Antimicrobial compounds

Abstract

An article comprising a compound of Formula I, wherein: R1 represents H or a C1-C12 hydrocarbon group that is optionally substituted or a water solubilising functional group; R2 represents a C1 or more hydrocarbon group that is optionally substituted; R3 represents H or a C1-12 hydrocarbon group that is optionally substituted; X represents O, NH, S or PH; and L represents a linker group, and wherein the article comprises: a) an underlying substrate and a surface layer, and the surface layer comprises the compound; and / or b) the compound dispersed in a binder.

Description

[0001] ANTIMICROBIAL COMPOUNDS

[0002] Field of the Invention

[0003] The present invention relates to amino acid-related compounds that display antimicrobial effects, for example antibacterial effects. The present invention relates to articles and compositions comprising the compounds. The present invention also relates to the use of the compounds as a medicament, for example as an antimicrobial agent and / or in the treatment of an infection.

[0004] Background of the Invention

[0005] Microorganisms such as bacteria are commonly transmitted through contact via a surface. The requirement for articles to be kept free of infectious microbes, such as bacteria, is consistently growing in importance. The ability to produce antimicrobial surfaces to lower the rate of transmission via this route is also desirable.

[0006] Microorganisms are also commonly transmitted through the air, as airborne particles. Therefore, there is also an important need for PPE and / or air handling apparatus that has antimicrobial properties, to lower the rate of transmission via this route.

[0007] Antimicrobial (e.g. antibiotic) resistance and the requirement for new antimicrobial compounds is a large and increasing challenge for the healthcare profession. Traditional antimicrobial agents, such as penicillin-based antimicrobial agents, are particularly affected by antimicrobial resistance. The provision of new antimicrobial compounds is desirable.

[0008] Peptide-based antimicrobial agents have been investigated. However, these agents are typically difficult to synthesise, chemically modify and / or purify. For example, the production of beta-lactam based antibiotics typically requires multistep synthetic routes. The difficulties in synthesis and chemical modification of these agents makes it difficult to optimise these agents. Furthermore, the complexity of these molecules presents challenges relating to the optimisation of their activity.

[0009] The invention has been devised with the foregoing in mind. Summary of the Invention

[0010] According to a first aspect the present invention provides an article comprising a compound of Formula I:

[0011] Formula I, wherein R1represents H or a Cl -Cl 2 hydrocarbon group that is optionally substituted or a water solubilising functional group (e.g. polyether); R2represents a Cl or more hydrocarbon group that is optionally substituted; R3represents a Cl-12 hydrocarbon group that is optionally substituted; X represents O, NH, S or PH; and L represents a linker group. The article comprises: an underlying substrate and a surface layer, and the surface layer comprises the compound; and / or the compound dispersed in a binder. Formula I is depicted by Figure 1 of the accompanying drawings.

[0012] Surprisingly, compounds of Formula I have been found to be effective antimicrobial (e.g. antibacterial, antiviral and / or antifungal) agents. In particular, compounds of Formula I have been found to display activity against a range of bacteria, including gram positive and gram negative strains, aerobic and anaerobic strains, and strains that are particularly susceptible to antibiotic resistance.

[0013] The article is preferably an article that multiple users will contact during use and / or that is used in applications where microbial control is particularly important. For instance, the article may be selected from the list consisting of healthcare apparatus, medical device, (electronic) display apparatus, imaging apparatus, packaging, agricultural equipment, air treatment and / or handling, water treatment and / or handling, and food and / or drink preparation.

[0014] The article (e.g. as packaging) preferably is transparent or comprises a transparent region, such as a window, which may be used to view products held by the packaging. The transparent region preferably comprises a compound of the invention. However, it will be appreciated that the compounds can provide beneficial antimicrobial effects when included in a translucent or opaque region of packaging.

[0015] Furthermore, compounds of Formula I have been found to display low cytotoxicity against human cell lines, making them excellent candidates for therapeutic applications.

[0016] Therefore, according to a second aspect the present invention provides a composition comprising a compound of Formula I and a carrier and / or diluent. The carrier and / or diluent is pharmaceutically or cosmetically acceptable, and / or the carrier and / or diluent is not tetrahydrofuran or triethylamine. The composition may be a paint or a surface cleaner.

[0017] The compounds of the present invention may find non-therapeutic uses as antimicrobial agents, for example as for frequently touched surfaces and in the treatment of a watercourse.

[0018] Certain compounds of the present invention have been found to form a glass when heated, as identified in the Examples. These material properties be beneficial for certain applications, such as providing antibacterial properties to surfaces where transparency is desirable, such as touch-screen displays.

[0019] According to a third aspect the present invention provides a non-therapeutic use of compound of Formula I, or a composition thereof, as an antimicrobial (e.g. antibacterial and / or antibiotic) agent. According to a fourth aspect the present invention provides a non-therapeutic method comprising contacting an article, water, soil and / or rock with a compound of Formula I or a composition thereof.

[0020] According to a fifth aspect the present invention provides a compound of Formula I for use in the prevention or treatment of a microbial (e.g. bacterial) infection. According to a sixth aspect, the present invention provides a compound of Formula I for use as a medicament.

[0021] Compounds of Formula I are relatively simple to synthesise and the antimicrobial activity of the compounds can relatively easily be optimised by altering the structure (within the bounds of Formula I). Baker, B.C., et al., European Polymer Journal 162 (2022) 1 10889 discloses the synthesis of a supramolecular glass made from a low molecular weight amino acid derivative. Specifically, the following compound IL (structure below) and its enantiomer ID were synthesised. However, the paper did not discuss any biological activity, such as antimicrobial properties, or in any way suggest that compounds ID and IL could have antimicrobial properties.

[0022] It will be understood that a compound of formula I may be used in a method of prevention or treatment of a microbial infection, wherein the method comprises administering a compound of Formula I to a subject. The present disclosure also provides the use of a compound of Formula I for the manufacture of a medicament, especially where the medicament is for the prevention or treatment of a microbial infection.

[0023] Surprisingly, compounds of Formula I readily form large transparent plates, and may be particularly suitable for forming articles. The provision of a compound of Formula I on the surface of an article will provide the antimicrobial properties of the compound of Formula I to the article.

[0024] According to a fifth aspect the present invention provides a compound of Formula I, with the proviso that the compound of Formula I is not represented by Formula II:

[0025] Formula II.

[0026] Scozzafava et al., Journal of Enzyme Inhibition (2010) 15(5), p425-432; CN 109704996 B and CN 109704983 B appear to generally allude to compounds having antibacterial effects. Kollu et al., Bioorganic Chemistry (2021), 1 1 1, 104837; WO 2018 / 167468 Al ; US 2021 / 0372959 Al ; WO 2022 / 096361 Al ; WO 2008 / 1 13992 A2; WO 2024 / 022910 Al appear to disclose other compounds but not antibacterial effects.

[0027] However, the present invention provides compounds with specific functionality that is new compared to these documents. It has been recognised that particular functionality in relation to the L, R1, R2and R3groups of Formula I provides beneficial effects.

[0028] For example, CN 109704996 B and CN 109704983 B describe LR2groups that contain carbamates, or alkyl- or acyl-functionalised amines.

[0029] There is also no disclosure of or teaching towards of the compounds of the present invention being successfully used in articles for providing an antibacterial surface, as is demonstrated by the present application.

[0030] The present disclosure also includes the subject-matter of the following clauses:

[0031] 1. An article comprising a compound of Formula I:

[0032] Formula I, wherein: R1represents H or a C l -Cl 2 hydrocarbon group that is optionally substituted or a water solubilising functional group; R2represents a C l or more hydrocarbon group that is optionally substituted; R3represents H or a Cl-12 hydrocarbon group that is optionally substituted; X represents O, NH, S or PH; and L represents a linker group, and wherein the article comprises: a) an underlying substrate and a surface layer, and the surface layer comprises the compound; and / or b) the compound dispersed in a binder.

[0033] 2. The article of clause 1, wherein the article is selected from the list consisting of healthcare apparatus, medical device, display apparatus, imaging apparatus, packaging, agricultural equipment, air treatment and / or handling, water treatment and / or handling, and food and / or drink preparation.

[0034] 3. The article of clause 2, wherein the article is as a medical device, packaging, a touch screen, a lens, a visor, or an article of healthcare equipment.

[0035] 4. A composition comprising a compound of Formula I and a carrier and / or diluent, wherein the carrier and / or diluent is pharmaceutically or cosmetically acceptable, and / or wherein the carrier and / or diluent is not tetrahydrofuran or triethylamine.

[0036] 5. The composition of clause 4, wherein the composition is selected from the list consisting of: a detergent composition, a disinfectant composition, a food and / or drink preservative, and a building material.

[0037] 6. The composition of clause 4 or clause 5, wherein the composition further comprises water, a surfactant, a pigment, a colourant, a binder / polymer, an oil, a preservative, a solidifier, a fragrance, an emollient, a bleach, a filler, an occlusive agent, a thickening agent, a humectant, dihydroxy acetone, a siloxane, and / or aluminum zirconium tetrachlorohydrex Gly.

[0038] 7. A non-therapeutic use of compound of Formula I, or a composition thereof, as an antimicrobial agent.

[0039] 8. A non-therapeutic method comprising contacting an article, water, soil and / or rock with a compound of Formula I or a composition thereof.

[0040] 9. A compound of Formula I for use in the prevention or treatment of a microbial infection.

[0041] 10. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding clause, wherein R2represents a C1-C50 alkyl and / or aryl group that is optionally substituted.

[0042] 11. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of clause 10, wherein R2represents a Cl -Cl 2 hydrocarbon group that is optionally substituted. 12. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding clause, wherein R2is optionally substituted by one or more group selected from the list consisting of -NO2, -O-, halide (e.g. -F, -Cl and - Br), -CN, -OH, CO2H, CO2R1, and -N(H)C(O)N(H)-.

[0043] 13. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding clause, wherein R3represents a Cl-12 alkyl and / or aryl group that is optionally substituted.

[0044] 14. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding clause, wherein R3is optionally substituted by one to four groups selected from the list consisting of -OH, -NH2, -CO2H, -CONH2, and - B(OH)2.

[0045] 15. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding clause, wherein X represents O or NH.

[0046] 16. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding clause, wherein R1represents H or an unsubstituted C1-C4 hydrocarbon group.

[0047] 17. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding clause, wherein L comprises or represents one or more groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea.

[0048] 18. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any one of clauses 1 to 9 or 12 to 17, wherein Formula I is represented by Formula III: Formula III, wherein: each of

[0049] R1, R3, X and L is independently as defined for Formula I, R4and R5each independently represent a Cl -Cl 2 hydrocarbon group that is optionally substituted, and n is 1 or more. 19. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding clause, whereimR1represents a H or a C1-C8 hydrocarbon group that is optionally substituted;R2represents a C1-C50 hydrocarbon group that is optionally substituted; R3represents H or a Cl-12 aryl and / or alkyl group that is optionally substituted; any substituents are selected from the list consisting of hydroxide, ether, nitro, nitrile and halide; X represents O, NH or S; and L comprises or represents one or more groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea. 20. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of clause 19, wherein: R1represents H or an unsubstituted C1-C2 hydrocarbon group; R2represents a C1-C42 alkyl or aryl group that is optionally substituted by one to four groups selected from the list consisting of -NO2, -O-, halide and -CN; R3represents a Cl-8 alkyl and / or aryl group that is optionally substituted by two or fewer groups selected from the list consisting of -OH and -NH2; X represents O; and L represents a thiourea group or a urea group.

[0050] 21. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of clause 19, wherein the compound is of one of the following structures:

[0051]

[0052]

[0053] 22. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding clause, wherein the compound has the following stereochemistry:

[0054] 23. A compound of Formula I for use as a medicament.

[0055] 24. A compound of Formula I, with the proviso that the compound of Formula I is not represented by Formula II: Formula II.

[0056] 25. The compound of clause 24, wherein the compound is represented by one of the following structures:

[0057]

[0058] 5 with the proviso that the compound of Formula I is not represented by Formula II. Detailed Description of the Invention

[0059] The term “CX-CY” where X and Y are integers refers to the number of carbon atoms in a given group. For example, a C1-C6 alkyl group contains from 1 to 6 carbon atoms, and a C3-C6 alkyl group contains from 3 to 6 carbon atoms.

[0060] Alkyl groups are partially or fully saturated hydrocarbon groups, and may be linear, branched and / or cyclic (“cycloalkyl”). Alkyl groups may therefore include one or more alkenyl, alkynyl and / or aryl groups. Examples of alkyl groups include methyl, ethyl, n- propyl, isopropyl, w-butyl, isobutyl, sec-butyl, / erz-butyl. w-pentyl, isopentyl, neopentyl or hexyl and the like. The term “cycloalkyl” refers to cyclic hydrocarbon groups. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and the like.

[0061] Alkenyl groups are hydrocarbon groups that comprise one or more carbon-carbon double bond, and may be linear, cyclic and / or branched. Alkenyl groups may therefore include one or more alkyl, alkynyl and / or aryl groups. Examples of alkenyl groups include vinyl, allyl, prenyl, isoprenyl and the like.

[0062] Alkynyl groups are hydrocarbon groups that comprise one or more carbon-carbon triple bond, and may be linear, cyclic and / or branched. Alkynyl groups may therefore include one or more alkenyl, alkyl and / or aryl groups.

[0063] Aryl groups are hydrocarbon groups that include one or more aromatic rings. Aryl groups may therefore include one or more alkyl, alkenyl and / or alkynyl groups. Examples of aryl groups include carbocyclic aromatic groups such as phenyl, naphthyl, anthracenyl, pyrenyl, chrysenyl, benz[a]anthracenyl, fluoranthene, indenyl, and tetrahydronaphthyl groups.

[0064] Substituted hydrocarbon groups include one or more heteroatoms (e.g. N, O, S, P, and / or halide (e.g. F, Cl and / or Br)). Preferably substituted hydrocarbon groups include one or more heteroatoms selected from the list consisting of N, O and halide (e.g. F and Cl). Substituted hydrocarbon groups include heterocyclic (e.g. heteroaromatic / heteroaryl), heteroalkyl, heteroalkenyl, and / or heteroalkynyl groups. Substituted hydrocarbon groups may include heteroatoms in the hydrocarbon chain (i.e. internal substituents, such as an ether) and / or attached to the hydrocarbon chain (i.e. external substituents, such as a halide).

[0065] Examples of substituents include those selected from the list consisting of: amine (primary, secondary and / or tertiary amine), amide, alcohol, ester, ether, thiol, thioether, sulfoxide, sulfone, sulfonamide, or halide (e.g. fluorine, chlorine, bromine and / or iodine), disulfide, sulfonate ester, thioketone, thioester, phosphine, phosphonate ester, phosphate ester, boronic ester, borinic ester, borane, aldehyde, ketone, carbamate, carbonate, carboxylic acid, carboxylic acid anhydride, urea, ketal, acetal, orthoester, orthocarbonate, nitrile, imine (e.g. an oxime and / or a Schiff base, such as a secondary ketamine and / or a secondary aldimine), imide, diimide, hydrazine, 1,2,3-triazole, hydrazone, nitro, acylhydrazone, semicarbazone, carbazate hydrazone, and hydrazone carboximidamide. Preferred substituents include those selected from the list consisting of: amine, amide, alcohol, ester, ether, thioether, sulfone, sulfonamide, or halide (e.g. fluorine, chlorine and / or bromine), thioketone, phosphonate ester, phosphate ester, boronic ester, aldehyde, ketone, carbamate, carbonate, carboxylic acid, urea, ketal, acetal, nitrile, imine, imide, 1,2,3-triazole and nitro. More preferred substituents include those selected from the list consisting of hydroxide, ethers (e.g. alkyl ethers, such as methoxyether), nitro, nitrile and halide (especially Cl).

[0066] Substituted hydrocarbon groups may contain from 1 to 10 heteroatoms, such as from 1 to 8, or from 1 to 6 heteroatoms. Substituted hydrocarbon groups may contain from 1 to 4 heteroatoms, such as 3, 2 or 1 heteroatoms.

[0067] Heterocyclic groups may be monocyclic or polycyclic (e.g. bicyclic) and / or may contain, 4 to 18 ring members, more usually 5 to 10 ring members, for example 5 or 6 ring members. A monocyclic group may include 3, 4, 5, 6, 7 or 8 ring members, more usually 4 to 7, and preferably 5, 6 or 7, more preferably 5 or 6 ring members. Examples of polycyclic (e.g. bicyclic) groups are those containing 6 to 18 ring members, more usually 8, 9 or 10 ring members. Heterocyclic groups may be selected from the list consisting of aziridine, azetidine, pyrrolidine, piperidine, piperazine, azepane, imidazolidine, tetrahydrofuran, oxirane, oxetane, oxane, oxepane, oxocane, 1,3- dioxolane, tetrahydrothiophene, pyrrolizidine, quinuclidine, 1 -azaadamantane, 2- azaadamantane, 1 -oxaspiro [4.5] decane, l,4-dioxa-7-azaspiro[4.4.]nonane, decahydroisoquinoline and decahydroquinoline. Heterocyclic groups include heteroaryl groups, such as polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. Examples of such polycyclic systems include l,4,5,6-tetrahydrocyclopenta[6]pyrrole, indoline, tetrahydroquinoline, tetrahydroisoquinoline, 1,2-dihydroquinoline, 1,2-dihydroisoquinoline, 2H- benzo[e] [l,3]oxazine, 2H-benzo[6] [ l,4]-oxazine, 2H-benzo[e] [ 1,2] oxazine, 1H- isochromene and 2H-chromene. Heteroaryl groups may be five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Heteroaryl groups may contain one or two or more ring nitrogen atoms. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole, 2H-isoindole, benzimidazole, 4-azaindole, 5- azaindole, 6-azaindole, 7-azaindole, benzofuran, isobenzofuran, benzo[c]thiophene, benzo[6]thiophene, benzo[t / ]isoxazole, benzo[ ]thiazole, quinolone, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline and 1,8-naphthyridine.

[0068] Rj_

[0069] R1represents H or a Cl -Cl 2 hydrocarbon group that is optionally substituted or a water solubilising functional group (e.g. polyether).

[0070] Preferably R1represents H or a C 1-C8 hydrocarbon group that is optionally substituted, for example H or a C1-C6 hydrocarbon group that is optionally substituted, preferably H or a C 1-C4 hydrocarbon group that is optionally substituted, for example H or a Cl, C2 or C3 hydrocarbon group that is optionally substituted. Preferably R1is unsubstituted.

[0071] Polyether groups are beneficial because they can increase the water solubility of the compound. The polyether of R1 may be a polyethylene glycol (PEG) group and / or a polypropylene glycol group. The polyether group may be represented by the formula:

[0072] Wherein R6is a Cl -10 hydrocarbon group, such as a Cl -8 hydrocarbon group or a Cl - 6 hydrocarbon group. R6may be a C2-10 hydrocarbon group, such as a C2-8 hydrocarbon group or a C2-6 hydrocarbon group. Preferably R6is a C2-5 hydrocarbon group, or a C2-4 hydrocarbon group, or a C2 or C3 hydrocarbon group, especially a C2 hydrocarbon group. Preferably the hydrocarbon group is an alkyl or an alkenyl group. More preferably the hydrocarbon group of R6is an alkyl group. More preferably R6is a C l-10 alkyl or alkenyl group, such as a Cl -8 alkyl or alkenyl group or a Cl -6 alkyl or alkenyl group, more preferably a C2-5 alkyl or alkenyl group, or a C2-4 alkyl or alkenyl group, or a C2 or C3 alkyl or alkenyl group, especially a C2 or C3 alkyl group. Preferably R6is a C2 alkyl (i.e. ethyl) group, such that the polyether is a polyethylene glycol group. n may be an average of 3 or more, or 5 or more, such as 10 or more, or 15 or more, such as 18 or more, n may be an average of 100 or less, such as 80 or less, or 60 or less, such as 50 or less, or 40 or less, for example 30 or less, or 25 or less, such as 22 or less, n may be an average of from 3 to 100, such as from 5 to 50, or from 10 to 30. The average may be a number average. The average value of n may be determined by NMR, for example by the integration of relevant peaks using NMR. Alternatively, the average value of n may be calculated using mass spectrometry.

[0073] The hydrocarbon group of R1may be an alkyl, alkenyl, aryl and / or alkynyl group that is optionally substituted. Preferably the hydrocarbon group of R1is an alkyl and / or alkenyl group (e.g. a C l-6 alkyl and / or alkenyl group), most preferably an alkyl group, that is optionally substituted. More preferably the hydrocarbon group of R1is an unsubstituted alkyl group, for example an unsubstituted C l-6 alkyl group.

[0074] The water solubilising functional group may be selected from the list consisting of: alcohols (e.g. polyols (such as branched polyols), glycerol), ethers (e.g. polyethers (such as polyethylene glycol)), a pluronic (i.e. hydrophilic poly(ethylene oxide) (PEO) and hydrophobic polypropylene oxide) (PPO), arranged in an A-B-A triblock structure), a carbohydrate group, amines (e.g. diamines), phosphates and sulfonates. The water solubilising group may be a polymer (e.g. polyol, polyether, pluronic, polysaccharide, polyamine, polyphosphate and / or polysulfonate) and / or a C l-50 (e.g. C2-30) hydrocarbon group substituted by one or more groups selected from the list consisting of alcohols, ethers, amines, phosphates and sulfonates. Water solubility may also be enhanced where R1represents H, especially in a basic environment and / or with heat. Most preferably R1represents H or a methyl group. As shown by the Examples, compounds where R1is H or a methyl group provide enhanced antibacterial activity compared to, for example, compounds where R1is a tert-butyl group.

[0075] The nature of R1may be controlled to modify the solubility of the compound. For example, the compound may be more soluble in water when R1is H.

[0076] R2

[0077] R2represents a Cl or more hydrocarbon group that is optionally substituted.

[0078] R2may represent a C2 or more hydrocarbon group, preferably a C4 or more hydrocarbon group, or a C5 or C6 or more hydrocarbon group. R2may represent a C 1-C50 hydrocarbon group, such as a C 1-C46 hydrocarbon group, or a C 1-C42 hydrocarbon group, preferably a C 1-C38 hydrocarbon group. R2may represent a C 1-C36 hydrocarbon group, or a C 1-C32 hydrocarbon group, or a C1-C30 hydrocarbon group, or a C 1-C28 hydrocarbon group. R2may represent a C 1-C24 hydrocarbon group, or a C l -20 hydrocarbon group, such as a C l -C l 6 hydrocarbon group, or a C l -C l 2 hydrocarbon group, or a Cl -C IO hydrocarbon group, or a C 1-C8 hydrocarbon group, or a C 1-C7 hydrocarbon group, such as a C1-C6 hydrocarbon group. R2may represent a C2-C50 hydrocarbon group, such as a C2-C42 hydrocarbon group, or a C4-C50 hydrocarbon group, such as a C4-C42 hydrocarbon group, or a C6-C50 hydrocarbon group, such as a C6-42 hydrocarbon group. R2may represent a C2-C20 hydrocarbon group, such as a C2-C12 hydrocarbon group, or a C4-C20 hydrocarbon group, such as a C4-C 12 hydrocarbon group, or a C6-C20 hydrocarbon group, for example a C6-C 12 hydrocarbon group. Each of the groups disclosed in this paragraph may optionally be substituted.

[0079] The hydrocarbon group of R2may be an alkyl, alkenyl, aryl and / or alkynyl group that is optionally substituted. Preferably the hydrocarbon group of R2is an alkyl, alkenyl and / or aryl group, most preferably an alkyl and / or an aryl group, that is optionally substituted. More preferably the hydrocarbon group of R2is an alkyl (e.g. cycloalkyl) and / or aryl group that is optionally substituted. Preferably R2represents a C l-50 alkyl, alkenyl and / or aryl group that is optionally substituted. More preferably R2represents a C 1-10 or C6-42 alkyl and / or aryl group that is optionally substituted. R2may specifically be substituted by one or more group selected from the list consisting of -NO2, -O-, halide (e.g. -F, -Cl and -Br), -CN, -OH, CO2H, COzR1, and -N(H)C(O)N(H)-. Preferably R2is substituted by one or more group selected from the list consisting of -NO2, -O-, halide (e.g. -F, -Cl and -Br) and -CN. Preferably R2is substituted by six or fewer groups, such as four or fewer, or three or fewer, or two or fewer groups. Preferably R2is substituted by one or no groups.

[0080] R2may represent a C4-12 cycloalkyl group (that is optionally substituted), such as a C4-10 cycloalkyl group, or a C4-8 cycloalkyl group. R2may represent a C5-12 cycloalkyl group (that is optionally substituted), such as a C6-12 cycloalkyl group, or a C6-8 cycloalkyl group, most preferably a C6 cycloalkyl group. Preferably the cycloalkyl group is not substituted. Most preferably the cycloalkyl group is cyclohexyl.

[0081] R2may represent a C4-12 aryl group (that is optionally substituted), such as a C4-10 aryl group, or a C4-8 aryl group. R2may represent a C5-12 aryl group (that is optionally substituted), such as a C6-12 aryl group, or a C6-8 aryl group, most preferably a C6 aryl group.

[0082] Where R2represents an aryl (e.g. C4-12 aryl, e.g. phenyl) group, preferably the aryl group is an unsubstituted C6-12 aryl group, or is a C4-12 aryl group substituted in one or both meta positions and / or the para position relative to the connection to the L group. As shown by the Examples, compounds where R2is phenyl display enhanced antibacterial properties where the phenyl group is unsubstituted, or is substituted in the meta- and / or para- positions compared to ortho-substituted compounds.

[0083] Preferably para substitution of a phenyl group of R2is by an electron withdrawing group, such as -NO2, halide (e.g. F, Cl and / or Br), -CN, CO2H and / or CO2R1; more preferably by -NO2, halide (especially Cl). As shown by the Examples, compounds where R2is substituted phenyl display enhanced antibacterial properties where the phenyl group is substituted by an electron withdrawing group (especially in the paraposition) compared to compounds with an electron donating group (e.g. 4-methoxy). Preferably R2does not represent 4-methoxyphenyl, especially where R3represents - CH2(4-hydroxyphenyl) or -CH2Ph. Meta-substitution by an electron donating group (e.g. 3 -methoxyphenyl) appears to achieve good effects. Good effects were also achieved where R2represented 2,4- dimethoxyphenyl .

[0084] Preferably a phenyl group of R2is unsubstituted (i.e. H) in both ortho positions, relative to the connection to the L group.

[0085] R2may represent a C 1-10 or C6-42 alkyl and / or aryl group that is optionally substituted with three or fewer (e.g. one or zero) groups selected from the list consisting of -NO2, -O-, halide (e.g. -F, -Cl and -Br) and -CN.

[0086] R2may comprise or represent a group selected from the list consisting of:

[0087] 3 -methoxyphenyl, 4-methoxyphenyl, 3 -chlorophenyl, 4-chlorophenyl, 3 -nitrophenyl,

[0088] 4-nitrophenyl, phenyl, 3 -cyanophenyl, butyl and cyclohexyl.

[0089] Preferably R2comprises or represents a group selected from the list consisting of 4-nitrophenyl, 3 -nitrophenyl, 3 -cyanophenyl, cyclohexyl, 3 -chlorophenyl, 4-chlorophenyl, 3 -methoxyphenyl, 4-methoxyphenyl, phenyl, 2,4-dimethoxyphenyl, butyl, and naphthyl. More preferably R2comprises or represents a group selected from the list consisting of 4-nitrophenyl, 3 -nitrophenyl, 3 -cyanophenyl, cyclohexyl,

[0090] 3-chlorophenyl, 4-chlorophenyl, 3 -methoxyphenyl, phenyl, 2,4-dimethoxyphenyl, butyl, and naphthyl. Most preferably R2comprises or represents a group selected from the list consisting of 3 -nitrophenyl, 3 -cyanophenyl, cyclohexyl, 3-chlorophenyl,

[0091] 4-chlorophenyl, 3 -methoxyphenyl, phenyl and butyl.

[0092] Preferably R2does not represent 3,4-dichlorophenyl, especially where XR1represents OH.

[0093] R2may comprise or represent: wherein

[0094] R in these structures corresponds to R1of Formula I, i.e. H or a C 1-C 12 hydrocarbon group that is optionally substituted.

[0095] Ri

[0096] R3represents H or a C l-12 hydrocarbon group that is optionally substituted.

[0097] R3may represent H or a C l-10 hydrocarbon group that is optionally substituted, for example H or a Cl -8 hydrocarbon group, or H or a Cl -7 hydrocarbon group, or H or a C l-6 hydrocarbon group that is optionally substituted. R3may represent a C l-12 alkyl, alkenyl and / or aryl group that is optionally substituted, or a C l -Cl 2 alkyl and / or aryl group that is optionally substituted, for example a C l-10 (e.g. C l -8) alkyl and / or aryl group that is optionally substituted. R3may represent a Cl-10 alkyl group, or a Cl -8 alkyl group, such as a Cl-6 alkyl group, or a Cl -4 alkyl group that is optionally substituted. R3may represent a C5-12 aryl group, or a C6-12 aryl group, such as a C5- 10 aryl group, or a C6-10 aryl group, or a C6-8 aryl group. Preferably R3represents a C6 aryl group, a C7 aryl group, a C4 alkyl group, a C3 alkyl group, or a Cl alkyl group. Preferably R3represents a C6 aryl group or a C l alkyl group.

[0098] R3(especially an aryl group of R3) may specifically be substituted by one or more group selected from the list consisting of -O-, -S-, -NH-, -CO2-, -CONH-, -SH, -OH, -NH2, - CO2H, -CONH2, and -B(OH)2. R3may specifically be substituted by one or more group selected from the list consisting of -OH, -NH2, -CO2H, -CONH2, and -B(OH)2. Preferably R3is substituted by one or more group selected from the list consisting of - OH and -NH2, more preferably -OH. R3may be substituted by four or fewer groups, such as three or two or fewer groups. Most preferably R3is substituted by one group, for example one -OH group. Where R3represents an alkyl group, preferably R3is not substituted. R3may represent a Cl-12 alkyl, alkenyl and / or aryl group that is optionally substituted by three or fewer groups selected from the list consisting of -O-, -S-, -NH-, -CO2-, - CONH-, -SH, -OH, -NH2, -CO2H, -CONH2, and -B(OH)2. R3may represent a Cl-12 alkyl, alkenyl and / or aryl group that is optionally substituted by three or fewer groups selected from the list consisting of -S-, -O-, -SH, -OH, -NH2, -CO2H, -CONH2, and - B(OH)2. R3may represent a Cl -8 alkyl and / or aryl group that is optionally substituted by two or fewer groups selected from the list consisting of -S-, -O-, -OH and -NH2.

[0099] R3may represent hydroxymethyl (i.e. -CH2OH), methyl or 4-hydroxyphenyl. R3may represents methyl or 4-hydroxyphenyl. R3preferably represents hydroxymethyl (i.e. - CH2OH), methyl, -CH2CH(CH3)2, -CH2Ph, -(CH2)2SMe, or 4-hydroxyphenylmethyl. R3preferably represents methyl or 4-hydroxyphenylmethyl.

[0100] Most preferably R3represents a C7 aryl group that is optionally substituted by an -OH group (especially -CH2Ph, more preferably -CH2(4-hydroxyphenyl)) or a Cl alkyl group (especially methyl).

[0101] X

[0102] X represents O, NH, S or PH. Preferably X represents O, NH or S. More preferably X represents O or NH. Most preferably X represents O.

[0103] L

[0104] L represents a linker group.

[0105] L may comprise or represent one or more groups selected from the list consisting of: amide, ester, amine, ether, thioether, disulfide, sulfoxide, sulfone, sulfonamide, sulfonate ester, thioketone, thioester, phosphine, phosphonate ester, phosphate ester, boronic ester, borinic ester, borane, ketone, carbamate, carbonate, carboxylic acid anhydride, urea, thiourea, ketal, acetal, orthoester, orthocarbonate, imide, diimide, hydrazine, hydroxylamine, 1,2, 3 -triazole, alkyl, alkenyl, alkynyl and aryl.

[0106] L may include 10 or fewer carbon atoms, such as 6 or fewer, or 4 or fewer, preferably 2 or fewer, such as 1 or 0 carbon atoms. L may include from 1 to 10 carbon atoms, such as from 1 to 4 carbon atoms, most preferably 1 carbon atom. Preferably L comprises or represents one or more groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea. More preferably L represents a urea or thiourea group, i.e. -N(H)C(O)N(H)- or -N(H)C(S)N(H)-. Most preferably L represents a urea group.

[0107] Preferred embodiments

[0108] In one embodiment: any substituents are selected from the list consisting of: amine, amide, alcohol, ester, ether, thioether, sulfone, sulfonamide, or halide (e.g. fluorine, chlorine and / or bromine), thioketone, phosphonate ester, phosphate ester, boronic ester, aldehyde, ketone, carbamate, carbonate, carboxylic acid, thiourea, urea, ketal, acetal, nitrile, imine, imide, 1,2,3-triazole and nitro;

[0109] X represents O, NH or S; and

[0110] L comprises or represents one or more groups selected from the list consisting of: amide, ester, amine, ether, thioether, disulfide, sulfoxide, sulfone, sulfonamide, sulfonate ester, thioketone, thioester, phosphine, phosphonate ester, phosphate ester, boronic ester, borinic ester, borane, ketone, carbamate, carbonate, carboxylic acid anhydride, thiourea, urea, ketal, acetal, orthoester, orthocarbonate, imide, diimide, hydrazine, hydroxylamine, 1,2,3-triazole, alkyl, alkenyl, alkynyl and aryl.

[0111] In one embodiment:

[0112] R1represents a H or a C1-C8 hydrocarbon group that is optionally substituted or a polyether;

[0113] R2represents a C1-C50 hydrocarbon group that is optionally substituted;

[0114] R3represents a Cl-10 hydrocarbon group that is optionally substituted; any substituents are selected from the list consisting of hydroxide, ethers (e.g. alkyl ethers, such as methoxyether), nitro, nitrile and halide (especially Cl);

[0115] X represents O, NH or S; and

[0116] L comprises or represents one or more groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea. In one embodiment:

[0117] R1represents H or an unsubstituted C1-C4 hydrocarbon group or a PEG group;

[0118] R2represents a C4-C50 alkyl and / or aryl group that is optionally substituted by one or more group selected from the list consisting of -NO2, -O-, halide (e.g. - F, -Cl and -Br), -CN, -OH, CO2H, CO2R1, and -N(H)C(O)N(H)-;

[0119] R3represents a Cl -8 alkyl and / or aryl group that is optionally substituted by one to four groups selected from the list consisting of -OH, -NH2, -CO2H, -CONH2, and -B(OH)2;

[0120] X represents O; and

[0121] L comprises or represents one to six groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea.

[0122] In one embodiment:

[0123] R1represents H or an unsubstituted C1-C2 hydrocarbon group;

[0124] R2represents a C6-C42 alkyl (e.g. cycloalkyl) or aryl group that is optionally substituted by one to four groups selected from the list consisting of -NO2, -O-, halide (e.g. -F, -Cl and -Br) and -CN;

[0125] R3represents a Cl -8 alkyl and / or aryl group that is optionally substituted by two or fewer groups selected from the list consisting of -OH and -NH2;

[0126] X represents O; and

[0127] L represents a urea group or a thiourea group.

[0128] In the compound of Formula I, the following may apply:

[0129] R1represents H or a Cl -Cl 2 hydrocarbon group that is optionally substituted or a polyether;

[0130] R2represents a Cl or more (e.g. C1-C24) hydrocarbon group that is optionally substituted;

[0131] R3represents a Cl-6 alkyl group that is optionally substituted or a C5-12 aryl group that is optionally substituted by two or fewer groups selected from the list consisting of -OH and -NH2;

[0132] X represents O; and

[0133] L comprises or represents one to six groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea. In the compound of Formula I, the following may apply:

[0134] R1represents H or a methyl group;

[0135] R2represents an unsubstituted C2-8 alkyl group, a C6-12 aryl group that is unsubstituted, or a C4-12 aryl group that is substituted in one or both of the meta positions and / or the para position;

[0136] R3represents a C7 aryl group that is optionally substituted by an -OH group, or a Cl alkyl group, or a C3 group that is optionally substituted by an -S- group, or a C4 alkyl group;

[0137] X represents O; and

[0138] L represents urea.

[0139] In the compound of Formula I, the following may apply:

[0140] R1represents H or a methyl group;

[0141] R2represents a C6-12 aryl group that is unsubstituted, or a C4-12 aryl group that is substituted in one or both of the meta positions and / or the para position;

[0142] R3represents a C7 aryl group that is optionally substituted by an -OH group, or a Cl alkyl group;

[0143] X represents O; and

[0144] L represents urea.

[0145] In the compound of Formula I, the following may apply:

[0146] R1represents H or a methyl group;

[0147] R2represents a C6-8 aryl group that is unsubstituted, or a C6-8 aryl group that is substituted in one or both of the meta positions and / or the para position by one or more groups selected from the list consisting of NO2, halide (e.g. F, Cl and / or Br), -CN and / or CO2R1;

[0148] R3represents -CH2PI1 that is optionally substituted by an -OH group, or methyl;

[0149] X represents O; and

[0150] L represents urea.

[0151] Where R3represents a group such as -CH2(4-hydroxyphenyl) and L represents urea, preferably R2represents butyl, 2,4-dimethoxyphenyl, naphthyl, 4-nitro-phenyl, 3-nitro- phenyl, 3 -cyano-phenyl, cyclohexyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-methoxy- phenyl or phenyl; and more preferably R2represents butyl, 3 -nitro-phenyl, 3 -cyanophenyl, cyclohexyl, 3 -chloro-phenyl, 3 -methoxy-phenyl or phenyl.

[0152] Where R3represents a group such as -CH3 and L represents urea, more preferably R2represents 3-chloro-phenyl, 4-chloro-phenyl, 4-nitro-phenyl, phenyl or cyclohexyl.

[0153] Where R3represents a group such as -CH2PI1 and L represents urea, preferably R2represents phenyl.

[0154] Where R3represents a group such as -CH2CH(CH3)2 and L represents urea, preferably R2represents 4-methoxy-phenyl or 4-chloro-phenyl.

[0155] Where R3represents a group such as -(CH2)2SMe and L represents urea, preferably R2represents 4-chlorophenyl or phenyl; more preferably phenyl.

[0156] In the compound of Formula I, the following may apply:

[0157] R1represents H or a methyl group;

[0158] R2represents an unsubstituted phenyl group, or a phenyl group that is substituted in one or both of the meta positions and / or the para position by one or more groups selected from the list consisting of -NO2 and / or halide (especially Cl);

[0159] R3represents -CH2PI1 that is optionally substituted by an -OH group, or methyl;

[0160] X represents O; and L represents urea.

[0161] For example, in the compound of Formula I, the following may apply:

[0162] R1represents H or a Cl -Cl 2 hydrocarbon group that is optionally substituted or a PEG group;

[0163] R2represents a C1-C12 (e.g. C1-C8) hydrocarbon group that is optionally substituted;

[0164] R3represents a Cl-4 alkyl group that is optionally substituted or a C5-8 aryl group that is optionally substituted by two or fewer groups selected from the list consisting of -OH and -NH2;

[0165] X represents O; and

[0166] L represents a urea group or a thiourea group. The compound of Formula I may be represented by one or more of the following structures:

[0167] wherein each R1independently represents H or a C1-C12 hydrocarbon group that is optionally substituted. Preferably each R1represents H or methyl.

[0168] The compound of Formula I may represent one of the compounds in the following table: In particular, the present invention relates in part to compounds 101, 103-108, 110-112, and 117 per se. Of these compounds, particular antibacterial benefits have been realised in relation to compounds 103-108 and 117.

[0169] The compound of Formula I may represent, as described below, compounds 201-248; especially compounds 202-210, 212-217, 219-221, 224-231, 233-236, 239, 241 and 243- 248; more preferably compounds 202-209, 214, 217, 219-221, 225-230, 233-234, 244 and 247; most preferably compounds 203-206, 208-209, 220, 225-229, and 247.

[0170] The compound of Formula I may be represented by Formula III:

[0171] Formula III

[0172] Wherein each R1, R3, X and L is independently as defined for Formula I, and wherein R4and R5each independently represent a Cl -Cl 2 hydrocarbon group that is optionally substituted, and n is 1 or more, such as from 1 to 4, or from 1 to 3, preferably 2.

[0173] R4and R5may each independently be a Cl-10 hydrocarbon group, such as a C1-C8 hydrocarbon group, or a C1-C6 hydrocarbon group that in each case is optionally substituted. R4and R5may each independently be a C2-C12 hydrocarbon group, such as a C3-C12 hydrocarbon group, or a C4-C12 hydrocarbon group. R4and R5may each independently optionally be substituted with four or fewer, such as two or one, substituents. Preferably R4and R5are unsubstituted.

[0174] Preferably R4and R5are each independently a Cl -Cl 2 alkyl, alkenyl or aryl group that is optionally substituted. More preferably R4is a C1-C8 alkyl or aryl group (e.g. a C2- C6 alkyl or aryl group) and R5is a C1-C6 alkyl group (e.g. a C1-C3 alkyl group). The compound of Formula I may be represented by one or more of the following structures: wherein each R1independently represents H or a C1-C12 hydrocarbon group that is optionally substituted.

[0175] The compounds of Formula I may be a compound as shown in Figure 2 of the accompanying drawings or Figure 3 of the accompanying drawings, wherein each R independently corresponds to R1, or a compound as shown in Figure 4 of the accompanying drawings.

[0176] Preferably the compound of Formula I has the following stereochemistry: Preferably the compound of Formula III has the following stereochemistry:

[0177] Articles

[0178] The antimicrobial (e.g. antibacterial) properties of the compounds of the present invention may persist when the compound is a surface layer on an underlying substrate and / or dispersed in (e.g. blended with) a binder (e.g. a polymer).

[0179] The compounds of the present invention may be used to form an article. The article comprises a compound of the present invention. The article is typically a solid phase object.

[0180] Where the article comprises the compound dispersed in a binder, the compound may be used to form at least the part of the surface of the article, or the compound may coat the surface of the article. The article may be formed from a composite comprising the compound and a binder (e.g. a structural material), such as a plastics material. The plastics material may, for example, be silicone (e.g. silicone rubber) and / or polyurethane.

[0181] The compound may be particularly useful as a surface coating on frequently touched surfaces, such as a handrail, a door, a door handle, a door push plate, a hospital bed, a wheelchair.

[0182] The article may be healthcare apparatus, medical device, display apparatus, imaging apparatus, packaging, agricultural equipment, air treatment and / or handling, water treatment and / or handling, and food and / or drink preparation.

[0183] Display apparatus may be a monitor screen, for example a touchscreen. The display apparatus may be a telephone, such as a mobile (cellular) telephone or smartphone, or a tablet computer, or a computer monitor. Imaging apparatus may be an endoscope (e.g. gastroscope, bronchoscope, cystoscope, ureteroscope, arthroscope or colonoscope), ophthalmoscope, or otoscope, or a lens.

[0184] The article (e.g. as packaging) preferably is transparent or comprises a transparent region, such as a window, which may be used to view products held by the packaging. The transparent region preferably comprises a compound of the invention. However, it will be appreciated that the compounds can provide beneficial antimicrobial effects when included in a translucent or opaque region of packaging.

[0185] At least part of the article may be opaque. The article may not be a lens.

[0186] The article may be an article of personal protective equipment (PPE), such as a face mask (e.g. a surgical mask or a respirator mask), a (face) visor, a shield, an apron, a gown, a glove, a pair of goggles or safety glasses. These articles are particularly useful in healthcare settings, where the prevention of transmission or propagation of microbes, such as bacteria, is particularly desirable. In one embodiment, the article is a component in a medical environment; preferably the article is a component in a hospital or a veterinary hospital.

[0187] The article may be another article where the prevention of transmission or propagation of microbes, such as bacteria, is particularly desirable, for example as a medical device such as a surgical instrument, or an implant or prosthesis, or a medical machine or component thereof.

[0188] In particular, the article may be selected from surgical instruments, such as forceps, reamers, pushers, pliers, or retractors; permanent implants, such as artificial heart valves, voice prostheses, prosthetic joints, implanted artificial lenses, stents (e.g. vascular stents), and shunts (e.g. hydrocephalus shunts); and non-permanent implants, such as pacemakers and pacemaker leads, drain tubes, endotracheal or gastrointestinal tubes, temporary or trial prosthetic joints, surgical pins, guidewires, surgical staples, cannulas, subcutaneous or transcutaneous ports, and indwelling catheters and catheter connectors, and contact lenses. The article may be a medical machine or component thereof, for example, it may be selected from dialysis machines, dialysis water delivery systems, water circuits within a dialysis unit and water delivery systems for respirator therapy. The article may be a dressing (e.g. a wound dressing). The article may be a catheter. Examples of indwelling catheters include urinary catheters, vascular catheters (e.g., central venous catheters, dialysis catheters, peripheral venous catheters, arterial catheters and pulmonary artery Swan-Ganz catheters), peritoneal dialysis catheters, central venous catheters and needleless connectors.

[0189] In one embodiment the article is a dressing, for example a hydrocolloid dressing, a hydrogel dressing, an alginate dressing, a collagen dressing, a foam dressing, a transparent dressing, a cloth dressing, gauze (e.g. paraffin gauze), a low adherent dressing, or a semipermeable film (e.g. polyurethane coated with acrylic) dressing.

[0190] The present invention allows the prevention of medical device-associated bacterial infections by providing the compound. For example, the compound of the present invention offers the possibility to effectively reduce catheter-related bacterial infections.

[0191] The compounds are also useful for coating onto food preparation surfaces, such as kitchen counters, cutting boards, sinks, stoves, refrigerator surfaces, or onto bathroom surfaces, such as toilets, sinks, bathtubs, showers, and drains. Other suitable treatable surfaces are floor surfaces, door surfaces and window surfaces.

[0192] In one embodiment, the article is a component of process equipment, such as cooling equipment, water treatment equipment, air treatment equipment or food processing equipment. In one such embodiment, the component is selected from: a cooling tower, a water treatment plant, a dairy processing plant, a food processing plant, a chemical process plant, and a pharmaceutical process plant. For example, the article may be a filter for a water treatment system and / or an air treatment system. The article may be an item of agricultural equipment.

[0193] The article may be a container, such as a drum, bottle, tub, carton, punnet, jar, pot, crate, or package. The article may be a vessel. In one embodiment, the article is a toilet bowl, a sink, a bathtub, a drain, a highchair, a work surface, a food processing machine, a food preparation area, an air handling unit (or component thereof), an air duct, an air filter, or an air conditioning unit.

[0194] The article may include the compound in an amount of 0.001 wt% or more, such as 0.01 wt% or more, or 0.1 wt% or more, such as 1 wt% or more, or 5 wt% or more. For example, the article may include the compound in an amount of 80 wt% or less, such as 50 wt% or less, or 20 wt% or less. The article may include the compound in an amount of from 0.001 wt% to 80 wt%, such as from 1 wt% to 50 wt%.

[0195] Compositions

[0196] The compounds of the invention may be included in a pharmaceutical or cosmetic composition that comprises a pharmaceutically or cosmetically acceptable carrier and / or diluent.

[0197] The compounds of the invention may be included in a composition comprising a carrier and / or diluent, wherein the carrier and / or diluent are not tetrahydrofuran or triethylamine. Such compositions may be a detergent composition, a disinfectant composition, a food and / or drink preservative, and / or a building material.

[0198] Building materials may be selected from the list consisting of concrete, caulk, wall paper, varnish and paint, especially from varnish and paint. Paints typically include pigment (e.g. titania, zinc oxide, kaolin, carbon black, zinc chromate, yellow dyes, benzidine yellows, chrome oxide green, phthalocyanine green, phthalocyanine blue, ultramarine blue (lapis lazuri), vermilion (mercuric sulfide), iron(III) oxide, iron(II) oxide, Red 170 and / or dioxazine violet), polymer / resin (e.g. polyvinyl pyrrolidone, vinyl pyrrolidone, acrylic, alkyd, epoxy, urethane, polycarbonate, polypropylene, urea, formaldehyde, melamine, phenolic, polyester, polysiloxane and / or moisture cured urethane, and / or vinyl acetate resin), dispersant / solvent (e.g. mineral turpentine spirits, xylene, toluene, C1-C6 alcohols, linseed oil, and / or water), and / or additive(s) (e.g. silica, talc, BaSC , aluminum silicate, and / or calcium carbonate, drying agent, plasticiser, fungicide, other biocide, insecticide, flow control agent, defoamer, emulsifier, UV stabilizer, anti-skinning agent, adhesion promoter, corrosion inhibitor and / or texturizer). Compositions may comprise any of the following components individually or in combination: water surfactant (e.g. a quaternary ammonium salt, such as cetrimonium chloride, Sodium Laureth Sulfate, Sodium Lauryl Sulfate, sodium lauroyl sarcosinate, sodium methyl cocoyl taurate, PEG-8 Distearate, Cocamidopropyl Betaine, Cocamide MEA, Glyceryl Stearate, and / or Stearic Acid), pigment (e.g. titania, zinc oxide, kaolin, carbon black, zinc chromate, yellow dyes, benzidine yellows, chrome oxide green, phthalocyanine green, phthalocyanine blue, ultramarine blue (lapis lazuli), vermilion (mercuric sulfide), iron(III) oxide, iron(II) oxide, Red 170 and / or dioxazine violet), colourant (e.g. mica, methicone, and / or bismuth oxychloride), binder / polymer (e.g. polyvinyl pyrrolidone, vinyl pyrrolidone, acrylic, alkyd, epoxy, urethane, polycarbonate, polypropylene, urea, formaldehyde, melamine, phenolic, polyester, polysiloxane and / or moisture cured urethane, and / or vinyl acetate resin), oil (e.g. hydrogenated castor oil, stearyl alcohol, castor oil, mineral oil, a vegetable oil, and / or cyclomethicone), preservative, solidifier (e.g. octyl palmitate, carnauba wax, ceresin, and / or microcrystalline wax), fragrance, emollient (e.g. coconut oil, a cetyl ester, and / or a silicone), bleach (e.g. hydrogen peroxide, and / or urea hydrogen peroxide), filler (e.g. talc, mica, sericite, and / or bismuth oxychloride), occlusive agent (e.g. petrolatum, mineral oil, and / or dimethicone), thickening agent (e.g. tragacanth gum, cellulose gums, and / or Carrageenan, and / or xanthan gum), humectant (e.g. glycerol, sorbitol, and / or xylitol), dihydroxyacetone (fake tanning agents), siloxane, and / or aluminum zirconium tetrachlorohydrex Gly (antiperspirants).

[0199] The composition may be a liquid, an emulsion, a slurry or a paste. The compound of Formula I may be incorporated into a composition comprising a carrier and / or diluent and used as a disinfectant composition / surface cleaner. Surface cleaners may include surfactants, which may be cationic, anionic, amphoteric, or nonionic. The surface cleaner may be formulated as a spray.

[0200] Non-ionic surfactants include C 10E6 and / or C 12E6, sophorolipids and / or rhamnolipids, surfactin, lauric acid), and / or polyoxyethylene lauryl ether (POLE), Ag-98 (80% octyl phenoxy-polyethoxyethanol), Alkylethoxylate, Alkylphenolethoxylates, Amine oxides, Bnj series e.g. Brij 58 (Polyoxyethylene-23-lauryl ether), Linear alkyl ethoxylates, Lissapol NX, Nonyl phenyl ethylene oxide, Octa(ethylene glycol)-mono-dodecylether (C12Ea), Octyl glucoside, Pluronic F68 (polyoxyethylene-polyoxypropylene block copolymer), Polyethylene esters of fatty acids, Polyethylene glycols, Polyethylene mercaptans, Polyoxyethylated 1 -dodecanol, Polyoxyethylene n-alkyl ester, Polyoxyethylene n-monosterate, Substituted alcohols, Tergitols, Tributyl phenyl ethylene oxide, Triton X-100 (polyoxyethylene glycol octyl phenol), Triton X 305 (polyoxyethylene glycol octyl phenol), Tween series e.g. Tween 80 (polyoxyethylene sorbitol esters). Amphoteric surfactants include dodicin, amine oxides and / or betaines. Cationic surfactants include quaternary ammonium compounds (e.g. alkyldimethylbenzylammonium chloride (ADBAC), alkyldimethylethyl benzylammonium chloride (ADEBAC), and didecylammonium chloride (DDAC)). Anionic surfactants include Aerosol OT (dioctyl sodium sulfosuccinate), Aerosol OS (Alkyl Naphthalene Sulfonate), P-D-glucopyranosyl-1 -alkyl phosphate, Dreft (alkyl sulfate), Sodium cholate, Sodium dodecyl sulfate, Sulfonated oils, Sodium 2- lauroyloxypropionatef Sodium alkyl sulfates, and Triton No. 720 (di-isobutyl phenyl diglycol ether sulfonate), linear alkylbenzene sulfonate (LAS), sodium dodecyl benzene sulfonate (SDBS), sodium lauryl sulfate (SLS).

[0201] The composition may include the compound in an amount of 0.001 wt% or more, such as 0.01 wt% or more, or 0.1 wt% or more, such as 1 wt% or more, or 5 wt% or more. For example, the composition may include the compound in an amount of 80 wt% or less, such as 50 wt% or less, or 20 wt% or less. The composition may include the compound in an amount of from 0.001 wt% to 80 wt%, such as from 1 wt% to 50 wt%.

[0202] The composition may include other components in an amount of 99.999 wt% or less, such as 99.99 wt% or less, or 99 wt% or less, such as 95 wt% or less. The composition may include the other components in an amount of 20 wt% or more, such as 50 wt% or more, or 80 wt% or more, such as 90 wt% or more. The composition may include other components in an amount of from 20 to 99.999 wt%, or from 90 to 99.99 wt%.

[0203] Applications as a medicament

[0204] The compounds of Formula I have been found to be effective at reducing the amount of microorganisms (e.g. bacteria, fungi and / or viruses, especially bacteria). The compounds, or compositions thereof, may be used to treat a microbial infection (especially a bacterial infection). The bacterial infection may be an infection by a bacteria of a genus selected from the list consisting of: Moraxella, Escherichia Staphylococcus and Klebsiella. The bacterial infection may be an infection by bacteria of a species selected from the list consisting of: Moraxella catarrhalis, Escherichia coli, Staphylococcus aureus and Klebsiella Pneumoniae . The bacteria causing the infection may be gram -positive or gram -negative.

[0205] The bacterial infection may be an infection of the throat, lung, skin, ear, gastrointestinal tract, heart, brain, blood or urethra. The infection may be chronic obstructive pulmonary disease (COPD, such as chronic bronchitis, mastitis, emphysema, and refractory asthma), conjunctivitis, meningitis, bronchitis, sinusitis, bronchitis, pneumonia, food poisoning, (acute) otitis media, bacterial rhinosinusitis, a urinary tract infection, cellulitis, impetigo, pneumococcal disease or bacterial vaginosis.

[0206] E. coli is known to cause gastrointestinal infections and urinary tract infections. M. catarrhalis can cause otitis media (especially in children and / or acute exacerbations thereof), COPD (especially acute exacerbations thereof), meningitis, conjunctivitis, sinusitis and (acute) bacterial rhinosinusitis. Staphylococcus can cause mastitis, endocarditis, skin infections, food poisoning, osteomyelitis, pneumonia, septicemia. Klebsiella can cause different types of healthcare-associated infections such as pneumonia, bloodstream infections, wound or surgical site infections, and meningitis.

[0207] In one embodiment the pharmaceutical composition (e.g. formulation) comprises at least one active compound of the invention together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well-known to those skilled in the art and optionally other therapeutic or prophylactic agents. To prepare the pharmaceutical compositions of this invention, an effective amount of a compound of the present invention, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.

[0208] These pharmaceutical compositions may be suitable for administration topically, orally; rectally, for example, by enema, suppository or catheter; or nasally, for example, endoscopically through a nasogastric or nasoduodenal tube.

[0209] For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.

[0210] It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient, calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.

[0211] The compound of the invention is to be administered in an amount sufficient to exert its antimicrobial, in particular, antibiotic activity.

[0212] The compounds according to the invention may be administered to a human or to an animal, which may be a mammal, e.g. it may be a farm animal or an animal kept as a pet, such as a dog, cat or horse. The present invention further relates to the use of a compound according to the invention in the manufacture of a pharmaceutical composition. The pharmaceutical composition may, for example, be for use an antimicrobial, in particular an antibiotic, i.e. for inhibiting the growth of bacteria.

[0213] Non-therapeutic uses and methods

[0214] The compounds of the present invention may find non-therapeutic uses as antimicrobial agents, for example in the treatment of a watercourse.

[0215] The third aspect the present invention provides a non-therapeutic use of compound of Formula I, or a composition thereof, as an antimicrobial (e.g. antibacterial and / or antibiotic) agent. The fourth aspect the present invention provides a non-therapeutic method of treatment comprising contacting an article, water (e.g. a body of water, such as a lake, and / or a watercourse, such as a river or a stream), soil (e.g. part or all of a field) and / or rock with a compound of Formula I or a composition thereof.

[0216] The article may be as defined in the section above. Therefore, the compound or a composition comprising the compound may be used as a surface cleanser.

[0217] The compound of Formula I may be used to treat a portion of the lithosphere (rock), the hydrosphere (water) and / or the pedosphere (soil). The portion may be treated with an amount of the compound that is 0.001 wt% or more, such as 0.01 wt% or more, or 0.1 wt% or more, such as 1 wt% or more, or 5 wt% or more relative to the weight of the portion without the compound. For example, the portion may be treated with an amount of the compound that is 80 wt% or less, such as 50 wt% or less, or 20 wt% or less relative to the weight of the portion without the compound. The portion may be treated with an amount of the compound that is from 0.001 wt% to 80 wt%, such as from 1 wt% to 50 wt% relative to the weight of the portion without the compound.

[0218] Examples

[0219] Synthesis

[0220] Figure 5 of the accompanying drawings illustrates a synthetic route to prepare modified amino acids (MAAs) of the invention. An example of the synthetic route is described in Baker, B.C. et al., European Polymer Journal 162 (2022) 110889 (especially Scheme 1 and “Section 3. Synthesis and characterisation data” on page 2).

[0221] To prepare “monomeric” compounds, such as those shown by Figure 2, the methyl ester of an amino acid (e.g. alanine, valine, phenylalanine, or L- or D-tyrosine) was reacted with a molar equivalent of an isocyanate (or isothiocyanate) in the presence of triethylamine (5 mL) in tetrahydrofuran (30 mL) at 25 °C to provide the corresponding urea derivative, which was isolated by filtration (45 pm) and removal of the solvent in vacuo.

[0222] These compounds can be hydrolysed by adding NaOH(aq) (5 mL, 2M) and then precipitated by the addition of HC1 to provide the corresponding carboxylic acid derivatives of the compounds. The carboxylic acid derivatives may have an increased aqueous solubility compared to the corresponding methyl ester derivatives.

[0223] “Dimeric” compounds, such as those shown by Figure 3, were prepared by reacting two molar equivalents of the methyl ester of L- or D-tyrosine with one molar equivalent of a diisocyanate in THF (30 mL) at 25 °C to provide the corresponding urea derivative, which was isolated by removal of the solvent in vacuo.

[0224] Figures 2 to 4 show a range of MAAs 1-5 and 7-17 that have been synthesised by the route shown in Figure 5. Compounds 101-118 and 201-248 (structures detailed in tables below) were synthesised according to similar procedures. Some compounds are represented under two or more of the series 1-5 and 7-17, 101-118 and 201-248.

[0225] Antimicrobial testing - methyl ester derivatives

[0226] The methyl esters of the MAA compounds shown in Figures 2 and 3 (where R=Me) were tested against four diverse bacterial strains (Moraxella catarrhalis [MX, gram negative], Escherichia coli [gram negative and penicillin resistant], Staphylococcus aureus [SA, gram positive] and Klebsiella Pneumoniae [KP, gram negative]). The testing protocol (modified from the ISO 22196 testing procedure) involved the addition of each sample (ca. 4 mg) to a separate bacterial suspension in PBS (2 mL, ODeoo count 0. 1-0.2) and incubating them for 24 hours at 37 °C. The mixtures were then plated onto HBHI growth media and colony forming units (CFUs) counted (average of 5 runs reported) after a further 24 hours of incubation at 37 °C. In all cases the control 1 represents the plated bacteria solution with no added MAA and control 2 represents the plated bacteria solution immediately after the MAA starting material is added [ca. 4 mg] for same procedure.

[0227] Figure 6 of the accompanying drawings shows the colony forming units (per 50 pL of plated solution) for each the bacterial strains E. coli, KP, MX and SA observed via plate count method after 24 hrs of incubation with respective MAAs 1-5 and 7-12 (where R = Me); where no bar is given no colonies were observed.

[0228] All compounds significantly reduced the amount of E. coli, KP and SA compared to the control samples.

[0229] No remaining E. Coli was observed in the presence of compounds 3, 7 and 10. Compounds 1, 2, 4, 5, 8, and 9, 11 and 12 almost completely reduced the amount of E. Coli.

[0230] Compounds 3-5 and 10 almost completely reduced the amount of KP. Compounds 1, 2, 7, 9, 11 and 12 were also particularly effective against KP. Compound 8 was also effective at reducing the amount of KP compared to the control samples.

[0231] Compounds 2, 4, and 7-12 were effective at reducing the amount of MX compared to the control. Particularly good results in relation to MX were observed for compounds 2 and 8-12.

[0232] For SA, no colonies were observed in the presence of compound 7. Compounds 2, 3 and 10 were also particularly effective against SA. All compounds reduced the number of SA colonies compared to either control sample.

[0233] Compounds 2, 4, 9 and 10 were found to be the most effective compounds against the bacteria. In comparison to penicillin they show equivalent exclusion zones when subjected to MX lawns.

[0234] Compounds 13, 14, 16 and 17 were also tested against SA using substantially the same method. Compounds 13 and 17 was partially effective against SA. Compounds 14 and 16 were completely effective against SA. Compounds 14 and 15 were also tested against E. Colt using substantially the same method. Compound 14 was partially effective against E. Coli, and compound 15 was completely effective against E. Coli.

[0235] Therefore, the compounds of Formula I where R1is a hydrocarbon group such as Me are effective antibacterial agents.

[0236] Furthermore, these tests show that a wide variety of functionality provides effective antibacterial effects. For instance, at least urea or thiourea groups are tolerated as the linker. The R3group has been shown to be effective with at least alkyl or aryl groups that are substituted or unsubstituted. The R2group has been shown to be effective with at least substituted or unsubstituted alkyl or aryl groups.

[0237] Antimicrobial testing - carboxylic acid derivatives

[0238] Hydrolysed compounds (where R = H):

[0239] The carboxylic acid derivatives of the MAA compounds (1-H to 5-H and 7-H to 12-H) shown in Figures 2 and 3 (where R=H) have been tested against E. coli using the same protocol outlined above to determine their antibiotic performance.

[0240] Figure 7 of the accompanying drawings shows the colony forming units (per 50 pL of plated solution) of E. coli observed via plate count method after 24 hrs of incubation with respective MAAs 1H-5H and 7H-12H on HBHI plates at 37 °C for 24 hrs. Where no bar is given colonies were not observed.

[0241] It can be seen that no E. coli colonies were observed with compounds 2-H to 7-H, 10-H or 12-H. Only traces of E. coli were observed with compounds 1-H, 8-H and 9-H. All compounds were more effective than the control sample at reducing the number of E. coli colonies.

[0242] Therefore, the compounds of Formula I where R1is H are effective antibacterial agents.

[0243] Antimicrobial testing - enantiomers

[0244] The L- and D- enantiomers of compound 3 as shown in Figures 2 and 3 (where R=Me) were tested against Staphylococcus aureus [SA, gram positive] as outlined above. Figure 8 of the accompanying drawings shows the colony forming units (per 50 pL of plated solution) observed via plate count method after 24 hrs of incubation with each enantiomer of compound 3.

[0245] It can be seen that the number of SA colonies observed in the presence of each enantiomer is similar to one another, and significantly lower than the number observed in the control.

[0246] Therefore, the enantiomer of a compound that is chosen appears to have limited effect on the antimicrobial activity of the compound.

[0247] Human cell compatibility

[0248] The cytotoxicity of compounds 1-5 and 7-12 and a control (no compound) against Caco- 2 human cells was determined using the alamarBlue assay procedure. Each compound was dispersed in PBS at 2 mg / mL. To a 96 microwell plate Caco-2 human cells were grown (24 hrs). Each compound (at 2 mg / mL) was then added to a well containing the cells and the cells were grown for a further 24 hrs. The PBS and compounds were then removed, AlamarBlue was added, and the cells were incubated for a further 2 hrs. Fluorescence was monitored to determine the level of cell survival.

[0249] Figure 9 of the accompanying drawings shows the results of this cytotoxicity investigation.

[0250] It was found that none of the compounds 1-5 and 7-12 showed significant levels of cytotoxicity compared to the control.

[0251] Therefore, all compounds tested were found to be substantially compatible with human cells.

[0252] Antibacterial data for compounds 101-118

[0253] Compounds 101-118 were subjected to antibacterial investigations against Staphylococcus aureus (SA), and Escherichia coli (EC). The functional groups of compounds 101-118 are tabulated below.

[0254] In each case, X represents O.

[0255] A small suspension of bacterial species was taken from the frozen bacteria (-80 °C) using a cell lifter. This was suspended in a vial consisting of 1 mL of Dulbecco’s phosphate buffered saline (DPBS). The optical density of bacteria was measured at 600 nm and for each different bacteria to give 102CFUs for SA and 104CFUs for EC (optimal colony counting conditions). After this a stock solution of each compound in DBPS (4 mg / mL) was added to the bacterial solution and kept in contact with the bacteria for 4 hours in the incubator at 37 °C. After, 4 hours of incubation, 20 pL aliquot was plated on the prepared HBHI agar plate using the cell spreader. The plates were then kept inside the incubator for the bacterial colonies to grow over 24 hrs. Bacterial colonies were counted to quantify the effectiveness of the materials.

[0256] Figure 10 of the accompanying drawings shows the results of the investigation into the antibacterial activity of compounds 101-118, presenting a graph of the percentage of living cells remaining in each test relative to control. It was found that all tyrosine derivatives demonstrated antibacterial properties against SA and / or EC.

[0257] Compounds 103, 106 and 108 gave the best results. In these compounds, R2represents an aromatic group (phenyl) with an electron withdrawing group (in these examples nitro or chloro), in the para or meta position.

[0258] Compounds where XR1=OMe displayed high activity (e.g. compounds 103, 104, 105, 106, 107, 108, 109 and 117, as did compounds where L=urea (i.e. -NHCONH-, e.g. compounds 103, 104, 105, 106, 107, 108, 109, 117 and 118).

[0259] Compound 117, where R3=Me, also displayed high antibacterial activity.

[0260] A variant of compound 103 where the ester had been hydrolysed to form the carboxylic acid (XR1=OH, compound 118), also showed effectiveness. This compound was water soluble and able to form a gel.

[0261] Variants of compound 103 where XR1was O-tert-butyl (compound 110), where R2was an aryl group with a nitro group in the ortho position (compound 111) or where L was an amide (compound 115) displayed diminished antimicrobial effectiveness. The same was seen for the derivatives of compound 109, namely compound 112: R1= tert-butyl; and compound 114: L = amide. However, these compounds were still effective to some extent. Compounds where L represented a thiourea (compound 113) showed lower antibacterial effects.

[0262] Cytotoxicity data for compounds 101-118

[0263] To test for toxicity, an alamarBlue™ test was conducted. The test for performed on a CaCo-2 cells. The frozen cell line (ImL vial) was pipetted out, 50 pL at once, in 20 m media consisting of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10 % fetal bovine serum (FBS)66 and 1% penicillin / streptomycin (P / S). After thawing the cells in the media, they were transferred to T 75 cell culture flask (CCF). It was then then kept in the incubator for 4-5 days for cell growth with the lid of CCF loosely closed to allow respiration. The cells were first rinsed with 15 mb of PBS and then 3 mb of trypsin was added and allowed to cleave the cells in the flask for 10-15 minutes at 37 °C. The cells were then centrifuged at 1500 rpm for 5 mins in a 50 mb falcon tube. The cells settled at the bottom of the flask and the media (supernatant) was discarded. These cells were then dispersed in 1 mL of media and pipetted out in another T 75 CCF. 14 mL of media was added into it to make the total volume 15 mL, a 96-well plate was taken and 7.75 pL of cells / media were pipetted into each well. Next, 100 pL media (15 mg / mL) was added in the wells and kept for overnight incubation. The media was pipetted out next day and compounds 101-118 dispersed in 200 pL media were added to the wells. After 24 hours of incubation, the media was taken out and 100 pL of alamarBlue™ solution (220 pL alarmarBlue™ in 2.2 mL of media) was added. The 96- well plate was then wrapped in an aluminum foil to prevent exposure from light and kept for incubation for 2 hours. Then the solution part consisting of alamarBlue™ solutions were transferred into a fresh 96-well plate and readings were taken using a multimode plate reader.

[0264] The results of this study are shown in Figure 11 of the accompanying drawings. Each of compounds 101-118 demonstrated significant biocompatibility.

[0265] Antibacterial and cytotoxicity data for compounds 201-248

[0266] Following the procedure described above for compounds 101-118, the antibacterial activity of compounds 201-248 was determined. Compounds 201-248 are described in the table below:

[0267] In each case, X represents O. * represents bond to the proximal nitrogen of the urea group to form a five-membered ring, as in proline.

[0268] Initial antibacterial investigations involved tyrosine derivatives 201-209 against four bacterial strains. The antibacterial properties of the samples were targeted against Staphylococcus aureus (SA), Klebsiella pneumoniae (KP), Moraxhella catarrhalis (M. catarrhalis) and Escherichia coli (E.Coli). Firstly, a small suspension of bacterial species was taken from the frozen bacteria (- 80 °C) using a cell lifter. This was suspended in a vial consisting of 1 mb of Dulbecco’s phosphate buffered saline (DPBS). The optical density (OD) of bacteria was measured at 600 nm and for each different bacteria, different values were optimized after several attempts. It was optimized that the bacterial suspension with OD600 nm ~ 0.05 diluted 102for SA and 104for Mx, E.Coli and K.P. After this the 201-209 stock solution, CMPs dispersed in DBPS (4 mg / mb), was added to the bacterial solution and kept in contact with the bacteria for 4 hours in the incubator at 37°C. After, 4 hours of incubation, 20 pL aliquot was plated on the prepared HBHI agar plate using the cell spreader. The plates were then kept inside the incubator for the bacterial colonies to grow over 24 Hrs. Bacterial colonies were counted to quantify the effectiveness of the materials.

[0269] The results are shown by Figure 12a of the accompanying drawings. Specifically, Figure 12a shows the antibacterial activity of preliminary study tyrosine-based MAAs against E.coli, Klebsiella Pneumonia, Moraxella Catarlis and Staphylococcus aureus where the MAAs were at 4mg / mL in PBS, incubated at 37 °C for 24 hrs then plated onto appropriate media and incubated for further 24 hrs at 37 °C before colony forming units were counted. It was found that, whilst all tyrosine derivatives demonstrated antibacterial properties, compounds 202,203 and 206 displayed the most versatility.

[0270] To test for the effects of potential solubility in PBS the compounds were held at 60 °C for 1 week, filtered and the solvent PBS checked for antimicrobial activity. The results are shown by Figure 12b of the accompanying drawings. Specifically, Figure 12b shows the results of leach testing. Limited activity was demonstrated, but the feasibility of solvating the compounds was demonstrated.

[0271] To test for toxicity, an AlamarBlue test was conducted. The test for performed on a CaCo-2 cells. The frozen cell line (ImL vial) was pipetted out, 50 pL at once, in 20 mL media consisting of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10 % fetal bovine serum (FBS)66 and 1% penicillin / streptomycin (P / S) . After thawing the cells in the media, they were transferred to T 75 cell culture flask (CCF). It was then then kept in the incubator for 4-5 days for cell growth with the lid of CCF loosely closed to allow respiration. The cells were first rinsed with 15mL of PBS and then 3mL of trypsin was added and allowed to cleave the cells in the flask for 10-15 minutes at 37°C. The cells were then centrifuged at 1500 rpm for 5 mins in a 50 mL falcon tube. The cells settled at the bottom of the flask and the media (supernatant) was discarded. These cells were then dispersed in ImL of media and pipetted out in another T 75 CCF. 14 mL of media was added into it to make the total volume 15 mL, a 96-well plate was taken and 7.75 pL of cells / media were pipetted into each well. Next, 100 pL media (15 mg / mL) was added in the wells and kept for overnight incubation. The media was pipetted out next day and 1-9 dispersed in 200 pL media was added in the well. After 24 hours of incubation, the media was taken out and 100 pL of AlamarBlue solution (220 pL alarm blue in 2.2 mL of media) was added. The 96-well plate was then wrapped in an aluminum foil to prevent exposure from light and kept for incubation for 2 hours. Then the solution part consisting of AlamarBlue solutions were transferred into a fresh 96-well plate and readings were taken using a multimode plate reader.

[0272] Figure 12c of the accompanying drawings shows the results of this study. Specifically, Figure 12c shows the non-cytotoxicity of the compounds against Caco-2 human cells (72hr) using an AlamarBlue assay procedure. In each case (a-c) error bars calculated as mean error from 5 runs Each compound demonstrated over 80% biocompatibility.

[0273] In order to expand the range of compounds tested a similar biocompatibility screening on compounds 201-248 was performed. All compounds displayed over 75% biocompatibility. Compound 211 exhibited the lowest biocompatibility (77%). Compound 211 is the only compound having a liquid, rather than a solid, form. The majority of compounds 201-248 were run against both SA and EC using the same conditions as described above in this section.

[0274] Compounds 202-210, 212-217, 219-221, 224-231, 233-236, 239, 241, and 243-248 displayed good antimicrobial effects, with 50% or less of at least one of the bacteria remaining after the test period.

[0275] Compounds 202-209, 214, 217, 219-221, 225, 230, 233, 234, 244 and 247 showed excellent antimicrobial effects, with 20% or less of at least one of the bacteria remaining after the test period.

[0276] Compounds 203-206, 208-209, 220, 225-229 and 247 displayed particularly excellent antimicrobial effects, with 20% or less of each bacteria remaining after the test period.

[0277] Figure 13 of the accompanying drawings shows the results of this study. Specifically, Figure 13 shows the antibacterial activity of most MAAs 201-248 against E. coll and Staphylococcus aureus where the MAAs were at 4mg / mL in PBS, incubated at 37 °C for 24 hrs then plated onto appropriate media and incubated for further 24 hrs at 37 °C before colony forming units counted.

[0278] It was noted that the amide bond of compounds 214, 215 and 218 significantly reduced the parent urea derivatives effectiveness against the two pathogens.

[0279] To investigate the efficacy of the compounds against higher concentrations of pathogens and in glass formation the three most effective compounds 203, 206 (tyrosine-based) and 228 (alanine-based) were cast on glass slides (16mg / mL equivalent) and put into higher concentrations of EC and SA (at 108 and 107 CFU / mL respectively) and the CFU counts were monitored over 24 hrs.

[0280] The results of this study are shown by Figure 14 of the accompanying drawings. It was found that all showed significant decrease in the CFUs for each compound and both bacteria over the 24 hrs. No bacteria were observed in the presence of any of the three compounds after 24 hrs. The effectiveness of compound 203 against WHO critical listed pathogens was determined, specifically in relation to various MRS A and VRSA pathogens. The bacterial strains tested were SH1000, Newman, MRSA252, TW20, E-MRSA15, JDK6159, Mu3, Mu50, SH1000-128, and LAC-128.

[0281] Figure 15 of the accompanying drawings shows the bacterial survival of colonies after exposure to control (initial, Oh), control ( 18h exposed to no compound of the invention) and invention (exposed to compound 203 for 18h). In each case, a significant increase in bacterial survival was observed between the initial control and the control exposed to no compound for 18h. However, exposure to compound 203 for 18h either maintained (no significant difference) or decreased the bacterial survival of these troublesome strains. Certainly, the rate of growth of each of the strains was attenuated.

[0282] It was also found that a glass film of compound 203 cast on slides was effective, showing a significant decrease in bacterial colony count, against the LAC-128 strain compared to controls of the bacteria alone and the bacteria on the slide without compound 203.

Claims

CLAIMS1. An article comprising a compound of Formula I:Formula I, wherein:R1represents H or a Cl -Cl 2 hydrocarbon group that is optionally substituted or a water solubilising functional group;R2represents a Cl or more hydrocarbon group that is optionally substituted;R3represents H or a Cl-12 hydrocarbon group that is optionally substituted;X represents O, NH, S or PH; andL represents a linker group, and wherein the article comprises: a) an underlying substrate and a surface layer, and the surface layer comprises the compound; and / or b) the compound dispersed in a binder.

2. The article of claim 1, wherein the article is selected from the list consisting of healthcare apparatus, medical device, display apparatus, imaging apparatus, packaging, agricultural equipment, air treatment and / or handling, water treatment and / or handling, and food and / or drink preparation.

3. The article of claim 2, wherein the article is as a medical device, packaging, a touch screen, a lens, a visor, or an article of healthcare equipment.

4. A composition comprising a compound of Formula I and a carrier and / or diluent, wherein the carrier and / or diluent is pharmaceutically or cosmetically acceptable, and / or wherein the carrier and / or diluent is not tetrahydrofuran or triethylamine.

5. The composition of claim 4, wherein the composition is selected from the list consisting of: a detergent composition, a disinfectant composition, a food and / or drink preservative, and a building material.

6. The composition of claim 4 or claim 5, wherein the composition further comprises water, a surfactant, a pigment, a colourant, a binder / polymer, an oil, a preservative, a solidifier, a fragrance, an emollient, a bleach, a filler, an occlusive agent, a thickening agent, a humectant, dihydroxy acetone, a siloxane, and / or aluminum zirconium tetrachlorohydrex Gly.

7. A non-therapeutic use of compound of Formula I, or a composition thereof, as an antimicrobial agent.

8. A non-therapeutic method comprising contacting an article, water, soil and / or rock with a compound of Formula I or a composition thereof.

9. A compound of Formula I for use in the prevention or treatment of a microbial infection.

10. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding claim, wherein R2represents a C 1-C50 alkyl and / or aryl group that is optionally substituted.1 1. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of claim 10, wherein R2represents a Cl -C l 2 hydrocarbon group that is optionally substituted.

12. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding claim, wherein R2is optionally substituted by one or more group selected from the list consisting of -NO2, -O-, halide (e.g. -F, -Cl and - Br), -CN, -OH, CO2H, CO2R1, and -N(H)C(O)N(H)-.

13. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding claim, wherein R3represents a Cl-12 alkyl and / or aryl group that is optionally substituted.

14. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding claim, wherein R3is optionally substituted by one to four groups selected from the list consisting of -OH, -NH2, -CO2H, -CONH2, and - B(OH)2.

15. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding claim, wherein X represents O or NH.

16. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding claim, wherein R1represents H or an unsubstituted C 1-C4 hydrocarbon group.

17. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding claim, wherein L comprises or represents one or more groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea.

18. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any one of claims 1 to 9 or 12 to 17, wherein Formula I is represented by Formula III:Formula III, wherein: each of R1, R3, X and L is independently as defined for Formula I,R4and R5each independently represent a C1-C 12 hydrocarbon group that is optionally substituted, and n is 1 or more.

19. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding claim, wherein:R1represents a H or a C1-C8 hydrocarbon group that is optionally substituted;R2represents a C1-C50 hydrocarbon group that is optionally substituted;R3represents H or a Cl-12 aryl and / or alkyl group that is optionally substituted; any substituents are selected from the list consisting of thioether, hydroxide, ether, nitro, nitrile and halide;X represents O, NH or S; andL comprises or represents one or more groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea.

20. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of claim 19, wherein:R1represents H or an unsubstituted C1-C2 hydrocarbon group;R2represents a C1-C42 alkyl or aryl group that is optionally substituted by one to four groups selected from the list consisting of -NO2, -O-, halide and -CN;R3represents a Cl -8 alkyl and / or aryl group that is optionally substituted by two or fewer groups selected from the list consisting of -OH and -NH2;X represents O; andL represents a thiourea group or a urea group.

21. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of claim 20, wherein:R1represents H or a methyl group;R2represents a C6-12 aryl group that is unsubstituted, or a C4-12 aryl group that is substituted in one or both of the meta positions and / or the para position by one to three groups selected from the list consisting of -NO2, halide and -CN;R3represents a C7 aryl group that is optionally substituted by an -OH group, or a Cl alkyl group;X represents O; andL represents urea.

22. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of claim 21, wherein:R1represents H or a methyl group; - R2represents an unsubstituted phenyl group, or a phenyl group that is substituted in one or both of the meta positions and / or the para position by one or more groups selected from the list consisting of -NO2 and / or Cl;R3represents -CH2PI1 that is optionally substituted by an -OH group, or methyl; X represents O; and - L represents urea.

23. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of claim 19, wherein the compound is of one of the following structures:

24. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of claim 19, wherein the compound is functionalised as defined by the following table:

25. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of claim 19, wherein the compound is functionalised as defined by the following table:

26. The article, composition, non-therapeutic use, non-therapeutic method, or compound for use of any preceding claim, wherein the compound has the following stereochemistry:

27. A compound of Formula I for use as a medicament.

28. A compound of Formula I, with the proviso that the compound of Formula I is not represented by Formula II:Formula II.

29. The compound of claim 28, wherein the compound is represented by one of the following structures:5 with the proviso that the compound of Formula I is not represented by Formula II.

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