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WO2025196442A1 - Composés antimicrobiens - Google Patents

Composés antimicrobiens

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Publication number
WO2025196442A1
WO2025196442A1 PCT/GB2025/050590 GB2025050590W WO2025196442A1 WO 2025196442 A1 WO2025196442 A1 WO 2025196442A1 GB 2025050590 W GB2025050590 W GB 2025050590W WO 2025196442 A1 WO2025196442 A1 WO 2025196442A1
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WO
WIPO (PCT)
Prior art keywords
compound
group
article
composition
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/GB2025/050590
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English (en)
Inventor
Benjamin Baker
Wayne Hayes
Darryl HILL
Matthew Hyder
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Bristol
Original Assignee
University of Bristol
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Publication date
Application filed by University of Bristol filed Critical University of Bristol
Publication of WO2025196442A1 publication Critical patent/WO2025196442A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/32—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C275/34—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by singly-bound oxygen atoms having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/30—Derivatives containing the group >N—CO—N aryl or >N—CS—N—aryl
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/26—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C335/04—Derivatives of thiourea
    • C07C335/16—Derivatives of thiourea having nitrogen atoms of thiourea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides an article comprising a compound of Formula I:
  • R 1 represents H or a Cl -Cl 2 hydrocarbon group that is optionally substituted or a water solubilising functional group (e.g. polyether);
  • R 2 represents a Cl or more hydrocarbon group that is optionally substituted;
  • R 3 represents 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.
  • compounds of Formula I have been found to be effective antimicrobial (e.g. antibacterial, antiviral and/or antifungal) agents.
  • 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.
  • 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.
  • 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.
  • the article e.g. as packaging
  • a transparent region such as a window
  • the transparent region preferably comprises a compound of the invention.
  • the compounds can provide beneficial antimicrobial effects when included in a translucent or opaque region of packaging.
  • the present invention provides a composition
  • 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.
  • 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.
  • 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.
  • 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.
  • an antimicrobial agent e.g. antibacterial and/or antibiotic
  • 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.
  • the present invention provides a compound of Formula I for use in the prevention or treatment of a microbial (e.g. bacterial) infection.
  • a microbial e.g. bacterial
  • the present invention provides a compound of Formula I for use as a medicament.
  • 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.
  • 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.
  • the present invention provides a compound of Formula I, with the proviso that the compound of Formula I is not represented by Formula II:
  • 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.
  • CN 109704996 B and CN 109704983 B describe LR 2 groups that contain carbamates, or alkyl- or acyl-functionalised amines.
  • R 1 represents H or a C l -Cl 2 hydrocarbon group that is optionally substituted or a water solubilising functional group
  • R 2 represents a C l or more hydrocarbon group that is optionally substituted
  • R 3 represents H or a Cl-12 hydrocarbon group that is optionally substituted
  • X represents O, NH, S or PH
  • L represents a linker group
  • 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.
  • 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.
  • 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.
  • a non-therapeutic method comprising contacting an article, water, soil and/or rock with a compound of Formula I or a composition thereof.
  • a compound of Formula I for use in the prevention or treatment of a microbial infection.
  • R 2 represents a C1-C50 alkyl and/or aryl group that is optionally substituted.
  • L comprises or represents one or more groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea.
  • R 1 , R 3 , X and L is independently as defined for Formula I, R 4 and R 5 each independently represent a Cl -Cl 2 hydrocarbon group that is optionally substituted, and n is 1 or more. 19.
  • R 1 represents a H or a C1-C8 hydrocarbon group that is optionally substituted
  • R 2 represents a C1-C50 hydrocarbon group that is optionally substituted
  • R 3 represents 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
  • L comprises or represents one or more groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea.
  • R 1 represents H or an unsubstituted C1-C2 hydrocarbon group
  • R 2 represents 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
  • R 3 represents 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
  • L represents a thiourea group or a urea group.
  • CX-CY where X and Y are integers refers to the number of carbon atoms in a given group.
  • a C1-C6 alkyl group contains from 1 to 6 carbon atoms
  • a C3-C6 alkyl group contains from 3 to 6 carbon atoms.
  • 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.
  • cycloalkyl refers to cyclic hydrocarbon groups. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl and the like.
  • 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.
  • 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.
  • 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.
  • aryl groups include carbocyclic aromatic groups such as phenyl, naphthyl, anthracenyl, pyrenyl, chrysenyl, benz[a]anthracenyl, fluoranthene, indenyl, and tetrahydronaphthyl groups.
  • 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).
  • 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.
  • 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.
  • substituents include those selected from the list consisting of hydroxide, ethers (e.g. alkyl ethers, such as methoxyether), nitro, nitrile and halide (especially Cl).
  • 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.
  • 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.
  • 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.
  • 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,
  • R 1 represents 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.
  • R 1 is unsubstituted.
  • 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:
  • R 6 is a Cl -10 hydrocarbon group, such as a Cl -8 hydrocarbon group or a Cl - 6 hydrocarbon group.
  • R 6 may be a C2-10 hydrocarbon group, such as a C2-8 hydrocarbon group or a C2-6 hydrocarbon group.
  • R 6 is a C2-5 hydrocarbon group, or a C2-4 hydrocarbon group, or a C2 or C3 hydrocarbon group, especially a C2 hydrocarbon group.
  • the hydrocarbon group is an alkyl or an alkenyl group. More preferably the hydrocarbon group of R 6 is an alkyl group.
  • R 6 is 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.
  • R 6 is 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.
  • the hydrocarbon group of R 1 may be an alkyl, alkenyl, aryl and/or alkynyl group that is optionally substituted.
  • the hydrocarbon group of R 1 is 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.
  • the hydrocarbon group of R 1 is an unsubstituted alkyl group, for example an unsubstituted C l-6 alkyl group.
  • 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.
  • R 1 represents H, especially in a basic environment and/or with heat. Most preferably R 1 represents H or a methyl group. As shown by the Examples, compounds where R 1 is H or a methyl group provide enhanced antibacterial activity compared to, for example, compounds where R 1 is a tert-butyl group.
  • R 1 may be controlled to modify the solubility of the compound.
  • the compound may be more soluble in water when R 1 is H.
  • R 2 may represent a C2 or more hydrocarbon group, preferably a C4 or more hydrocarbon group, or a C5 or C6 or more hydrocarbon group.
  • R 2 may 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.
  • R 2 may 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.
  • R 2 may 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.
  • R 2 may 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.
  • R 2 may 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.
  • a C2-C20 hydrocarbon group such as a C2-C12 hydrocarbon group
  • a C4-C20 hydrocarbon group such as a C4-C 12 hydrocarbon group
  • a C6-C20 hydrocarbon group for example a C6-C 12 hydrocarbon group.
  • the hydrocarbon group of R 2 may be an alkyl, alkenyl, aryl and/or alkynyl group that is optionally substituted.
  • the hydrocarbon group of R 2 is an alkyl, alkenyl and/or aryl group, most preferably an alkyl and/or an aryl group, that is optionally substituted.
  • the hydrocarbon group of R 2 is an alkyl (e.g. cycloalkyl) and/or aryl group that is optionally substituted.
  • R 2 represents a C l-50 alkyl, alkenyl and/or aryl group that is optionally substituted.
  • R 2 represents a C 1-10 or C6-42 alkyl and/or aryl group that is optionally substituted.
  • R 2 may specifically be substituted by one or more group selected from the list consisting of -NO 2 , -O-, halide (e.g. -F, -Cl and -Br), -CN, -OH, CO 2 H, COzR 1 , and -N(H)C(O)N(H)-.
  • R 2 is substituted by one or more group selected from the list consisting of -NO 2 , -O-, halide (e.g. -F, -Cl and -Br) and -CN.
  • R 2 is substituted by six or fewer groups, such as four or fewer, or three or fewer, or two or fewer groups.
  • R 2 is substituted by one or no groups.
  • R 2 may represent a C4-12 cycloalkyl group (that is optionally substituted), such as a C4-10 cycloalkyl group, or a C4-8 cycloalkyl group.
  • R 2 may 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.
  • the cycloalkyl group is not substituted.
  • the cycloalkyl group is cyclohexyl.
  • R 2 may represent a C4-12 aryl group (that is optionally substituted), such as a C4-10 aryl group, or a C4-8 aryl group.
  • R 2 may 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.
  • R 2 may comprise or represent a group selected from the list consisting of:
  • R 2 comprises 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 R 2 comprises or represents a group selected from the list consisting of 4-nitrophenyl, 3 -nitrophenyl, 3 -cyanophenyl, cyclohexyl,
  • R 2 comprises or represents a group selected from the list consisting of 3 -nitrophenyl, 3 -cyanophenyl, cyclohexyl, 3-chlorophenyl,
  • R 2 does not represent 3,4-dichlorophenyl, especially where XR 1 represents OH.
  • R 2 may comprise or represent: wherein
  • R in these structures corresponds to R 1 of Formula I, i.e. H or a C 1-C 12 hydrocarbon group that is optionally substituted.
  • R 3 represents H or a C l-12 hydrocarbon group that is optionally substituted.
  • R 3 may 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.
  • R 3 may 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.
  • R 3 may 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.
  • R 3 may 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.
  • R 3 represents a C6 aryl group, a C7 aryl group, a C4 alkyl group, a C3 alkyl group, or a Cl alkyl group.
  • R 3 represents a C6 aryl group or a C l alkyl group.
  • R 3 (especially an aryl group of R 3 ) 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.
  • R 3 may specifically be substituted by one or more group selected from the list consisting of -OH, -NH2, -CO2H, -CONH2, and -B(OH)2.
  • R 3 is substituted by one or more group selected from the list consisting of - OH and -NH2, more preferably -OH.
  • R 3 may be substituted by four or fewer groups, such as three or two or fewer groups. Most preferably R 3 is substituted by one group, for example one -OH group. Where R 3 represents an alkyl group, preferably R 3 is not substituted. R 3 may 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, -NH 2 , -CO 2 H, -CONH 2 , and -B(OH) 2 .
  • R 3 may 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, -NH 2 , -CO 2 H, -CONH 2 , and - B(OH) 2 .
  • R 3 may 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 -NH 2 .
  • R 3 may represent hydroxymethyl (i.e. -CH 2 OH), methyl or 4-hydroxyphenyl.
  • R 3 may represents methyl or 4-hydroxyphenyl.
  • R 3 preferably represents hydroxymethyl (i.e. - CH 2 OH), methyl, -CH 2 CH(CH3) 2 , -CH 2 Ph, -(CH 2 ) 2 SMe, or 4-hydroxyphenylmethyl.
  • R 3 preferably represents methyl or 4-hydroxyphenylmethyl.
  • R 3 represents a C7 aryl group that is optionally substituted by an -OH group (especially -CH 2 Ph, more preferably -CH 2 (4-hydroxyphenyl)) or a Cl alkyl group (especially methyl).
  • X represents O, NH, S or PH.
  • X represents O, NH or S. More preferably X represents O or NH. Most preferably X represents O.
  • L represents a linker group
  • 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.
  • 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.
  • 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;
  • halide e.g. fluorine, chlorine and/or bromine
  • X represents O, NH or S
  • 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.
  • R 1 represents a H or a C1-C8 hydrocarbon group that is optionally substituted or a polyether
  • R 2 represents a C1-C50 hydrocarbon group that is optionally substituted
  • R 3 represents 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);
  • ethers e.g. alkyl ethers, such as methoxyether
  • nitro, nitrile and halide especially Cl
  • X represents O, NH or S
  • L comprises or represents one or more groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea.
  • amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea In one embodiment:
  • R 1 represents H or an unsubstituted C1-C4 hydrocarbon group or a PEG group
  • R 2 represents a C4-C50 alkyl and/or aryl group that is optionally substituted by one or more group selected from the list consisting of -NO 2 , -O-, halide (e.g. - F, -Cl and -Br), -CN, -OH, CO 2 H, CO2R 1 , and -N(H)C(O)N(H)-;
  • halide e.g. - F, -Cl and -Br
  • R 3 represents a Cl -8 alkyl and/or aryl group that is optionally substituted by one to four groups selected from the list consisting of -OH, -NH 2 , -CO2H, -CONH2, and -B(OH) 2 ;
  • X represents O
  • L comprises or represents one to six groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea.
  • R 1 represents H or an unsubstituted C1-C2 hydrocarbon group
  • R 2 represents 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;
  • X represents O
  • L represents a urea group or a thiourea group.
  • R 1 represents H or a Cl -Cl 2 hydrocarbon group that is optionally substituted or a polyether
  • R 2 represents a Cl or more (e.g. C1-C24) hydrocarbon group that is optionally substituted;
  • R 3 represents 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 -NH 2 ;
  • X represents O
  • L comprises or represents one to six groups selected from the list consisting of: amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea.
  • amide, ester, carbamate, carbonate, carboxylic acid anhydride, thiourea and urea In the compound of Formula I, the following may apply:
  • R 1 represents H or a methyl group
  • R 2 represents 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;
  • R 3 represents 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;
  • X represents O
  • L represents urea
  • R 1 represents H or a methyl group
  • R 2 represents 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;
  • R 3 represents a C7 aryl group that is optionally substituted by an -OH group, or a Cl alkyl group;
  • X represents O
  • L represents urea
  • R 1 represents H or a methyl group
  • R 2 represents 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 CO2R 1 ;
  • R 3 represents -CH2PI1 that is optionally substituted by an -OH group, or methyl;
  • X represents O
  • L represents urea
  • R 3 represents a group such as -CH2(4-hydroxyphenyl) and L represents urea
  • R 2 represents 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 R 2 represents butyl, 3 -nitro-phenyl, 3 -cyanophenyl, cyclohexyl, 3 -chloro-phenyl, 3 -methoxy-phenyl or phenyl.
  • R 3 represents a group such as -CH3 and L represents urea
  • R 2 represents 3-chloro-phenyl, 4-chloro-phenyl, 4-nitro-phenyl, phenyl or cyclohexyl.
  • R 3 represents a group such as -CH2PI1 and L represents urea, preferably R 2 represents phenyl.
  • R 3 represents a group such as -CH2CH(CH3)2 and L represents urea, preferably R 2 represents 4-methoxy-phenyl or 4-chloro-phenyl.
  • R 3 represents a group such as -(CH2)2SMe and L represents urea, preferably R 2 represents 4-chlorophenyl or phenyl; more preferably phenyl.
  • R 1 represents H or a methyl group
  • R 2 represents 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);
  • R 3 represents -CH2PI1 that is optionally substituted by an -OH group, or methyl;
  • X represents O; and L represents urea.
  • R 1 represents H or a Cl -Cl 2 hydrocarbon group that is optionally substituted or a PEG group
  • R 2 represents a C1-C12 (e.g. C1-C8) hydrocarbon group that is optionally substituted;
  • R 3 represents 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;
  • X represents O
  • 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:
  • each R 1 independently represents H or a C1-C12 hydrocarbon group that is optionally substituted.
  • each R 1 represents H or methyl.
  • the compound of Formula I may represent one of the compounds in the following table:
  • the present invention relates in part to compounds 101, 103-108, 110-112, and 117 per se.
  • compounds 101, 103-108, 110-112, and 117 per se.
  • particular antibacterial benefits have been realised in relation to compounds 103-108 and 117.
  • 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.
  • the compound of Formula I may be represented by Formula III:
  • each R 1 , R 3 , X and L is independently as defined for Formula I, and wherein R 4 and R 5 each 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.
  • R 4 and R 5 may 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.
  • R 4 and R 5 may each independently be a C2-C12 hydrocarbon group, such as a C3-C12 hydrocarbon group, or a C4-C12 hydrocarbon group.
  • R 4 and R 5 may each independently optionally be substituted with four or fewer, such as two or one, substituents.
  • R 4 and R 5 are unsubstituted.
  • R 4 and R 5 are each independently a Cl -Cl 2 alkyl, alkenyl or aryl group that is optionally substituted. More preferably R 4 is a C1-C8 alkyl or aryl group (e.g. a C2- C6 alkyl or aryl group) and R 5 is 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 R 1 independently represents H or a C1-C12 hydrocarbon group that is optionally substituted.
  • 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 R 1 , or a compound as shown in Figure 4 of the accompanying drawings.
  • the compound of Formula I has the following stereochemistry:
  • the compound of Formula III has the following stereochemistry:
  • 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).
  • a binder e.g. a polymer
  • 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.
  • 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.
  • a binder e.g. a structural material
  • the plastics material may, for example, be silicone (e.g. silicone rubber) and/or polyurethane.
  • 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.
  • 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.
  • 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.
  • the article e.g. as packaging
  • a transparent region such as a window
  • the transparent region preferably comprises a compound of the invention.
  • the compounds can provide beneficial antimicrobial effects when included in a translucent or opaque region of packaging.
  • 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.
  • a medical device such as a surgical instrument, or an implant or prosthesis, or a medical machine or component thereof.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention allows the prevention of medical device-associated bacterial infections by providing the compound.
  • the compound of the present invention offers the possibility to effectively reduce catheter-related bacterial infections.
  • 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.
  • food preparation surfaces such as kitchen counters, cutting boards, sinks, stoves, refrigerator surfaces
  • bathroom surfaces such as toilets, sinks, bathtubs, showers, and drains.
  • Other suitable treatable surfaces are floor surfaces, door surfaces and window surfaces.
  • the article is a component of process equipment, such as cooling equipment, water treatment equipment, air treatment equipment or food processing equipment.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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%.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • additive(s) e.g.
  • compositions may comprise any of the following components individually or in combination: water surfactant (e.g.
  • 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 e.g. octyl palmitate, carnauba wax, ceresin, and/or microcrystalline wax
  • fragrance emollient
  • 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 siloxane
  • aluminum zirconium tetrachlorohydrex Gly antiperspirants
  • 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.
  • 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)).
  • ADBAC alkyldimethylbenzylammonium chloride
  • ADEBAC alkyldimethylethyl benzylammonium chloride
  • DDAC didecylammonium chloride
  • 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
  • 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.
  • 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%.
  • 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%.
  • 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.
  • COPD chronic obstructive pulmonary disease
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of the invention is to be administered in an amount sufficient to exert its antimicrobial, in particular, antibiotic activity.
  • 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.
  • the compounds of the present invention may find non-therapeutic uses as antimicrobial agents, for example in the treatment of a watercourse.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • carboxylic acid derivatives 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.
  • “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.
  • 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.
  • the methyl esters of the MAA compounds shown in Figures 2 and 3 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.
  • 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.
  • 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.
  • SA Staphylococcus aureus
  • EC Escherichia coli
  • X represents O
  • 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 10 2 CFUs for SA and 10 4 CFUs 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.
  • DPBS Dulbecco’s phosphate buffered saline
  • 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.
  • R 2 represents an aromatic group (phenyl) with an electron withdrawing group (in these examples nitro or chloro), in the para or meta position.
  • an alamarBlueTM 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.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS % fetal bovine serum
  • P/S penicillin/streptomycin
  • 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.
  • X represents O.
  • * represents bond to the proximal nitrogen of the urea group to form a five-membered ring, as in proline.
  • 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.
  • Figure 12b shows the results of leach testing. Limited activity was demonstrated, but the feasibility of solvating the compounds was demonstrated.
  • 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) .
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • P/S penicillin/streptomycin
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • control initial, Oh
  • control 18h exposed to no compound of the invention
  • invention exposed to compound 203 for 18h.
  • a significant increase in bacterial survival was observed between the initial control and the control exposed to no compound for 18h.
  • exposure to compound 203 for 18h either maintained (no significant difference) or decreased the bacterial survival of these troublesome strains.
  • the rate of growth of each of the strains was attenuated.

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Abstract

L'invention concerne un article comprenant un composé de formule I : R1 représente H ou un groupe hydrocarboné en C1-C12 éventuellement substitué ou un groupe fonctionnel hydrosolubilisant ; R2 représente un groupe hydrocarboné en C1 ou plus qui est éventuellement substitué ; R3 représente H ou un groupe hydrocarboné en C1-12 qui est éventuellement substitué ; X représente O, NH, S ou PH ; et L représente un groupe de liaison, et l'article comprenant : a) un substrat sous-jacent et une couche de surface, et la couche de surface comprenant le composé ; et/ou b) le composé dispersé dans un liant.
PCT/GB2025/050590 2024-03-20 2025-03-20 Composés antimicrobiens Pending WO2025196442A1 (fr)

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WO2008113992A2 (fr) 2007-03-20 2008-09-25 Pliva Hrvatska D.O.O. Compositions de gels
WO2017023907A1 (fr) * 2015-08-05 2017-02-09 Allergan, Inc. Analogues de phénylurée en tant qu'agonistes sélectifs de récepteur de peptides n-formylés (fpr1)
WO2018167468A1 (fr) 2017-03-13 2018-09-20 NodThera Limited Composés chimiques
CN109704983B (zh) 2019-02-26 2021-06-04 安阳工学院 通过脱mom保护合成3-碘-n-保护-l-酪氨酸甲酯的方法
CN109704996B (zh) 2019-02-26 2021-06-08 安阳工学院 一种制备3-卤代-n-保护-l-酪氨酸甲酯的方法
US20210372959A1 (en) 2020-05-26 2021-12-02 University Of South Carolina Nanopore Method for Identifying Single Amino Acid in Oligopeptides
WO2022096361A1 (fr) 2020-11-03 2022-05-12 Deutsches Krebsforschungszentrum Composés imidazo[4,5-c]quinoléine et leur utilisation en tant qu'inhibiteurs de kinase atm
WO2024022910A1 (fr) 2022-07-26 2024-02-01 Syngenta Crop Protection Ag Dérivés de 1-[1-[2-(pyrimidin-4-yl)-1,2,4-triazol-3-yl]éthyl]-3-[2,4-dichloro-5-phényl]urée et composés similaires utilisés comme pesticides

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Publication number Priority date Publication date Assignee Title
WO2008113992A2 (fr) 2007-03-20 2008-09-25 Pliva Hrvatska D.O.O. Compositions de gels
WO2017023907A1 (fr) * 2015-08-05 2017-02-09 Allergan, Inc. Analogues de phénylurée en tant qu'agonistes sélectifs de récepteur de peptides n-formylés (fpr1)
WO2018167468A1 (fr) 2017-03-13 2018-09-20 NodThera Limited Composés chimiques
CN109704983B (zh) 2019-02-26 2021-06-04 安阳工学院 通过脱mom保护合成3-碘-n-保护-l-酪氨酸甲酯的方法
CN109704996B (zh) 2019-02-26 2021-06-08 安阳工学院 一种制备3-卤代-n-保护-l-酪氨酸甲酯的方法
US20210372959A1 (en) 2020-05-26 2021-12-02 University Of South Carolina Nanopore Method for Identifying Single Amino Acid in Oligopeptides
WO2022096361A1 (fr) 2020-11-03 2022-05-12 Deutsches Krebsforschungszentrum Composés imidazo[4,5-c]quinoléine et leur utilisation en tant qu'inhibiteurs de kinase atm
WO2024022910A1 (fr) 2022-07-26 2024-02-01 Syngenta Crop Protection Ag Dérivés de 1-[1-[2-(pyrimidin-4-yl)-1,2,4-triazol-3-yl]éthyl]-3-[2,4-dichloro-5-phényl]urée et composés similaires utilisés comme pesticides

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KOLLU ET AL., BIOORGANIC CHEMISTRY, vol. 111, 2021, pages 104837
KOLLU ET AL., BIOORGANIC CHEMISTRY, vol. 111, 2021, pages 104837, XP086579892 *
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