Dibenzylideneacetone compounds, preparation methods thereof and applications in antibacterial treatment

Abstract

The present invention relates to the preparation and application of dibenzylideneacetone compounds represented by Formula I. By modifying these compounds, a class of compounds capable of selectively killing Staphylococcus aureus at low concentrations was synthesized. Upon illumination, the compounds further interact with ambient molecular oxygen to generate highly reactive species (ROS), such as free radicals or free radical ions, thereby enhancing bactericidal efficiency. This method prevents the development of drug-resistant bacteria and has excellent application value. #imgabs0#

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to dibenzylidene acetone compounds, a preparation method thereof and an application thereof in antibacterial treatment, and especially relates to an application of dibenzylidene acetone compounds in photodynamic sterilization. Background Art

[0002] Bacterial infections have long threatened human health. Due to the limited availability of direct diagnostic methods, treatment often lags behind. This allows pathogens to invade the bloodstream, grow, and multiply, ultimately causing systemic infection. The discovery of antibiotics addressed this problem, but their overuse has induced bacterial evolution over the past century, leading to the development of drug resistance. Therefore, the design and preparation of new antibacterial drugs and novel antibacterial approaches are of great significance.

[0003] Photodynamic therapy (PDT) is one of the most promising treatment modalities. It is a photochemical process that utilizes photosensitizers, light, and oxygen. During this process, photosensitizers (PSs) interact with ambient molecular oxygen to generate highly reactive species (ROS) such as free radicals or radical ions. This approach avoids the development of drug-resistant bacteria and has garnered widespread attention due to its high specificity, minimal invasiveness, low toxicity, and repeatable treatment options. Summary of the Invention

[0004] The present invention provides a compound represented by Formula I, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound:

[0005]

[0006] Among them, Q is selected from Or does not exist, when Q does not exist, X does not exist; X - is selected from halide; X1 and X2 can be independently selected from O, S, NR; Y is selected from -CHR, O, S, NR; R is H, C 1-6 Alkyl, C 6-14 Aryl; A1, A2 are selected from N, P; Z1, Z2 are selected from CH, N, P; R1, R2, R3, R4, R5, R6, R7, R8, R9, R 10 、R 11 may be the same or different and independently selected from H, F, Cl, Br, I, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkyl-C(O)-, C 1-6 Alkyl-C(O)NH-, C 1-6Alkyl-C(O)O-, C 6-14 Aryl, 3-12 membered heterocyclic-NH-, C 6-14 Aryl-NH-, 5-14 membered heteroaryl-NH-, 3-12 membered heterocyclyl-O-, C 6-14 Aryl-O-, 5-14 membered heteroaryl-O-; m is selected from an integer of 1-6.

[0007] According to an embodiment of the present invention, X - Can be selected from F - 、Cl - Br - , I - ; X1, X2 can be independently selected from O, S, NR; Y can be selected from O, S, NR; A1, A2 can be selected from N; R, R1-R 11 may be the same or different and independently selected from H, F, Cl, Br, I, C 1-6 Alkyl; m can be selected from 1, 2, 3, 4, 5 or 6. Z1, Z2 can be selected from CH, N

[0008] According to an embodiment of the present invention, R1, R2, R3, R4, R5, and R6 may be the same or different and are independently selected from H, CH3, CH2CH3, F, Cl, and Br;

[0009] X1 can be selected from O, NH or S;

[0010] X2 can be selected from O or CH3N-;

[0011] Y may be selected from O, S, CH2 or NH;

[0012] According to an embodiment of the present invention, A1 and A2 are selected from N;

[0013] According to an embodiment of the present invention, Z1 is selected from N, Z2 is selected from CH; or Z1 is selected from CH, Z2 is selected from N;

[0014] According to an embodiment of the present invention, R7-R 11 may be the same or different and independently selected from H, F, Cl, Br, I, CH3, CH2CH3, N(CH3)2 or -NHCH3;

[0015] m can be selected from 1, 2 or 3.

[0016] According to an embodiment of the present invention, Q is 2,4-difluorobenzyl bromide or is absent; R1, R2, R3, R4, R5, and R6 are selected from H;

[0017] X1 can be selected from O;

[0018] X2 can be selected from O;

[0019] Y can be selected from O;

[0020] R7, R 11 may be the same or different and independently selected from H or F;

[0021] m can be selected from 1, 2 or 3.

[0022] According to an embodiment of the present invention, the compound represented by formula (I) has the structure shown below:

[0023]

[0024] The present invention also provides a method for preparing the compound represented by formula (I), comprising the following steps:

[0025]

[0026] wherein L and L1 are selected from leaving groups, for example, F, Cl, Br, I, OH, and SH; Q, X1, X2, Y, A, A1, R1, R2, R3, R4, R5, R6, N1, N2, N3, N4, N5, and m have the meanings described above;

[0027] (a) Compound (V) and The reaction is carried out to obtain compound (IV);

[0028] (b) reacting compound (IV) with acetone under alkaline conditions to obtain compound (III);

[0029] (c) When Q is absent, compound (III) is reacted with The reaction yields a compound represented by formula (I);

[0030] (d) When Q is When the product of step (c) is further mixed with Reaction to obtain a compound represented by formula (I);

[0031] According to an embodiment of the present invention, in step (a), the reaction is carried out in the presence of a solvent, which may be an organic solvent, preferably acetonitrile;

[0032] According to an embodiment of the present invention, in step (a), the reaction is carried out in the presence of an inorganic base, and the inorganic base can be selected from at least one of sodium carbonate, potassium carbonate, and cesium carbonate;

[0033] According to an embodiment of the present invention, in step (a), compound (V) and The molar ratio can be 1:(2-10), preferably 1:5;

[0034] According to an embodiment of the present invention, in step (a), the reaction temperature is 40-120° C., for example, 80° C., and the reaction time is 10-48 h, for example, 24 h.

[0035] According to an embodiment of the present invention, in step (b), the reaction is carried out in the presence of a solvent, and the solvent may be a mixed solution of an organic solvent and water; the solvent is preferably a mixed solvent consisting of ethanol and water;

[0036] According to an embodiment of the present invention, in step (b), the reaction is carried out in the presence of an inorganic base, and the inorganic base can be selected from at least one of sodium hydroxide, potassium hydroxide, and lithium hydroxide;

[0037] According to an embodiment of the present invention, in step (b), the molar ratio of compound (IV) to acetone may be 1:(2-10), for example 1:5, preferably 1:3.

[0038] According to an embodiment of the present invention, in step (b), the reaction temperature is 10-40°C, such as room temperature, and the reaction time is 6-24h, such as 12h.

[0039] According to an embodiment of the present invention, in step (c), the reaction is carried out in the presence of a solvent, which may be an organic solvent, preferably acetonitrile.

[0040] According to an embodiment of the present invention, in step (c), the reaction is carried out in the presence of an inorganic base, and the inorganic base can be selected from at least one of sodium carbonate, potassium carbonate, and cesium carbonate;

[0041] According to an embodiment of the present invention, in step (c), the molar ratio of compound (III) to the compound providing ring A may be 1:(1-5), preferably 1:2;

[0042] According to an embodiment of the present invention, in step (c), the reaction may be carried out in the presence of a catalyst, and the catalyst may be selected from at least one of tetrabutylammonium bromide, tetrabutylammonium iodide, and tetrabutylammonium chloride;

[0043] According to an embodiment of the present invention, in step (c), the reaction temperature is 40-80°C, for example 60°C, and the reaction time is 6-24h, for example 12h, to obtain compound (I).

[0044] According to an embodiment of the present invention, in step (d), the reaction is carried out in the presence of a solvent, which may be an organic solvent, preferably acetonitrile.

[0045] According to an embodiment of the present invention, in step (d), the compound (I) and The molar ratio can be 1: (1-5), preferably 1: 2;

[0046] According to an embodiment of the present invention, in step (d), the reaction temperature is 60-120°C, for example, 80°C; and the reaction time is 6-24h, for example, 12h.

[0047] According to an embodiment of the present invention, in steps (a), (b), (c) and (d), the organic solvent may be selected from at least one of the following: alcohols, such as methanol, ethanol, isopropanol, n-butanol; ethers, such as ethyl propyl ether, n-butyl ether, anisole, phenethyl ether, cyclohexyl methyl ether, dimethyl ether, ethyl ether, dimethyl ethylene glycol, biphenyl ether, propyl ether, isopropyl ether, isobutyl ether, isopentyl ether, ethylene glycol dimethyl ether, isopropyl ethyl ether, methyl tert-butyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, dichlorodiethyl ether, and polyethers of ethylene oxide and / or propylene oxide; aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, heptane, octane, nonane, and hydrocarbons which may be substituted by fluorine and / or chlorine atoms, such as methylene chloride, dichloromethane, chloroform, carbon tetrachloride, fluorobenzene, chlorobenzene or dichlorobenzene; cyclohexane, methylcyclohexane, petroleum ether, acetone, octane, benzene, toluene, chlorobenzene, bromobenzene, xylene; esters, such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate and dimethyl carbonate, dibutyl carbonate or ethylene carbonate.

[0048] According to an embodiment of the present invention, the compound (V) of the reaction is a commercial compound, the compounds (III) and (IV) obtained by the above reaction can be separated and purified by normal phase silica gel column chromatography, and the compound represented by general formula (I) obtained by the above reaction can be separated and purified by reverse phase silica gel column chromatography.

[0049] The present invention also provides the use of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound in the preparation of antibacterial drugs.

[0050] According to an embodiment of the present invention, the bacteria may be Gram-positive Staphylococcus aureus or Gram-negative Escherichia coli.

[0051] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polymorph, pharmaceutically acceptable salt or prodrug compound thereof.

[0052] According to an embodiment of the present invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0053] According to an embodiment of the present invention, the pharmaceutical composition may further contain one or more additional therapeutic agents.

[0054] The present invention also provides the use of the compound represented by formula (I) in killing bacteria, such as the use in in vitro photodynamic sterilization.

[0055] According to an embodiment of the present invention, the bacteria may be Gram-positive Staphylococcus aureus or Gram-negative Escherichia coli.

[0056] According to an embodiment of the present invention, all detections were performed in PBS buffer solution.

[0057] The present invention also provides use of the compound represented by formula (I) in bacterial imaging.

[0058] Beneficial effects

[0059] 1) The compound of general formula (I) of the present invention, a dibenzylideneacetone derivative, has near-infrared emission properties and can be used for bacterial imaging. The compound of general formula (I) has a solvation effect through intramolecular charge transfer.

[0060] 2) The compounds of formula (I) described herein can target the bacterial wall of Staphylococcus aureus at extremely low concentrations. At this concentration, they have no killing effect on Gram-negative bacteria. Such compounds can be used for photodynamic sterilization, exhibiting excellent bacterial killing ability and a certain degree of bacterial selectivity. Ionic liquid-formulated compounds of formula (I) exhibit even superior technical effects.

[0061] 3) The compound of general formula (I) of the present invention binds to the bacterial outer wall through electrostatic interaction and embeds into the bacterial outer wall to achieve the effect of destroying the bacterial wall. After being irradiated with light, the compound of general formula (I) is activated to a singlet excited state by absorbing light of a specific wavelength, and then converted to an excited triplet state through intersystem crossing. The excited triplet photosensitizer can interact with molecular oxygen in the surrounding environment in two ways. One is to directly react with the substrate to generate free radicals or free radical ions and other highly active radicals (ROS) through electron transfer, such as hydroxyl radicals (·OH), superoxide anions (O2 – ), the other is that the photosensitizer molecules in the triplet excited state transfer energy with molecular oxygen to form singlet oxygen ( 1 O2). These highly active ROS can react with nearby amino acids, fatty acids, and nucleic acids to produce toxic photochemical products, which further damage the structure of bacteria and ultimately achieve a bactericidal effect. At the same time, it prevents the development of bacterial resistance. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] Figure 1The fluorescence spectra of compound (3) and compound (4) prepared in Example 3 and Example 4 in solvents of different polarities are shown;

[0063] Figure 2 The graph shows the bactericidal effects of compound (3) and compound (4) prepared in Example 3 and Example 4 on Staphylococcus aureus at different concentrations;

[0064] Figure 3 The scanning electron microscope morphology images of compound (3) and compound (4) prepared in Example 3 and Example 4 targeting Staphylococcus aureus are shown.

[0065] Definitions and Explanations of Terms

[0066] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the subject matter of the claims pertains. It should be understood that the foregoing brief description and the following detailed description are exemplary and illustrative only and do not limit the subject matter of this application in any way. Throughout this application, unless otherwise indicated, the term "include," as well as its alternative forms such as "comprises," "includes," and "comprising" are not intended to be limiting.

[0067] The term "C 1-6 The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like or isomers thereof.

[0068] The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 14 carbon atoms. The term "C 6-14 "Aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl) such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 "aryl"), for example anthracenyl.

[0069] The term "5-14 membered heteroaryl" is understood to mean a monocyclic, bicyclic and tricyclic ring system containing 5-14 ring atoms, or 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms (e.g., N, O, S, Se, etc.), wherein each ring system contains a ring consisting of 5-7 atoms and has one or more connection points connected to the rest of the molecule. The heteroaryl group is optionally substituted with one or more substituents described herein. In some embodiments, the heteroaryl group consisting of 5-10 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S, Se and N. In other embodiments, the heteroaryl group consisting of 5-6 atoms contains 1, 2, 3 or 4 heteroatoms independently selected from O, S, Se and N. Examples of monocyclic heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, etc.; or acinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc.

[0070] The term "3-12 membered heterocyclyl" refers to a monocyclic, bicyclic or tricyclic ring system, wherein one or more atoms in the ring are independently optionally substituted with heteroatoms, the ring may be fully saturated or contain one or more unsaturations, but is not aromatic, and has one or more points of attachment to other molecules, preferably "3-8 membered heterocyclyl". One or more hydrogen atoms in the ring may be independently unsubstituted or substituted with one or more substituents described herein. In some embodiments, the "heterocyclyl" is a monocyclic ring composed of 3-7 atoms or a bicyclic ring composed of 7-10 atoms, which contains 1-5, preferably 1-3, heteroatoms selected from N, O, S and Se. In particular, the heterocyclic group may include, but is not limited to, a four-membered ring such as azetidinyl, oxetanyl; a five-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a six-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a seven-membered ring such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, for example, but not limited to, a 5,5-membered ring such as hexahydrocyclopenta [c] pyrrole-2 (1H) -yl ring, or a 5,6-membered bicyclic ring such as hexahydropyrrolo [1,2-a] pyrazine-2 (1H) -yl ring. The ring containing the nitrogen atom may be partially unsaturated, i.e., it may contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolinyl, 1,3-benzoxazolyl, 1,3-benzodioxolyl.

[0071] Unless otherwise indicated, heterocyclyl and heteroaryl include all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, pyridyl or pyridinylene include pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-ylene, and pyridin-4-ylene; thienyl or thienylene include thien-2-yl, thien-2-ylene, thien-3-ylene, and thien-3-ylene. DETAILED DESCRIPTION

[0072] The technical solutions of the present invention will be described in further detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are encompassed within the scope of protection that the present invention is intended to protect.

[0073] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0074] Example 1

[0075] Preparation of compound (1)

[0076]

[0077] 4-Diethylamino salicylaldehyde (51.78mmol, 10g) and potassium carbonate (103.56mmol, 14.31g) were added to the flask. Under argon protection, anhydrous acetonitrile solvent (100mL) and 1,2-dibromoethane (0.259mol, 22mL) were added to the flask in sequence using a disposable syringe. Under vigorous stirring, the reaction system was refluxed at 80°C for 24h. After the reaction was completed, it was cooled to room temperature, and the excess solid potassium carbonate in the solution was removed by filtration, and the obtained solvent was evaporated under vacuum. It was then extracted three times with ethyl acetate (50mL), dried over anhydrous magnesium sulfate, and the organic solvent was removed in vacuo. The crude product was purified by chromatography on a silica gel column, wherein the eluent was petroleum ether / ethyl acetate (6:1, v / v), to obtain 6.45g of a light red solid. ESI (C 13 H 18 BrNO2):[M+1] + =300.0594. 1 H-NMR (300MHz, CD3OD), δ10.07(s,1H),7.65(d,J=9.0Hz,1H),6.41(d,J=9.1Hz,1H),6.16(d,J=1.8 Hz,1H),4.45(t,J=5.5Hz,2H),3.79(t,J=5.5Hz,2H),3.50(q,J=7.1Hz,4H),1.23(t,J=7.1Hz,6H).

[0078] Example 2

[0079] Preparation of compound (2)

[0080]

[0081] Compound 1 (18.15mmol, 5.45g) was added to a flask, followed by addition of acetone (40mL) and gradual dropwise addition of a 1M sodium hydroxide (40mL) aqueous solution, and stirred at room temperature for 16h. After the reaction was complete, the organic solvent was removed under vacuum, extracted three times with ethyl acetate, and a bright yellow liquid intermediate was obtained after being spin-dried. The intermediate crude product obtained was vacuum-dried for 12h, ethanol (50mL) was added to dissolve and transferred to a new round-bottom flask. An equivalent amount of compound 4-diethylamino-2-methoxy-benzaldehyde was added to the round-bottom flask, followed by dropwise addition of a 1M sodium hydroxide aqueous solution. The mixture was stirred at room temperature for 1h, and after the reaction was complete, the system was extracted with ethyl acetate three times, and the organic solvent was removed in vacuo after drying over anhydrous magnesium sulfate. The crude product obtained after the organic phase was spin-dried was purified by chromatography on a silica gel column using petroleum ether / ethyl acetate (4:1, v / v) as the developing solvent, to ultimately obtain 0.80g of a red compound. ESI (C 28 H 37 BrN2O3):[M+1] + =529.2060. 1 H-NMR (300MHz, CD3OD), δ8.03(d,J=10.5Hz,1H),7.97(d,J=10.6Hz,1H),7.55–7.46(m,2H),7.15(d,J=15.8Hz,1H),7.00(d,J=15.7Hz,1H),6.3 9(t,J=10.3Hz,2H),6.23(s,2H),4.44(t,J=5.3Hz,2H),3.93(s,3H),3.87(t,J=5.5Hz,2H),3.48(dd,J=7.0,2.6Hz,8H),1.23(t,J=6.2Hz,12H).

[0082] Example 3

[0083] Preparation of compound (3)

[0084]

[0085] Compound 2 (0.75 g, 1.42 mmol), triazole (0.15 g, 2.12 mmol), potassium carbonate (0.29 g, 2.12 mmol) and tetrabutylammonium bromide (0.074 g, 0.23 mmol) were added to a 100 mL two-necked round-bottom flask. After evacuation three times, 67 mL of anhydrous acetonitrile was added and the mixture was refluxed at 60°C for 12 h. After the reaction was completed, the mixture was cooled to room temperature, the acetonitrile was removed in vacuo, and the mixture was extracted three times with ethyl acetate (10 mL). The mixture was dried over anhydrous magnesium sulfate, the organic solvent was removed in vacuo, and the mixture was purified by chromatography on an ethyl acetate / ethanol (10:1, v / v) column to obtain 0.55 g of a dark red solid compound. ESI (C 30 H39 N5O3):[M+1] + =518.3126. 1 H-NMR (300MHz, CD3OD), δ8.64 (s, 1H), 8.04 (d, J = 16.2Hz, 2H), 7.91 (d, J = 15.6 Hz,1H),7.57(d,J=8.8Hz,1H),7.49(d,J=8.7Hz,1H),6.93(t,J=16.0Hz,2H), 6.38(d,J=8.5Hz,2H),6.20(d,J=20.4Hz,2H),4.75(d,J=3.9Hz,2H),4.50(d, J=4.3Hz,2H),3.92(s,3H),3.57–3.37(m,8H),1.21(dd,J=12.9,6.2Hz,12H).

[0086] Example 4

[0087] Preparation of compound (4)

[0088]

[0089] Compound 3 (0.50 g, 0.97 mmol) was added to a round-bottom flask. Under argon protection, anhydrous acetonitrile (50 mL) and 2,4-difluorobenzyl bromide (0.40 g, 1.933 mmol) were added in sequence. The mixture was refluxed at 80°C for 12 h, and the reaction was monitored by a plate. After the reaction was completed, the acetonitrile was removed in vacuo, and the mixture was extracted three times with ethyl acetate (10 mL), dried, and the organic solvent was removed in vacuo. The mixture was purified using a C18 reverse phase column and water / methanol (2:5, v / v) was used to obtain 0.1326 g of a dark red product. ESI (C 37 H 44 F2N5O3):[M] + =644.3407. 1 H NMR(400MHz, DMSO), δ10.45(s,1H),9.39(s,1H),7.84(d,J=15.2Hz,1H),7.66(d,J=6.6Hz,1H),7.57(d,J=14.7Hz,2H),7.44–7.07(m,3H ),6.89(dd,J=33.2,15.5Hz,2H),6.29(d,J=54.3Hz,4H),5.65(s,2H),4.92(s,2H),4.57(s,2H),3.87(s,3H),3.42(s,8H),1.13(s,12H).

[0090] Example 5

[0091] Compound 3 obtained in Example 3 was placed in solvents of different polarities. Tetrahydrofuran, acetonitrile, ethanol, methanol and aqueous solution containing 10 μM of compound 3 were obtained. The changes in emission wavelength under different solvents were then measured. Figure 1 It can be concluded that the compound has an excellent solute color change effect. With the increase of solvent polarity, the maximum emission wavelength of the compound red-shifts by about 120nm.

[0092] Example 6

[0093] Compound 3 obtained in Example 3 was used to inhibit Staphylococcus aureus in vitro. The bacterial solution in the exponential growth phase was centrifuged (6000 rpm, 3 min), and the supernatant was removed. The bacteria were dispersed into 30 mL of PBS buffer solution with a pH of 7.4. The number of bacteria in the centrifuge tube was 10 8 CFU mL -1 1 mL of bacterial solution was taken and added to 1.5 mL centrifuge tubes, and then different concentrations of drugs (0 μM, 0.25 μM, 0.5 μM, 1 μM, 2 μM) were added and incubated with bacteria at 37°C for 30 min. After the drug interacted with the bacteria, a 520 nm light source (18 mW cm -2 ) irradiated for 4 min. Meanwhile, bacteria without drug or light treatment served as control group. Finally, the bacteria were diluted with PBS to countable (10 2 CFU mL -1 ) and then dripped onto the bacterial test piece and incubated at 37°C for 24h. Figure 2 As can be seen from a, compound 3 has a certain dark toxicity to Staphylococcus aureus, killing about 50% of the bacteria at a drug concentration of 0.25 μM. Subsequently, after irradiation with 520 nm light for 4 minutes, nearly 85% of the Staphylococcus aureus were killed.

[0094] Example 7

[0095] Compound 3 obtained in Example 3 was placed under a scanning electron microscope to observe the effect of the drug on the morphology of Staphylococcus aureus. 2 mL of bacteria in the exponential growth phase were taken and then washed twice with PBS (pH = 7.4). 1 mL of PBS solution containing different drug concentrations was added and incubated in a shaker at 37°C and 40 rpm for 30 minutes. Then, a 520 nm light source (18 mW cm -2) for 4 minutes. At the same time, bacteria that were only treated with light were used as the control group. After illumination, the corresponding bacteria were obtained by centrifugation, washed twice with PBS, and then 2.5% glutaraldehyde was added, and then placed in a 4°C refrigerator for 12 hours to fix the surface morphology of the bacteria. Finally, the glutaraldehyde-treated bacteria were dehydrated twice with 20%, 50%, 60%, 70%, 80%, 90%, 95%, and 100% ethanol solutions (1 mL) in sequence. Take 10 μL of bacterial solution and add it to the silicon wafer. The sample was dried and sprayed with gold for scanning electron microscopy detection. From Figure 3 As can be seen from a, the control group had a complete, very clear and smooth bacterial wall. However, after adding the drug and irradiating with light, the bacterial wall surface of Staphylococcus aureus was severely damaged. Therefore, compound 3 disrupted the bacterial morphology.

[0096] Example 8

[0097] Compound 4 obtained in Example 4 was placed in solvents of different polarities. Tetrahydrofuran, acetonitrile, ethanol, methanol and aqueous solutions containing 10 μM of compound 4 were obtained. The change in emission wavelength under each solution was then measured. Figure 1 As can be seen from Figure b, the compound exhibits strong solvatochromic properties. With increasing solvent polarity, the compound's emission shifts by 130 nm toward longer wavelengths. This is primarily due to the increased dipole moment of the excited-state molecules in polar solvents, leading to a red-shift in emission.

[0098] Example 9

[0099] Compound 4 obtained in Example 4 was used to inhibit Staphylococcus aureus in vitro. The bacterial solution in the logarithmic growth phase was centrifuged (6000 rpm, 3 min) and the supernatant was removed. The bacteria were then dispersed in a PBS buffer solution with a pH of 7.4. 1 mL of the bacterial suspension (10 8 CFU mL -1 ), and then different concentrations of drugs (0 μM, 0.25 μM, 0.5 μM, 1 μM, 2 μM) were added and incubated with bacteria at 37°C for 30 min. After the drug interacted with the bacteria, a 520 nm light source (18 mW cm -2 ) irradiated for 4 min. Meanwhile, bacteria without drug or light treatment served as control group. Finally, the bacteria were diluted with PBS to countable (10 2 CFU mL -1 ) and then dripped onto the test piece of the corresponding bacteria and incubated at 37°C for 24h. Figure 2As shown in Figure b, compound 4 exhibits a certain degree of dark toxicity against Staphylococcus aureus, with only 0.25 μM required to inactivate approximately 60% of the bacteria. Subsequently, after irradiation with 520 nm light for 4 minutes, nearly 96% of the Staphylococcus aureus were killed, indicating that the generation of reactive oxygen species by light further enhances the antibacterial activity.

[0100] Example 10

[0101] Compound 4 obtained in Example 4 was placed under a scanning electron microscope to observe the effect of the drug on the morphology of Staphylococcus aureus. 2 mL of bacteria in the logarithmic growth phase were taken and then washed twice with PBS (pH = 7.4). 1 mL of PBS solution containing different drug concentrations was added and incubated in a shaker at 37°C and 40 rpm for 30 minutes. Then, a 520 nm light source (18 mW cm -2 ) for 4 minutes. At the same time, bacteria that were only treated with light were used as the control group. After illumination, the corresponding bacteria were obtained by centrifugation, washed twice with PBS, and then 2.5% glutaraldehyde was added, and then placed in a 4°C refrigerator for 12 hours to fix the surface morphology of the bacteria. Finally, the glutaraldehyde-treated bacteria were dehydrated twice with 20%, 50%, 60%, 70%, 80%, 90%, 95%, and 100% ethanol solutions (1 mL) in sequence. In order to observe the morphology of bacteria, 10 μL of bacterial solution was added to a silicon wafer, the sample was dried and sprayed with gold for scanning electron microscopy. From Figure 3 As can be seen in Figure b, the control group has a complete, very clear and smooth bacterial wall. However, after adding the drug and irradiating with light, the bacterial wall surface of Staphylococcus aureus is severely damaged. Therefore, compound 4 can indeed be used for photodynamic sterilization.

[0102] The above describes the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

Claims

1. A compound represented by formula I, its racemate, stereoisomer, tautomer, isotope-labeled substance, or pharmaceutically acceptable salt thereof: in, Q is selected from Or does not exist, when Q does not exist, X - Does not exist; X - selected from halide ions; X1 and X2 are independently selected from O and S; Y is selected from O, S; A1 and A2 are selected from N; Z1 is selected from N, Z2 is selected from CH; or Z1 is selected from CH, Z2 is selected from N; R1, R2, R3, R4, R5, R6 are the same or different and are independently selected from H, CH3, CH2CH3, F, Cl, Br; R7, R8, R9, R 10 、R 11 the same or different, independently selected from H, F, Cl, Br, I, CH3, CH2CH3; m is selected from 1, 2 or 3.

2. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt thereof, characterized in that: Q is 2,4-difluorobenzyl or is absent.

3. The compound according to claim 1, its racemate, stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) has the structure shown below: X - Having the definition described in claim 1.

4. A method for preparing the compound of formula I, comprising the following steps: (a) Compound (V) and The reaction is carried out to obtain compound (IV); (b) reacting compound (IV) with acetone under alkaline conditions; (c) When Q is absent, compound (III) is reacted with The reaction yields a compound represented by formula (I); (d) When Q is When the product of step (c) is further mixed with reaction, Obtaining a compound represented by formula (I); in, L, L1 are selected from F, Cl, Br, I; Q, X1, X2, X - ,A1,A2,R1,R2,R3,R4,R5,R6,R7,R8,R9,R 10 、R 11 , Z1, Z2, m have the definitions as described in claim 1; X is selected from halogen; Y is O.

5. Use of the compound according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope-labeled substance or pharmaceutically acceptable salt thereof in the preparation of an antibacterial drug; The types of the bacteria are Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli.

6. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotope-labeled substance, or pharmaceutically acceptable salt thereof.

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