Photosensitiser compounds and methods thereof

Abstract

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

Description

[0001] PHOTOSENSITISER COMPOUNDS AND METHODS THEREOF

[0002] Technical Field

[0003] The present invention relates, in general terms, to photosensitiser compounds and a synthesis method and application thereof.

[0004] Background

[0005] Bacterial infections, especially those caused by drug-resistant bacteria, have become a major health crisis facing humanity. Over the past few decades, widespread and prolonged antibiotic abuse has led to the development of resistance in some pathogens. Infections caused by drug-resistant bacteria therefore pose a major challenge to humans, as evidenced by rising transmission rates and increased mortality. The problem has also been made worse by the slowdown in the development of new antibiotics. Without immediate action to discover and develop new antibiotics, deaths from drugresistant infections are projected to exceed 10 million a year by 2050.

[0006] Recent efforts to revitalise antibiotic research have focused on modifying compounds that have similar antimicrobial mechanisms to traditional antibiotics. However, this approach increases the likelihood of resistance, as mutations in drug targets reduce the effectiveness of antibiotics. Conversely, drugs that have multiple antibacterial targets or are able to physically damage pathogens (such as photosensitisers or cationic coatings) are less prone to developing resistance. However, the use of these substances in living bodies is limited. Therefore, there is an urgent need to design new antibiotics to meet the urgent clinical need to treat resistant bacteria that may act on multiple sites simultaneously and are capable of physically damaging pathogens in vivo.

[0007] At present, photodynamic therapy (PDT) for the elimination of bacteria is an effective method to solve the problem of bacterial resistance. However, the existing photosensitisers for PDT generally have the problem of low singlet oxygen (ROS) production and poor binding ability to bacteria. Most photosensitisers used for PDT bactericide bind well to Gram-positive, however, Gram-negative bacteria with more complex cell membrane structure are not effectively bound and eliminated by PDT.

[0008] It would be desirable to overcome or ameliorate at least one of the above-described problems.

[0009] Summary The present disclosure concerns a compound comprising two rigid hydrophobic structures and a cation. The present disclosure also concerns a synthesis method of the compound.

[0010] The present disclosure concerns a compound of Formula (la), or a solvate thereof: wherein

[0011] X is selected from S or O;

[0012] R1and R2are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0013] R3and R4are independently selected from H, 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

[0014] R5, R5, R7, and R5are independently selected from H, optionally substituted alkyl, and optionally substituted alkenyl.

[0015] In some embodiments, R1and R2are independently selected from optionally substituted alkyl.

[0016] In some embodiments, R3and R4are independently selected from H and optionally substituted alkyl.

[0017] In some embodiments, R5, R6, R7, and R5are independently selected from H and optionally substituted alkyl.

[0018] In some embodiments, the compound of Formula (la) is selected from:

[0019]

[0020] In some embodiments, the compound is a photosensitiser.

[0021] In some embodiments, the compound generates reactive oxygen species when irradiated with light.

[0022] In some embodiments, the compound is characterised by a rate of generation reactive oxygen species of about 0.15 x 10-3mmol / s to about 0.3 x 10-3mmol / s mmol / s.

[0023] In some embodiments, the compound is characterised by a reactive oxygen species yield of about 80% to about 95%.

[0024] In some embodiments, the compound is characterised by an increase in fluorescence with an increase in reactive oxygen species generated.

[0025] In some embodiments, the compound binds to Gram-positive and / or Gram-negative bacterial cells.

[0026] In some embodiments, the compound is characterised by an antibacterial activity against antibiotics resistant bacterial cells.

[0027] 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 a haloalkane:

[0028]

[0029] In some embodiments, a mole ratio of compound of Formula (II) to haloalkane is about 1 : 1.5 to about 1:3.

[0030] In some embodiments, the haloalkane is iodomethane.

[0031] In some embodiments, the method further comprises a step before step a) of reacting a compound of Formula (III) with a heterocyclic acid to form compound of Formula (II): wherein Y is halo; wherein the reaction is conducted in the presence of a catalyst and a base.

[0032] In some embodiments, a mole ratio of compound of Formula (II) to heterocyclic acid is about 2:3 to about 2:7.

[0033] In some embodiments, the heterocyclic acid is pyridine-4-boronic acid.

[0034] In some embodiments, the method further comprises a step before step a) of reacting a compound of Formula (IV) with a cyclic dicarboximide to form compound of Formula (HI):

[0035]

[0036] In some embodiments, a mole ratio of compound of Formula (IV) to cyclic dicarboximide is about 5:9 to about 5:12.

[0037] In some embodiments, the cyclic dicarboximide is / V-bromosuccinimide.

[0038] In some embodiments, the method further comprises a step before step a) of reacting a compound of Formula (V) with an optionally substituted biphenyl halide to form compound of Formula (IV): wherein the reaction is conducted in the presence of a catalyst and a base.

[0039] In some embodiments, a mole ratio of compound of Formula (V) to optionally substituted biphenyl halide is about 10:8 to about 10:20.

[0040] In some embodiments, the optionally substituted biphenyl halide is selected from 4- bromobiphenyl and 4-iodobiphenyl.

[0041] 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.

[0042] The present disclosure also concerns a compound of Formula (la) or pharmaceutically acceptable salt or solvate thereof for use in therapy.

[0043] The present disclosure also concerns a compound of Formula (la) or a salt or solvate thereof for use in the imaging and / or treatment of a disease or disorder associated with bacteria. The present disclosure also concerns a use of compound of Formula (la) or pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the imaging and / or treatment of a disease or disorder associated with bacteria.

[0044] 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 or solvate thereof.

[0045] In some embodiments, the disease or disorder associated with bacteria has a resistance against antibiotics.

[0046] 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).

[0047] Brief description of the drawings

[0048] Embodiments of the present invention will now be described, by way of non-limiting example, with reference to the drawings in which :

[0049] Figure 1 shows (A) the synthesis route of the compound; (B) shows the UV-VIS spectrum of PBS solution of PT2PyPh and PBS solution of PO2PyPh; (C) shows the photoluminescence spectrum of the compound in PBS solution; (D) shows the photoluminescence spectrum of PBS solution of PT2PyPh (red) and PBS suspension. (E) shows the photoluminescence spectra of PBS solution and PBS suspension of PO2PyPh. Figure 2 shows (A) the UV-VIS absorption spectrum of the solution containing Rose Bengal (RB) tested at 0, 30, 60, 90, 120, 150 and 180s; (B) the UV-VIS absorption spectrum of the solution containing PT2PyPh at 0, 30, 60, 90, 120, 150 and 180s. (C) shows the UV-VIS absorption spectrum of the solution containing PO2PyPh at 0, 30, 60, 90, 120, 150 and 180s; (D) shows the PL spectrum of the solution to be tested when the third solution contains RB after being irradiated by white light at different times. (E) shows the PL spectrum of the solution containing PT2PyPh after being irradiated by white light for different time; (F) shows the PL spectrum of the solution containing PO2PyPh after being irradiated by white light for different time; (G) shows the absorbance change at 399 nm of ABDA absorption peak at different time points of the same illumination in the solution to be measured configured by ABDA in RB, PT2PyPh or PO2PyPh. (H) shows the change of PL intensity at 525 nm of DCFH emission peak at different time points of the same illumination in the liquid to be measured configured by RB, PT2PyPh or PO2PyPh. (I) shows the absorbance change of the compound absorption peak of the solution under 10 mW cm'2white light irradiation, which is obtained by the solution containing PT2PyPh and the solution containing PO2PyPh.

[0050] Figure 3 shows (A) a confocal fluorescence image of Staphylococcus aureus (S. aureus}, E. coll and P. aeruginosa cultured with PO2PyPh. (B) to (D) shows the photodynamic bacteria killing efficiency of PO2PyPh against MRSA, KREC and Pseudomonas aeruginosa under white light irradiation.

[0051] Detailed description

[0052] "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, iso- butyl, n-hexyl, and the like.

[0053] "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=CH3), n-propenyl (-CH2CH=CH2), / so-propenyl (-C(CH3)=CH2), but-2-enyl (-CH2CH=CHCH3), and the like.

[0054] "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.

[0055] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo.

[0056] "Oxo / hydroxy" refers to groups =0, HO-.

[0057] "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.

[0058] "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).

[0059] 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.

[0060] "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.

[0061] "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, R2or 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.

[0062] 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]thiophene, thiazole, thiadiazoles, oxadiazole, oxatriazole, tetrazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, triazole, and the like. 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 di-alkylamino, 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.

[0063] The present disclosure concerns a compound of Formula (I), or a solvate thereof: wherein

[0064] X is selected from S or 0;

[0065] R is independently selected from H, alkyl, unsaturated alkyl, heteroatomic alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, alkoxy, or one or more chromophores capable of conjugation with one or more fluorescent substances.

[0066] The present disclosure concerns a compound of Formula (I), or a solvate thereof:

[0067] wherein

[0068] X is selected from S or O;

[0069] R is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, and a chromophore.

[0070] In some embodiments, the compound of Formula (I) is represented by Formula (la) or wherein

[0071] X is selected from S or 0;

[0072] R1and R7are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

[0073] R5and R4are independently selected from H, 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

[0074] R5, R5, R7, and R5are independently selected from H, optionally substituted alkyl, and optionally substituted alkenyl. In some embodiments, R1and R2are independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl. In some embodiments, R1and R2are independently selected from optionally substituted alkyl, and optionally substituted alkenyl. In some embodiments, R1and R2are independently selected from optionally substituted alkyl. In some embodiments, R1and R2are independently selected from optionally substituted C1-C6alkyl. In some embodiments, R1and R2are independently selected from optionally substituted methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl and tert-butyl.

[0075] In some embodiments, R3and R4are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, and a chromophore. In some embodiments,

[0076] R3and R4are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, and optionally substituted alkoxy. In some embodiments, R3and R4are independently selected from H, optionally substituted alkyl, and optionally substituted alkenyl. In some embodiments, R3and R4are independently selected from H and optionally substituted alkyl. In some embodiments, R3and R4are independently selected from H, and optionally substituted C1-C6alkyl. In some embodiments, R3and R4are independently selected from H and optionally substituted methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl and tert-butyl. In some embodiments, R3and R4are independently selected from H.

[0077] In some embodiments, R5, R6, R7, and R5are independently selected from H and optionally substituted alkyl. In some embodiments, R5, R6, R7, and R5are independently selected from H and optionally substituted C1-C6alkyl. In some embodiments, R5, R6, R7, and R5are independently selected from H and optionally substituted methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, sec-butyl and tert-butyl. In some embodiments, R5, R6, R7, and R5are independently selected from H.

[0078] The optional substituent in R1-R5may 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, heteroaryloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, oxyacyl, oxime, oxime ether, hydrazone, oxyacylamino, oxysulfonylamino, and aminoacyloxy.

[0079] 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, which may allow for delocalisation of electrons and the absorption of specific wavelengths of light. The presence of electronwithdrawing and electron-donating groups within the chromophore structure may influence the wavelength of light absorbed. The specific arrangement and composition of the chromophore determines the wavelength of light it absorbs, and thus the colour it appears. For example, fluorescein and / or quinine may be conjugated via the hydroxyl moiety or alkenyl moiety.

[0080] 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.

[0081] In some embodiments, the compound of Formula (I) and (la) is selected from:

[0082] The compound of Formula (I) may be a photosensitiser. A photosensitiser is a molecule that may generate reactive oxygen species (ROS) upon light exposure. When the compound absorbs light of a specific wavelength, the compound may be excited. The excited singlet state compound may then undergo intersystem crossing where it may transition to a triplet excited state, which may be a more stable and longer-lived excited state. In the triplet excited state, the compound may transfer its energy to nearby oxygen molecules which are in ground state triplet configuration. The transfer of energy may result in the formation of reactive oxygen species such as singlet oxygen, superoxide radical and hydroxyl radical. The generated ROS may then initiate various oxidative processes, leading to the destruction of target molecules such as bacterial cells. The process of ROS generation by photosensitisers may be applied to phototherapeutic applications such as photodynamic therapy (PDT) for the treatment of bacterial infections. Photodynamic therapy is a treatment that uses a photosensitising drug or compound and light to kill abnormal cells. The photosensitising compound may be activated with light, which may cause a reaction that damages nearby cells, e.g. unwanted bacterial cells. The compound may have a high ROS production rate and may also effectively bind to various Gram-negative / positive bacteria through electrostatic and hydrophobic action, and kill bacteria through PDT action.

[0083] In some embodiments, the compound of Formula (I) is characterised by an absorption wavelength of about 300 nm to about 600 nm. In some embodiments, the compound of Formula (I) is characterised by an absorption peak wavelength of about 480 nm to about 500 nm.

[0084] In some embodiments, the compound of Formula (I) is characterised by an emission peak wavelength of not more than about 700 nm. In some embodiments, the compound of Formula (I) is characterised by an emission peak wavelength of about 640 nm to about 690 nm.

[0085] In some embodiments, the compound generates reactive oxygen species when irradiated with light. In some embodiments, the compound generates Type II ROS (superoxide radical).

[0086] In some embodiments, the compound of Formula (I) is characterised by a rate of generation reactive oxygen species of about 0.15 x 10-3mmol / s to about 0.3 x 10-3mmol / s mmol / s. In other embodiments, the rate is about 0.15 x 10-3mmol / s to about 0.25 x 10-3, about 0.15 x 10-3mmol / s to about 0.2 x 10-3, about 0.2 x 10-3mmol / s to about 0.3 x 10-3, about 0.2 x 10-3mmol / s to about 0.25 x 10-3, or about 0.25 x 10-3mmol / s to about 0.3 x 10-3.

[0087] In some embodiments, the compound of Formula (I) is characterised by a reactive oxygen species yield of about 80% to about 95%. A higher yield of ROS may lead to destruction of more bacterial cells and hence, a more efficient photodynamic therapy. In other embodiments, the yield is about 80% to about 90%, about 80% to about 85%, about 85% to about 95%, about 85% to about 90%, or about 90% to about 95%.

[0088] In some embodiments, the compound is characterised by an increase in fluorescence with an increase in reactive oxygen species. Fluorescence is the emission of light by a substance that has absorbed light or other electromagnetic radiation.

[0089] In some embodiments, the compound binds to Gram-positive and / or Gram-negative bacterial cells. The intensity of emission peaks of the compound may be enhanced due to the enhanced fluorescence caused by the restriction of intramolecular rotation of the compound after binding with bacteria. This allows for labelling of the bacterial cells.

[0090] The compound may have good water solubility, strong bacterial binding ability and efficient Type II reactive oxygen species (ROS) generation efficiency, and may effectively bind to drug-resistant bacteria, such as P. aeruginosa which may be difficult to target due to poor membrane permeability. This may result in a high photodynamic bactericidal effect.

[0091] In some embodiments, the compound of Formula (I) is characterised 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), drug-resistant Escherichia coll (MDR E. coll), such as Kanamycin resistant Escherichia coli (KREC), or P. aeruginosa. In some embodiments, the compound is characterised by an antibacterial activity against antibiotics resistant bacterial cells.

[0092] The synthesis method of the above compounds includes the following step:

[0093] Step 1 : Preparation of Compound al: Mix a reactant, biphenyl halide, Pd(OAc)2, a first base and t-BuaP'HBFi, dissolve with toluene under nitrogen or inert atmosphere at 90~110°C for 10~15h, follow by cooling to room temperature, then adding into ethyl acetate, extract with saturated salt water, spin dry to obtain a crude product, purify the crude product, obtain a white to light yellow solid Compound al. The mole ratio of reactant, biphenyl halide, Pd(OAc)2 and the first base is 10: (10~15) : (0.2~l) : (10~15), and the mass ratio of Pd(OAc)2 and t-BusP'HBF4 ratio is 1:2.

[0094] The structural formula of the reactant is as follows: wherein X is S or 0.

[0095] The structural formula of Compound al is as follows:

[0096]

[0097] In Step 1, the biphenyl halide is 4-bromobiphenyl or 4-iodobiphenyl.

[0098] In Step 1, the first base is potassium tert-butoxide, sodium tert-butoxide, potassium acetate or sodium acetate.

[0099] In Step 1, the purification is by silica gel column chromatography, which uses a mixture of dichloromethane and n-hexane as eluent with a volume ratio of dichloromethane: n- hexane =1: (5~15).

[0100] In Step 1, the ratio of the quantity of reactant to the volume of toluene is less than or equal to 10:20, wherein the quantity of reactant is measured in mmol and the volume of toluene is measured in mL.

[0101] In Step 1, the ratio of the quantity of reactant to the volume of ethyl acetate is less than or equal to 10:20, wherein the quantity of reactant is measured in mmol, and the volume of ethyl acetate is measured in mL.

[0102] In Step 1, anhydrous sodium sulfate is used for drying.

[0103] Step 2: Preparation of Compound a2: Mix and cool Compound al and DCM to 0~4°C to obtain a first solution. Dissolve / V-bromosuccinimide in DCM to obtain a second solution. Add the second solution to the first solution, stir at 0~4°C in the dark for 0.5~2 hours, heat to room temperature and stir while avoiding light for 10~15h, quench with water, extract an organic layer with DCM. Wash the organic layer with water, evaporate the solvent under pressure, dry the organic layer and purify to obtain Compound a2. The mole ratio of Compound al to / V-bromosuccinimide is 5: (10~ll).

[0104] The structural formula of Compound a2 is as follow:

[0105]

[0106] In Step 2, NaS04 is used for drying.

[0107] In Step 2, the purification is performed by silica gel chromatography, using a mixture of dichloromethane and n-hexane as eluent with a volume ratio of dichloromethane: n- hexane of 1 : (3-5).

[0108] In Step 2, the concentration of compound al in the first solution is 0.1-0.3 mmol / mL, and the concentration of / V-bromosuccinimide in the second solution is 0.3-0.5 mmol / mL.

[0109] Step 3: Preparation of Compound a3: Mix Compound a2, a second base and pyridine- 4-boronic acid with a catalyst Pd(PPh3)4, add 1,4-dioxane aqueous solution, stir under the under nitrogen or inert atmosphere at 90-105 °C for 10-15h, cool to room temperature, add into ethyl acetate, extract with water, dry the resulting organic layer and evaporate the solution under pressure, purify to obtain an orange yellow solid Compound a3. The mole ratio of Compound a2 to pyridine-4-boronic acid is 2: (4-6) and the mole ratio of pyridine-4-boronic acid to the second base is 1: (1-1.5).

[0110] The structural formula of Compound a3 is as follow:

[0111] In Step 3, the second bases are K2CO3, Na2COa, potassium acetate, cesium carbonate, or sodium acetate.

[0112] In Step 3, the mole ratio of Compound a2 to Pd(PPha)4 is 2: (0.1-0.2). In Step 3, the ratio of the quantity of Compound a2 to the volume of 1,4-dioxane aqueous solution is less than or equal to 2:20, and the quantity of the substance is measured in mmol and the volume is measured in mL.

[0113] In Step 3, an aqueous solution of 1, 4-dioxane is a mixture of 1, 4-dioxane and water, and the ratio of 1, 4-dioxane to water in an aqueous solution of 1, 4-dioxane by volume is (4 to 5) : 1.

[0114] In Step 3, the ratio of the quantity of Compound a2 to the volume of ethyl acetate is less than or equal to 2:40, and the quantity of Compound a2 is measured in mmol and the volume is measured in mL.

[0115] In Step 3, NaSCu is used for drying.

[0116] In Step 3, purification is performed by silica gel chromatography using a mixture of ethyl acetate and n-hexane as eluent, in volume parts, ethyl acetate: n-hexane = 1: (4~10).

[0117] Step 4: Preparation of compound of Formula (I): Dissolve Compound a3 in ACN under nitrogen or inert atmosphere, add iodomethane, stir at 70~80°C for 10~15 h, remove solvent under reduced pressure, and orange solid crude product is obtained. Add the crude product into a first solvent to dissolve the crude product, and a second solvent is added to obtain an orange precipitate as a compound of Formula (I). The mole ratio of the Compound a3 to iodomethane is 1: (2~2.5).

[0118] In Step 4, the ratio of the quantity of Compound a3 to the volume of ACN is less than or equal to 1:20, the quantity of the Compound a3 is measured in mmol, and the volume of ACN is measured in mL.

[0119] In Step 4, the ratio of the quantity of the Compound a3 to the volume of the second solvent solvent is less than or equal to 1:20, the unit of the quantity of the substance is mmol, and the unit of the volume of undesirable is mL.

[0120] Accordingly, the present disclosure also concerns a method of synthesising a compound of Formula (I) or Formula (la), or a salt or solvate thereof, comprising: a) reacting compound of Formula (II) with a haloalkane:

[0121]

[0122] In some embodiments, a mole ratio of compound of Formula (II) to haloalkane is about 1 : 1.5 to about 1:3. In other embodiments, the mass ratio is about 1:1.5 to about 1:2.5, about 1: 1.5 to about 1:2, about 1:2 to about 1:3, about 1:2 to about 1:2.5, or about 1 :2.5 to about 1:3. In some embodiments, the mass ratio is about 1:2 to about 1:2.5.

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

[0124] In some embodiments, the reaction is conducted at a temperature of about 60 °C to about 100 °C. In other embodiments, the temperature is about 60 °C to about 90 °C, about 60 °C to about 80 °C, about 60 °C to about 70 °C, about 70 °C to about 100 °C, about 70 °C to about 90 °C, about 70 °C to about 80 °C, about 80 °C to about 100 °C, or about 80 °C to about 90 °C. In some embodiments, the temperature is about 70 °C to about 80 °C.

[0125] In some embodiments, the reaction is conducted for a duration of about 5 hours to about 20 hours. In other embodiments, the duration is about 5 hours to about 18 hours, about 5 hours to about 15 hours, about 5 hours to about 12 hours, about 5 hours to about 10 hours, about 10 hours to about 20 hours, about 10 hours to about 18 hours, about 10 hours to about 15 hours, or about 15 hours to about 20 hours. In some embodiments, the duration is about 10 hours to about 15 hours.

[0126] In some embodiments, the compound of Formula (II) is dissolved in ACN. In some embodiments, a ratio of compound of Formula (II) to ACN is about 1 mmol: 15 mL to about 1 mmol:25 mL.

[0127] In some embodiments, the reacted product is mixed with a solvent to precipitate compound of Formula (I) or Formula (la) as a solid. In some embodiments, a ratio of compound of Formula (II) to solvent is about 1 mmol: 15 mL to about 1 mmol:25 mL. In some embodiments, the solvent is ethyl ether.

[0128] In some embodiments, the method further comprises a step before step a) of reacting a compound of Formula (III) with a heterocyclic acid to form compound of Formula (II): wherein Y 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, Na2COa, potassium acetate, caesium carbonate, or sodium acetate.

[0130] In some embodiments, a mole ratio of compound of Formula (III) to heterocyclic acid is about 2:3 to about 2:7. In other embodiments, the mole ratio is about 2:3 to about 2:6, about 2:3 to about 2:5, about 2:3 to about 2:4, about 2:4 to about 2:7, about 2:4 to about 2:6, about 2:4 to about 2: 5, about 2:5 to about 2:7, about 2:5 to about 2:6, or about 2:6 to about 2:7. In some embodiments, the mole ratio is about 2:4 to about 2:6.

[0131] In some embodiments, a mole ratio of heterocyclic acid to base is about 1 :0.5 to about 1 :2. In other embodiments, the mole ratio is about 1:0.5 to about 1: 1.5, about 1:0.5 to about 1 :1, about 1: 1 to about 1:2, about 1 : 1 to about 1: 1.5, or about 1: 1.5 to about 1 :2. In some embodiments, the mole ratio is about 1:1 to about 1 : 1.5.

[0132] In some embodiments, a mole ratio of compound of Formula (III) to catalyst is about 2:0.05 to about 2:1. In other embodiments, the mole ratio is about 2:0.05 to about 2:0.5, about 2:0.05 to about 2:0.2, about 2:0.05 to about 2:0.1, about 2:0.1 to about 2: 1, about 2:0.1 to about 2:0.5, about 2:0.1 to about 2:0.2, about 2:0.2 to about 2: 1, or about 2:0.2 to about 2:0.5. In some embodiments, the mole ratio is about 2:0.1 to about 2:0.2.

[0133] In some embodiments, the heterocyclic acid is pyridine-4-boronic acid. In some embodiments, the reaction is conducted at a temperature of about 60 °C to about 150 °C. In other embodiments, the temperature is about 60 °C to about 120 °C, about 60 °C to about 100 °C, about 60 °C to about 80 °C, about 80 °C to about 150 °C, about 80 °C to about 120 °C, about 80 °C to about 100 °C, about 100 °C to about 150 °C, or about 100 °C to about 120 °C. In some embodiments, the temperature is about 90 °C to about 105 °C.

[0134] In some embodiments, the reaction is conducted for a duration of about 5 hours to about 20 hours. In other embodiments, the duration is about 5 hours to about 18 hours, about 5 hours to about 15 hours, about 5 hours to about 12 hours, about 5 hours to about 10 hours, about 10 hours to about 20 hours, about 10 hours to about 18 hours, about 10 hours to about 15 hours, or about 15 hours to about 20 hours. In some embodiments, the duration is about 10 hours to about 15 hours.

[0135] In some embodiments, the compound of Formula (III) is mixed with an aqueous solution. The aqueous solution may be 1,4-dioxane. In some embodiments, a ratio of compound of Formula (III) to aqueous solution is less than or equal to about 2 mmol: 15 mL. In other embodiments, the ratio is less than or equal to about 2 mmol: 18 mL, about 2 mmol:20 mL, about 2 mmol:25 mL. In some embodiments, the ratio is less than or equal to about 2 mmol:20 mL.

[0136] In some embodiments, the aqueous solution is a mixture of 1,4-dioxane and water. In some embodiments, a volume ratio of 1,4-dioxane to water in the aqueous solution is about 2: 1 to about 8:1. In other embodiments, the volume ratio is about 2: 1 to about 6: 1, about 2: 1 to about 5: 1, about 2: 1 to about 4: 1, about 2: 1 to about 3: 1, about 3: 1 to about 8: 1, about 3:1 to about 6: 1, about 3:1 to about 5: 1, about 3:1 to about 4: 1, about 4: 1 to about 8: 1, about 4:1 to about 6: 1, about 4: 1 to about 5: 1, about 5: 1 to about 8: 1, or about 5: 1 to about 6: 1. In some embodiments, the volume ratio is about 4: 1 to about 5:1.

[0137] In some embodiments, the reacted product is mixed with ethyl acetate to obtain an organic layer. In some embodiments, a ratio of compound of Formula (III) to volume of ethyl acetate is less than or equal to about 2 mmol: 30 mL. In other embodiments, the ratio is less than or equal to about 2 mmol:35 mL, about 2 mmol:40 mL, about 2 mmol:45 mL. In some embodiments, the ratio is less than or equal to about 2 mmol:40 mL. In some embodiments, the reacted product is purified using silica gel chromatography to obtain the compound of Formula (II).

[0138] In some embodiments, the method further comprises a step before step a) of reacting a compound of Formula (IV) with a cyclic dicarboximide to form compound of Formula (HI):

[0139] In some embodiments, a mole ratio of compound of Formula (IV) to cyclic dicarboximide is about 5:9 to about 5: 12. In other embodiments, the mole ratio is about 5:9 to about 5: 11, about 5:9 to about 5: 10, about 5: 10 to about 5: 12, about 5: 10 to about 5: 11, or about 5:11 to about 5: 12. In some embodiments, the mole ratio is about 5:10 to about 5: 11.

[0140] In some embodiments, the cyclic dicarboximide is / V-bromosuccinimide.

[0141] In some embodiments, the compound of Formula (IV) is mixed with DCM to obtain a first solution. In some embodiments, the concentration of the compound of Formula (IV) in the first solution is about 0.1 mmol / mL to about 1 mmol / mL. In other embodiments, the concentration is about 0.1 mmol / mL to about 0.8 mmol / mL, about 0.1 mmol / mL to about 0.5 mmol / mL, about 0.1 mmol / mL to about 0.3 mmol / mL, about 0.3 mmol / mL to about 1 mmol / mL, about 0.3 mmol / mL to about 0.8 mmol / mL, or about 0.3 mmol / mL to about 0.5 mmol / mL. In some embodiments, the concentration is about 0.1 mmol / mL to about 0.3 mmol / mL.

[0142] In some embodiments, the cyclic dicarboximide is dissolved in DCM to obtain a second solution. In some embodiments, the concentration of cyclic dicarboximide in the second solution is about 0.1 mmol / mL to about 1 mmol / mL. In other embodiments, the concentration is about 0.1 mmol / mL to about 0.8 mmol / mL, about 0.1 mmol / mL to about 0.5 mmol / mL, about 0.1 mmol / mL to about 0.3 mmol / mL, about 0.3 mmol / mL to about 1 mmol / mL, about 0.3 mmol / mL to about 0.8 mmol / mL, or about 0.3 mmol / mL to about 0.5 mmol / mL. In some embodiments, the concentration is about 0.3 mmol / mL to about 0.5 mmol / mL.

[0143] In some embodiments, the first solution and the second solution are reacted to obtain the compound of Formula (III).

[0144] In some embodiments, the reaction is conducted at a temperature of about -1 °C to about 10 °C for a duration of about 0.1 hours to about 5 hours. In other embodiments, the reaction is conducted at a temperature of about -1 °C to about 8 °C, about -1 °C to about 6 °C, about -1 °C to about 4 °C, about 0 °C to about 10 °C, about 0 °C to about 8 °C, about 0 °C to about 6 °C, or about 0 °C to about 4 °C for a duration of about 0.1 hours to about 3 hours, about 0.1 hours to about 2 hours, about 0.5 hours to about 5 hours, about 0.5 hours to about 3 hours, or about 0.5 hours to about 2 hours. In some embodiments, the reaction is conducted at a temperature of about 0 °C to about 4 °C for a duration of about 0.5 hours to about 2 hours.

[0145] In some embodiments, the reaction further comprises heating and stirring at a temperature of about 20 °C to about 30 °C for a duration of about 5 hours to about 20 hours. In other embodiments, the reaction further comprises heating and stirring at a temperature of about 20 °C to about 28 °C, about 20 °C to about 25 °C, about 25 °C to about 30 °C, or about 25 °C to about 28 °C for a duration of about 5 hours to about 18 hours, about 5 hours to about 15 hours, about 10 hours to about 20 hours, about 10 hours to about 18 hours, or about 10 hours to about 15 hours.

[0146] In some embodiments, the reacted product is purified using silica gel chromatography to obtain the compound of Formula (III).

[0147] In some embodiments, the method further comprises a step before step a) of reacting a compound of Formula (V) with an optionally substituted biphenyl halide to form compound of Formula (IV):

[0148] In some embodiments, the reaction is conducted in the presence of a catalyst. The catalyst may be Pd(OAc)2. The transition metal-catalysed reaction may be conducted in presence of a ligand. The ligand may be t-BuaP’HBR. In some embodiments, the reaction is conducted in the presence of a base. The base may be potassium tert- butoxide, sodium tert-butoxide, potassium acetate or sodium acetate.

[0149] In some embodiments, a mole ratio of compound of Formula (V) to optionally substituted biphenyl halide is about 10:8 to about 10:20. In other embodiments, the mole ratio is about 10:8 to about 10: 18, about 10:8 to about 10: 15, about 10:8 to about 10: 10, about 10: 10 to about 10:20, about 10: 10 to about 10:18, about 10: 10 to about 10: 15, about 10: 15 to about 10:20, or about 10:15 to about 10: 18. In some embodiments, the mole ratio is about 10: 10 to about 10: 15.

[0150] In some embodiments, a mole ratio of compound of Formula (V) to optionally substituted biphenyl halide to catalyst to base is about 10: (8-20): (0.1-1.5): (8-20). In other embodiments, the mole ratio is about 10:8:0.1:8, about 10:8:0.1:20, about 10:8: 1.5:8, about 10:8:1.5:20, about 10:20:0.1:8, about 10:20:0.1:20, about 10:20: 1.5:8, about 10:20: 1.5:20, about 10: 10:0.2:10, about 10: 10:0.2:15, about 10: 10: 1: 10, about 10: 10: 1: 15, about 10: 15:0.2: 10, about 10: 15:0.2:10, about 10: 15: 1: 10, or about 10: 15: 1: 15. In some embodiments, the mole ratio is about 10: (10-15): (0.2-1): (10-15).

[0151] In some embodiments, a mole ratio of catalyst to ligand is about 1:1 to about 1:4. In other embodiments, the mole ratio is about 1: 1 to about 1:3, about 1: 1 to about 1:2, about 1:2 to about 1:4, about 1:2 to about 1:3, or about 1:3 to about 1 :4. In some embodiments, the mole ratio is about 1:2.

[0152] In some embodiments, the biphenyl halide is 4-bromobiphenyl or 4-iodobiphenyl.

[0153] In some embodiments, the compound of Formula (IV) is dissolved in toluene. In some embodiments, the ratio of the quantity of compound of Formula (IV) to the volume of toluene is less than or equal to about 10 mmol: 15 mL. In other embodiments, the ratio is less than or equal to about 10 mmol: 18 mL, about 10 mmol:20 mL, or about 10 mmol: 25 mL. In some embodiments, the ratio is less than or equal to about 10 mmol / 20 mL.

[0154] In some embodiments, the reaction is conducted at a temperature of about 60 °C to about 150 °C. In other embodiments, the temperature is about 60 °C to about 120 °C, about 60 °C to about 100 °C, about 60 °C to about 80 °C, about 80 °C to about 150 °C, about 80 °C to about 120 °C, about 80 °C to about 100 °C, about 100 °C to about 150 °C, or about 100 °C to about 120 °C. In some embodiments, the temperature is about 90 °C to about 105 °C. In some embodiments, the reaction is conducted for a duration of about 5 hours to about 20 hours. In other embodiments, the duration is about 5 hours to about 18 hours, about 5 hours to about 15 hours, about 5 hours to about 12 hours, about 5 hours to about 10 hours, about 10 hours to about 20 hours, about 10 hours to about 18 hours, about 10 hours to about 15 hours, or about 15 hours to about 20 hours. In some embodiments, the duration is about 10 hours to about 15 hours.

[0155] In some embodiments, the reacted product is purified using silica gel column chromatography.

[0156] The compound of Formula (I) and / or Formula (la) may be used as antimicrobial drugs. The compound may be used in selective imaging of bacteria cells. The compound may be used as photosensitisers to increase ROS production rate.

[0157] Compared with the prior art, the disclosed compounds have the following beneficial effects:

[0158] The molecular structure of the disclosed compounds may have a rigid hydrophobic structure, which may help the molecule to better insert into the bacterial outer membrane. In addition, the structure of pyridine salts in the compound molecules makes the molecules electropositive, which may help the molecules to bind to electronegative bacteria. The strong D-A interaction between the reactants and the pyridine salt structure may effectively promote the separation of intramolecular charge, so that the molecules may have an efficient ROS generation rate. These properties established the basis for efficient sterilisation of photosensitisers.

[0159] Through the combination of two rigid hydrophobic structures and cations, the disclosed compounds may have strong membrane penetration ability, so that the obtained photosensitiser may effectively combine and kill bacteria with poor membrane permeability (such as P. aeruginosa). In addition, the modification of the two cations may enable the disclosed compounds to have good hydrophilicity, and the ROS quenching due to the aggregation-caused quenching (ACQ) effect may not reduce the antibacterial effect of the photosensitiser in the physiological environment.

[0160] As photosensitisers, the disclosed compounds may effectively produce Type II ROS under low light intensity (10 mW / cm2) white light irradiation while little to no ROS production may be detected under the same conditions compared with the commercial photosensitiser Rose Bengal. The results indicated that disclosed compounds were highly effective in producing reactive oxygen species. In vitro experiments showed that the disclosed compounds had non-specific and extensive bactericidal ability against MRSA, KREC and P. aeruginosa.

[0161] 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 salt or solvate thereof.

[0162] The bacteria may be Gram-negative and / or Gram-positive bacterial cells. The bacteria may be selected from Methicillin-resistant Staphylococcus aureus (MRSA), Kanamycin resistant Escherichia coli (KREC), E. coli, S. aureus, P. aeruginosa and a combination thereof.

[0163] The bacterial cells may be detected via the fluorescence emitted when the compound binds with the bacterial cells.

[0164] The method may further comprise a step of irradiating a sample or the bacterial cells to electromagnetic radiation of about 300 nm to about 800 nm, or about 400 nm to about 700 nm.

[0165] 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.

[0166] The present disclosure also concerns a compound of Formula (I) or (la) or pharmaceutically acceptable salt or solvate thereof for use in therapy.

[0167] In some embodiments, the therapy is photodynamic therapy.

[0168] The present disclosure also concerns a compound of Formula (I) or (la) or a salt or solvate thereof for use in the imaging and / or treatment of a disease or disorder associated with bacteria.

[0169] The present disclosure also concerns a use of compound of Formula (I) or (la) or pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the imaging and / or treatment of a disease or disorder associated with bacteria.

[0170] 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 (I) or (la) or pharmaceutically acceptable salt or solvate thereof.

[0171] The method may further comprise a step of irradiating a sample or the bacterial cells to activate the compound of Formula (I) or (la). The compound of Formula (I) or (la) may act as a photosensitiser and may bind to the bacterial cells. The sample may then be irradiated with electromagnetic radiation of a wavelength of about 300 nm to about 800 nm. Upon exposure to the electromagnetic radiation, the compound may be excited from its ground state to a higher energy state. The energy may be transferred to nearby oxygen molecule, generating reactive oxygen species such as single oxygen and free radicals. The ROS may damage various cellular components within the bacterial and the selective damage may be more pronounced in the bacterial cells due to higher concentration of the compound compared to healthy surrounding cells. The oxidative damage caused by ROS may lead to the death of the bacterial cell through mechanisms such as apoptosis, necrosis or autophagy.

[0172] 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, abscesses, cellulitis), soft tissue infection, respiratory disease (e.g. pneumonia, sinusitis), bloodstream infections (e.g. sepsis), heart valve infections, ear infections, urinary tract infections, wound infections, food poisoning, sexually transmitted infections, meningitis, gastroenteritis (diarrhoea), tuberculosis, meningococcal disease. Legionnaires’ disease, Q fever, strep throat, whooping cough (pertussis) or any other life-threatening systemic disease.

[0173] 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. 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.

[0174] Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium.

[0175] 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.

[0176] 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 a!., Chapter 31 (Academic Press); and A Textbook of Drug Design and Development, 1991, Bundgaard et al., Chapter 5, (Harwood Academic Publishers).

[0177] 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.

[0178] 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. 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.

[0179] 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 1000 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 800 mg per kg of body weight per dosage. In yet another embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage, such as up to 250 mg per body weight per dosage.

[0180] 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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).

[0185] 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. 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.

[0186] The compound or composition 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 100 mg / m2.

[0187] The compound or composition 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] The compound of the invention may be suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain antioxidants, buffers, bactericides and solutes which render the compound, composition or combination isotonic with the blood of the intended recipient; and aqueous and nonaqueous 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.

[0192] 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.

[0193] 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.

[0194] Examples

[0195] The compound of the invention comprises two rigid hydrophobic structures and a cation.

[0196] The rigid hydrophobic structure may be and , X is S or O. The compound may have a high ROS production rate and may also effectively bind to various Gram-negative / positive bacteria through electrostatic and hydrophobic action, and kill bacteria through PDT action. The compound may act as a photosensitiser. The compound may have good water solubility, strong bacterial binding ability and efficient Type II reactive oxygen species (ROS) generation efficiency, and may effectively bind to drug-resistant bacteria, such as P. aeruginosa which may be difficult to target due to poor membrane permeability. This may result in a high photodynamic bactericidal effect. have the formula or , wherein R is independently selected from H, alkyl, unsaturated alkyl, heteroatomic alkyl, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, alkoxy, or one or more chromophores capable of conjugation with one or more fluorescent substances.

[0197] The technical scheme of the invention is described in detail in combination with the attached drawings and embodiments. The temperature of saturated salt water is 21-25°C. The pH of PBS in the following embodiment is 7.4.

[0198] S. aureus purchased from ATCC (Strain designation: NCTC 8532);

[0199] E. coll purchased from ATCC (Strain designation: HB101);

[0200] P. aeruginosa purchased from ATCC (Strain designation: PRD-10 [CIP 103467, NCIB 10421, PCI 812]);

[0201] Methicillin-resistant Staphylococcus aureus (MRSA) was purchased from ATCC (Strain designation: F-182).

[0202] The preparation method of the compound of the invention is as shown in Figure 1A.

[0203] Example 1

[0204] A method for preparing a compound (PT2PyPh) comprises the following steps:

[0205] SI. Preparation of Compound 1: Phenothiazine (1.99 g, 10 mmol), 4-iodobiphenyl (2.8g, 10 mmol), Pd(OAc)2 (0.5 mmol), potassium tert-butoxide (15 mmol) and t- Bu3P'HBF4 (1 mmol) were added to a 100 mL round-bottomed flask. 50 mL toluene was added to dissolve it, and the reaction bottle was sealed under nitrogen atmosphere, and heated in an oil bath at 90 °C for 12 h. After the reaction was finished and cooled to room temperature, the solution was poured into 100 mL of ethyl acetate, and the organic phase was extracted with saturated salt water. The organic phase was dried with anhydrous sodium sulfate and spun dry to obtain a crude product. The crude product was purified by silica gel column chromatography, using a mixture of dichloromethane and n-hexane as eluent (in volume fraction, dichloromethane: n- hexane = 1: 10) to obtain a white to yellowish solid of 1.72g (compound al) with a yield Compound 1

[0206] S2. Preparation of Compound 2: Compound 1 (1.75 g, 5 mmol) and 30 ml DCM were added to a 100 ml round-bottled flask and cooled to 0 °C in an ice bath to obtain the first solution. / V-bromosuccinimide (1.72 g, 10 mmol) was dissolved in 30 mL DCM to obtain the second solution, and the second solution was added to the first solution through the dropping funnel. Stir at 0 °C ice bath for 1 hour away from light, then heat up to room temperature and stir away from light for 12 h. After quenching with water, an organic layer was extracted with DCM. The organic layer is washed with water and dried on NaSC4. After the solvent was evaporated under pressure, the crude product obtained was purified by silica gel chromatography. A mixture of dichloromethane and n-hexane was used as eluent (in volume parts, dichloromethane: n-hexane = 1:4) to obtain a white to yellowish solid as Compound 2, the yield (2.45 g, 97%).

[0207] S3. Preparation of Compound 3: Compound 2 (1010 mg, 2 mmol), K2CO3(828 mg, 6 mmol) and pyridine-4-boronic acid (541.2 mg, 4.4 mmol) were added to 100 ml round- bottomed flask, and Pd(PPh3)4(0.1 mmol) was added as a catalyst. After adding 25 ml of 1,4-dioxane aqueous solution (the ratio of 1,4-dioxane to water in 1,4-dioxane aqueous solution is 4: 1 by volume), the flask is sealed and stirred under nitrogen atmosphere at 90 °C for 12 h. The resulting solution was cooled to room temperature and then poured into 100mL ethyl acetate and an organic layer was extracted with water. The organic layer is dried with NaSC4and the solvent evaporated under reduced pressure. The crude product was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as eluent (in volume parts, ethyl acetate: n-hexane = 4: 1) to obtain an orange-yellow solid as Compound 3 at yield (787 mg, 78%).

[0208] S4. Preparation of compound (PT2PyPh): Compound 3 (505 mg, 1 mmol) is dissolved in 50 ml of ACN in a 100 ml round-bottomed flask. The flask is sealed under nitrogen atmosphere. lodomethane (0.137 ml, 2.2 mmol) is then added to this solution under nitrogen. The reaction is stirred at 70°c for 12 h. After the solvent is removed under reduced pressure, an orange solid (crude product) is obtained. A minimum amount of methanol that may dissolve the crude product was added, dissolving the crude product. 100 mL of ethyl ether is added to obtain the orange precipitate as a compound (PT2PyPh). Yield (710 mg, 90%). 1H NMR (400 MHz, DMSO) 5 8.91 (d, J = 6.8Hz, 4H), 8.40-8.37 (m, 4H), 8.10 - 8.06 (m, 2H), 7.93 (d, J = 2.3Hz, 2H), 7.86 7.82 (m, 2 h), 7.71 (dd, J = 8.8, 2.3 Hz, 2 h), 7.66 7.62 (m, 2 h), 7.58 7.54 (m, 2 h), 7.50 7.44 (m, 1 h), 6.27 (d, J = 8.8Hz, 2H), 4.28 (s, 6H).

[0209] Compound (PT2PyPh)

[0210] Example 2

[0211] A method for preparing a compound PO2PyPh comprises the following steps:

[0212] SI . Preparation of Compound 4: Phenoxazine (1.83 g, 10 mmol), 4-iodobiphenyl (2.8g, 10 mmol), Pd(OAc)2(0.5mmol), potassium tert-butoxide (15 mmol), and t-Bu3P'HBF4(lmmol) were added to a 100 mL round-bottomed flask. Add 50 mL toluene to dissolve it. The reaction bottle was sealed under nitrogen, and heated in an oil bath at 90 °C for 12 h. After the solution was cooled to room temperature, the solution was poured into 100 mL of ethyl acetate and the organic phase was extracted with saturated salt water. The organic phase is dried with anhydrous sodium sulfate and spun dry to obtain a crude product. The crude product was purified by silica gel column chromatography, using a mixture of dichloromethane and n-hexane was used as eluent (by volume fraction, dichloromethane: n-hexane = 1 : 10), and 1.84g of white to light yellow solid was obtained, with a yield of 54%. Compound 4

[0213] S2. Preparation of Compound 5: Compound 4 (1.68 g, 5 mmol) and 30 ml DCM were added to a 100 ml round-bottled flask and cooled to 0 °C in an ice bath to obtain the first solution. / V-bromosuccinimide (1.72 g, 10 mmol) was dissolved in 30 mL DCM to obtain the second solution, and the second solution was added to the first solution through the dropping funnel. The solution was stirred in a 0 °C ice bath for 1 hour away from light, then heated to room temperature and stirred away from light for 12h. After quenching with water, an organic layer was extracted with DCM. The organic layer is washed with water and dried on NaSC4. After the solvent was evaporated under pressure, the crude product obtained was purified by silica gel chromatography, using a mixture of dichloromethane and n-hexane was used as eluent (in volume parts, dichloromethane: n-hexane = 1 :4) to obtain a white to yellowish solid as Compound 5, the yield (2.34 g, 95%). Compound 5

[0214] S3. Preparation of compound 6: Compound 5 (986 mg, 2 mmol), K2CO3(828 mg, 6 mmol) and pyridine-4-boronic acid (541.2 mg, 4.4 mmol) were added to 100 ml round- bottled flask, and Pd(PPh3)4(0.1mmol) was added as a catalyst. After adding 25 ml of 1,4-dioxane aqueous solution (the ratio of 1,4-dioxane to water in 1,4-dioxane aqueous solution is 4: 1 by volume), the flask is sealed and stirred at 90 °C for 12h under nitrogen atmosphere. The resulting solution was cooled to room temperature and then poured into 100mL ethyl acetate and extracted with water. The organic layer is dried with NaSO4and evaporated under reduced pressure. The crude product was purified by silica gel chromatography using a mixture of ethyl acetate and n-hexane as eluent (in volume parts, ethyl acetate: n-hexane = 4: 1) to obtain an orange-yellow solid as Compound 6 at yield (665 mg, 68%).

[0215] S4. Preparation of compound (PO2PyPh): Compound 6 (489 mg, 1 mmol) is dissolved in 50 ml of ACN in a 100 ml round-bottomed flask. The flask is sealed under nitrogen atmosphere. lodomethane (0.137 mL, 2.2 mmol) was then added to this solution under nitrogen. The reaction is stirred at 70 °C for 12h. After the solvent is removed under reduced pressure, an orange solid (crude product) is obtained. After the crude product is added to the minimum amount of methanol that can dissolve it, 100 mL of ethyl ether is added to obtain the orange precipitate as a compound (PO2PyPh). Yield (719 mg, 93%). 1H NMR (400 MHz, DMSO) δ 8.88 (d, J = 6.6Hz, 4H), 8.40-8.36 (m, 4H), 8.09 - - 8.04 (m, 2H), 7.84 - 7.81 (m, 2H), 7.67 7.63 (m, 2 h), 7.56 (DDD, J = 12.2, 6.1, 2.9 Hz, 7 h), 6.15 (d, J = 8.4 Hz, 2 h), 4.28 (s, 6 h).

[0216] PT2PyPh and PO2PyPh are photosensitisers designed and synthesized for photodynamic therapy (PDT). The photosensitiser molecules are obtained by introducing a "ring fixation" strategy of S and O atoms on the TPP based luminous skeleton.

[0217] Among them, the structure of the TPP luminous skeleton is:

[0218] PT2PyPh and PO2PyPh were dissolved in DMSO to form a first solution with a compound concentration of 10 mM, and lpl of the first solution was added to 999 μL of PBS to prepare 1 mL of PBS solution with a compound concentration of 10 μM . The photophysical properties of PBS solution were tested. Due to their good water solubility, both PT2PyPh and PO2PyPh may be well dissolved in PBS. As shown in Figure IB, the PBS solutions of PT2PyPh and PO2PyPh exhibit a wide adsorption spectrum between 300-600 nm. The peak values were 488 nm (PT2PyPh) and 495 nm (PO2PyPh).

[0219] The fluorescence emission of PBS solution of PT2PyPh and PBS solution of PO2PyPh was tested by FS5 fluorescence spectrometer. As shown in Figure 1C, when dissolved in PBS, the maximum emission wavelength of PT2PyPh was 645 nm and that of PO2PyPh was 689 nm.

[0220] After adding 106 CFU of Staphylococcus aureus into PBS solution of PT2PyPh and PBS solution of PO2PyPh and mixing them evenly, PBS suspension was obtained, as shown in Figures ID and IE. Compared with PBS solution (PT2PyPh of Figure ID and PO2PyPh in Figure IE), PBS suspension was obtained. The intensity of emission peaks in PBS suspensions ("PT2PyPh+ S. aureus" in Figure ID and "PO2PyPh+ S. aureus" in Figure IE) was significantly enhanced, which was mainly due to the enhanced fluorescence caused by the restriction of intramolecular rotation of the compound molecules after binding with bacteria, indicating that the compound may have a strong affinity for bacteria.

[0221] A second solution of 10 mM was prepared by dissoluting RB (Rose Bengal) or compound in DMSO, and 1 μL of the second solution was added to 999 μL PBS (pH = 7.4) containing 50 μM 9,10-anthracene diyl-bis(methylene)dimalonic acid (ROS indicator, ABDA). 1 mi- solution was prepared to be tested. The final concentration of RB or compound in the solution to be tested is 10 μM, the final concentration of ROS indicator is about 50 μM, and the compound is PT2PyPh or PO2PyPh. The solution to be tested was irradiated with a white light source of 10 mW / cm2, and the absorption of the solution was measured by UV-Vis spectrometer at 0, 30, 60, 90, 120, 150 and 180s respectively. As can be seen from Figures 2A to 2C and 2G, the absorption peak of reactive oxygen species indicator ABDA in the tested solution containing PT2PyPh and PO2PyPh decreased rapidly under the same conditions, while the absorption peak of ABDA in the tested solution containing RB did not decrease significantly. The results indicated that PT2PyPh and PO2PyPh had high ROS yield. It was observed that under the white light irradiation of 10mW / cm2that the absorption peak (488 nm) intensity of PT2PyPh gradually decreased, while the absorption peak (495 nm) intensity of PO2PyPh did not change significantly under the same conditions, indicating that PO2PyPh had better light stability (Figure 21).

[0222] To further verify this conclusion, another reactive oxygen species indicator was selected for testing. RB (Rose Bengal) or the compound was dissolved in DMSO to prepare a third solution at a concentration of 10 mM, and 1 μL of the third solution was added to 999 μL of PBS containing 50 μM 2',7'-dichlorodihydrofluorescein (DCFH) to prepare 1 mL of the solution to be tested . DCFH may be oxidized by ROS to produce DCF and emit green fluorescence. The fluorescence intensity may gradually increase with the increase of ROS in the solution. Therefore, the fluorescence of the solution after white light irradiation (10 mW cm2) at different time intervals (0, 30, 60, 90, 120, 150 and 180s) was tested with FS5 fluorescence spectrometer to evaluate the ROS generation efficiency of the solution. It may be seen from Figures 2D to 2F and 2H that under the same conditions, the fluorescence in the solution containing PT2PyPh and PO2PyPh is significantly enhanced, while the fluorescence intensity in the liquid under test containing RB is less increased.

[0223] Further, the binding ability of PO2PyPh to Gram-positive / Gram-negative bacteria was studied by confocal microscopy. In order to verify whether PO2PyPh has good bacterial binding ability, a bacterium P. aeruginosa, which has poor membrane penetration and is difficult to image, was selected. PO2PyP in DMSO with a concentration of 10 mM was added to 1 mL of S. aureus, E. coli or P. aeruginosa containing 108 CFU, respectively, so that the final concentration of PO2PyPh was 10 μM, and the solution to be measured was obtained. After incubation for 5 minutes, 30μL of the measured solution drops were taken from each group and placed on a slide, and the slide was sealed with a cover. The imaging effect was observed by confocal microscopy. As seen from Figure 3A, PO2PyPh clearly images S. aureus, E. coli and P. aeruginosa, and the edges of bacterial imaging are clear with good contrast. These results indicate that PO2PyPh may effectively bind to bacteria.

[0224] In view of PO2PyPh's good photostability, high ROS production efficiency and good bacterial binding ability, the photodynamic bactericidal effect of PO2PYPh was further evaluated. Methicillin-resistant Staphylococcus aureus (MRSA), Kanamycin resistant Escherichia coli (KREC) and P. aeruginosa were selected as the targets. PO2PyP in DMSO with a concentration of 10 mM was added to 1 mL PBS containing 106 CFU resistant bacteria, so that the final concentrations of PO2PyPh were 0.1, 0.2, 0.5, 1, 2, 5, 10 and 20 μM, and multiple first incubators with different concentrations of PO2PyPh were obtained. In addition, 1 mL of PBS containing 106 CFU resistant bacteria was prepared as the second incubator. After incubating the second and multiple first incubators for 5 min each, the solution of each group was irradiated with 30 mW / cm2white light source for 10 min. After irradiation, 30 μL was taken from each group and the number of colonies in the mixture was counted by plate counting method. Figure 3B to 3D showed that with the increase of PO2PyPh concentration, the number of viable bacteria in the mixed solution decreased significantly, indicating that PO2PyPh had a photodynamic killing effect on MRSA, KREC and P. aeruginosa.

[0225] The diagnosis of bacterial infections remains a major challenge in the field of medicine. Although many contrast agents have been developed for bacterial imaging, their clinical impact has been minimal. This is mainly due to their inability to detect small amounts of bacteria and to image Gram-negative or drug-resistant bacteria with low membrane permeability. Pseudomonas aeruginosa is a bacterium that can cause serious and often life-threatening infections, especially in people with compromised immunity or those with cystic fibrosis. Infections caused by Pseudomonas aeruginosa are often challenging due to its poor membrane permeability and biofilm formation. This makes it resistant to most antimicrobial therapies and immune responses, causing it to evade treatment. PT2PyPh and PO2PyPh as photosensitisers may improve membrane permeability and effectively label and kill Pseudomonas aeruginosa through reasonable molecular design.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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:whereinX is selected from S or O;R1and R2are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;R3and R4are independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkoxy, and a chromophore; andR5R6, R7, and R8are independently selected from H, optionally substituted alkyl, and optionally substituted alkenyl.

2. The compound according to claim 1, wherein R1and R2are independently selected from optionally substituted alkyl.

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

4. The compound according to any one of claims 1 to 3, wherein R,5R6, R7, and R5are independently selected from H and optionally substituted alkyl.

5. The compound according to any one of claims 1 to 4, wherein the compound of Formula (la) is selected from:

6. The compound according to any one of claims 1 to 5, wherein the compound is a photosensitiser.

7. The compound according to any one of claims 1 to 6, wherein the compound generates reactive oxygen species when irradiated with light.

8. The compound according to claim 7, wherein the compound is characterised by a rate of generation reactive oxygen species of about 0.15 x 10-3mmol / s to 0.3 x 10-3mmol / s.

9. The compound according to claim 7 or 8, wherein the compound is characterised by a reactive oxygen species yield of about 80% to about 95%.

10. The compound according to any one of claims 7 to 9, wherein the compound is characterised by an increase in fluorescence with an increase in reactive oxygen species generated.

11. The compound according to any one of claims 1 to 10, wherein the compound binds to Gram-positive and / or Gram-negative bacterial cells.

12. The compound according to any one of claims 1 to 11, wherein the compound is characterised by an antibacterial activity against antibiotics resistant bacterial cells.

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

14. The method according to claim 13, wherein a mole ratio of compound of Formula (II) 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 (III) with a heterocyclic acid to form compound of Formula (II):wherein Y 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 (II) to heterocyclic acid is about 2:3 to about 2:7.

18. The method according to claim 16 or 17, wherein the heterocyclic acid is pyridine-4-boronic acid.

19. The method according to any one of claims 13 to 18, wherein the method further comprises a step before step a) of reacting a compound of Formula (IV) with a cyclic dicarboximide to form compound of Formula (III):

20. The method according to claim 19, wherein a mole ratio of compound of Formula (IV) to cyclic dicarboximide is about 5:9 to about 5: 12.

21. The method according to claim 19 or 20, wherein the cyclic dicarboximide is N- bromosuccinimide.

22. The method according to any one of claims 13 to 21, wherein the method further comprises a step before step a) of reacting a compound of Formula (V) with an optionally substituted biphenyl halide to form compound of Formula (IV):wherein the reaction is conducted in the presence of a catalyst and a base.

23. The method according to claim 22, wherein a mole ratio of compound of Formula (V) to biphenyl halide is about 10:8 to about 10:20.

24. The method according to claim 22 or 23, wherein the biphenyl halide is selected from 4-bromobiphenyl and 4-iodobiphenyl.

25. 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.

26. A compound of Formula (la) or pharmaceutically acceptable salt or solvate thereof for use in therapy.

27. A compound of Formula (la) or a salt or solvate thereof for use in the imaging and / or treatment of a disease or disorder associated with bacteria.

28. Use of compound of Formula (la) or pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the imaging and / or treatment of a disease or disorder associated with bacteria.

29. 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 or solvate thereof.

30. The compound for use, use or method according to any one of claims 26 to 29, wherein the disease or disorder associated with bacteria has a resistance against antibiotics.

31. The compound for use, use or method according to any one of claims 26 to 30, 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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