Near infrared fluorescence compounds and methods thereof

Abstract

This disclosure concerns near infrared organic fluorescence compounds, synthesis methods and applications thereof. The near infrared organic fluorescence compounds may be used for treating a disease or disorder associated with bacteria.

Description

[0001]

[0002] Near Infrared Fluorescence Compounds and Methods Thereof

[0003] Technical Field

[0004] The present disclosure relates, in general terms, to near infrared organic fluorescence compound and a synthesis method and application thereof.

[0005] Background

[0006] Bacterial resistance to antimicrobial agents is an important challenge in the treatment of infectious diseases and has attracted much attention. Over the past few decades, widespread and prolonged antibiotic abuse has led to the development of resistance in some pathogens. The transmission rate of infections caused by drug-resistant bacteria is increasing, and the death rate is increasing year by year. Moreover, a shortage of new antibiotics has contributed to the emergence and spread of resistance. Without immediate action to discover and develop new antibiotics, deaths from drug-resistant infections are expected to exceed 10 million per year by 2050. Current research is still focused on modifying existing antibiotics to achieve better antibacterial effects, but this does not solve the current widespread problem of resistance. Therefore, the development of new and highly effective antibiotics is needed to curb drugresistant bacterial infections.

[0007] At present, the revitalization of new antibiotic research is mainly focused on the chemical structure of molecules with similar antibacterial mechanisms to traditional antibiotics. However, bacteria are prone to DNA replication errors during transmission, easily producing mutants that are insensitive to antibiotics with traditional antimicrobial mechanisms, which can alter the antibiotic's affinity for molecular targets or promote abnormal antibiotic efflux. Thus, this approach further promotes the emergence and spread of bacterial resistance. In contrast, drugs that have multiple antibacterial targets or are capable of physically damaging pathogens (such as photosensitizers or cationic coatings) are less likely to develop resistance. However, due to the depth of photosensitizer excitation light penetration and the targeting of drug delivery in vivo, the application of these substances in vivo is still limited. Therefore, there is an urgent need to develop new antibiotics to meet the urgent clinical need to treat drug-resistant bacteria that can act on multiple sites simultaneously and are capable of physically damaging pathogens in vivo.

[0008] In addition to the difficulty of antibiotic development, another major challenge in the treatment of bacterial infections is the identification and localization of the infection, as bacterial infections have similar symptoms to a variety of other diseases, such as inflammation and cancer. This often leads to inappropriate use of antibiotics, often administered empirically, which accelerates the development of resistance. Therefore, there is an urgent problem to identify and treat bacterial infection in clinic. Previous studies have used peptides, antibiotics, and sugars combined with luciferin to help identify bacteria, but these bacterial imaging reagents have not been commonly used in clinical Settings. Therefore, designing antibiotics that effectively target bacterial infections has the potential for practical applications and it can prevent the problem of resistance caused by the overuse of antibiotics.

[0009] Another challenge in the treatment of bacterial infections is how to achieve the killing of targeted infective bacteria without damaging host (mammalian) cells. This challenge is caused by similarities in the structure of bacterial and mammalian cell membranes, which often results in molecules that can bind to bacteria also binding to mammalian cells. Traditional antibiotics do not have the ability of bacterial imaging, and further improvement is needed in the identification and localization of infection sites. Therefore, it is common to obtain a low signal-to-noise ratio when imaging bacteria or bacterial infections in vivo.

[0010] For the above reasons, there is a need to design fluorescent antibacterial drugs that can selectively image and kill mammalian cells / bacteria, so as to prevent the abuse of antibiotic drugs, improve the effective utilization of drugs, avoid damage to host cells, and improve the biosafety of drugs.

[0011] It would be desirable to overcome or ameliorate at least one of the abovedescribed problems.

[0012] Summary

[0013] The present disclosure concerns a near infrared organic fluorescence compound. The present disclosure also concerns a synthesis method of the near infrared organic fluorescence compounds, which can be obtained by side chain modification of the TPA2Py skeletal precursor. The near infrared organic fluorescent compounds are antibacterial drugs with fluorescent groups, have low drug resistance and fluorescence characteristics, and have bactericidal ability against bacteria.

[0014] The present disclosure concerns a compound of Formula (la), or a solvate thereof: wherein

[0015] Ri and R2are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0016] Rs and R4 are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkoxy;

[0017] Rs is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, and a chromophore; and

[0018] R6, R7, R8, R9 and R10 are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl.

[0019] In some embodiments, Ri and R2 are independently selected from optionally substituted alkyl.

[0020] In some embodiments, R3 and R4 are independently selected from H, optionally substituted alkyl, and optionally substituted alkenyl.

[0021] In some embodiments, R5is selected from optionally substituted alkyl, and optionally substituted alkenyl.

[0022] In some embodiments, R6, R7, R8, R9 and Rio are independently selected from H, and optionally substituted alkyl.

[0023] In some embodiments, the compound of Formula (la) is selected from:

[0024]

[0025] In some embodiments, the compound of exhibits luminescence when aggregated and / or when associated with a polynucleotide and / or lipid.

[0026] In some embodiments, the compound is characterized by an antibacterial activity against Gram-negative and / or Gram-positive bacterial cells. In some embodiments, the compound is characterized by an antibacterial activity against antibiotics resistant bacterial cells.

[0027] In some embodiments, the compound is characterized by a minimum inhibitory concentration (MIC) against bacterial cells of about 1 pM to about 100 pM.

[0028] The present disclosure also concerns a method of synthesising a compound of Formula (la), or a salt or solvate thereof, comprising: a) reacting compound of Formula (II) with compound of Formula (III):

[0029] In some embodiments, a mass ratio of compound of Formula (II) to compound of Formula (III) is about 1:0.3 to about 1:0.8.

[0030] In some embodiments, the method further comprises a step before a) of reacting a compound of Formula (IV) with haloalkane to form compound of

[0031] Formula (II): (IV).

[0032] In some embodiments, a mole ratio of compound of Formula (IV) to haloalkane is about 1 : 1.5 to about 1 :3.

[0033] In some embodiments, the haloalkane is iodomethane.

[0034] In some embodiments, the method further comprises a step before step a) of reacting a compound of Formula (V) with compound of Formula (VI) to form compound of Formula wherein x is halo; wherein the reaction is conducted in the presence of a catalyst and a base.

[0035] In some embodiments, a mole ratio of compound of Formula (V) to compound of Formula (VI) is about 1: 1.5 to about 1 : 3.

[0036] The present disclosure also concerns a method of labelling and / or imaging bacterial cells, comprising contacting the bacterial cells with a compound of Formula (la) or a salt or solvate thereof.

[0037] The present disclosure also concerns a method of detecting the presence of bacterial cells in a sample, comprising contacting the sample with a compound of Formula (la) or a salt or solvate thereof.

[0038] The present disclosure also concerns a compound of Formula (la) or pharmaceutically acceptable salt and solvate thereof for use in therapy.

[0039] The present disclosure also concerns a compound of Formula (la) or a solvate thereof for use in the imaging and / or treatment of a disease or disorder associated with bacteria.

[0040] The present disclosure also concerns a use of compound of Formula (la) or pharmaceutically acceptable salt and solvate thereof in the manufacture of a medicament for the imaging and / or treatment of a disease or disorder associated with bacteria.

[0041] The present disclosure also concerns a method of imaging and / or treating a disease or disorder associated with bacteria in a subject thereof, comprising administering to the subject a therapeutically effective amount of compound of Formula (la) or pharmaceutically acceptable salt and solvate thereof.

[0042] In some embodiments, the disease or disorder associated with bacteria has a resistance against antibiotics.

[0043] In some embodiments, the disease or disorder is selected from skin infection, a respiratory disease, food poisoning or any other life-threatening systemic disease, sepsis, urinary tract infection, meningitis, wound infection, tuberculosis, diarrhoea, Legionnaires' disease, meningococcal disease, Q fever, strep throat, and whooping cough (pertussis).

[0044] Brief description of the drawings

[0045] Embodiments of the present invention will now be described, by way of nonlimiting example, with reference to the drawings in which:

[0046] Figure 1A shows the synthesis route of near-infrared organic fluorescent compounds and TPA2PyCHO;

[0047] Figure IB shows the UV-visible absorption spectra of TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex in the first solution;

[0048] Figure 1C shows the photoluminescence spectra of TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex in the first solution;

[0049] Figure ID shows the photoluminescence spectrum of TPA2PyBu in dye solution; Figure IE shows the relationship curve between the relative emission intensity of TPA2PyCHO and NIR organic fluorescence compounds and toluene volume fraction in solvent, where Io represents the peak photoluminescence intensity of NIR organic fluorescence compounds / TPA2PyCHO in DMSO, and I represents the peak photoluminescence intensity of near-infrared organic fluorescent compounds / TPA2PyCHO in the mixture of DMSO and toluene;

[0050] Figure IF shows the ratio of emission intensity of NIR organic fluorescent compounds / TPA2PyCHO in mixed solution containing ctDNA and NIR organic fluorescent compounds / TPA2PyCHO aqueous solution, where Io represents the peak photoluminescence intensity of near-infrared organic fluorescent compounds / TPA2PyCHO in aqueous solution of near-infrared organic fluorescent compounds / TPA2PyCHO, and I represents the peak photoluminescence intensity of near-infrared organic fluorescent compounds / TPA2PyCHO in mixed solution containing ctDNA;

[0051] Figure 1G shows the emission intensity ratio of TPA2PyCHO / NIR organic fluorescence compounds in the phospholipid solution to be tested and the PBS solution to be tested, where Io represents the peak photoluminescence intensity of NIR organic fluorescence compounds / TPA2PyCHO in the PBS solution to be tested, and I represents the NIR organic fluorescence class The peak photoluminescence intensity of near infrared organic fluorescent compounds / TPA2PyCHO in the phospholipid solution to be measured;

[0052] Figure 1H shows the schematic diagram of binding mode 1 of TPA2PyBu and DNA fragment;

[0053] Figure II shows the schematic diagram of the binding mode of TPA2PyBu to DNA fragment 2;

[0054] Figure 2A shows the antibacterial activity (MIC) of TPA2PyCHO / near-infrared organic fluorescent compounds against Staphylococcus aureus (S. aureus), methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coll (E. coli) and drug-resistant Escherichia coli (MDR E. coli);

[0055] Figure 2B shows the relationship between the absorption of TPA2PyCHO / nearinfrared organic fluorescence compounds by Staphylococcus aureus and the change of incubation time (bacterial concentration is 10BCFUs);

[0056] Figure 2C shows is the relationship between the absorption of TPA2PyCHO / near-infrared fluorescence compounds by Escherichia coli and the change of incubation time (bacterial concentration is 10sCFUs);

[0057] Figure 2D shows confocal images of E. coli, TPA2PyCHO / near-infrared organic fluorescent compounds and PBS incubated for 30min (scale 10pm);

[0058] Figure 3 shows confocal images of Staphylococcus aureus cells or E. coli cells; Figure 4 shows the flow cytometry analysis of membrane potential and permeability of E. coli cells;

[0059] Figure 5A shows the MIC of 20 resistance tests of different antibiotics against MRSA;

[0060] Figure 5B shows the change of antibiotic sensitivity of MRSA;

[0061] Figure 5C shows the ratio of MIC of TPA2PyBu to cells and MIC of TPA2PyBu to bacteria;

[0062] Figure 6 shows the fluorescence spectra of the "TPA2PyBu" group, the

[0063] "TPA2PyBu+Hela" group and the "TPA2PyBu+S. aureus" group; and

[0064] Figure 7 shows the imaging of mice with the IVIS small animal imager.

[0065] Detailed description

[0066] "Alkyl" refers to monovalent alkyl groups which may be straight chained or branched and preferably have from 1 to 10 carbon atoms or more preferably 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, n- propyl, / so-propyl, n-butyl, / so-butyl, n-hexyl, and the like.

[0067] "Alkenyl" refers to a monovalent alkenyl group which may be straight chained or branched and preferably have from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and have at least 1 and preferably from 1-2, carbon to carbon, double bonds. Examples include ethenyl (-CH = CH2), n-propenyl (- CH2CH=CH2), / so-propenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), and the like.

[0068] "Alkoxy" refers to the group alkyl-O- where the alkyl group is as described above. Examples include, methoxy, ethoxy, n-propoxy, / so-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0069] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0070] "Oxo / hydroxy" refers to groups =0, HO-.

[0071] "Aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (eg. phenyl) or multiple condensed rings (eg. naphthyl or anthryl), preferably having from 6 to 14 carbon atoms. Examples of aryl groups include phenyl, naphthyl and the like.

[0072] "Heteroaryl" refers to a monovalent aromatic heterocyclic group which fulfils the Huckel criteria for aromaticity (ie. contains 4n + 2 n electrons) and preferably has from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur within the ring (and includes oxides of sulfur, selenium and nitrogen). Such heteroaryl groups can have a single ring (eg. pyridyl, pyrrolyl or N-oxides thereof or furyl) or multiple condensed rings (eg. indolizinyl, benzoimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl).

[0073] Examples of heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiophene, benzo[b]thiophene, triazole, imidazopyridine and the like.

[0074] "Cycloalkyl" refers to cyclic alkyl groups having a single cyclic ring or multiple condensed rings, preferably incorporating 3 to 11 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, indanyl, 1, 2,3,4- tetrahydronapthalenyl and the like.

[0075] "Heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur, oxygen, selenium or phosphorous within the ring. The most preferred heteroatom is nitrogen. It will be understood that where, for instance, R2 or R' is an optionally substituted heterocyclyl which has one or more ring heteroatoms, the heterocyclyl group can be connected to the core molecule of the compounds of the present invention, through a C-C or C-heteroatom bond, in particular a C-N bond.

[0076] Examples of heterocyclyl and heteroaryl groups include, but are not limited to, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, isothiazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thio hene, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetra hydrofuranyl, triazole, and the like.

[0077] In this specification "optionally substituted" is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, halogen, nitro, phosphono, sulfo, phosphorylamino, phosphinyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, aminoacyloxy, trihalomethyl, trialkylsilyl, pentafluoroethyl, trifluoromethoxy, difluoromethoxy, trifluoromethanethio, trifluoroethenyl, mono- and dialkylamino, mono-and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclyl amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, aryl, heteroaryl and heterocyclyl, and the like, and may also include a bond to a solid support material, (for example, substituted onto a polymer resin). For instance, an "optionally substituted amino" group may include amino acid and peptide residues.

[0078] The present disclosure concerns a compound of Formula (I), or a solvate thereof: wherein R is independently hydrogen, alkyl, unsaturated alkyl, heteroatomic alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, alkoxy or one or more chromophores that can be conjugated with one or more fluorescent substances.

[0079] The present disclosure concerns a compound of Formula (I), or a solvate thereof: wherein R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy or a chromophore.

[0080] In some embodiments, the compound of Formula (I) is represented by Formula (la), or a solvate thereof:

[0081] wherein

[0082] Ri and R2are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0083] R3 and R4 are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkoxy;

[0084] R5 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, and a chromophore; and

[0085] R6, R7, Rs, R9 and Rio are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl.

[0086] In some embodiments, Ri and R2 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl. In some embodiments, Ri and R2 are independently selected from optionally substituted alkyl, and optionally substituted alkenyl. In some embodiments, Ri and R2 are independently selected from optionally substituted alkyl. In some embodiments, Ri and R2 are independently selected from optionally substituted Ci-Ce alkyl. In some embodiments, Ri and R2 are independently selected from optionally substituted methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl and tertbutyl.

[0087] In some embodiments, R3 and R< are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted alkoxy. In some embodiments, R3 and R4 are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkoxy. In some embodiments, R3 and R4 are independently selected from H, optionally substituted alkyl, and optionally substituted alkenyl. In some embodiments, R3 and R4 are independently selected from H, and optionally substituted Ci-Ce alkyl. In some embodiments, R3 and R4 are independently selected from H and optionally substituted methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl and tert-butyl.

[0088] In some embodiments, R5is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkoxy. In some embodiments, Rs is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl. In some embodiments, R5 is selected from optionally substituted alkyl, and optionally substituted alkenyl. In some embodiments, R5 is optionally substituted C1-C10 alkyl and optionally substituted C2-C10 alkenyl. In some embodiments, Rs is optionally substituted C3-C10 alkyl and optionally substituted C4-C10 alkenyl. In some embodiments, Rs is optionally substituted C5-C10 alkyl and optionally substituted C5-C10 alkenyl. The alkyl and alkenyl may be a straight chain.

[0089] In some embodiments, Re, R7, Rs, R9 and Rw are independently selected from

[0090] H, and optionally substituted alkyl. In some embodiments, Re, R7, Rs, R9 and Rio are independently selected from H and optionally substituted Ci-Cg alkyl. In some embodiments, R6, R7, R8, R9 and R10 are independently selected from H and optionally substituted methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl and tert-butyl.

[0091] The optional substituent in R1-R10 may be independently selected from halo, hydroxyl, acyl, alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, alkynyloxy, amino, aminoacyl, thio, arylalkyl, arylalkoxy, aryl, aryloxy, carboxyl, acylamino, cyano, nitro, heteroaryl, heteroarylalkyl, heteroaryl oxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, and aminoacyloxy.

[0092] A chromophore is a part of a molecule that absorbs specific wavelengths of light, giving the molecule its colour. Chromophores typically contain conjugated systems of carbon-carbon double bonds and / or aromatic rings. The specific arrangement and composition of the chromophore determines the wavelength of light it absorbs, and thus the colour it appears.

[0093] The compound of Formula (I) may thus further comprise a covalently bonded chromophore. For example, fluorescein and / or quinine may be conjugated via the hydroxyl moiety or alkenyl moiety. For example, the compound of Formula (I) may be a dimer, as shown below:

[0094]

[0095] Compound of Formula (I) and (la) are charged at the pyridinyl moieties. To balance this charges, anions may be associated with the compound. The anion may be halide, hydroxide, sulfate, sulfide, sulfite, nitride, nitrite, nitrate, phosphate, hydrogen phosphate, dihydrogen phosphate, hydrogen sulfate, perchlorate, iodate, chlorate, bromate, chlorite, hypochlorite, hypobromite, carbonate, chromate, bicarbonate, dichromate, acetate, formate, or oxalate. In some embodiments, the compound of Formula (I) and (la) is selected from:

[0096]

[0097] In some embodiments, the compound of Formula (I) is characterised by an absorption wavelength of about 350 nm to about 500 nm. In some embodiments, the compound of Formula (I) is characterised by an absorption peak wavelength of about 420 nm.

[0098] In some embodiments, the compound of Formula (I) is characterised by an emission wavelength of about 500 nm to about 750 nm. In some embodiments, the compound of Formula (I) is characterised by an emission peak wavelength of about 630 nm.

[0099] In some embodiments, the compound of Formula (I) exhibits aggregate induced luminescence (AIE) characteristics. The compound may aggregate with another compound of Formula (I). In some embodiments, the compound of Formula (I) exhibits luminescence when associated with a polynucleotide. The polynucleotide may be DNA and / or RNA. In some embodiments, the compound of Formula (I) exhibits luminescence when associated with lipid. In some embodiments, the compound of Formula (I) exhibits luminescence when associated with phospholipid. The phospholipid may be DOPC (dipalmitoylphosphatidylcholine).

[0100] In some embodiments, the compound of Formula (I) is characterized by an antibacterial activity. The antibacterial activity may be against Gram-negative and / or Gram-positive bacterial cells. The bacteria may be Staphylococcus aureus (S. aureus), methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coll (E. coll), or drug-resistant Escherichia coli (MDR E. coli). In some embodiments, the compound of Formula (I) is characterized by an antibacterial activity against antibiotics resistant bacterial cells.

[0101] In some embodiments, the compound of Formula (I) is characterized by a minimum inhibitory concentration (MIC) against bacterial cells of about 1 pM to about 100 pM. In other embodiments, the MIC is about 1 pM to about 90 pM, about 1 pM to about 80 pM, about 1 pM to about 70 pM, about 1 pM to about 60 pM, about 1 pM to about 50 pM, about 1 pM to about 40 pM, about 1 pM to about 30 pM, about 1 pM to about 20 pM, about 1 pM to about 10 pM, or about

[0102] 5 pM to about 10 pM.

[0103] The synthesis method of the above near infrared organic fluorescent compounds includes the following steps:

[0104] Step 1 : Mix the TPA2Py skeleton precursor with the first solvent, stir it under nitrogen or inert atmosphere at 60-80 °C for 10-15 h, add iodomethane under nitrogen or inert atmosphere, remove the solvent under reduced pressure, obtain the first crude product, recrystalize the first crude product, and obtain the orange solid TPA2PyCHO. The mass ratio of the TPA2Py skeleton precursor to iodomethane is 1 : (2-2.5).

[0105] The structural formula of the TPA2Py skeleton precursor is as follows: wherein R is independently hydrogen, alkyl, unsaturated alkyl, heteroatomic alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, alkoxy, or one or more chromophores that can be conjugated with one or more fluorescent substances.

[0106] In step 1, the first solvent is a mixture of one or more of acetonitrile, tetra hydrofuran, and / V, / V-dimethylformamide.

[0107] In step 1, the ratio of the quantity of the substance of the TPA2Py skeleton precursor to the volume of the first solvent is 1 : (50~100), the unit of the quantity of the substance is mmol, and the unit of the volume is mL.

[0108] Step 2: Mix the TPA2PyCHO, phosphine reagent and the second solvent, reflux at 85-90 °C for 2-4 hours, cool to room temperature, remove the solvent under pressure, obtain the orange solid as the second crude product, dissolve the second crude product in methanol, and then mix with the third solvent, pump and filter to obtain the solid, purify the solid, and obtain near infrared organic fluorescent compounds. The mass ratio of the TPA2PyCHO and the phosphine reagent is 1 : (0.0013-0.0021), the unit of the mass fraction is mg, the unit of the quantity of the substance is mmol, and the structural formula of the phosphine reagent is one of P1-P6: In step 2, the ratio of the volume portion of the second solvent to the mass portion of the TPA2PyCHO is 1 : (1-4), the unit of the mass portion is mg, and the unit of the volume portion is mL.

[0109] In step 2, the mass of the methanol is the minimum amount capable of dissolving the second crude product.

[0110] In step 2, the second solvent is EtOH.

[0111] In step 2, the purification is performed by HPLC.

[0112] In step 2, the third solvent is ether.

[0113] In step 2, the ratio of the volume portion of the third solvent to the mass portion of the TPA2PyCHO is 1: (1-4), the unit of the mass portion is mg, and the unit of the volume portion is mL.

[0114] Accordingly, the present disclosure concerns a method of synthesising a compound of Formula (I) or (la), or a salt or solvate thereof, comprising: a) reacting compound of Formula (II) with compound of Formula (III):

[0115] In some embodiments, the mass ratio of compound of Formula (II) to compound of Formula (III) is about 1:0.3 to about 1:0.8. In other embodiments, the mass ratio is about 1 :0.3 to about 1 :0.7, about 1 :0.3 to about 1 :0.6, about 1 :0.3 to about 1:0.5, about 1:0.3 to about 1:0.4, about 1 :0.4 to about 1 :0.8, about 1:0.4 to about 1 :0.7, about 1 :0.4 to about 1:0.6, about 1:0.4 to about 1:0.5, about 1 :0.5 to about 1 :0.8, about 1:0.5 to about 1:0.7, about 1:0.5 to about 1:0.6, about 1:0.6 to about 1 :0.8, or about 1:0.6 to about 1 :07.

[0116] In some embodiments, the mole ratio of compound of Formula (II) to compound of Formula (III) is about 1 : 1 to about 1:3. In other embodiments, the mole ratio is about 1: 1 to about 1 :2.5, about 1: 1 to about 1:2, about 1 : 1 to about 1 : 1.5, about 1: 1.5 to about 1:3, about 1: 1.5 to about 1:2.5, about 1 : 1.5 to about 1 :2, about 1:2 to about 1:3, or about 1 :2 to about 1:2.5. In some embodiments, the mole ratio is about 1 : 1.5.

[0117] In some embodiments, the reaction is conducted at reflux. In some embodiments, the solvent is ethanol. In some embodiments, the reaction is conducted at a temperature of about 60°C to about 100°C. In some embodiments, the reaction is conducted for a duration of about 1 h to about 5 h.

[0118] In some embodiments, the reacted product is purified using methanol. In some embodiments, a ratio of methanol to compound of Formula (II) is about ImLi lmg to about lmL:4mg.

[0119] In some embodiments, the reacted product in methanol is mixed with ether to precipitate compound of Formula (I) or (la) as a solid. In some embodiments, a ratio of ether to compound of Formula (II) is about lmL: lmg to about lmL:4mg.

[0120] In some embodiments, the compound of Formula (I) or (la) is purified using HPLC.

[0121] In some embodiments, the method further comprises a step before a) of reacting a compound of Formula (IV) with haloalkane to form compound of

[0122] Formula (II): (IV).

[0123] In some embodiments, the haloalkane is iodomethane.

[0124] In some embodiments, a mole ratio of compound of Formula (IV) to haloalkane is about 1 : 1.5 to about 1 :3. In some embodiments, a mole ratio of compound of Formula (IV) to haloalkane is about 1:2.2.

[0125] In some embodiments, the reaction is conducted at a temperature of about 50°C to about 90°C. In some embodiments, the reaction is conducted for a duration of about 6 h to about 20 h.

[0126] In some embodiments, the reaction is conducted in a solvent selected from acetonitrile, tetra hydrofuran, / V, / V-dimethylformamide, and a mixture thereof.

[0127] In some embodiments, a ratio of compound of Formula (IV) to the solvent is about 1 mmol:50 mL to about 1 mmol : 100 mL.

[0128] In some embodiments, the method further comprises a step before step a) of reacting a compound of Formula (V) with compound of Formula (VI) to form compound of Formula (IV): wherein x is halo.

[0129] In some embodiments, the reaction is conducted in the presence of a catalyst. The catalyst may be Pd(PPh3)4. In some embodiments, the reaction is conducted in the presence of a base. The base may be K2CO3.

[0130] In some embodiments, a mole ratio of compound of Formula (V) to compound of Formula (VI) is about 1 : 1.5 to about 1 :3. In some embodiments, a mole ratio of compound of Formula (V) to compound of Formula (VI) is about 1:2.2.

[0131] The near infrared organic fluorescent compounds may be used as antimicrobial drugs. The near infrared organic fluorescent compounds may be used in selective imaging of mammalian cells and bacteria.

[0132] Compared with the prior art, the disclosed compounds have the following beneficial effects:

[0133] 1. The near infrared organic fluorescence compounds have a bactericidal mechanism different from that of traditional antibiotics. The near infrared organic fluorescence compound is obtained by modifying the TPA2Py skeleton precursor. The near infrared organic fluorescence compound is a luminous substance with positive charge and linear hydrophobic groups (methyl ester, ethyl ester, butyl ester and hexester). The positive charge binds to the negatively charged bacterial outer membrane through electrostatic action, changes the membrane potential by destroying the permeability barrier of the bacterial membrane, and significantly enhances the penetration of NIR. organic fluorescent compounds on the bacterial membrane. The linear hydrophobic groups bind to the bacteria through hydrophobic interaction and further help the NIR organic fluorescent compounds penetrate the bacterial membrane. After penetrating the bacterial membrane, the near-infrared organic fluorescent compounds can bind to the DNA in the bacteriomimetic nucleus and induce it to aggregate, thus realizing antibacterial effect and exhibiting excellent antibacterial performance, that is, the near-infrared organic fluorescent compounds of the invention can change the membrane potential and induce the bacteriomimetic nucleus by destroying the permeability barrier of the bacterial membrane The dual mechanism of DNA aggregation effectively kills bacteria (e.g. gram-positive and Gram-negative bacteria), and effectively inhibit the growth of bacteria. The minimum inhibitory concentration (MIC) of near-infrared organic fluorescent compounds is 1 pM for Gram-positive bacteria (e.g. S. aureus and MRSA) and 5 pM for Gram-negative bacteria (e.g. E. coli and MDR E. coli).

[0134] 2. The near infrared organic fluorescent compound of the invention can emit obvious fluorescence signals after combining with bacteria, and has the bacterial imaging ability that traditional antibiotics do not have, and has certain potential in identifying and locating infection sites, and can be used for specific imaging of bacterial infection in vivo. TPA2PyBu in near infrared organic fluorescent compounds has excellent selectivity to bacteria. Near-infrared organic fluorescent compounds show strong emission when bound to bacteria, but only weak fluorescence when bound to mammalian cells. This property enables nearinfrared organic fluorescence compounds to distinguish between tumor tissue and bacterial infections in vivo, and to efficiently treat bacterial infections in vivo.

[0135] 3. The near infrared organic fluorescent compound of the invention has low toxicity to normal mammalian cells.

[0136] 4. The near infrared organic fluorescent compounds of the invention have not been observed to have any drug tolerance.

[0137] The present disclosure also concerns a method of labelling and / or imaging bacterial cells, comprising contacting the bacterial cells with a compound of Formula (I) or (la), or a solvate thereof.

[0138] The present disclosure also concerns a method of selectively labelling and / or imaging bacterial cells from a sample of mammalian cells and bacterial cells, comprising contacting the sample with a compound of Formula (I) or (la), or a solvate thereof.

[0139] The bacteria may be Gram-positive and / or Gram-negative bacterial cells. The bacteria may be selected from E. coli, P. aeruginosa, S. aureus, E. faecalis, S. oneidensis, B. megaterium or a combination thereof.

[0140] The bacterial cells may be detected via the fluorescence emitted when the compound associates with the bacterial cells. Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation.

[0141] The method may further include a step of exposing the sample or bacterial cell to electromagnetic radiation having a wavelength of less than 600 nm, or about 350 nm to about 500 nm.

[0142] The present disclosure also concerns a method of detecting the presence of bacterial cells in a sample, comprising contacting the sample with a compound of Formula (I) or (la) or a salt or solvate thereof. The sample may be obtained from a patient having a disease or disorder associated with bacteria.

[0143] The present disclosure also concerns a compound of Formula (I) or (la), or pharmaceutically acceptable salt and solvate thereof for use in therapy.

[0144] The present disclosure also concerns a compound of Formula (I) or (la), or a solvate thereof for use in the imaging and / or treatment of a disease or disorder associated with bacteria.

[0145] The present disclosure also concerns a use of compound of Formula (I) or (la) or pharmaceutically acceptable salt and solvate thereof in the manufacture of a medicament for the imaging and / or treatment of a disease or disorder associated with bacteria.

[0146] The present disclosure concerns a method of imaging and / or treating a disease or disorder associated with bacteria in a subject thereof, comprising administering to the subject a therapeutically effective amount of compound of Formula (I) or (la) or pharmaceutically acceptable salt and solvate thereof.

[0147] The disease or disorder associated with bacteria may be a bacterial infection. The disease or disorder associated with bacteria may have a resistance against antibiotics. The disease or disorder may be skin infection (e.g. boils), a respiratory disease (e.g. sinusitis, pneumonia), food poisoning or any other lifethreatening systemic disease. The disease or disorder may be sepsis, urinary tract infection, meningitis, wound infection, tuberculosis, diarrhoea, Legionnaires' disease, meningococcal disease, Q fever, strep throat, or whooping cough (pertussis).

[0148] The present disclosure pertains to compounds and their various forms, including ionic forms, tautomers, isomers, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, esters, prodrugs, and protected forms. The disclosure also encompasses methods of utilizing these compounds for various purposes. It should be noted that terms like "crystalline form," "polymorph," can be used interchangeably to include all crystalline and amorphous forms, such as polymorphs, pseudopolymorphs, solvates (including hydrates), co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms, and mixtures thereof, unless a specific crystalline or amorphous form is specified. In certain embodiments, the compounds and their subgroups include polymorphs, solvates, co-crystals, isomers, tautomers, and / or oxides. In other embodiments, they may include polymorphs, solvates, and / or co-crystals.

[0149] The compound of the invention can be administered to a subject as a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts include, but are not limited to salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, maleic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benezenesulphonic, salicyclic sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0150] Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium. In particular, the present invention includes within its scope cationic salts eg sodium or potassium salts, or alkyl esters (eg methyl, ethyl) of the phosphate group.

[0151] Basic nitrogen-containing groups may be quarternised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

[0152] It will be appreciated that any compound that is a prodrug of the compound of formula (I) is also within the scope and spirit of the invention. Thus the compound of the invention can be administered to a subject in the form of a pharmaceutically acceptable pro-drug. The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compound of the invention. Such derivatives would readily occur to those skilled in the art. Other texts which generally describe prodrugs (and the preparation thereof) include: Design of Prodrugs, 1985, H. Bundgaard (Elsevier); The Practice of Medicinal Chemistry, 1996, Camille G. Wermuth et al., Chapter 31 (Academic Press); and A Textbook of Drug Design and Development, 1991, Bundgaard et al., Chapter 5, (Harwood Academic Publishers).

[0153] The compound of the invention may be in crystalline form either as the free compound or as a solvate (e.g. hydrate) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.

[0154] The compound of the invention, or a pharmaceutically acceptable salt, solvate or prodrug thereof is administered to the patient in a therapeutically effective amount. As used herein, a therapeutically effective amount is intended to include at least partially attaining the desired effect, or delaying the onset of, or inhibiting the progression of, or halting or reversing altogether the onset or progression of macular degeneration.

[0155] The term "therapeutic effect" refers to some extent of relief of one or more of the symptoms of a disorder (e.g., a neoplasia or tumor) or its associated pathology. "Therapeutically effective amount" as used herein refers to an amount of an agent which is effective, upon single or multiple dose administration to the cell or subject, in prolonging the survivability of the patient with such a disorder, reducing one or more signs or symptoms of the disorder, preventing or delaying, and the like beyond that expected in the absence of such treatment. "Therapeutically effective amount" is intended to qualify the amount required to achieve a therapeutic effect. A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the "therapeutically effective amount" (e.g., ED50) of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the invention employed in a pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0156] As used herein, the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages may lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.

[0157] Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the severity of the condition as well as the general age, health and weight of the patient to be treated.

[0158] The compound of the invention may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition. The formulation of such compositions is well known to those skilled in the art. The composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.

[0159] The carrier must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the patient. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

[0160] The compound of the invention can be administered to the vitreous of the eye using any intravitreal or transscleral administration technique. For example, the compound can be administered to the vitreous of the eye by intravitreal injection. Intravitreal injection typically involves administering a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug in a total amount between 0.1 ng to 10 mg per dose.

[0161] Injectables for such use can be prepared in conventional forms, either as a liquid solution or suspension or in a solid form suitable for preparation as a solution or suspension in a liquid prior to injection, or as an emulsion. Carriers can include, for example, water, saline (e.g., normal saline (NS), phosphate- buffered saline (PBS), balanced saline solution (BSS)), sodium lactate Ringer's solution, dextrose, glycerol, ethanol, and the like; and if desired, minor amounts of auxiliary substances, such as wetting or emulsifying agents, buffers, and the like can be added. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by using surfactants. By way of example, the compound, composition or combination can be dissolved in a pharmaceutically effective carrier and be injected into the vitreous of the eye with a fine gauge hollow bore needle (e.g., 30 gauge, 1 / 2 or 3 / 8 inch needle) using a temporal approach (e.g., about 3 to about 4 mm posterior to the limbus for human eye to avoid damaging the lens).

[0162] A person skilled in the art will appreciate that other means for injecting and / or administering the compound, composition or combinations to the vitreous of the eye can also be used. These other means can include, for example, intravitreal medical delivery devices. These devices and methods can include, for example, intravitreal medicine delivery devices, and biodegradable polymer delivery members that are inserted in the eye for long term delivery of medicaments. These devices and methods can further include transscleral delivery devices.

[0163] Other modes of administration including topical or intravenous administration may also be possible. For example, solutions or suspensions of the compound, composition or combinations of the invention may be formulated as eye drops, or as a membranous ocular patch, which is applied directly to the surface of the eye. Topical application typically involves administering the compound of the invention in an amount between 0.1 ng and 10 mg.

[0164] The compound of the invention may also be suitable for intravenous administration. For example, a compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug thereof may be administered intravenously at a dose of up to 16 mg / m2.

[0165] The compound of the invention may also be suitable for oral administration and may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste. In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, solvate or prodrug is orally administerable.

[0166] A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder (e.g inert diluent, preservative disintegrant (e.g. sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

[0167] The compound of the invention may be suitable for topical administration in the mouth including lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0168] The compound of the invention may be suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like. Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. Transdermal patches may also be used to administer the compounds of the invention.

[0169] The compound of the invention may be suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the compound, composition or combination isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compound, composition or combination may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0170] Preferred unit dosage composition or combinations are those containing a daily dose or unit, daily sub-dose, as herein above described, or an appropriate fraction thereof, of the active ingredient.

[0171] It should be understood that in addition to the active ingredients particularly mentioned above, the composition or combination of this invention may include other agents conventional in the art having regard to the type of composition or combination in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and / or time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include cornstarch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of Wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[0172] Examples

[0173] The near infrared organic fluorescent compound of the invention can kill bacteria through a unique dual mechanism without developing drug resistance. A comprehensive analysis using microscopy and bioassay techniques showed that near-infrared organic fluorescence-like compounds kill bacteria by damaging their membrane integrity and inducing DNA aggregation. The technical scheme of the disclosure is further explained in combination with specific embodiments.

[0174] Purity and source of purchase of the drug in the following embodiments: 4-(diphenyl amino) benzaldehyde: 97%, Sigma Aldrich; / V-bromosuccinimide: 99%, Sigma Aldrich; KzCO3:99%, Sigma Aldrich; Pyridine-4-boronic acid : 90%, Sigma Aldrich; Tetratriphenylphosphine palladium (Pd(PPh3)<) : 99%, Sigma Aldrich; Bromo-acetyl bromide: 98%, Sigma Aldrich; Triphenylphosphine: 99%, Sigma Aldrich; lodomethane: 99%, Sigma Aldrich.

[0175] The temperature of saturated salt solution in the following embodiment is 23 °C. The PBS used in the following embodiments all have a pH of 7.4.

[0176] Raw 264.7 cells, HEK-293 cells, Hela cells and NIH-3T3 cells, Staphylococcus aureus (S. aureus), methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coll (E. coll) and drug-resistant Escherichia coli (MDR E. coll) were purchased from atcc.

[0177] Test method for MIC (minimum inhibitory concentration) of the compound to be tested on bacteria : The bacteria of 105CFU were inoculated in 100 pL LB medium containing different concentrations of compounds to be measured. After inoculation, the bacteria were incubated at 220 rpm at 37 °C for 14 hours. The absorbance (OD600) of the LB medium at 600 nm was measured. The minimum concentration of the compound under test with no visible bacterial growth is the MIC value of the compound under test against the bacterium.

[0178] Compound 1 (4- (bis(4-Bromophenyl)amino)benzaldehyde) is synthesised by the following steps (Dyes and Pigments (2019), 164, 244-256) : Add 4-

[0179] (diphenylamino) benzaldehyde (2.73 g, 10 mmol) and 30 mL DCM to a 100 mL round-bottomed flask, cool to 0°C with an ice bath, and mix N- bromosuccinimide (3.54 g, 20 mmol) and DCM (30 mL). After mixing, the liquid is added to the above-mentioned round-bottom flask with a drip hopper, stirred at 0 °C for 1 hour, heated to room temperature and stirred away from light for 12h, quenched with water, extracted with DCM, cleaned with water and dried with NaSO4, the extracted organic layer was evaporated under reduced pressure, and the crude product was purified by silica gel chromatography. A mixture of ethyl acetate and n-hexane was used as eluent (by volume, ethyl acetate: n-hexane = 1 :4) and recrystallized by MeOH to obtain the yellow solid compound 1. The yield of compound 1 was 3.85 grams, and the yield was 89.9%.

[0180] The structural formula for compound 1 is:

[0181] TPA2Py skeleton precursor (compound 2) is synthesised by the following steps (Chemical Science (2019), 10(43), 10053-10064) : Compound 1 (846 mg, 2 mmol), K2CO3 (828 mg, 6 mmol) and pyridine-4-boronic acid (541.2 mg, 4.4 mmol) were mixed in a 100 ml round-bottled flask, and Pd(PPh3)4(0.1 mmol) was added as catalyst. In the addition of 25 ml of 1, 4-dioxane aqueous solution (1, 4-dioxane aqueous solution of 1, 4-dioxane, the volume ratio of 1, 4-dioxane to water is 4: 1) After that, the round-bottom flask was sealed and protected by nitrogen, stirred at 90°C for 12h, cooled to room temperature, poured into 100 mL EA, washed with water, the organic layer was dried with NaSCU and evaporated under reduced pressure, and the crude product was purified by silica gel chromatography, using a mixture of ethyl acetate and n-hexane as eluent

[0182] (in volume parts, ethyl acetate: N-hexane = 1 :4), the yellow solid was TPA2Py skeleton precursor, and the yield of TPA2Py skeleton precursor was 614.8 mg, and the yield was 71.9%.

[0183] The structural formula for compound 2 (4-(bis(4-(pyridin-4- yl)phenyl)amino) benzaldehyde) is:

[0184] Bromoacetate E1-E6 are obtained by lipid condensation reaction, and the preparation method of bromoacetate is carried out in accordance with the following steps (Organic Letters (2018), 20(9), 2663-2666): Superdry DCM (20mL), bromoacetyl bromide (0.43 mL, 0.5 mmol) and NaHCOa (168 mg, 2 mmol) were added to a 100 ml round-bottomed flask, stirred under ice bath conditions, and cooled to 0°C. Another 20 mL DCM was mixed with the corresponding alkyl alcohols (0.6 mmol), and then added to the above roundbottom flask with a drip hopper. After stirring at room temperature for 30 minutes, lOOmL water was added to quench the reaction, the organic layer was collected and cleaned with water 3 times, and the solvent was removed under reduced pressure to obtain bromoacetate E1~E6 without further purification.

[0185] The structural formula of bromoacetate E1-E6 is as follows:

[0186]

[0187] The structural formula of alkyl alcohols for the above-mentioned bromoacetate E1-E6 is as follows:

[0188] "-"""OH ■""""■ •"■ ''""■''■''OH

[0189] The synthesis method of phosphine reagents P1-P6 in the following embodiments (Organic Letters (2020), 22(7), 2645-2650) follows the following steps: Under magnetic agitation, lOmmol of bromoacetate was added to 50 ml of triphenylphosphine ethyl acetate solution (50 ml of triphenylphosphine ethyl acetate solution contained 2.86 g (11 mmol) of triphenylphosphine) to form a white precipitating mixture. The resulting white precipitated mixture was stirred continuously for 12 h, filtered on a glass fiber filter, and washed with toluene and n-hexane to obtain a white solid phosphate. Dissolve the phosphate of the white solid in H2O (50 ml) and add an aqueous solution of NaOH (2M) to maintain pH ~12, stir for 30 minutes and add CH2CI2 (50 ml) (white solid will appear during agitation). Separate the organic layer, wash with saturated salt water (50 ml), and dry on magnesium sulfate. The filtrate was concentrated to obtain a yellowish solid, which was recrystallized from DCM and ether to obtain a white solid as phosphine reagent P1-P6 (yield 90-94%).

[0190] The structural formula of P1-P6 is as follows:

[0191] Example 1

[0192] The preparation method of TPA2PyCHO is as follows: 1 mmol compound 2

[0193] (TPA2Py skeleton precursor) and 50 mL of the first solvent (acetonitrile) were mixed in a 100 ml round-bottom flask, the round-bottom flask was sealed, protected with nitrogen, stirred at 70°C for 12 h, 2.2 mmol iodomethanes

[0194] (0.137 mL) were added under nitrogen, and the solvent was removed under reduced pressure. The first crude of orange solid was obtained, the first crude was dissolved in MeOH (good solvent), and then the bad solvent ether (100 mL) was added for recrystallization, and the orange solid was TPA2PyCHO, where the mass of MeOH was the minimum amount that could dissolve the first crude.

[0195] The yield of TPA2PyCHO obtained in this embodiment is 676 mg with a yield of 95%. The nuclear magnetic data of TPA2PyCHO are as follows: 1H NMR (400 MHz, DMSO-d6, 6): 9.95 (s, 1 h), 8.98 (d, J = 6.4 Hz, 4 h), 8.48 (d, J = 6.3 Hz,

[0196] Examples 2 to 5

[0197] The preparation of near-infrared organic fluorescent compounds is carried out according to the following steps: The 72 mg TPA2PyCHO and 0.15 mmol phosphine reagents obtained in embodiment 1 were dissolved in a round-bottom flask containing 30 ml of the second solvent (EtOH), heated at 85°C for reflux for 3 hours, cooled to room temperature and reduced pressure to remove the solvent, the orange solid was obtained as the second crude product, and the second crude product was dissolved in methanol. Then it was mixed with 30 mt of the third solvent (ether), pumped and filtered to remove most of the impurities to obtain a solid, and the solid was purified by HPLC to obtain nearinfrared organic fluorescent compounds. Among them, the mass of methanol was the minimum amount that could dissolve the second crude product.

[0198] The numbers of phosphine reagents and near-infrared organic fluorescent compounds used in embodiments 2 to 5 are shown in Table 1.

[0199] Table 1

[0200] The resulting products in examples 2 to 5 are orange solids, and the yield of TPA2PyMe is 80%, and TPA2PyEt is 80%. The yield of TPA2PyBu was 85%, that of TPA2PyHex was 85% and that of TPA2Pyhex was 81%.

[0201] The structure of TPA2PyMe is as follows:

[0202] Example 2 obtained nuclear magnetic data of NIR organic fluorescent compounds as follows: 1H NMR (400 MHz, DMSO-d6, 5) : Delta 8.95 (s, 4 h), 8.46 (s, 4 h), 8.12 (s, 4 h), 7.79 (s, 2 h), 7.67 (d, J = 14.3 Hz, 1 h), 7.25 (d, J = 41.0 Hz, 6 h), 6.61 (d, J = 15.5 Hz, 1 h), 4.32 (s, 6 h), 3.73 (s, 3 h).

[0203] The formula for TPA2PyEt is as follows:

[0204] Example 3 obtained nuclear magnetic data of NIR organic fluorescent compounds as follows: 1H NMR (400 MHz, DMSO-d6, 5) : 8.95 (d, J = 6.4 Hz, 4 h), 8.46 (d, J = 6.4 Hz, 4 h), 8.12 (d, J = 8.4 Hz, 4 h), 7.80 (d, J = 8.4 Hz, 2 h), 7.30 (d, J = 8.2 Hz, 4 h), 7.21 (d, J = 8.2 Hz, 2 h), 6.62 (d, J = 16.0 Hz, 1 h), 4.31 (s, 6 h), 4.20 (q, J = 7.1 Hz, 2 h), 1.31-1.23 (m, 3H).

[0205] The structure of TPA2PyBu is as follows:

[0206] The nuclear magnetic data of NIR organic fluorescent compounds obtained in Example 4 are as follows: 1H NMR (400 MHz, DMSO-d6, 6): 8.96 (d, J = 6.4 Hz, 4 h), 8.46 (d, J = 6.4 Hz, 4 h), 8.16 8.07 (m, 4 h), 7.81 (d, J = 8.2 Hz, 2 h), 7.67 (d, J = 16.0 Hz, 1 h), 7.33 7.28 (m, 4 h), 7.21 (d, J = 8.1 Hz, 2 h), 6.63 (d, J = 16.0 Hz, 1 h), 4.31 (s, 6 h), 4.16 (t, J = 6.6 Hz, 3 h), 1.64 (2 h p, J = 6.8 Hz), 1.39 (h, J = 7.6 Hz, 2 h), 0.93 (dd, J = 8.0, 6.8 Hz, 3 h).

[0207] The structure of TPA2PyHex is as follows: Example 5 obtained nuclear magnetic data of NIR organic fluorescent compounds as follows: 1H NMR (400 MHz, DMSO-d6, 6): 8.96 (d, J = 6.4 Hz, 4 h), 8.46 (d, J = 6.4 Hz, 4 h), 8.16 8.07 (m, 4 h), 7.81 (d, J = 8.2 Hz, 2 h), 7.67 (d, J = 16.0 Hz, 1 h), 7.33 7.28 (m, 4 h), 7.21 (d, J = 8.1 Hz, 2 h), 6.63 (d, J

[0208] = 16.0 Hz, 1 h), 4.31 (s, 6 h), 4.16 (t, J = 6.6 Hz, 3 h), 1.64 (2 h p, J = 6.8 Hz), 1.39 (h, J = 7.6 Hz, 2 h), 0.93 (dd, J = 8.0, 6.8 Hz, 3 h).

[0209] TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu, and TPA2PyHex are synthesized by the route shown in A in Figure 1. TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex are synthesized based on compound 2. Compound 1 is prepared by bromination based on / V-bromosuccinimide. The yield of compound 1 is 89.9%. Compound 2 was obtained by Suzuki reaction of compound 1 with pyridine-4-boronic acid, the yield of compound 2 was 71.9%. Compound 2 was methylated with iodomethane to obtain TPAPyCHO. Finally, a phosphine reagent in P1-P6 was reacted with TPAPyCHO to obtain near-infrared organic fluorescent compounds with a yield of 80-85%.

[0210] The photophysical properties of TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex are shown in Figure 1B-1G. TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex were dissolved in water to obtain 5 first solutions with a concentration of 10 pM, and the absorption / emission spectra of the 5 first solutions were tested respectively. Since TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex have the same conjugate skeleton, the aqueous solutions of TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex have similar absorption spectra. The range is from 350 nm to 500 nm, with a peak of 420 nm (as shown in Figure IB). TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu, and TPA2PyHex have emission peaks at about 630 nm with a Stokes shift of 200 nm, which is conducive to avoiding interference from background signals during biological imaging (as shown in Figure 1C).

[0211] A dye solution with a solute concentration of lOpM was prepared using TPA2PyCHO and one of the near-infrared organic fluorescent compounds as solute, and a mixture of DMSO and toluene or pure DMSO as solvent. Among them, toluene in the solvent was regarded as a bad solvent. The percentage of toluene by volume in the solvent is 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 99%. The fluorescence intensity of dye solution with different toluene volume percentage was tested. The relationship between the relative emission intensity of near-infrared organic fluorescent compounds and TPA2PyCHO and the volume fraction of toluene in the solvent is shown in Figure IE, and the photoluminescence spectrum of TPA2PyBu in the dye solution is shown in Figure ID. As the volume ratio of toluene in the solvent increases from 0% to 80%, the emission intensity hardly changes. Subsequently, as the volume ratio of toluene in the solvent continued to increase to 99%, the emission intensity of TPA2PyBu increased significantly. In the dye solution of TPA2PyCHO, TPA2PyMe, TPA2PyHex, TPA2PyEt and TPA2PyBu, when the volume percentage of toluene in the solvent is 99%, compared with pure DMSO as a solvent (the volume percentage of toluene in the solvent is 0%), the emission intensity increases by about 17, 36, 75, 97 and 110 times, respectively. The results showed that the near infrared organic fluorescence compounds showed significant aggregate induced luminescence (AIE) characteristics.

[0212] In addition, TPA2PyCHO or near-infrared organic fluorescence compounds (NIR organic fluorescence compounds are TPA2PyMe, TPA2PyHex, TPA2PyEt, or TPA2PyBu) are separately dissolved in DMSO to prepare mother liquor with a concentration of 10 mM. The mother liquor of the sample was added into the aqueous solution containing ctDNA to prepare a mixed solution with a concentration of NIR organic fluorescence compounds of 10 pM (the final concentration of ctDNA was 2 pg / mL). The fluorescence test of the mixed solution showed that the fluorescence intensity of the mixed solution was significantly enhanced. Compared with near-infrared organic fluorescence compounds / TPA2PyCHO aqueous solution with a concentration of 10 pM ("nearinfrared organic fluorescence compounds / TPA2PyCHO aqueous solution" means near-infrared organic fluorescence compounds aqueous solution or TPA2PyCHO aqueous solution, "Near- infra red organic fluorescent compounds / TPA2PyCHO" means one of the near-infrared organic fluorescent compounds and TPA2PyCHO), the fluorescence intensity of the mixed solution containing ctDNA increased by 14, 32, 94, 102 and 70 times, respectively (as shown in Figure IF). The increase in fluorescence intensity can be attributed to the binding of

[0213] TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu, and TPA2PyHex to ctDNA, thereby limiting the intramolecular motion of the molecules and activating their fluorescence processes.

[0214] In addition, the mother liquor of 2pL TPA2PyCHO / NIR organic fluorescent compounds with a concentration of 10 mM was added to the phospholipid solution with a concentration of 2 pg / mL, so that the final concentration of TPA2PyCHO / NIR organic fluorescent compounds was 2uM, and the phospholipid liquid under test was obtained. Phospholipid solution is a mixture of phosphate buffer salt solution (PBS, pH=7.4) and phospholipid. The mother liquor of 2 pL TPA2PyCHO / NIR organic fluorescence compounds with a concentration of 10 mM was added to the phosphate buffer salt solution (PBS, pH=7.4), so that the final concentration of TPA2PyCHO / NIR organic fluorescence compounds was 2uM, and the PBS solution was obtained. Peak photoluminescence intensity of TPA2PyCHO / NIR organic fluorescent compounds in phospholipid and PBS solution under test, as shown in FIG. 1G, the fluorescence intensity was also significantly enhanced after the addition of phospholipid (DOPC). These results indicate that TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex have strong affinity with the main components of cell membrane. Thus, the DNA-binding ability and membrane affinity give TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu, and TPA2PyHex the ability to perform bacterial imaging. As shown in FIG. 1H and II, simulation results by Autodock software show that TPA2PyBu can bind to DNA in two ways: alkyl chain part inserted into the DNA double helix structure (method 1), alkyl chain on the outside, and two pyridine salt structure inserted into the DNA structure (method 2). The binding energies were -8.4 kcal / mol and -8.0 kcal / mol, respectively, which further indicated that NIR organic fluorescent compounds had strong binding ability with DNA.

[0215] To evaluate the antibacterial effects of TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu, and TPA2PyHex, Minimum inhibitory concentrations (MIC) of TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu, and TPA2PyHex against bacteria (Gram-negative or Gram-positive) were measured. The bacteria are

[0216] Staphylococcus aureus (S. aureus), methicillin-resistant Staphylococcus aureus (MRSA, USA300), Escherichia coll (E. coll), or drug -resista nt Escherichia coli (MDR E. coli). As shown in Figure 2A, TPA2PyCHO, TPA2PyMe and TPA2PyEt showed general inhibitory effects on the growth of Staphylococcus aureus and MRSA, with MIC ranging from 5 to 10 |jM. However, TPA2PyCHO, TPA2PyMe and TPA2PyEt showed a weak inhibitory effect on the bacterial growth of E. coli (MIC > 50 pM). On the other hand, both TPA2PyBu and TPA2PyHex significantly inhibited the growth of a variety of Gram-negative and Gram-positive pathogen strains, including MRSA and MDR E. coli, with MIC values ranging from 1 to 10 pM. In addition, TPA2PyBu and TPA2PyHex showed similar bactericidal activity against clinical isolates of MRSA (USA300), suggesting that the activity of TPA2PyBu and TPA2PyHex is not specific to bacterial species.

[0217] To further investigate the effect of alkyl chain length, cell uptake experiments were conducted to investigate the internalization of TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex on Gram-positive Staphylococcus aureus and Gram-negative Escherichia coli in PBS medium. Bacteria with a final concentration of 108CFU / mL, TPA2PyC HO / near- infra red organic fluorescent compounds with a final concentration of 2 pM and PBS (pH=7.4) were incubated for different times (15 min, 30 min, 60 min, 120 min, 240 min). After centrifugation at 3000 rpm for 3 min, the supernatant was collected, and the bacteria were Staphylococcus aureus or Escherichia coli. The absorption of the supernatant was analyzed by UV-visible spectrophotometer, and the test results were shown in FIG. 2B and 2C. Confocal laser scanning microscope (CLSM) was used to observe the confocal images of Escherichia coli, TPA2PyCHO / nearinfrared organic fluorescence compounds and PBS (the final concentration of bacteria was 108CFU / mL, and the final concentration of TPA2PyCHO / nearinfrared organic fluorescence compounds was 2 pM) after incubation for 30min. The excitation wavelength is 420 nm, and the wavelength range of the received signal is 600-650 nm. The test results are shown in Figure 2D. According to Figure 2B and 2C, after incubation with bacteria, the total uptake of TPA2PyBu and TPA2PyHex by Staphylococcus aureus and Escherichia coli significantly increased with the absorption time, indicating that the uptake of PA2PyBu and TPA2PyHex by Staphylococcus aureus and Escherichia coli cells was obvious. In contrast, bacterial uptake of TPA2PyCHO, TPA2PyMe and TPA2PyEt was generally lower than that of TPA2PyBu and TPA2PyHex. This may be due to the increased length of the alkyl chain, which can promote the interaction between the material and the bacterial outer membrane and enhance membrane penetration, resulting in higher absorption rates of TPA2PyBu and TPA2PyHex. Confocal laser scanning microscopy (CLSM) was used to observe TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu, and TPA. Figure 2D shows that E. coli showed weak fluorescence signals after incubation with TPA2PyCHO, TPA2PyMe, and TPA2PyEt for 30 min, indicating that TPA2PyCHO, TPA2PyMe, and TPA2PyEt could not penetrate E. coli cells effectively. In contrast, after incubation with TPA2PyBu and TPA2PyHex, a strong fluorescent signal was observed in E. coli, indicating that TPA2PyBu and TPA2PyHex effectively penetrated E. coli cells.

[0218] After confirming the effectiveness of TPA2PyCHO, TPA2PyMe, TPA2PyEt, TPA2PyBu and TPA2PyHex on bacterial growth inhibition, the possible mechanism of action of them was further investigated. As shown in Figure 3, the final concentration of 108CFU / mL Staphylococcus aureus or Escherichia coli was treated with TPA2PyBu of 2 times MIC in PBS buffer for 30min. Then, the morphology of bacteriomitroid and outer membrane was observed by staining co-localization imaging with Hoechst (final concentration 1 pg / mL) or FM4-64 (final concentration 1 pg / mL). Bacteria not treated with TPA2PyBu (in the column of "Control" in Figure 3) showed intact membranes and evenly distributed nuclei, but bacteria treated with TPA2PyBu (in the column of "TPA2PyBu" in Figure 3) showed significant DNA aggregation. Therefore, these results suggest that the mechanism of action of TPA2PyBu is to block DNA translation by inducing DNA aggregation.

[0219] DNA aggregation induced by TPA2PyBu can be clearly observed by confocal laser scanning microscopy (CLSM), but it cannot provide important information about the effect of TPA2PyBu on membrane morphology. In order to further quantify the effect of TPA2PyBu on the bacterial membrane, the morphology and permeability of the bacterial membrane were studied by flow cytometry (Figure 4). FIG. 4 shows the flow cytometry analysis of membrane potential and permeability of E. coli cells after incubation with different substances for 30 minutes (final concentration of E. coli ~108CFU / mL). In the first diagram, the substance represented by "DMSO" is the control solvent, and the control solvent is the mixture of 1% DMSO and 99%PBS (v / v). The substance represented by "CCCP" is a mixture of the control solvent and CCCP with a final concentration of 5 pM. The substance represented by "Nisin" is a mixture of Nisin with a final concentration of 25 pg / mL and a control solvent. The substance represented by "Ciprofloxacin" is a mixture of ciprofloxacin with a final concentration of 1 pM and the control solvent. The substance represented by "TPA2PyBu" is a mixture of TPA2PyBu with a final concentration of 10 pM and a control solvent, which describes the bacterial outer membrane state of different regional reactions. The effects of PA2PyBu on membrane potential and permeability were quantified by DiOC2(3) and TO-PRO-3, respectively. DiOC2(3) specifically redshifts its emission after accumulating in the cytoplasm of bacteria with positive membrane potential, while TO-Pro-3 selectively accumulates in cells with membrane damage to provide information about membrane permeability. CCCP and Nisin were used as positive controls for DiOC2 (3) and TO-PRO-3 staining results. CCCP is a known membrane decoupling agent that affects membrane potential, while Nisin is a pore-forming peptide that affects membrane potential and permeability. Ciprofloxacin, a non-membrane targeted antibiotic, is used as a negative control and does not alter DiOC2(3) or TO-PRO-3 staining. After E. coli was cultured with TPA2PyBu for 30 minutes, the staining results of DiOC2(3) and TO-PRO-3 were significantly changed, indicating that TPA2PyBu destroyed the permeability barrier and membrane potential of bacteria at the same time.

[0220] Example 6-8

[0221] To further validate TPA2PyBu's potential as an antibiotic, methicillin-resistant Staphylococcus aureus (USA300) was used to determine the frequency of bacterial resistance to TPA2PyBu. Methicillin-resistant Staphylococcus aureus

[0222] (USA300) was tested for resistance 20 times with TPA2PyBu and one of two commercial antibiotics (Nisin and Ciprofloxacin). The specific method for each resistance test was: First, the MIC values of antibiotics against MRSA were tested. Then, the aforementioned methicillin-resistant Staphylococcus aureus growing at an antibiotic concentration of 0.5xMIC was isolated and then amplified in the LB medium without antibiotics (220 rpm, 37 °C, incubation for 14 hours). The amplified methicillin-resistant Staphylococcus aureus was retested for MIC and the value of MIC obtained was used as the MIC of this resistance test, that is, a resistance test was completed, in which antibiotics were Nisin, Ciprofloxacin or TPA2PyBu.

[0223] The MIC of 20 resistance tests of different antibiotics against methicillin- resistant Staphylococcus aureus (USA300) was shown in Figure 5A to observe whether Nisin, Ciprofloxacin and TPA2PyBu would develop resistance, respectively. As shown in Figure 5A, in 20 generations of culture, mutants resistant to Nisin and Ciprofloxacin were present (ciprofloxacin and Nissin- resistant mutants were obtained by successive passage in their respective antibiotics), while no mutants resistant to TPA2PyBu were observed. The MIC of nisin and ciprofloxacin against methicillin-resistant Staphylococcus aureus increased gradually, indicating that the mutant's resistance to these two antibiotics gradually increased, while the resistance level to TPA2PyBu did not change significantly, indicating that methicillin-resistant Staphylococcus aureus did not acquire resistance to TPA2PyBu.

[0224] Example 9-14

[0225] To test the MIC of MRSA obtained after 20 resistance tests of antibiotics against Embodiment 6 or Embodiment 7 and use it as the MIC Resistant strain. The MIC resistant strain was divided by the MIC of the first resistance test of the antibiotic against methicillin-resistant Staphylococcus aureus. The results obtained were shown in the longitudinal coordinate of Figure 5B, indicating that these resistant mutants did not show cross-resistance to TPA2PyBu. Among them, the antibiotics were Nisin, Ciprofloxacin or TPA2PyBu.

[0226] Example 15

[0227] The cells were inoculated in 96-well plates (~5000 cells / well) and incubated in cell incubators containing different concentrations of TPA2PyBu at 37°c and 5% (volume fraction) CO2 for 48 hours. The cells were one of Raw 264.7 cells, HEK- 293 cells, Hela cells and NIH-3T3 cells. After incubation, the cell medium (DMEM) was discarded and the cells were rinsed with PBS three times, and cell medium (DMEM) containing lOpM CCK8 was added to each cell containing well and the blank well without cell (as the following "blank control") for continued incubation for 4 hours. After incubation, the absorbance of each hole was tested with enzyme labeling instrument (450 nm). When the absorbance of the hole containing cells was not significantly different from that of the blank control, the concentration of TPA2PyBu corresponding to the hole containing cells was the MIC of TPA2PyBu on the cell. The MIC of TPA2PyBu on cells is divided by the MIC of TPA2PyBu on bacteria, and the resulting value is shown in Figure 5C, where the bacteria are S. aureus or E. coll. As shown in Figure 5C, MIC of TPA2PyBu on Raw 264.7 cells, HEK-293 cells, Hela cells and NIH-3T3 cells was about 1000 times that of MIC of TPA2PyBu on S. aureus. The MIC of TPA2PyBu against Raw 264.7 cells, HEK-293 cells, Hela cells, and NIH-3T3 cells was about 100 times that of TPA2PyBu against E. coli, indicating low cytotoxicity and biosafety of TPA2PyBu at working concentrations.

[0228] Example 16

[0229] TPA2PyBu was dissolved in DMSO to prepare the mother liquor with the concentration of TPA2PyBu at 10 mM. The mother liquor is operated according to the "TPA2PyBu" group, "TPA2PyBu+Hela" group and "TPA2PyBu+S. aureus" group. The fluorescence spectra of the "TPA2PyBu" group, the "TPA2PyBu + Hela" group and the "TPA2PyBu+S. aureus" group were respectively tested, as shown in Figure 6. Among them, "TPA2PyBu" group: 2pL mother liquor was mixed with ImL PBS; "TPA2PyBu+Hela" group: 2 pL mother liquor was mixed with 1 mL PBS containing ~106 Hela cells; "TPA2PyBu+S. aureus" group: 2 pL of mother liquor was mixed with 1 mL of PBS containing ~106 CFU S. aureus.

[0230] As can be seen from Figure 6, NIR organic fluorescent compounds show strong emission when combined with bacteria, but only weak fluorescence when combined with mammalian cells. This property enables near-infrared organic fluorescence compounds to distinguish between tumor tissue and bacterial infection in vivo.

[0231] Example 17

[0232] BALB / c mice (10 weeks, 20-25 g) were inoculated with Hela cells (~106cells), 30 pL turpentine (turpentine) and S. aureus (~108CFUs) in each subcutaneous area of the back as shown in Figure 7, and the tumor tissue, chemical infection and bacterial infection models were constructed, respectively. 12 h after inoculation, a mixture of TPA2PyBu and PBS was injected through the tail vein (the concentration of TPA2PyBu in the mixture was 20 pg mL-1), and the calculated dose of TPA2PyBu was: 40 pg kg1), and mice were imaged with IVIS small animal Imager at 1 h, 2 h, 4 h, and 6 h time points. As shown in Figure 7, at the experimental time point, the fluorescence at the site of bacterial infection gradually increased, while no obvious fluorescence signal was generated near chemical infection and tumor tissue, indicating that TPA2PyBu could effectively distinguish chemical infection, tumor tissue and bacterial infection in vivo.

[0233] It will be appreciated that many further modifications and permutations of various aspects of the described embodiments are possible. Accordingly, the described aspects are intended to embrace all such alterations, modifications, and variations that fall within the spirit and scope of the appended claims.

[0234] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

[0235] Throughout this specification and the claims which follow, unless the context requires otherwise, the phrase "consisting essentially of", and variations such as "consists essentially of" will be understood to indicate that the recited element(s) is / are essential i.e. necessary elements of the invention. The phrase allows for the presence of other non-recited elements which do not materially affect the characteristics of the invention but excludes additional unspecified elements which would affect the basic and novel characteristics of the method defined.

[0236] The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

Claims1. A compound of Formula (la), or a solvate thereof:whereinRi and R2are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;R3 and R4 are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted alkoxy;R5 is selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, and a chromophore; andR6, R7, R8, R9 and Rio are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl.

2. The compound according to claim 1, wherein Ri and R2are independently selected from optionally substituted alkyl.

3. The compound according to claim 1 or 2, wherein R3and R4are independently selected from H, optionally substituted alkyl, and optionallysubstituted alkenyl.

4. The compound according to any one of claims 1 to 3, wherein R5is selected from optionally substituted alkyl, and optionally substituted alkenyl.

5. The compound according to any one of claims 1 to 4, wherein Re, R?, Rs, R9 and Rio are independently selected from H, and optionally substituted alkyl.

6. The compound according to any one of claims 1 to 5, wherein the compound of Formula (la) is selected from:The compound according to any one of claims 1 to 6, wherein the compound of exhibits luminescence when aggregated and / or when associatedwith a polynucleotide and / or lipid.

8. The compound according to any one of claims 1 to 7, wherein the compound is characterized by an antibacterial activity against Gram-negative and / or Gram-positive bacterial cells.

9. The compound according to any one of claims 1 to 8, wherein the compound is characterized by an antibacterial activity against antibiotics resistant bacterial cells.

10. The compound according to any one of claims 1 to 9, wherein the compound is characterized by a minimum inhibitory concentration (MIC) against bacterial cells of about 1 pM to about 100 pM.

11. A method of synthesising a compound of Formula (la), or a salt or solvate thereof, comprising: a) reacting compound of Formula (II) with compound of Formula (III):

12. The method according to claim 11, wherein a mass ratio of compound ofFormula (II) to compound of Formula (III) is about 1:0.3 to about 1 :0.8.

13. The method according to claim 11 or 12, wherein the method further comprises a step before a) of reacting a compound of Formula (IV) with haloalkane to form compound of Formula (II):

14. The method according to claim 13, wherein a mole ratio of compound of Formula (IV) to haloalkane is about 1 : 1.5 to about 1:3.

15. The method according to claim 13 or 14, wherein the haloalkane is iodomethane.

16. The method according to any one of claims 13 to 15, wherein the method further comprises a step before step a) of reacting a compound of Formula (V) with compound of Formula (VI) to form compound of Formula (IV):wherein x is halo;wherein the reaction is conducted in the presence of a catalyst and a base.

17. The method according to claim 16, wherein a mole ratio of compound of Formula (V) to compound of Formula (VI) is about 1 : 1.5 to about 1:3.

18. A method of labelling and / or imaging bacterial cells, comprising contacting the bacterial cells with a compound of Formula (la) according to any one of claims 1 to 10, or a salt or solvate thereof.

19. A method of detecting the presence of bacterial cells in a sample, comprising contacting the sample with a compound of Formula (la) according to any one of claims 1 to 10, or a salt or solvate thereof.

20. A compound of Formula (la) according to any one of claims 1 to 10, or pharmaceutically acceptable salt and solvate thereof for use in therapy.

21. A compound of Formula (la) according to any one of claims 1 to 10, or a solvate thereof for use in the imaging and / or treatment of a disease or disorder associated with bacteria.

22. Use of compound of Formula (la) according to any one of claims 1 to 10, or pharmaceutically acceptable salt and solvate thereof in the manufacture of a medicament for the imaging and / or treatment of a disease or disorder associated with bacteria.

23. A method of imaging and / or treating a disease or disorder associated with bacteria in a subject thereof, comprising administering to the subject a therapeutically effective amount of compound of Formula (la) according to anyone of claims 1 to 10, or pharmaceutically acceptable salt and solvate thereof.

24. The compound for use, use or method according to any one of claims 20 to 23, wherein the disease or disorder associated with bacteria has a resistance against antibiotics.

25. The compound for use, use or method according to any one of claims 20 to 24, wherein the disease or disorder is selected from skin infection, a respiratory disease, food poisoning or any other life-threatening systemic disease, sepsis, urinary tract infection, meningitis, wound infection, tuberculosis, diarrhoea, Legionnaires' disease, meningococcal disease, Q fever, strep throat, and whooping cough (pertussis).

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