2, 3-naphthalenedicarboxylic acid crude product (0.25g, 1mmol) and dissolving in a small amount of acetic anhydride (4-5 ml), heating to 140 ℃, refluxing for 2-3h, detecting by TLC (thin-layer chromatography) (dilution in advance), removing acetic anhydride by high-temperature rotary evaporation to obtain a dark brown solid, namely 5-methoxy-2, 3-naphthalenedicarboxylic anhydride.
Example 3Preparation of N-benzylmaleimide
Maleic anhydride (0.98g, 10mmol) was dissolved in glacial acetic acid (15ml), benzylamine (0.83g, 6.67mmol) was slowly added dropwise with electromagnetic stirring, and the reaction was heated to 120 ℃ and stirred under reflux for 4 h. TLC detection reaction is almost complete, stop stirring, cool to room temperature, dilute with prepared dilute sodium hydroxide solution (8g/100ml) and neutralize the reaction solution, extract three times with ethyl acetate (30 ml. times.3), collect the organic phase, and dry the organic phase with anhydrous sodium sulfate for 12 h. Filtering, taking the filtrate, and carrying out silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether 1:10 gave 0.41g of white solid in 30.0% yield.
Wherein, the N-m-fluorobenzylmaleimide can be prepared by the same method.
Example 4Preparation of N-phenylmaleimide
Maleic anhydride (0.98g, 10mmol) and aniline (1.17g, 10.5mmol) were each separately dissolved in dichloromethane (15ml), and a dichloromethane solution of maleic anhydride was added dropwise to a dichloromethane solution of aniline, and the reaction system was stirred at normal temperature for 2 h. A large amount of yellow solid was found to precipitate gradually, which was filtered, the filter cake was washed two to three times with the filtrate, and the filter cake was dried to give 1.94g of crude intermediate yellow solid in 93% yield.
The crude product obtained after the previous step was dried was dissolved in a small amount of acetic anhydride (5ml), 0.4g of sodium acetate was added to the reaction solution, and the reaction system was heated to 120 ℃ and stirred under reflux for 2 hours. The reaction was essentially complete by TLC and the stirring was stopped. The reaction solution was diluted with 100ml of an ice-water mixture, extracted twice with ethyl acetate (30 ml. times.2), and the organic phases were collected and dried over anhydrous sodium sulfate for 12 hours. Filtering, taking the filtrate, and carrying out silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether 1:5 gave 1.27g of a pale yellow oily liquid in 71.6% yield.
The total yield of the reaction was 66.5% in the two steps.
Wherein, the N-m-fluorobenzylmaleimide can be prepared by the same method.
Example 5Preparation of 5-methoxy-N-benzyl-2, 3-naphthalimide (Compound JCB-1)
5-methoxy-2, 3-naphthalic anhydride (prepared in example 2) obtained after the rotary evaporation was dissolved in pyridine (5ml), benzylamine (0.12g, 1.1mmol) was added dropwise to the mixed solution, and the reaction system was heated to 120 ℃ and refluxed for 12 hours with stirring thoroughly. TLC detection of essentially complete reaction, high temperature rotary evaporation to remove pyridine solvent, dissolving the residue with dichloromethane (50ml), and purificationThe solution was washed twice with dilute hydrochloric acid (30 ml. times.2), and the organic phase was collected and dried over anhydrous sodium sulfate for 12 hours. Filtering, taking the filtrate, and carrying out silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether 1:10 to give a yellow powdery solid in 37.9% yield, mp:198-200 ℃, Rf0.55 (developing solvent: ethyl acetate: petroleum ether: 2:5), with intense fluorescence.
Example 6Preparation of 5-methoxy-N-phenyl-2, 3-naphthalimide (Compound JCB-9)
The dark brown solid 5-methoxy-2, 3-naphthalic anhydride (prepared in example 2) obtained after the rotary evaporation was dissolved in pyridine (5ml), aniline (0.11g, 1.1mmol) was added dropwise to the mixture, stirred well and heated to 120 ℃ for reflux for 12 h. TLC detection of the reaction was essentially complete, pyridine solvent was removed by rotary evaporation at elevated temperature, the residue obtained after rotary evaporation was dissolved in dichloromethane (50ml), the solution was washed twice with dilute hydrochloric acid (30 ml. times.2), the organic phase was collected and dried over anhydrous sodium sulfate for 12 h. Filtering, taking the filtrate, and carrying out silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether 1:10 to give 81mg of a brown solid, 26.7% yield, mp: 203-205 ℃, Rf 0.55 (developing solvent: ethyl acetate: petroleum ether: 2:5), with intense fluorescence.
Example 7Preparation of 5-methoxy-N-phenylethyl-2, 3-naphthalimide (Compound JCB-29)
The dark brown solid 5-methoxy-2, 3-naphthalic anhydride (prepared in example 2) obtained after the rotary evaporation was dissolved in pyridine (5ml), phenethylamine (0.13g, 1.1mmol) was added dropwise to the mixture, stirred well and heated to 120 ℃ for reflux for 12 h. TLC detection of the reaction was essentially complete, pyridine solvent was removed by rotary evaporation at elevated temperature, the residue obtained after rotary evaporation was dissolved in dichloromethane (50ml), the solution was washed twice with dilute hydrochloric acid (30 ml. times.2), the organic phase was collected and dried over anhydrous sodium sulfate for 12 h. Filtering, taking the filtrate, and carrying out silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether 1:10 gave a yellow powdery solid in 34.4% yield, mp:190-192 ℃, Rf 0.60 (developing solvent: ethyl acetate: petroleum ether 2:5) with intense fluorescence.
Example 8Preparation of 5-methoxy-N-N-hexyl-2, 3-naphthalimide (Compound JCB-36)
The dark brown solid 5-methoxy-2, 3-naphthalic anhydride (prepared in example 2) obtained after the rotary evaporation was dissolved in pyridine (5ml), n-hexylamine (0.13g, 1.1mmol) was added dropwise to the mixture, stirred well and the reaction system was heated to 120 ℃ and refluxed for 12 h. TLC detection of the reaction was essentially complete, pyridine solvent was removed by rotary evaporation at elevated temperature, the residue obtained after rotary evaporation was dissolved in dichloromethane (50ml), the solution was washed twice with dilute hydrochloric acid (30 ml. times.2), the organic phase was collected and dried over anhydrous sodium sulfate for 12 h. Filtering, taking the filtrate, and carrying out silica gel column chromatography, wherein an eluent is ethyl acetate: petroleum ether 1:10 gave a yellow powdery solid in 39.5% yield, mp:125-127 ℃, Rf 0.80 (developing solvent: ethyl acetate: petroleum ether 2:5) with intense fluorescence.
Example 9Preparation of 5-methoxy-N-m-fluorobenzyl-2, 3-naphthalimide (Compound JCB-4)
α, α, α ', α' -tetrabromo-3-methoxy-o-xylene (0.68g, 1.5mmol) prepared in example 1, N-m-fluorobenzylmaleimide (0.21g, 1mmol) prepared according to the method of example 3, and a solid potassium iodide (1.16g, 7mmol) were respectively put into N, N-dimethylformamide (20ml), the reaction system was heated to 70 ℃ and stirred for 6 h.the completion of the reaction was detected, the stirring was stopped by cooling, DMF was rotary evaporated at high temperature, the residual liquid was diluted with a saturated sodium bisulfite solution (100ml), extracted three times with ethyl acetate (50ml × 3), the organic phase was collected, dried over anhydrous sodium sulfate for 12h and filtered, and the filtrate was chromatographed on a silica gel column with ethyl acetate: petroleum ether ═ 1:10 as an eluent to give 104mg of an opalescent solid, the yield was 31.0%, mp: 178-180 ℃ and Rf ═ 0.40 (ethyl acetate: petroleum ether: 1:5 as an eluent).
Example 10Preparation of 5-methoxy-N-m-fluorobenzyl-2, 3-naphthalimide (Compound JCB-4)
α, α, α ', α' -tetrabromo-3-methoxy-o-xylene (0.68g, 1.5mmol) prepared in example 1, N-m-fluorobenzylmaleimide (0.21g, 1mmol) prepared according to the method of example 4, and a solid potassium iodide (1.16g, 7mmol) were respectively put into N, N-dimethylformamide (20ml), the reaction system was heated to 70 ℃ and stirred for 6 h.the completion of the reaction was detected, the stirring was stopped by cooling, DMF was rotary evaporated at high temperature, the residual liquid was diluted with a saturated sodium bisulfite solution (100ml), extracted three times with ethyl acetate (50ml × 3), the organic phase was collected, dried over anhydrous sodium sulfate for 12h and filtered, and the filtrate was chromatographed on a silica gel column with ethyl acetate: petroleum ether ═ 1:10 as an eluent to give 104mg of an opalescent solid, the yield was 31.0%, mp: 178-180 ℃ and Rf ═ 0.40 (ethyl acetate: petroleum ether: 1:5 as an eluent).
The preparation methods of the compounds JCB-2 to JCB-3, JCB5 to JCB-8, JCB-11 to JCB-13, JCB-15, JCB-18, JCB-20 to JCB-28, JCB-30 to JCB-35 and JCB-37 to JCB-42 are the same as the example 5, the molar ratio of the used raw materials is the same as the example 5, and the yield of each product ranges from 4 percent to 92 percent.
The preparation methods of the compounds JCB-4, JCB-10, JCB-14, JCB-16, JCB-17 and JCB-19 are the same as the example 9, the molar ratio of the used raw materials is the same as the example 9, and the yield of each product ranges from 8 percent to 35 percent.
And (3) confirming the structure of the compound:
example 11Determination of antibacterial synergistic activity of 2, 3-naphthalimide derivatives
Eliminating the influence of the target compound on engineering bacteria during combined medication by measuring the Minimum Inhibitory Concentration (MIC) of the target compound on E.coli BW25113 (wild type, AcrB protein overexpression) and E.coli BW25113 (delta AcrB, AcrB deletion strain), and determining the concentration range of the target compound during combined medication
MIC of each 2, 3-naphthalimide derivative (namely the compounds JCB-1-JCB-42) and Erythromycin (ERY), Chloramphenicol (CAM), Triphenylphosphine (TPP) and Levofloxacin (LEV) is determined by adopting a continuous micropore double dilution method, the drug concentration range of the erythromycin, chloramphenicol, triphenylphosphine and levofloxacin when the erythromycin, chloramphenicol, triphenylphosphine and levofloxacin are respectively combined with the compounds JCB-1-JCB-42 is determined according to the result of MIC, and the antibacterial sensitization effect of the compounds JCB-1-JCB-42 under the concentration of 8 mu g/mL, 16 mu g/mL, 32 mu g/mL, 64 mu g/mL and 128 mu g/mL is determined.
And (3) screening out the 2, 3-naphthalimide derivatives with stronger antibacterial and synergistic effects by using a chessboard micropore double dilution method according to the combined application result.
And (4) screening results: compounds JCB-1, JCB-2, JCB-5, JCB-6, JCB-19, JCB-21, JCB-34, JCB-36, JCB-37, JCB-38, JCB-40 and JCB-42 show certain antibacterial sensitization activity, wherein the compounds JCB-21, JCB-36, JCB-37 and JCB-40 show antibacterial sensitization activity when used together with four antibacterial drugs (ERY, CAM, TPP and LEV), the compounds JCB-1 show antibacterial sensitization activity when used together with three antibacterial drugs (ERY, CAM and TPP), the compounds JCB-2, JCB-19, JCB-38 and JCB-42 show antibacterial sensitization activity when used together with two antibacterial drugs of ERY, CAM, TPP and LEV, the compounds JCB-6 and JCB-34 show antibacterial sensitization activity when used together with ERY, CAM, TPP and LEV, One antibacterial drug in LEV is combined to show the antibacterial sensitization activity. The results are shown in Table 1.
TABLE 1 in vitro antibacterial Activity of the target Compounds in combination with antibacterial drugs
Example 12Determination of efflux inhibition Activity of 2, 3-naphthalimide derivative
An efflux pump inhibitor must be capable of reducing the efflux level of an efflux substrate, nile red is an efflux substrate of escherichia coli over-expressing AcrB, and the ability of a 2, 3-naphthalimide derivative as an efflux pump inhibitor to reduce the efflux level is evaluated by inhibiting the efflux of nile red. Nile Red exhibits extremely weak fluorescence in an aqueous solution, but its fluorescence intensity rapidly increases in a nonpolar solution such as a cell membrane, and is preloaded in cells containing and not containing the 2, 3-naphthalenedicarboxylic imide derivatives (compounds JCB-1 to JCB-42) of the present invention, and when the cells are activated, the level of the efflux inhibition activity of the 2, 3-naphthalenedicarboxylic imide derivatives (compounds JCB-1 to JCB-42) of the present invention is evaluated by observing the change in fluorescence intensity.
The experimental results show that the compounds JCB-21 and JCB-36 can completely inhibit the discharge of Nile red at the concentration of 100 mu M, and in addition, the compounds JCB-1, JCB-5 and JCB-6 can prevent the preassembly of the Nile red on cells.
In conclusion, the 2, 3-naphthalimide derivatives have good antibacterial synergistic activity and efflux inhibition activity on AcrB-carrying bacteria, and certain compounds can prevent the efflux action of bacterial nile red, and are found in the compounds for the first time.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (9)
1. A compound of formula I or an isomer or solvate or pharmaceutically acceptable salt thereof:
wherein R is1One or more selected from straight-chain or branched alkyl, saturated or unsaturated cycloalkyl, alkoxy, aromatic group, five-membered or six-membered aromatic heterocycle containing one or more heteroatoms or aliphatic heterocycle, which is mono-or polysubstituted on the naphthalene ring; whereinThe heteroatoms, which may be the same or different, are selected from N, O, S; r2Selected from benzene ring, substituted benzene ring, aromatic group, substituted aromatic group, benzyl group, substituted benzyl group, straight chain or branched chain alkyl, saturated or unsaturated cycloalkyl.
2. A compound or isomer or solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein R is1Is selected from C1-C22Straight or branched alkyl, C3-C22Saturated or unsaturated cycloalkyl, C1-C22Alkoxy, aryl, five-membered or six-membered aromatic heterocycle or aliphatic heterocycle containing one or more heteroatoms;
preferably, said R is2Selected from benzene ring, substituted benzene ring, aromatic group, substituted aromatic group, benzyl, substituted benzyl and C1-C22Straight or branched alkyl, C3-C22A saturated or unsaturated cycloalkyl group;
preferably, said R is1Is selected from C1-C8Straight or branched alkyl, C3-C8Saturated or unsaturated cycloalkyl, C1-C8Alkoxy, aryl, five-membered or six-membered aromatic heterocycle or aliphatic heterocycle containing one or more heteroatoms;
preferably, said R is1Substitution, preferably mono-or disubstituted, at the 5-8 position of the naphthalene ring; preferably, said R is1Mono-substituted on the 5, 6, 7 or 8 position of the naphthalene ring;
preferably, said R is1Is C1-C8An alkoxy group; preferably, said R is1Selected from methoxy, ethoxy, propoxy, isopropoxy n-butoxy, isobutoxy, tert-butoxy; preferably, said R is1Is methoxy, ethoxy or propoxy;
preferably, said R is2Selected from benzene ring, substituted phenyl, aryl, substituted aryl, benzyl, substituted benzyl, C1-C12Straight or branched alkyl of (2), C3-C6Saturated or unsaturated cycloalkyl groups of (a); wherein the benzene ring,The aryl and benzyl groups can be respectively and independently substituted or unsubstituted by halogen1-C8Straight or branched alkyl, C substituted or unsubstituted by halogen1-C8Alkoxy radical, C3-C6Substituted with saturated or unsaturated cycloalkyl, phenyl;
preferably, the halogen is selected from F, Cl, Br, I;
preferably, said R is2Selected from benzene ring, substituted benzene ring, benzyl, substituted benzyl, phenethyl, substituted phenethyl, C1-C12Straight or branched alkyl of (2), C3-C6Saturated or unsaturated cycloalkyl groups of (a);
preferably, said R is2Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl ring, benzyl, phenethyl;
wherein the benzene ring, benzyl, phenethyl can be unsubstituted or each independently be selected from halogen, C which is mono-or poly-substituted or unsubstituted by the same or different halogen1-C8Straight-chain or branched alkyl, C mono-or polysubstituted or unsubstituted by identical or different halogens1-C8Alkoxy radical, C3-C6Substituted by a saturated or unsaturated cycloalkyl, phenyl, said substitution being mono-or polysubstituted;
preferably, the benzene ring, benzyl, phenethyl can be unsubstituted or each independently be substituted by a halogen, C mono-or poly-substituted or unsubstituted with the same halogen1-C5Straight-chain or branched alkyl, C mono-or polysubstituted or unsubstituted by the same halogen1-C5Alkoxy radical, C3-C6Substituted by a saturated or unsaturated cycloalkyl, phenyl, said substitution being mono-or polysubstituted;
preferably, the mono-or poly-substitution may be mono-, di-or tri-substitution;
preferably, the substitution on the phenyl ring, benzyl, phenethyl can occur in the para, meta or ortho position, preferably in the ortho position;
preferably, the benzene ring, benzyl, phenethyl can be unsubstituted or each independently be trisubstituted or unsubstituted by a group selected from halogen, C being the same halogen1-C4Straight or branched alkyl, C tri-substituted or unsubstituted by the same halogen1-C3Alkoxy substituted, the substitution is mono-substitution, and the halogen is F or Cl; preferably, said benzene ring, benzyl, phenethyl may be unsubstituted or C, trisubstituted or unsubstituted by F, selected from F, Cl1-C4Straight or branched alkyl, C trisubstituted or unsubstituted by F1-C2Alkoxy is monosubstituted; preferably, said benzene ring, benzyl, phenethyl may be unsubstituted or C, trisubstituted or unsubstituted by F, selected from F, Cl1-C4Linear or branched alkyl, methoxy or trifluoromethoxy monosubstituted; preferably, said R is2Selected from methyl, isopropyl, tert-butyl, n-pentyl, n-hexyl, phenyl or benzyl ortho or para substituted by methyl, ethyl or isopropyl, phenyl or benzyl ortho or para substituted by F or Cl, phenyl or benzyl ortho or para substituted by methoxy or trifluoromethoxy.
3. A compound of formula II or an isomer or solvate or pharmaceutically acceptable salt thereof:
wherein R is2As claimed in claim 1 or 2.
4. A compound of formula I according to claim 1 or 2, or an isomer or solvate or pharmaceutically acceptable salt thereof, or a compound of formula II according to claim 3, or an isomer or solvate or pharmaceutically acceptable salt thereof, comprising the structure:
5. a method for preparing a compound shown as a formula II takes 2, 3-xylenol as an initial raw material, and comprises the steps of performing methylation reaction, bromination reaction, Diels-Alder reaction and amide condensation to obtain the compound shown as the formula II;
preferably, the method uses 2, 3-xylenol as a starting material, and comprises the steps of sequentially carrying out methylation reaction, bromination reaction, Diels-Alder reaction and amide condensation to obtain a compound of a formula II, namely the method obtains the compound of the formula II by a reaction route 1;
preferably, scheme 1 is as follows:
wherein R is2As claimed in claim 1 or 2;
preferably, scheme 1 comprises the steps of:
(1) 2, 3-xylenol is used as an initial raw material, and methylation reaction is carried out on the initial raw material and methyl iodide under an alkaline condition to obtain a compound 2;
(2) carrying out bromination reaction on the compound 2 and excessive N-bromosuccinimide to obtain a compound 3;
(3) carrying out Diels-Alder reaction on the compound 3 and maleic anhydride under the catalysis of solid potassium iodide to obtain a compound 4;
(4) dehydrating the compound 4 at high temperature to obtain a compound 5;
(5) compound 5 and R2-NH2Amide condensation to give compounds of formula II, wherein R2As claimed in claim 1 or 2;
preferably, scheme 1 comprises the steps of:
(1) dissolving 2, 3-xylenol in a methylation solvent, adding solid anhydrous potassium carbonate, adding methyl iodide liquid under a dark condition, heating the mixture, stirring and refluxing to react; after the reaction is finished, stopping stirring, diluting with water, extracting with ethyl acetate, combining organic phases, fully drying, filtering, and removing an ethyl acetate solvent by rotary evaporation to obtain a crude compound 2;
(2) diluting and dissolving the crude product of the compound 2 by using a solvent, adding N-bromosuccinimide and an initiator azodiisobutyronitrile into the mixed liquid, uniformly mixing, heating, stirring and refluxing for reaction; after the reaction is completed, cooling, filtering, washing the filtrate with saturated sodium bisulfite solution, standing for layering, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound 3;
(3) putting the compound 3, maleic anhydride and potassium iodide solid into N, N-dimethylformamide, uniformly stirring, and heating and stirring a reaction system; after the reaction is completed, cooling and stopping stirring, pouring the reaction solution into a dilute sodium bisulfite solution, separating out yellow solid, filtering, and drying a filter cake to obtain a crude product yellow solid of the compound 4;
(4) dissolving the crude product of the compound 4 in a solvent, and heating and refluxing for reaction; detecting that the reaction is basically complete, and removing the solvent by high-temperature rotary evaporation to obtain a dark brown solid compound 5 crude product;
(5) dissolving the crude compound 5 in solvent, and adding R dropwise into the mixed solution2-NH2Fully and uniformly stirring, and heating a reaction system to reflux for reaction; after the detection reaction is completed, removing the solvent by high-temperature rotary evaporation, dissolving the residue obtained after the rotary evaporation by using dichloromethane, washing the solution by using dilute hydrochloric acid, collecting an organic phase, drying the organic phase by using anhydrous sodium sulfate, filtering, and taking the filtrate to perform silica gel column chromatography to obtain a compound shown in a formula II;
preferably, in step (1), the methylating solvent is selected from the group consisting of acetone, N-dimethylformamide, tetrahydrofuran, ethyl acetate and acetonitrile, preferably acetone; preferably, in the step (1), the molar ratio of the anhydrous potassium carbonate, the iodomethane and the 2, 3-dimethylphenol is 1.5-3.0: 1.5-3.0: 1.0, preferably 3: 3: 1; preferably, in the step (1), the mixture is heated to 30-60 ℃, stirred and reacted for 12-48 h, preferably heated to 50 ℃, and stirred and reacted for 24 h;
preferably, in step (2), the solvent is selected from benzene and carbon tetrachloride, preferably carbon tetrachloride; preferably, in step (2), the molar ratio of compound 2 to N-bromosuccinimide is 1.0: 3.0-8.0, preferably 1: 6.8; preferably, in the step (2), the molar ratio of the added amount of the initiator azodiisobutyronitrile to the compound 2 is 0.05-0.10: 1; preferably, in the step (2), the reactants are heated to 77 ℃ after being uniformly mixed, stirred and refluxed for 12-48 hours, preferably 24 hours;
preferably, in step (3), the molar ratio of compound 3, maleic anhydride and potassium iodide solid is 1.0: 1.0-2.0: 5.0-7.0, preferably 1: 1: 7; preferably, in the step (3), the concentration of the dilute sodium bisulfite is 0.2-0.4 mol/L, preferably 0.25 mol/L; preferably, in the step (3), the reaction system is heated to 50-100 ℃ and stirred for 8-16 h, preferably 70 ℃ and stirred for 8 h;
preferably, in step (4), the solvent is selected from acetic anhydride, oxalyl chloride, thionyl chloride, preferably acetic anhydride; preferably, in the step (4), the crude compound 4 is dissolved in a solvent, heated to 100-140 ℃ and reacted for 2-3h, preferably heated to 100 ℃ and reacted for 2-3 h;
preferably, in step (5), the solvent is selected from pyridine, hydroxylamine hydrochloride, glacial acetic acid and N, N-dimethylformamide, preferably pyridine; preferably, in step (5), the compound 5 is reacted with R2-NH2Is 1.0: 1.0 to 1.5, preferably 1: 1.5; preferably, in the step (5), the reaction system is heated to 80-120 ℃ for reaction for 12-24 h, preferably the reaction system is heated to 120 ℃ for reaction for 12 h;
or, preferably, the method uses 2, 3-xylenol as a starting material, and comprises the following steps of sequentially carrying out methylation reaction, bromination reaction, amide condensation and Diels-Alder reaction to obtain the compound of the formula II, namely, the method obtains the compound of the formula II by a reaction route 2;
preferably, scheme 2 is as follows:
wherein R is2As claimed in claim 1 or 2;
preferably, scheme 2 comprises the steps of:
(a) 2, 3-xylenol is used as an initial raw material, and methylation reaction is carried out on the initial raw material and methyl iodide under an alkaline condition to obtain a compound 2;
(b) carrying out bromination reaction on the compound 2 and excessive N-bromosuccinimide to obtain a compound 3;
(c) get R2-NH2Amide condensation reaction with maleic anhydride to obtain a compound 7, wherein R2As claimed in claim 1 or 2;
(d) carrying out Diels-Alder reaction on the compound 3 and the compound 7 to obtain a compound shown in a formula II;
preferably, scheme 2 comprises the steps of:
(a) dissolving 2, 3-xylenol in a methylation solvent, adding solid anhydrous potassium carbonate, adding methyl iodide liquid under a dark condition, and heating, stirring and refluxing the mixture to react; after the reaction is finished, stopping stirring, diluting with water, extracting with ethyl acetate, combining organic phases, fully drying, filtering, and removing an ethyl acetate solvent by rotary evaporation to obtain a crude compound 2;
(b) diluting and dissolving the crude product of the compound 2 by using a solvent, adding N-bromosuccinimide and an initiator azodiisobutyronitrile into the mixed liquid, uniformly mixing, heating, stirring and refluxing for reaction; after the reaction is completed, cooling, filtering, washing the filtrate with saturated sodium bisulfite solution, standing for layering, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound 3;
(c) dissolving maleic anhydride in glacial acetic acid, and slowly dripping R while electromagnetically stirring2-NH2Heating, stirring and refluxing the reaction liquid to carry out reaction; stopping stirring after detecting reaction, cooling to room temperature, diluting the neutralized reaction solution with dilute sodium hydroxide solution, extracting with ethyl acetate, collecting organic phase, drying with anhydrous sodium sulfate, filtering, collecting filtrate, subjecting to silica gel column chromatography,to obtain a compound 7;
(d) respectively putting the compound 3, the compound 7 and the potassium iodide solid into N, N-dimethylformamide, heating the reaction system and stirring; detecting complete reaction, cooling, stopping stirring, performing high-temperature rotary evaporation on N, N-dimethylformamide, diluting residual liquid with saturated sodium bisulfite solution, extracting with ethyl acetate, collecting organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound of formula II;
preferably, in step (a), the methylating solvent is selected from the group consisting of acetone, N-dimethylformamide, tetrahydrofuran, ethyl acetate and acetonitrile, preferably acetone; preferably, in the step (a), the molar ratio of the anhydrous potassium carbonate, the iodomethane and the 2, 3-dimethylphenol is 1.5-3.0: 1.5-3.0: 1.0, preferably 3: 3: 1; preferably, in the step (a), the mixture is heated to 30-60 ℃, stirred and refluxed for 12-48 h, and preferably heated to 50 ℃, and stirred and reacted for 24 h;
preferably, in step (b), the solvent is selected from benzene and carbon tetrachloride, preferably carbon tetrachloride; preferably, in step (b), the molar ratio of compound 2 to N-bromosuccinimide is 1.0: 3.0-8.0, preferably 1: 6.8; preferably, in the step (b), the molar ratio of the added amount of the initiator azodiisobutyronitrile to the compound 2 is 0.05-0.10: 1; preferably, in the step (b), the reactants are heated to 77 ℃ after being uniformly mixed, stirred and refluxed for 12-48 hours, and preferably 24 hours;
preferably, in step (c), the maleic anhydride is reacted with R2-NH2Is 1.0: 1.0 to 1.5, preferably 1: 1.5; preferably, in the step (c), the reaction solution is heated to 80-120 ℃ and stirred for reaction for 4 hours, preferably heated to 120 ℃ and stirred for reaction for 4 hours;
preferably, in the step (d), the molar ratio of the compound 3 to the compound 7 to the potassium iodide solid is 1.0-1.5: 1.0: 5.0-7.0, preferably 1.5: 1: 7; preferably, in the step (d), the reaction system is heated to 50-100 ℃ and stirred for reaction for 6 hours, preferably heated to 70 ℃ and stirred for reaction for 6 hours;
or, preferably, the method uses 2, 3-xylenol as a starting material, and comprises the steps of sequentially carrying out methylation reaction, bromination reaction, amide condensation, cyclic amidation and Diels-Alder reaction to obtain the compound of the formula II, namely, the method obtains the compound of the formula II by a reaction route 3;
preferably, scheme 3 is as follows:
wherein R is2As claimed in claim 1 or 2;
preferably, scheme 3 comprises the steps of:
(i) 2, 3-xylenol is used as an initial raw material, and methylation reaction is carried out on the initial raw material and methyl iodide under an alkaline condition to obtain a compound 2;
(ii) carrying out bromination reaction on the compound 2 and excessive N-bromosuccinimide to obtain a compound 3;
(iii)R2-NH2amide condensation reaction with maleic anhydride to obtain compound 8, wherein R2As claimed in claim 1 or 2;
(iv) further cycloamidating the compound 8 to give a compound 7;
(v) carrying out Diels-Alder reaction on the compound 7 and the compound 3 to obtain a target compound;
preferably, scheme 3 comprises the steps of:
(i) dissolving 2, 3-xylenol in a methylation solvent, adding solid anhydrous potassium carbonate, adding methyl iodide liquid under a dark condition, heating the mixture, stirring and refluxing to react; after the reaction is finished, stopping stirring, diluting with water, extracting with ethyl acetate, combining organic phases, fully drying, filtering, and removing an ethyl acetate solvent by rotary evaporation to obtain a crude compound 2;
(ii) diluting and dissolving the crude product of the compound 2 by using a solvent, adding N-bromosuccinimide and an initiator azodiisobutyronitrile into the mixed liquid, uniformly mixing, heating, stirring and refluxing for reaction; after the reaction is completed, cooling, filtering, washing the filtrate with saturated sodium bisulfite solution, standing for layering, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound 3;
(iii) mixing maleic anhydride and R2-NH2Each separately dissolved in dichloromethane, a solution of maleic anhydride in dichloromethane was added dropwise to R2-NH2Stirring the reaction system at normal temperature in the dichloromethane solution to find that a compound 8 is separated out;
(iv) dissolving the crude product of the compound 8 in acetic anhydride, adding a small amount of sodium acetate into a reaction solution, heating the reaction system, and stirring and refluxing to perform reaction; after the reaction is detected to be complete, stopping stirring, diluting the reaction solution with an ice-water mixture, extracting with ethyl acetate, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound 7;
(v) respectively putting the compound 3, the compound 7 and the potassium iodide solid into N, N-dimethylformamide, heating the reaction system and stirring; detecting complete reaction, cooling, stopping stirring, performing rotary evaporation on DMF at high temperature, diluting the residual liquid with saturated sodium bisulfite solution, extracting with ethyl acetate, collecting an organic phase, drying the organic phase with anhydrous sodium sulfate, filtering, and performing silica gel column chromatography on the filtrate to obtain a compound of formula II;
preferably, in step (i), the methylating solvent is selected from acetone, N-dimethylformamide, tetrahydrofuran, ethyl acetate and acetonitrile, preferably acetone; preferably, in step (i), the molar ratio of the anhydrous potassium carbonate, methyl iodide and 2, 3-dimethylphenol is 1.5-3.0: 1.5-3.0: 1.0, preferably 3: 3: 1; preferably, in the step (i), the mixture is heated to 30-60 ℃ and stirred for reaction for 12-48 h, preferably heated to 50 ℃ and stirred for reaction for 24 h;
preferably, in step (ii), the solvent is selected from benzene and carbon tetrachloride, preferably carbon tetrachloride; preferably, in step (ii), the molar ratio of compound 2 to N-bromosuccinimide is 1.0: 3.0-8.0, preferably 1: 6.8; preferably, in step (ii), the molar ratio of the added amount of the initiator azodiisobutyronitrile to the compound 2 is 0.05-0.10: 1; preferably, in the step (ii), the reactants are heated to 77 ℃ after being uniformly mixed, stirred and refluxed for 12-48 hours, preferably 24 hours;
preferably, in step (iii), the maleic anhydride is reacted with R2-NH2Is 1.0: 1.0 to 1.5, preferably 1: 1.5;
preferably, in step (iv), the sodium acetate is added in a molar ratio to maleic anhydride of 1.0: 2.0: 1;
preferably, in step (v), the molar ratio of the compound 3 to the compound 7 to the potassium iodide solid is 1.0 to 1.5: 1.0: 5.0-7.0, preferably 1.5: 1: 7; preferably, in the step (v), the reaction system is heated to 80-120 ℃ and stirred for 8h, preferably heated to 70 ℃ and stirred for 8 h.
6. A pharmaceutical composition comprising a compound of formula I as described in claim 1 or 2 or an isomer or solvate or pharmaceutically acceptable salt thereof or a compound of formula II as described in claim 3 or an isomer or solvate or pharmaceutically acceptable salt thereof.
7. Use of a compound of formula I as described in claim 1 or 2 or an isomer or solvate or pharmaceutically acceptable salt thereof, or a compound of formula II as described in claim 3 or an isomer or solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 6, for the manufacture of a medicament for the treatment of a bacterial infection; preferably, the compound of formula I or formula II or its isomer or solvate or pharmaceutically acceptable salt has antibacterial sensitization activity to bacteria; preferably, the bacterium is an AcrB-bearing bacterium, preferably a gram-negative bacterium that overexpresses AcrB.
8. Use of a compound of formula I as described in claim 1 or 2 or an isomer or solvate or pharmaceutically acceptable salt thereof, or a compound of formula II as described in claim 3 or an isomer or solvate or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 6, for the manufacture of a bacterial medicament carrying an AcrB efflux pump; preferably, the compound of formula I or formula II or an isomer or solvate or pharmaceutically acceptable salt thereof has efflux inhibiting activity against bacteria; preferably, the bacterium is an AcrB-bearing bacterium, preferably a gram-negative bacterium that overexpresses AcrB.
9. A combination comprising a compound of formula I as claimed in claim 1 or 2 or an isomer or solvate or pharmaceutically acceptable salt thereof and an antibacterial agent, or a compound of formula II as claimed in claim 3 or an isomer or solvate or pharmaceutically acceptable salt thereof and an antibacterial agent, for the treatment of a bacterial infection; preferably, the antibacterial drug is selected from erythromycin, chloramphenicol, triphenylphosphine, and levofloxacin.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH06287290A (en) * | 1993-04-01 | 1994-10-11 | Mitsui Toatsu Chem Inc | Aromatic polycarbonate |
| US20160015686A1 (en) * | 2014-07-18 | 2016-01-21 | Woods Hole Oceanographic Institution | Methods and Compositions for Increasing Antibiotic Activity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH06287290A (en) * | 1993-04-01 | 1994-10-11 | Mitsui Toatsu Chem Inc | Aromatic polycarbonate |
| US20160015686A1 (en) * | 2014-07-18 | 2016-01-21 | Woods Hole Oceanographic Institution | Methods and Compositions for Increasing Antibiotic Activity |
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| CN115385886A (en) * | 2022-06-28 | 2022-11-25 | 山东大学 | AcrB efflux pump inhibitor and preparation method and application thereof |
| CN115385886B (en) * | 2022-06-28 | 2024-04-19 | 山东大学 | AcrB efflux pump inhibitor and preparation method and application thereof |
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