Antimicrobial compounds

Abstract

An article comprising a compound of formula I, wherein: R 1 Represents H, or optionally substituted C1-C12 hydrocarbon groups, or water-soluble functional groups; R 2 Indicates C1 or an optional substituted higher hydrocarbon group; R 3 The compound represents H or an optionally substituted C1-12 hydrocarbon group; X represents O, NH, S or PH; and L represents a linking group, and the article comprises: a) an underlayer substrate and a surface layer, wherein the surface layer contains the compound; and / or b) the compound dispersed in an adhesive.

Description

Technical Field

[0001] This invention relates to amino acid-related compounds that exhibit antimicrobial effects (e.g., antibacterial effects). This invention also relates to articles and compositions comprising said compounds. Furthermore, this invention relates to the use of said compounds as pharmaceuticals, such as as antimicrobial agents and / or for the treatment of infections. Background Technology

[0002] Microorganisms such as bacteria are typically spread through contact with surfaces. The importance of keeping products free of infectious microorganisms such as bacteria is growing. The ability to develop antimicrobial surfaces to reduce the rate of transmission via this route is also desired.

[0003] Microorganisms are also frequently transmitted through the air as airborne particles. Therefore, there is a great need for personal protective equipment (PPE) and / or air handling units with antimicrobial properties to reduce the rate of transmission via this route.

[0004] Antimicrobial resistance (e.g., antibiotic resistance) and the need for novel antimicrobial compounds pose a significant and growing challenge to the healthcare profession. Traditional antimicrobial agents, such as penicillin-based antimicrobials, are particularly affected by antimicrobial resistance. There is a strong desire to develop novel antimicrobial compounds.

[0005] Peptide-based antimicrobial agents have been studied. However, these agents are often difficult to synthesize, chemically modify, and / or purify. For example, the production of β-lactam-based antibiotics typically requires multi-step synthetic pathways. The difficulties in the synthesis and chemical modification of these agents make optimization challenging. Furthermore, the complexity of these molecules also presents challenges in optimizing their activity.

[0006] This invention was designed with the foregoing in mind. Summary of the Invention

[0007] According to a first aspect, the present invention provides an article comprising a compound of formula I: Formula I, Where R 1 Represents H, or optionally substituted C1-C12 hydrocarbon groups, or water-soluble functional groups (e.g., polyethers); R 2 Indicates C1 or an optional substituted higher hydrocarbon group; R 3The symbol represents an optionally substituted C1-12 hydrocarbon group; X represents O, NH, S, or PH; and L represents a linking group. The article comprises: a substrate and a surface layer, wherein the surface layer contains the compound; and / or the compound is dispersed in an adhesive. Formula I is illustrated in the accompanying drawings. Figure 1 To depict.

[0008] Surprisingly, compounds of formula I have been found to be effective antimicrobial agents (e.g., antibacterial, antiviral, and / or antifungal). In particular, compounds of formula I have been found to exhibit activity against a wide variety of bacteria, including Gram-positive and Gram-negative strains, aerobic and anaerobic strains, and strains that are particularly susceptible to antibiotic resistance.

[0009] The article is preferably an article that multiple users will come into contact with during use, and / or an article used in applications where microbial control is particularly important. For example, the article may be selected from a list of the following: health care devices, medical devices, (electronic) display devices, imaging devices, packaging, agricultural facilities, air treatment and / or disposal components, water treatment and / or disposal components, and food and / or beverage preparations.

[0010] The article (e.g., packaging) is preferably transparent or includes transparent areas, such as windows, that allow viewing of the product held by the packaging. The transparent areas preferably contain the compounds of the present invention. However, it should be understood that the compounds, when contained in translucent or opaque areas of the packaging, can provide beneficial antimicrobial effects.

[0011] Furthermore, compounds of formula I have been found to exhibit low cytotoxicity to human cell lines, making them excellent candidates for therapeutic applications.

[0012] Therefore, according to a second aspect, the present invention provides a composition comprising a compound of formula I and a carrier and / or a 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 coating or a surface cleaner.

[0013] The compounds of the present invention can be used as antimicrobial agents for non-therapeutic purposes, such as for frequently touched surfaces and for water treatment.

[0014] It has been found that some compounds of the present invention form a glassy substance when heated, as identified in the examples. These material properties are beneficial for certain applications, such as providing antimicrobial properties for surfaces requiring transparency, such as touchscreen displays.

[0015] According to a third aspect, the present invention provides non-therapeutic use of a 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.

[0016] According to a fifth aspect, the present invention provides a compound of formula I for preventing or treating microbial (e.g., bacterial) infections. According to a sixth aspect, the present invention provides a compound of formula I for use as a medicament.

[0017] The synthesis of compounds of Formula I is relatively simple, and the antimicrobial activity of these compounds can be relatively easily optimized by modifying their structure (within the scope of Formula I).

[0018] Baker, BC, et al., European Polymer Journal 162 (2022) 110889 discloses the synthesis of supramolecular glassy substances made from low molecular weight amino acid derivatives. Specifically, the following compound 1L (structure shown below) and its enantiomer 1D were synthesized. However, the paper does not discuss any biological activities, such as antimicrobial properties, nor does it suggest in any way that compounds 1D and 1L may have antimicrobial properties.

[0019] It should be understood that the Formula I compound can be used in methods for preventing or treating microbial infections, said methods including administering the Formula I compound to a subject. This disclosure also provides for the use of the Formula I compound in the manufacture of medicaments, particularly in cases where said medicaments are used for the prevention or treatment of microbial infections.

[0020] Surprisingly, compounds of formula I readily form large, transparent plates and may be particularly suitable for forming articles. Providing a compound of formula I on the surface of an article will impart the antimicrobial properties of the compound of formula I to the article.

[0021] According to a fifth aspect, the present invention provides a compound of formula I, provided that the compound of formula I is not represented by formula II: Formula II.

[0022] Scozzafava et al., Journal of Enzyme Inhibition (2010) 15(5), p425-432, CN 109704996 B and CN 109704983 B seem to generally suggest compounds with antibacterial effects. Kollu et al., Bioorganic Chemistry (2021), 111, 104837; WO 2018 / 167468 A1; US ​​2021 / 0372959 A1; WO 2022 / 096361 A1; WO 2008 / 113992 A2; WO 2024 / 022910 A1 seem to disclose other compounds, but not antibacterial effects.

[0023] However, compared to these documents, the present invention provides novel compounds with specific functionalities. It has been recognized that the L and R of formulation I... 1 R 2 and R 3 Group-related specific functionality provides beneficial effects.

[0024] For example, CN 109704996 B and CN 109704983 B describe LRs of amines containing urethane or alkyl or acyl functionalization. 2 Group.

[0025] There is no disclosure or teaching that the compounds of the present invention have been successfully used in articles of manufacture to provide an antibacterial surface, as demonstrated in this application.

[0026] This disclosure also includes the subject matter of the following articles: 1. An article comprising a compound of formula I: Equation I, where: R 1 Represents H, or optionally substituted C1-C12 hydrocarbon groups, or water-soluble functional groups; R 2 Indicates C1 or an optional substituted higher hydrocarbon group; R 3 Represents H or an optionally substituted C1-12 hydrocarbon group; X represents O, NH, S, or PH; and L represents a linking group, and the article comprises: a) a substrate and a surface layer, wherein the surface layer contains the compound; and / or b) The compound dispersed in the adhesive.

[0027] 2. The article of manufacture according to item 1, wherein the article of manufacture is selected from the list consisting of: health care devices, medical devices, display devices, imaging devices, packaging, agricultural facilities, air treatment and / or treatment components, water treatment and / or treatment components, and food and / or beverage preparations.

[0028] 3. The article of manufacture according to item 2, wherein the article of manufacture is an article of manufacture of a medical device, packaging, touch screen, lens, light shield, or health care facility.

[0029] 4. A composition comprising a compound of formula I and a carrier and / or a 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.

[0030] 5. The composition according to item 4, wherein the composition is selected from the list of the following: detergent compositions, disinfectant compositions, food and / or beverage preservatives, and building materials.

[0031] 6. The composition according to item 4 or item 5, wherein the composition further comprises water, surfactant, pigment, colorant, binder / polymer, oil, preservative, curing agent, fragrance, emollient, bleaching agent, filler, blocking agent, thickener, humectant, dihydroxyacetone, siloxane and / or tetrachlorohydroxyaluminum zirconium (GLY).

[0032] 7. Non-therapeutic use of compounds of formula I or combinations thereof as antimicrobial agents.

[0033] 8. A non-treatment method comprising contacting an article, water, soil and / or rock with a compound of formula I or a combination thereof.

[0034] 9. A compound of formula I, said compound of formula I for the prevention or treatment of microbial infections.

[0035] 10. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding entries, wherein R 2 This indicates the optional substituted C1-C50 alkyl and / or aryl groups.

[0036] 11. Articles, compositions, non-therapeutic uses, non-therapeutic methods, or compounds according to item 10, wherein R 2 This indicates that the C1-C12 hydrocarbon groups are substituted.

[0037] 12. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding entries, wherein R 2Optionally substituted with one or more groups selected from the list of the following: -NO2, -O-, halogens (e.g., -F, -Cl and -Br), -CN, -OH, CO2H, CO2R 1 And -N(H)C(O)N(H)-.

[0038] 13. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding entries, wherein R 3 This indicates the optional substituted C1-12 alkyl and / or aryl groups.

[0039] 14. Articles, compositions, non-therapeutic uses, non-therapeutic treatments, or compounds according to any of the preceding entries, wherein R 3 Optionally, it may be substituted with one to four groups selected from the list of the following groups: -OH, -NH2, -CO2H, -CONH2, and -B(OH)2.

[0040] 15. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding entries, wherein X represents O or NH.

[0041] 16. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding entries, wherein R 1 It represents H or an unsubstituted C1-C4 hydrocarbon group.

[0042] 17. Articles, compositions, non-therapeutic uses, non-therapeutic methods, or compounds used according to any of the preceding entries, wherein L comprises or represents one or more groups selected from the list of the following: amides, esters, carbamates, carbonates, carboxylic anhydrides, thioureas, and ureas.

[0043] 18. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any one of items 1 to 9 or 12 to 17, wherein formula I is represented by formula III: Formula III, wherein: R 1 R 3 X and L are each defined independently as for equation I, R 4 and R 5 Each of the substituted C1-C12 hydrocarbon groups is independently represented, and n is 1 or greater.

[0044] 19. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding entries, wherein: R 1 Represents H or an optional substituted C1-C8 hydrocarbon group; R 2 Indicates the optional substituted C1-C50 hydrocarbon group; R 3The substituent represents H or an optional substituted C1-12 aryl and / or alkyl group; any substituent is selected from the list of the following groups: hydroxyl, ether, nitro, nitrile, and halogen; X represents O, NH, or S; and L contains or represents one or more groups selected from the list of the following groups: amide, ester, carbamate, carbonate, carboxylic anhydride, thiourea, and urea.

[0045] 20. The article, composition, non-therapeutic use, non-treatment method, or compound used according to item 19, wherein: R 1 Represents H or an unsubstituted C1-C2 hydrocarbon group; R 2 R represents a C1-C42 alkyl or aryl group optionally substituted with one to four groups selected from the list consisting of -NO2, -O-, halogen, and -CN; 3 The symbol represents a C1-8 alkyl and / or aryl group that is optionally substituted by two or fewer groups selected from the list of groups consisting of -OH and -NH2; X represents O; and L represents a thiourea group or a urea group.

[0046] 21. The article, composition, non-therapeutic use, non-treatment method, or compound used according to item 19, wherein said compound has one of the following structures: .

[0047] 22. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding entries, wherein said compound has the following stereochemistry: .

[0048] 23. A compound of formula I, said compound of formula I, used as a drug.

[0049] 24. A compound of formula I, wherein the compound of formula I is not represented by formula II: Formula II.

[0050] 25. The compound according to item 24, wherein the compound is represented by one of the following structures: , The condition is that the compound of formula I is not represented by formula II. Detailed Implementation

[0051] The term "CX-CY," where X and Y are integers, refers to the number of carbon atoms in a given group. For example, C1-C6 alkyl groups contain 1 to 6 carbon atoms, and C3-C6 alkyl groups contain 3 to 6 carbon atoms.

[0052] An alkyl group is a partially or fully saturated hydrocarbon group and can be straight-chain, branched, and / or cyclic (“cycloalkyl”). Therefore, an alkyl group may contain one or more alkenyl, ynyl, and / or aryl groups. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl. The term “cycloalkyl” refers to a cyclic hydrocarbon group. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0053] An alkenyl group is a hydrocarbon group containing one or more carbon-carbon double bonds and can be straight-chain, cyclic, and / or branched. Therefore, an alkenyl group can contain one or more alkyl, alkynyl, and / or aryl groups. Examples of alkenyl groups include vinyl, allyl, prenyl, isoprenyl, etc.

[0054] An alkynyl group is a hydrocarbon group containing one or more carbon-carbon triple bonds and can be straight-chain, cyclic, and / or branched. Therefore, an alkynyl group can contain one or more alkenyl, alkyl, and / or aryl groups.

[0055] An aryl group is a hydrocarbon group comprising one or more aromatic rings. Therefore, an aryl group may comprise one or more alkyl, alkenyl, and / or alkynyl groups. Examples of aryl groups include carbocyclic aromatic groups, such as phenyl, naphthyl, anthraceneyl, and pyreneyl. Benzyl, benzo[ a Anthrayl, fluoranthracene, indole, and tetrahydronaphthyl groups.

[0056] The substituted hydrocarbon group comprises one or more heteroatoms (e.g., N, O, S, P) and / or halogens (e.g., F, Cl, and / or Br). Preferably, the substituted hydrocarbon group comprises one or more heteroatoms selected from the list of the following: N, O, and halogens (e.g., F and Cl). The substituted hydrocarbon group includes heterocyclic (e.g., heteroaromatic / heteroaryl), heteroalkyl, heteroalkenyl, and / or heteroynyl groups. The substituted hydrocarbon group may comprise heteroatoms in the hydrocarbon chain (i.e., internal substituents, such as ethers) and / or attached to the hydrocarbon chain (i.e., external substituents, such as halogens).

[0057] Examples of substituents include those selected from the list of the following: amines (primary, secondary, and / or tertiary amines), amides, alcohols, esters, ethers, thiols, thioethers, sulfoxides, sulfones, sulfonamides, or halogens (e.g., fluorine, chlorine, bromine, and / or iodine), disulfides, sulfonates, thioketones, thioesters, phosphine, phosphonates, phosphates, boronic esters, boronic esters, boranes, aldehydes, ketones, carbamates, carbonates, carboxylic acids, carboxylic anhydrides, ureas, ketals, acetals, orthoesters, orthocarbonates, nitriles, imines (e.g., oximes and / or Schiff bases, such as secondary ketamine and / or secondary aldehyde imines), imides, diimides, hydrazines, 1,2,3-triazoles, hydrazones, nitro groups, acyl hydrazones, saccharin, carbazide hydrazones, and hydrazone formamidinium. Preferred substituents include those selected from the list of the following compositions: amines, amides, alcohols, esters, ethers, thioethers, sulfones, sulfonamides or halogens (e.g., fluorine, chlorine and / or bromine), thioketones, phosphonates, phosphates, borates, aldehydes, ketones, carbamates, carbonates, carboxylic acids, ureas, ketals, acetals, nitriles, imines, imides, 1,2,3-triazoles, and nitro groups. More preferred substituents include those selected from the list of the following compositions: hydroxyl groups, ethers (e.g., alkyl ethers, such as methoxy ethers), nitro groups, nitrile groups, and halogens (especially Cl).

[0058] The substituted hydrocarbon group may contain 1 to 10 heteroatoms, such as 1 to 8 heteroatoms or 1 to 6 heteroatoms. The substituted hydrocarbon group may contain 1 to 4 heteroatoms, such as 3, 2 or 1 heteroatoms.

[0059] The heterocyclic group can be monocyclic or polycyclic (e.g., bicyclic), and / or may contain 4 to 18 ring members, more commonly 5 to 10 ring members, such as 5 or 6 ring members. Monocyclic groups may include 3, 4, 5, 6, 7, or 8 ring members, more commonly 4 to 7, preferably 5, 6, or 7, and more preferably 5 or 6 ring members. Examples of polycyclic (e.g., bicyclic) groups are those containing 6 to 18 ring members, more commonly 8, 9, or 10 ring members. Heterocyclic groups can be selected from the following list of compositions: aziridine, aziridine butane, pyrrolidine, piperidine, piperazine, aziridine heptane, imidazoline, tetrahydrofuran, ethylene oxide, oxacyclobutane, oxacyclohexane, oxacycloheptane, oxacyclooctane, 1,3-dioxolane, tetrahydrothiophene, pyrrolizidine, quinine ring, 1-azaadamantane, 2-azaadamantane, 1-oxaspiro[4.5]decane, 1,4-dioxa-7-azaspiro[4.4]nonane, decahydroisoquinoline, and decahydroquinoline. Heterocyclic groups include heteroaryl groups, such as polycyclic (e.g., bicyclic) cyclic systems, wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. Examples of such polycyclic systems include 1,4,5,6-tetrahydrocyclopentano[ b Pyrrole, indoline, tetrahydroquinoline, tetrahydroisoquinoline, 1,2-dihydroquinoline, 1,2-dihydroisoquinoline 2H -benzo[ e [1,3]oxazine, 2H-benzo[ b [1,4]Oxazine, 2H -benzo[ e [1,2]Oxazine, 1H -isochrome and 2H -chromene. The heteroaryl group can be a five- or six-membered monocyclic structure, or a bicyclic structure formed by fused five-membered and six-membered rings or two fused six-membered rings. The heteroaryl group may contain one or two or more cyclic nitrogen atoms. Examples of heteroaryl groups include pyrrole, furan, thiophene, imidazole, furazolidone, oxazole, oxadiazole, oxtriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole, triazole, tetraazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole, 2H -Isoindole, benzimidazole, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, benzofuran, isobenzofuran, benzo[ c Thiophene, benzo[ b Thiophene, benzo[ d Isoxazole, benzo[ d Thiazoles, quinolones, isoquinolines, quinoxaline, phthalazine, quinazoline, cyclophosphine, and 1,8-naphthylidine.

[0060] R 1 R 1It represents H, or an optional substituted C1-C12 hydrocarbon group, or a water-soluble functional group (e.g., polyether).

[0061] Preferably, R 1 Represents H or an optionally substituted C1-C8 hydrocarbon group, such as H or an optionally substituted C1-C6 hydrocarbon group, preferably H or an optionally substituted C1-C4 hydrocarbon group, such as H or an optionally substituted C1, C2, or C3 hydrocarbon group. Preferably, R 1 It is not replaced.

[0062] Polyether groups are beneficial because they can improve the water solubility of compounds. 1 The polyether can be a polyethylene glycol (PEG) group and / or a polypropylene glycol group. The polyether group can be represented by the following formula: Where R 6 It is a C1-10 hydrocarbon group, such as a C1-8 hydrocarbon group or a C1-6 hydrocarbon group. R 6 It can be a C2-10 hydrocarbon group, such as a C2-8 hydrocarbon group or a C2-6 hydrocarbon group. Preferably, R 6 It is 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 alkenyl group. More preferably, R 6 The hydrocarbon group is an alkyl group. More preferably, R 6 It is a C1-10 alkyl or alkenyl group, such as a C1-8 alkyl or alkenyl group or a C1-6 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, R 6 It is a C2 alkyl (i.e. ethyl) group, which makes the polyether a polyethylene glycol group.

[0063] n can be 3 or greater, or 5 or greater, such as 10 or greater, or 15 or greater, such as an average of 18 or greater. n can be 100 or less, such as 80 or less, or 60 or less, such as 50 or less, or 40 or less, such as 30 or less, or 25 or less, such as an average of 22 or less. n can be 3 to 100, such as an average of 5 to 50, or 10 to 30. The average value may be a numerical average. The average value of n can be obtained through NMR, for example by using... 1 The relevant peaks are determined by integrating ¹H NMR. Alternatively, mass spectrometry can be used to calculate the average value of n.

[0064] R 1 The hydrocarbon group can be an optionally substituted alkyl, alkenyl, aryl, and / or alkynyl group. Preferably, R1 The hydrocarbon group is optionally substituted alkyl and / or alkenyl groups (e.g., C1-6 alkyl and / or alkenyl groups), most preferably optionally substituted alkyl groups. More preferably, R 1 The hydrocarbon group is an unsubstituted alkyl group, such as an unsubstituted C1-6 alkyl group.

[0065] Water-soluble functional groups may be selected from the list of the following: alcohols (e.g., polyols such as branched polyols, glycerol), ethers (e.g., polyethers such as polyethylene glycol), pluronic groups (i.e., hydrophilic poly(ethylene oxide), PEO, and hydrophobic poly(propylene oxide), PPO, arranged in an ABA triblock structure), carbohydrate groups, amines (e.g., diamines), phosphates, and sulfonates. Water-soluble groups may be polymers (e.g., polyols, polyethers, pluronic groups, polysaccharides, polyamines, polyphosphates, and / or polysulfonates), and / or C1-50 (e.g., C2-30) hydrocarbon groups substituted with one or more groups selected from the list of alcohols, ethers, amines, phosphates, and sulfonates. In R 1 In the case of H, especially in alkaline environments and / or when heat is used, water solubility is also enhanced.

[0066] Most preferably, R 1 Represents an H or methyl group. As shown in the examples, where R 1 Compounds that are H or methyl groups and, for example, where R 1 Compared to compounds with tert-butyl groups, it provides enhanced antibacterial activity.

[0067] R can be controlled 1 The properties of R can alter the solubility of a compound. For example, when R... 1 When H is present, the compound may be more soluble in water.

[0068] R 2 R 2 It indicates C1 or an optional higher hydrocarbon group that has been substituted.

[0069] R 2 It can represent a C2 or higher hydrocarbon group, preferably a C4 or higher hydrocarbon group, or a C5 or C6 or higher hydrocarbon group. R 2 It can represent C1-C50 hydrocarbon groups, such as C1-C46 hydrocarbon groups, or C1-C42 hydrocarbon groups, preferably C1-C38 hydrocarbon groups. R 2 It can represent C1-C36 hydrocarbon groups, or C1-C32 hydrocarbon groups, or C1-C30 hydrocarbon groups, or C1-C28 hydrocarbon groups. R 2It can represent C1-C24 hydrocarbon groups, or C1-20 hydrocarbon groups, such as C1-C16 hydrocarbon groups, or C1-C12 hydrocarbon groups, or C1-C10 hydrocarbon groups, or C1-C8 hydrocarbon groups, or C1-C7 hydrocarbon groups, such as C1-C6 hydrocarbon groups. R 2 It can represent C2-C50 hydrocarbon groups, such as C2-C42 hydrocarbon groups, or C4-C50 hydrocarbon groups, such as C4-C42 hydrocarbon groups, or C6-C50 hydrocarbon groups, such as C6-42 hydrocarbon groups. R 2 It can represent a C2-C20 hydrocarbon group, such as a C2-C12 hydrocarbon group, or a C4-C20 hydrocarbon group, such as a C4-C12 hydrocarbon group, or a C6-C20 hydrocarbon group, such as a C6-C12 hydrocarbon group. Each of the groups disclosed in this paragraph may optionally be substituted.

[0070] R 2 The hydrocarbon group can be an optionally substituted alkyl, alkenyl, aryl, and / or alkynyl group. Preferably, R 2 The hydrocarbon group is optionally substituted alkyl, alkenyl, and / or aryl groups, most preferably optionally substituted alkyl and / or aryl groups. More preferably, R 2 The hydrocarbon group is optionally a substituted alkyl (e.g., cycloalkyl) and / or aryl group. Preferably, R 2 This indicates the optionally substituted C1-50 alkyl, alkenyl, and / or aryl groups. More preferably, R 2 This indicates the optional substituted C1-10 or C6-42 alkyl and / or aryl groups.

[0071] R 2 It can be specifically substituted by one or more groups selected from the list of the following: -NO2, -O-, halogens (e.g., -F, -Cl and -Br), -CN, -OH, CO2H, CO2R 1 And -N(H)C(O)N(H)-. Preferably, R 2 The substance is substituted with one or more groups selected from the list of the following: -NO2, -O-, halogens (e.g., -F, -Cl, and -Br), and -CN. Preferably, R 2 It is replaced by six or fewer groups, such as four or fewer, three or fewer, or two or fewer groups. Preferably, R 2 It may be substituted by a group or not substituted by a group.

[0072] R 2 It can represent (optionally substituted) C4-12 cycloalkyl groups, such as C4-10 cycloalkyl groups or C4-8 cycloalkyl groups. R 2It can represent (optionally substituted) C5-12 cycloalkyl groups, such as C6-12 cycloalkyl groups or C6-8 cycloalkyl groups, most preferably C6 cycloalkyl groups. Preferably, the cycloalkyl group is unsubstituted. Most preferably, the cycloalkyl group is cyclohexyl.

[0073] R 2 It can represent (optionally substituted) C4-12 aryl groups, such as C4-10 aryl groups or C4-8 aryl groups. R 2 It can represent (optionally substituted) C5-12 aryl groups, such as C6-12 aryl groups or C6-8 aryl groups, most preferably C6 aryl groups.

[0074] In R 2 In cases where the aryl group (e.g., C4-12 aryl, such as phenyl) is represented, preferably, the aryl group is an unsubstituted C6-12 aryl group, or a C4-12 aryl group that is substituted in one or more of the meta and / or para positions relative to the connection with the L group. As shown by the examples, compared with ortho-substituted compounds, in cases where the phenyl group is unsubstituted or substituted at the meta and / or para positions, where R 2 Compounds containing phenyl groups exhibit enhanced antibacterial properties.

[0075] Preferably, R 2 The para-substitution of the phenyl group is achieved through electron-withdrawing groups such as -NO2, halogens (e.g., F, Cl and / or Br), -CN, CO2H and / or CO2R. 1 More preferably, it is carried out via -NO2, halogens (especially Cl). As shown by the examples, compared with compounds having electron-donating groups (e.g., 4-methoxy), when the phenyl group is substituted with an electron-withdrawing group (especially at the para position), wherein R 2 Compounds substituted with phenyl groups exhibit enhanced antibacterial properties. Preferably, R... 2 Does not represent 4-methoxyphenyl, especially in R 3 In the case of -CH2(4-hydroxyphenyl) or -CH2Ph.

[0076] Meta-substitution via electron-donating groups (e.g., 3-methoxyphenyl) appears to achieve a favorable effect. In R 2 Even when 2,4-dimethoxyphenyl is represented, a good effect is achieved.

[0077] Preferably, R 2 The phenyl group is unsubstituted (i.e., H) at both adjacent positions relative to the L group.

[0078] R 2It can represent a C1-10 or C6-42 alkyl and / or aryl group that is optionally substituted by three or fewer (e.g., one or zero) groups selected from the list of -NO2, -O-, halogens (e.g., -F, -Cl and -Br) and -CN.

[0079] R 2 It may contain or represent groups selected from the list of the following: 3-methoxyphenyl, 4-methoxyphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-nitrophenyl, 4-nitrophenyl, phenyl, 3-cyanophenyl, butyl, and cyclohexyl.

[0080] Preferably, R 2 Contains or represents a group selected from the list of the following compositions: 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 It contains or represents a group selected from the list of the following compositions: 4-nitrophenyl, 3-nitrophenyl, 3-cyanophenyl, cyclohexyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, phenyl, 2,4-dimethoxyphenyl, butyl, and naphthyl. Most preferably, R 2 It contains or represents groups selected from the list of the following: 3-nitrophenyl, 3-cyanophenyl, cyclohexyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, phenyl, and butyl.

[0081] Preferably, R 2 Does not represent 3,4-dichlorophenyl, especially in XR 1 In the case of OH.

[0082] R 2 It may contain or represent: or In these structures, R corresponds to R in Equation I. 1 That is, H or an optional substituted C1-C12 hydrocarbon group.

[0083] R 3 R 3 It represents H or an optional substituted C1-12 hydrocarbon group.

[0084] R 3 It can represent H or an optional substituted C1-10 hydrocarbon group, such as H or an optional substituted C1-8 hydrocarbon group, or H or an optional substituted C1-7 hydrocarbon group, or H or an optional substituted C1-6 hydrocarbon group. R 3It can represent optionally substituted C1-12 alkyl, alkenyl, and / or aryl groups, or optionally substituted C1-C12 alkyl and / or aryl groups, such as optionally substituted C1-10 (e.g., C1-8) alkyl and / or aryl groups. R 3 It can represent an optionally substituted C1-10 alkyl group or an optionally substituted C1-8 alkyl group, such as an optionally substituted C1-6 alkyl group or an optionally substituted C1-4 alkyl group. R 3 It can 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, R 3 This indicates a C6 aryl group, a C7 aryl group, a C4 alkyl group, a C3 alkyl group, or a C1 alkyl group. Preferably, R 3 It represents a C6 aryl group or a C1 alkyl group.

[0085] R 3 (especially R) 3 The aryl group can be specifically substituted by one or more groups selected from the list of the following: -O-, -S-, -NH-, -CO2-, -CONH-, -SH, -OH, -NH2, -CO2H, -CONH2, and -B(OH)2. 3 Specifically, it can be replaced by one or more groups selected from the list of the following: -OH, -NH2, -CO2H, -CONH2, and -B(OH)2. Preferably, R 3 Substituted with one or more groups selected from the list of the following groups: -OH and -NH2, more preferably -OH. R 3 It can be substituted by four or fewer groups, such as three, two, or fewer groups. Most preferably, R 3 It is replaced by a group, such as a -OH group. In R 3 In the case of an alkyl group, R is preferred. 3 It has not been replaced.

[0086] R 3 It can represent a C1-12 alkyl, alkenyl, and / or aryl group optionally substituted with three or fewer groups selected from the list of the following: -O-, -S-, -NH-, -CO2-, -CONH-, -SH, -OH, -NH2, -CO2H, -CONH2, and -B(OH)2. 3 It can represent a C1-12 alkyl, alkenyl, and / or aryl group optionally substituted with three or fewer groups selected from the list of the following: -S-, -O-, -SH, -OH, -NH2, -CO2H, -CONH2, and -B(OH)2. 3It can represent a C1-8 alkyl and / or aryl group that is optionally substituted by two or fewer groups selected from the list of the following: -S-, -O-, -OH and -NH2.

[0087] R 3 It can represent hydroxymethyl (i.e., -CH2OH), methyl, or 4-hydroxyphenyl. R 3 It can represent methyl or 4-hydroxyphenyl. R 3 Preferably, it represents hydroxymethyl (i.e., -CH2OH), methyl, -CH2CH(CH3)2, -CH2Ph, -(CH2)2SMe, or 4-hydroxyphenylmethyl. 3 Preferably, it represents methyl or 4-hydroxyphenylmethyl.

[0088] More preferably, R 3 It represents a C7 aryl group (especially -CH2Ph, more preferably -CH2(4-hydroxyphenyl)) optionally substituted with a -OH group, or a C1 alkyl group (especially methyl).

[0089] X 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.

[0090] L L represents a linking group.

[0091] L may contain or represent one or more groups selected from the list of the following: amide, ester, amine, ether, thioether, disulfide, sulfoxide, sulfone, sulfonamide, sulfonate, thione, thioester, phosphine, phosphonate, phosphate, borate, boronite, borane, ketone, carbamate, carbonate, carboxylic anhydride, urea, thiourea, ketal, acetal, orthoester, orthocarbonate, imide, diimide, hydrazine, hydroxylamine, 1,2,3-triazole, alkyl, alkenyl, alkynyl, and aryl.

[0092] L may contain 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 contain 1 to 10 carbon atoms, such as 1 to 4 carbon atoms, more preferably 1 carbon atom.

[0093] Preferably, L comprises or represents one or more groups selected from the list of the following: amides, esters, carbamates, carbonates, carboxylic anhydrides, thioureas, and ureas. More preferably, L represents a urea group or a thiourea group, i.e., -N(H)C(O)N(H)- or -N(H)C(S)N(H)-. Most preferably, L represents a urea group.

[0094] Preferred Implementation In one implementation: - Any substituent may be selected from the following list of components: amine, amide, alcohol, ester, ether, thioether, sulfone, sulfonamide or halogen (e.g., fluorine, chlorine and / or bromine), thion, phosphonate, phosphate, borate, aldehyde, ketone, carbamate, carbonate, carboxylic acid, thiourea, urea, ketal, acetal, nitrile, imine, imide, 1,2,3-triazole and nitro. -X represents O, NH, or S; and -L contains or represents one or more groups selected from the list of the following: amide, ester, amine, ether, thioether, disulfide, sulfoxide, sulfone, sulfonamide, sulfonate, thione, thioester, phosphine, phosphonate, phosphate, borate, boronite, borane, ketone, carbamate, carbonate, carboxylic anhydride, thiourea, urea, ketal, acetal, orthoester, orthocarbonate, imide, diimide, hydrazine, hydroxylamine, 1,2,3-triazole, alkyl, alkenyl, alkynyl, and aryl.

[0095] In one implementation: -R 1 Represents H, or optionally substituted C1-C8 hydrocarbon groups, or polyethers; -R 2 Indicates the optional substituted C1-C50 hydrocarbon group; -R 3 This indicates the optional substituted C1-10 hydrocarbon group; - Any substituent may be selected from the following list of components: hydroxyl, ether (e.g., alkyl ethers, such as methoxy ethers), nitro, nitrile, and halogen (especially Cl). -X represents O, NH, or S; and -L contains or represents one or more groups selected from the list of the following: amides, esters, carbamates, carbonates, carboxylic anhydrides, thioureas, and ureas.

[0096] In one implementation: -R 1 This indicates H, or an unsubstituted C1-C4 hydrocarbon group, or a PEG group; -R 2 This indicates a C4-C50 alkyl and / or aryl group optionally substituted with one or more groups selected from the list of the following: -NO2, -O-, halogens (e.g., -F, -Cl and -Br), -CN, -OH, CO2H, CO2R. 1 and -N(H)C(O)N(H)-; -R 3The C1-8 alkyl and / or aryl groups are optionally substituted with one to four groups selected from the list of the following: -OH, -NH2, -CO2H, -CONH2 and -B(OH)2; -X indicates O; and -L contains or represents one to six groups selected from the list of the following: amides, esters, carbamates, carbonates, carboxylic anhydrides, thioureas, and ureas.

[0097] In one implementation: -R 1 Indicates H or an unsubstituted C1-C2 hydrocarbon group; -R 2 The C6-C42 alkyl (e.g., cycloalkyl) or aryl group is optionally substituted with one to four groups selected from the list of the following: -NO2, -O-, halogen (e.g., -F, -Cl and -Br) and -CN; -R 3 This indicates a C1-8 alkyl and / or aryl group that is optionally substituted by two or fewer groups selected from the list of groups consisting of -OH and -NH2; -X indicates O; and -L indicates a urea group or a thiourea group.

[0098] For compounds of formula I, the following are applicable: -R 1 Represents H, or optionally substituted C1-C12 hydrocarbon groups, or polyethers; -R 2 This indicates that the C1 or higher hydrocarbon group (e.g., C1-C24) may be substituted. -R 3 This indicates a C1-6 alkyl group optionally substituted with two or fewer groups selected from the list of the following groups, or a C5-12 aryl group optionally substituted with two or fewer groups selected from the list of the following groups: -OH and -NH2; -X indicates O; and -L contains or represents one to six groups selected from the list of the following: amides, esters, carbamates, carbonates, carboxylic anhydrides, thioureas, and ureas.

[0099] For compounds of formula I, the following are applicable: -R 1 Indicates an H or methyl group; -R 2 This indicates an unsubstituted C2-8 alkyl group, an unsubstituted C6-12 aryl group, or a C4-12 aryl group substituted in one or both of the meta and / or para positions. -R 3This indicates a C7 aryl group, or a C1 alkyl group, or a C3 group, or a C4 alkyl group, which may be optionally substituted with a -OH group; -X indicates O; and -L indicates urea.

[0100] For compounds of formula I, the following are applicable: -R 1 Indicates an H or methyl group; -R 2 This indicates an unsubstituted C6-12 aryl group, or a C4-12 aryl group substituted in one or more of the meta and / or para positions; -R 3 This indicates a C7 aryl group or a C1 alkyl group that is optionally substituted with a -OH group; -X indicates O; and -L indicates urea.

[0101] In compounds of formula I, the following are applicable: -R 1 Indicates an H or methyl group; -R 2 This indicates an unsubstituted C6-8 aryl group, or a C6-8 aryl group substituted in one or more of the meta and / or para positions according to the list of the following: NO2, halogens (e.g., F, Cl and / or Br), -CN and / or CO2R. 1 ; -R 3 This indicates -CH2Ph ​​or methyl, which may be optionally substituted with a -OH group; -X indicates O; and -L indicates urea.

[0102] In R 3 This indicates a group such as -CH2(4-hydroxyphenyl) and When L represents urea, R is preferred. 2 The following compounds are used: butyl, 2,4-dimethoxyphenyl, naphthyl, 4-nitrophenyl, 3-nitrophenyl, 3-cyanophenyl, cyclohexyl, 3-chlorophenyl, 4-chlorophenyl, 3-methoxyphenyl, or phenyl; and more preferably, R 2 It represents butyl, 3-nitro-phenyl, 3-cyano-phenyl, cyclohexyl, 3-chloro-phenyl, 3-methoxy-phenyl or phenyl.

[0103] In R 3 In the case where a group such as -CH3 is represented and L represents urea, R is more preferably used. 2 It represents 3-chloro-phenyl, 4-chloro-phenyl, 4-nitro-phenyl, phenyl, or cyclohexyl.

[0104] In R 3 In the case where a group such as -CH2Ph ​​is represented and L represents urea, R is preferred. 2 It represents phenyl.

[0105] In R 3 When a group such as -CH2CH(CH3)2 is represented and L represents urea, R is preferred. 2 It represents 4-methoxy-phenyl or 4-chloro-phenyl.

[0106] In R 3 In the case where a group such as -(CH2)2SMe is represented and L represents urea, R is preferred. 2 It represents 4-chlorophenyl or phenyl; more preferably phenyl.

[0107] In compounds of formula I, the following are applicable: -R 1 Indicates an H or methyl group; -R 2 The term indicates an unsubstituted phenyl group, or a phenyl group substituted in one or more of the meta and / or para positions by one or more groups selected from a list consisting of -NO2 and / or halogens (especially Cl). -R 3 This indicates -CH2Ph ​​or methyl, which may be optionally substituted with a -OH group; -X indicates O; and -L indicates urea.

[0108] For example, in compounds of formula I, the following may apply: -R 1 Represents H, or optionally substituted C1-C12 hydrocarbon groups, or PEG groups; -R 2 This indicates that the C1-C12 (e.g., C1-C8) hydrocarbon groups are optionally substituted; -R 3 This indicates a C1-4 alkyl group optionally substituted with two or fewer groups selected from the list of the following groups, or a C5-8 aryl group optionally substituted with two or fewer groups selected from the list of the following groups: -OH and -NH2; -X indicates O; and -L indicates a urea group or a thiourea group.

[0109] Compounds of Formula I can be represented by one or more of the following structures: , Each R 1 Independently representing H or optionally substituted C1-C12 hydrocarbon groups. Preferably, each R 1 It indicates H or methyl.

[0110] Compound of formula I can represent one of the compounds in the table below: In particular, the present invention relates in part to compounds 101, 103-108, 110-112, and 117 themselves. Among these compounds, compounds 103-108 and 117 have been shown to have particular antibacterial benefits.

[0111] As described below, compounds of formula I may represent 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.

[0112] Compounds of formula I can be represented by formula III: Formula III Where R 1 R 3 X and L are each defined independently as for equation I, and R is where X and L are defined independently as for equation I. 4 and R 5 Each independently represents an optional substituted C1-C12 hydrocarbon group, and n is 1 or greater, such as 1 to 4, or 1 to 3, preferably 2.

[0113] R 4 and R 5 Each can be an independent C1-10 hydrocarbon group, such as a C1-C8 hydrocarbon group, or in each case, the C1-C6 hydrocarbon group can be optionally substituted. 4 and R 5 Each can be an independent C2-C12 hydrocarbon group, such as a C3-C12 hydrocarbon group or a C4-C12 hydrocarbon group. R 4 and R 5 Each can be optionally substituted independently by four or fewer (such as two or one) substituents. Preferably, R 4and R 5 It is not replaced.

[0114] Preferably, R 4 and R 5 Each group is independently a optionally substituted C1-C12 alkyl, alkenyl, or aryl group. More preferably, R 4 It is a C1-C8 alkyl or aryl group (e.g., a C2-C6 alkyl or aryl group), and R 5 It is a C1-C6 alkyl group (e.g., a C1-C3 alkyl group).

[0115] Compounds of Formula I can be represented by one or more of the following structures: Each R 1 Independently represents H or an optional substituted C1-C12 hydrocarbon group.

[0116] Compound I can be one of the compounds shown in the attached figure. Figure 2 Or the attached diagram Figure 3 The compounds shown, where each R independently corresponds to R 1 Or as shown in the attached image. Figure 4 The compound shown.

[0117] Preferably, the compound of formula I has the following stereochemistry: .

[0118] Preferably, the compound of formula III has the following stereochemistry: .

[0119] Products The antimicrobial (e.g., antibacterial) properties of the compounds of the present invention can persist when the compounds are a surface layer on an underlying substrate and / or dispersed in an adhesive (e.g., a polymer) (e.g., blended with the adhesive).

[0120] The compounds of the present invention can be used to form articles. The articles comprise the compounds of the present invention. The articles are typically solid-phase substances.

[0121] When the article contains a compound dispersed in an adhesive, the compound can be used to form at least a portion of the surface of the article, or the compound can be coated onto the surface of the article. The article may be formed from a composite comprising the compound and an adhesive (e.g., a structural material) (such as a plastic material). The plastic material may be, for example, silicone (e.g., silicone rubber) and / or polyurethane.

[0122] The compound is particularly suitable for use as a surface coating on frequently touched surfaces such as railings, doors, door handles, door pushers, hospital beds, and wheelchairs.

[0123] The articles may be health care devices, medical devices, display devices, imaging devices, packaging, agricultural facilities, air treatment and / or treatment components, water treatment and / or treatment components, and food and / or beverage preparations.

[0124] The display device may be a monitor screen, such as a touchscreen. The display device may be a telephone, such as a mobile (cellular) phone or smartphone, or a tablet computer, or a computer monitor. The imaging device may be an endoscope (e.g., a gastroscopy, bronchoscope, cystoscope, ureteroscope, arthroscopy, or colonoscope), an ophthalmoscope, or an otoscope, or a lens.

[0125] The article (e.g., packaging) is preferably transparent or includes transparent areas, such as windows, that allow viewing of the product held by the packaging. The transparent areas preferably contain the compounds of the present invention. However, it should be understood that the compounds, when contained in translucent or opaque areas of the packaging, can provide beneficial antimicrobial effects.

[0126] At least a portion of the article may be opaque. The article may not be a lens.

[0127] The article may be personal protective equipment (PPE) articles, such as face shields (e.g., surgical masks or respirator masks), face shields, protective covers, aprons, protective clothing, gloves, goggles, or safety glasses. These articles are particularly useful in healthcare environments, where it is particularly desirable to prevent the spread or reproduction of microorganisms such as bacteria. In one embodiment, the article is a component in a medical environment; preferably, the article is a component in a hospital or veterinary hospital.

[0128] The article may be another article in which it is particularly desired to prevent the spread or reproduction of microorganisms such as bacteria, such as medical devices (such as surgical instruments, or implants, or prostheses), or medical machines or components thereof.

[0129] Specifically, the article may be selected from: surgical instruments such as forceps, retractors, pushers, clamps, or retractors; permanent implants such as artificial heart valves, vocal prostheses, prosthetic joints, implantable intraocular lenses, stents (e.g., vascular stents), and shunts (e.g., hydrocephalus shunts); and non-permanent implants such as pacemakers and pacemaker leads, drainage tubes, endotracheal tubes or gastrointestinal tubes, temporary or trial-fit prosthetic joints, surgical pins, guidewires, surgical staples, cannulas, subcutaneous or percutaneous ports, indwelling catheters and catheter connectors, and contact lenses. The article may be a medical device or a component thereof, for example, it may be selected from dialysis machines, dialysis water delivery systems, water circuits within dialysis units, and ventilator therapeutic water delivery systems. The article may be a dressing (e.g., a wound dressing).

[0130] The product 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 needle-free connectors.

[0131] In one embodiment, the article is a dressing, such as a hydrocolloid dressing, hydrogel dressing, alginate dressing, collagen dressing, foam dressing, transparent dressing, cloth dressing, gauze (e.g., paraffin gauze), low-adhesion dressing, or semi-permeable membrane (e.g., polyurethane coated with acrylate) dressing.

[0132] This invention provides compounds for preventing medical device-associated bacterial infections. For example, the compounds of this invention offer the potential to effectively reduce catheter-related bacterial infections.

[0133] The compound can also be applied to food preparation surfaces (such as kitchen countertops, cutting boards, sinks, stovetops, and refrigerator surfaces) or bathroom surfaces (such as toilets, sinks, bathtubs, showers, and drains). Other suitable treatable surfaces include floor surfaces, door surfaces, and window surfaces.

[0134] In one embodiment, the article is a component of a process facility (such as a cooling facility, water treatment facility, air treatment facility, or food processing facility). In one such embodiment, the component is selected from cooling towers, water treatment plants, dairy processing plants, food processing plants, chemical processing plants, and pharmaceutical processing plants. For example, the article may be a filter for a water treatment system and / or an air treatment system. The article may also be an agricultural facility.

[0135] The article may be a container, such as a bucket, bottle, basin, carton, flat basket, jar, pot, crate, or packaging. The article may be a vessel.

[0136] In one embodiment, the article may be a toilet, sink, bathtub, drain pipe, bar chair, work surface, food processor, food preparation area, air handling unit (or components thereof), air duct, air filter, or air conditioning unit.

[0137] The article may contain 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 of the compound. For example, the article may contain 80 wt% or less, such as 50 wt% or less, or 20 wt% or less of the compound. The article may contain from 0.001 wt% to 80 wt%, such as 1 wt% to 50 wt% of the compound.

[0138] Composition The compounds of the present invention may be included in pharmaceutical or cosmetic compositions containing pharmaceutically or cosmetically acceptable carriers and / or diluents.

[0139] The compounds of the present invention can be included in compositions comprising a carrier and / or a diluent, wherein the carrier and / or diluent is not tetrahydrofuran or triethylamine. Such compositions can be detergent compositions, disinfectant compositions, food and / or beverage preservatives, and / or building materials.

[0140] Building materials can be selected from the following list: concrete, grout, wallpaper, varnish, and paint, especially varnish and paint. Coatings typically contain pigments (such as titanium dioxide, zinc oxide, kaolin, carbon black, zinc chromate, yellow dyes, benzidine yellow, chromium oxide green, phthalocyanine green, phthalocyanine blue, ultramarine, lapis lazuli). Lazuri), cinnabar (mercury sulfide), iron oxide (III), iron oxide (II), Red 170 and / or dioxazine violet), polymers / resins (e.g., polyvinylpyrrolidone, vinylpyrrolidone, acrylics, alkyd resins, epoxy resins, urethanes, polycarbonates, polypropylene, urea, formaldehyde, melamine, phenolic resins, polyesters, polysiloxanes and / or moisture-curing polyurethanes and / or vinyl acetate resins), dispersants / solvents (e.g., mineral turpentine, xylene, toluene, C1-C6 alcohols, linseed oil and / or water), and / or additives (e.g., silica, talc, BaSO4, aluminum silicate and / or calcium carbonate, desiccants, plasticizers, fungicides, other biocides, insecticides, flow control agents, defoamers, emulsifiers, ultraviolet (UV) stabilizers, anti-skinning agents, adhesion promoters, corrosion inhibitors and / or texture agents).

[0141] The composition may contain any of the following components, either alone or in combination: -water - Surfactants (e.g., quaternary ammonium salts such as cetrimonium chloride, sodium lauryl ether sulfate, sodium lauryl sulfate, sodium lauroyl sarcosinate, sodium methyl cocoyl taurate, PEG-8 distearate, cocamidopropyl betaine, cocamidoMEA, glyceryl stearate and / or stearic acid). - Pigments (e.g., titanium dioxide, zinc oxide, kaolin, carbon black, zinc chromate, yellow dyes, benzidine yellow, chromium oxide green, phthalocyanine green, phthalocyanine blue, ultramarine (lapis lazuli), cinnabar (mercuric sulfide), iron oxide (III), iron oxide (II), red 170 and / or dioxazine violet), - Colorants (e.g., mica, polydimethylsiloxane and / or bismuth oxychloride). - Adhesives / polymers (e.g., polyvinylpyrrolidone, vinylpyrrolidone, acrylics, alkyd resins, epoxy resins, urethanes, polycarbonates, polypropylene, urea, formaldehyde, melamine, phenolic resins, polyesters, polysiloxanes and / or moisture-curing polyurethanes and / or vinyl acetate resins). - Oils (such as hydrogenated castor oil, stearyl alcohol, castor oil, mineral oil, vegetable oil and / or cyclodimethylsiloxane), -preservative, - Curing agents (e.g., octyl palmitate, carnauba wax, ceresin and / or microcrystalline wax). -spices, - Emollients (such as coconut oil, cetyl esters and / or silicones). - Bleaching agents (such as hydrogen peroxide and / or urea peroxide). - Fillers (e.g., talc, mica, sericite and / or bismuth oxychloride). - Sealing agents (such as petrolatum, mineral oil and / or polydimethylsiloxane). - Thickeners (e.g., tragacanth gum, cellulose gum and / or carrageenan gum and / or xanthan gum). - Moisturizers (such as glycerin, sorbitol and / or xylitol). - Dihydroxyacetone (tanning agent). -siloxanes, and / or -Tetrachloroaluminumzirconium (GLY) (antiperspirant).

[0142] The composition may be a liquid, emulsion, slurry, or paste.

[0143] The compound of Formula I can be incorporated into a composition containing a carrier and / or a diluent and used as a disinfectant composition / surface cleaner. The surface cleaner may contain a surfactant, which can be cationic, anionic, amphoteric, or nonionic. The surface cleaner can be formulated as a spray.

[0144] Nonionic surfactants include C10E6 and / or C12E6, sophorolipids and / or rhamnolipids, surfactants, lauric acid and / or polyoxyethylene lauryl ether (POLE), Ag-98 (80% octylphenoxy-polyethoxyethanol), alkyl ethoxylates, alkylphenol polyoxyethylene ethers, amine oxides, Brij series (e.g., Brij 58 (polyoxyethylene-23-lauryl ether)), linear alkyl ethoxylates, Lissapol NX, nonylphenyl ethylene oxide, octyl(ethylene glycol)-mono-dodecyl ether (C12Ea), octyl glucoside, and Pluronic. F68 (polyoxyethylene-polyoxypropylene block copolymer), fatty acid polyethylene esters, polyethylene glycol, polyethylene glycol thiols, polyoxyethylated 1-dodecyl alcohol, polyoxyethylene n-alkyl esters, polyoxyethylene n-monostearate, substituted alcohols, tergitols, tributylphenyl ethylene oxide, Triton X-100 (polyoxyethylene glycol octylphenol), Triton X 305 (polyoxyethylene glycol octylphenol), and the Tween series (e.g., Tween 80 (polyoxyethylene sorbitan ester)). Amphoteric surfactants include didecyl, amine oxides, and / or betaine. Cationic surfactants include quaternary ammonium compounds (e.g., alkyldimethylbenzylammonium chloride (ADBAC), alkyldimethylethyl benzylammonium chloride (ADEBAC), and dialcylammonium chloride (DDAC)). Anionic surfactants include Aerosol OT (sodium dioctyl sulfosuccinate), Aerosol OS (alkyl naphthalene sulfonate), β-D-glucopyranosyl-1-alkyl phosphate, Dreft (alkyl sulfate), sodium cholate, sodium dodecyl sulfate, sulfonated oil, sodium 2-lauroyloxypropionate, sodium alkyl sulfate, and Triton No. 720 (diisobutylphenyl diethylene glycol ether sulfonate), linear alkylbenzene sulfonate (LAS), sodium dodecyl benzenesulfonate (SDBS), and sodium lauryl sulfate (SLS).

[0145] The composition may contain 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 of the compound. For example, the composition may contain 80 wt% or less, such as 50 wt% or less, or 20 wt% or less of the compound. The composition may contain from 0.001 wt% to 80 wt%, such as from 1 wt% to 50 wt% of the compound.

[0146] The composition may contain 99.999% by weight or less, such as 99.99% by weight or less, or 99% by weight or less, for example, 95% by weight or less of other components. The composition may contain 20% by weight or more, such as 50% by weight or more, or 80% by weight or more, such as 90% by weight or more of other components. The composition may contain 20% by weight to 99.999% by weight, or 90% by weight to 99.99% by weight of other components.

[0147] As a medicine Compounds of Formula I have been found to effectively reduce the amount of microorganisms (e.g., bacteria, fungi, and / or viruses, especially bacteria). The compounds or combinations thereof can be used to treat microbial infections (especially bacterial infections). Bacterial infections may be caused by bacteria selected from the following genera: *Moraxella* spp. (…). Moraxella Escherichia coli ( ) Escherichia Staphylococcus spp. Staphylococcus ) and Klebsiella spp. Klebsiella Bacterial infections can be caused by bacteria selected from the following list of species: Moraxella catarrhalis (… Moraxella catarrhalis ), Escherichia coli ( Escherichia coli Staphylococcus aureus ( Staphylococcus aureus ) and Klebsiella pneumoniae ( Klebsiella Pneumoniae The bacteria that cause the infection can be Gram-positive or Gram-negative.

[0148] Bacterial infections can occur in the throat, lungs, skin, ears, gastrointestinal tract, heart, brain, blood, or urinary tract. Infections can also be caused by chronic obstructive pulmonary disease (COPD) (such as chronic bronchitis, mastitis, emphysema, and refractory asthma), conjunctivitis, meningitis, bronchitis, sinusitis, pneumonia, food poisoning, (acute) otitis media, bacterial sinusitis, urinary tract infection, cellulitis, impetigo, pneumococcal disease, or bacterial vaginosis.

[0149] Known Escherichia coli ( E. coli Moraxella catarrhalis can cause gastrointestinal and urinary tract infections. M. catarrhalis Staphylococcus spp. can cause otitis media (especially in children and / or its acute exacerbations), COPD (especially its acute exacerbations), meningitis, conjunctivitis, sinusitis, and (acute) bacterial sinusitis. Staphylococcus spp. can cause mastitis, endocarditis, skin infections, food poisoning, osteomyelitis, pneumonia, and sepsis. Klebsiella spp. can cause various types of healthcare-associated infections, such as pneumonia, bloodstream infections, wound or surgical site infections, and meningitis.

[0150] In one embodiment, the pharmaceutical composition (e.g., a formulation) comprises at least one active compound of the present invention, and one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials well known to those skilled in the art, and optionally other therapeutic or preventative agents.

[0151] To prepare the pharmaceutical composition of the present invention, an effective amount of the compound of the present invention as the active ingredient is tightly mixed with a pharmaceutically acceptable carrier, which may take various forms depending on the desired form of preparation for administration. The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, ocular, ocular, rectal, vaginal, or transdermal administration.

[0152] These pharmaceutical compositions are suitable for topical, oral, rectal (e.g., via enema, suppository, or catheter), or nasal (e.g., via nasogastric tube or nasoduodenal tube via endoscopy).

[0153] For example, in preparing oral dosage forms, any commonly used pharmaceutical medium can be used, such as water, glycol, oil, alcohol, etc., in the case of oral liquid preparations (such as suspensions, syrups, elixirs, and solutions); or solid carriers such as starch, sugar, kaolin, lubricants, binders, and disintegrants in the case of powders, pills, capsules, and tablets.

[0154] Of particular advantage is the formulation of the above-described pharmaceutical compositions in unit dosage form to achieve ease of administration and uniform dosage. As used herein in this specification and claims, unit dosage form refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of the active ingredient, calculated to produce the desired therapeutic effect, and bound to a desired drug carrier. Examples of such unit dosage forms are: tablets (including scored or coated tablets), capsules, pills, powder packets, thin films, solutions or suspensions for injection, teaspoon amounts, tablespoon amounts, etc., and their discrete multiples.

[0155] The compounds of the present invention shall be applied in an amount sufficient to exert their antimicrobial activity, particularly antibiotic activity.

[0156] The compounds according to the invention can be applied to humans or animals, which can be mammals, such as farm animals or animals kept as pets, such as dogs, cats or horses.

[0157] The present invention further relates to the use of the compounds according to the invention in the manufacture of pharmaceutical compositions. For example, the pharmaceutical compositions can be used as antimicrobial agents, particularly antibiotics, i.e., for inhibiting bacterial growth.

[0158] Non-therapeutic uses and methods The compounds of the present invention can be used as antimicrobial agents for non-therapeutic purposes, such as for water treatment.

[0159] In a third aspect, the invention provides the non-therapeutic use of a compound of formula I or a composition thereof as an antimicrobial (e.g., antibacterial and / or antibiotic) agent. In a fourth aspect, the invention provides a non-therapeutic treatment method comprising contacting an article, water (e.g., a body of water, such as a lake and / or a waterway, such as a river or stream), soil (e.g., part or all of a field), and / or rock with a compound of formula I or a composition thereof.

[0160] The article can be as defined in the preceding subsections. Therefore, the compound or a composition containing the compound can be used as a surface cleaner.

[0161] The compound of Formula I can be used to treat a portion of the lithosphere (rock), hydrosphere (water), and / or pedosphere (soil). The portion may be treated with an amount of the compound 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, relative to the portion without the compound. For example, the portion may be treated with an amount of the compound of 80 wt% or less, such as 50 wt% or less, or 20 wt% or less, relative to the portion without the compound. The portion may be treated with an amount of the compound of 0.001 wt% to 80 wt%, such as 1 wt% to 50 wt%, relative to the portion without the compound.

[0162] Example synthesis In the attached diagram Figure 5 The synthetic pathway for preparing the modified amino acid (MAA) of this invention is illustrated. An example of the synthetic pathway is described at Baker, BC. et al., European Polymer Journal 162 (2022) 110889 (especially Scheme 1 and “Section 3. Synthesis and characterisation data” on page 2).

[0163] In order to prepare "monomer" compounds (such as Figure 2 The methyl esters of amino acids (e.g., alanine, valine, phenylalanine, L-tyrosine, or D-tyrosine) are reacted with a molar equivalent of isocyanate (or isothiocyanate) in tetrahydrofuran (30 mL) in the presence of triethylamine (5 mL) at 25 °C to provide the corresponding urea derivatives, which are then separated by filtration (45 µm) and vacuum removal of the solvent.

[0164] These compounds can be synthesized by adding NaOH. （水溶液） Hydrolysis was performed using 5 mL of 2M solution, followed by precipitation with the addition of HCl to provide the corresponding carboxylic acid derivative of the compound. This carboxylic acid derivative may exhibit increased water solubility compared to the corresponding methyl ester derivative.

[0165] "Dimer" compounds (such as those made from...) Figure 3 Those shown are prepared by reacting two molar equivalents of methyl ester of L-tyrosine or D-tyrosine with one molar equivalent of diisocyanate in THF (30 mL) at 25 °C to provide the corresponding urea derivative, and separating the corresponding urea derivative by removing the solvent under vacuum.

[0166] Figures 2 to 4 It has been shown that it has been passed Figure 5 The pathway shown represents the synthesis of a series of MAA 1 to MAA 5 and MAA 7 to MAA 17. Compounds 101 to 118 and 201 to 248 (structures detailed in the table below) were synthesized according to a similar procedure. Some compounds are represented by two or more of series 1 to 5 and series 7 to 17, series 101 to 118 and series 201 to 248.

[0167] Antimicrobial test—methyl ester derivatives Tests were performed on four different 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]). Figure 2 and Figure 3The methyl ester of the MAA compound shown is (where R = Me). The test protocol (modified from ISO 22196 test procedure) involves adding each sample (approximately 4 mg) to MAA and adding a separate bacterial suspension (2 mL, OD) to PBS. 600 The bacterial cells were counted in the range of 0.1–0.2 and incubated at 37°C for 24 hours. The mixture was then plated onto HBHI growth medium and incubated at 37°C for another 24 hours. The colony forming units (CFU) were counted (average of the 5 reported rounds). In all cases, Control 1 represented plated bacterial solutions without the addition of MAA, and Control 2 represented bacterial solutions plated immediately after the addition of the MAA starting material [approximately 4 mg] for the same procedure.

[0168] In the attached diagram Figure 6 Colony-forming units (per 50 µL of plate solution) of each bacterial strain of Escherichia coli, KP, MX and SA observed by plate counting after incubation for 24 h with the corresponding MAA 1 to MAA5 and MAA 7 to 12 (where R=Me) are shown; no colonies were observed where no strips were given.

[0169] Compared with the control sample, all compounds significantly reduced the levels of Escherichia coli, KP, and SA.

[0170] No residual E. coli was observed in the presence of compounds 3, 7, and 10. Compounds 1, 2, 4, 5, 8, 9, 11, and 12 almost completely reduced the amount of E. coli.

[0171] Compounds 3 through 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 also effectively reduced the amount of KP compared to the control sample.

[0172] Compared to the control, compounds 2, 4, and 7 to 12 effectively reduced the amount of MX. Particularly good results were observed for compounds 2 and 8 to 12 related to MX.

[0173] No colonies were observed in the presence of compound 7 for SA. Compounds 2, 3, and 10 were also particularly effective against SA. All compounds reduced the number of SA colonies compared to the control sample.

[0174] Compounds 2, 4, 9, and 10 were found to be the most effective compounds against bacteria. They exhibited the same exclusion zone as penicillin in the MX bacterial flora test.

[0175] Compounds 13, 14, 16, and 17 were also tested against SA using essentially the same method. Compounds 13 and 17 were partially effective against SA. Compounds 14 and 16 were fully effective against SA.

[0176] Compounds 14 and 15 were also tested against Escherichia coli using essentially the same method. Compound 14 was partially effective against E. coli, and compound 15 was completely effective against E. coli.

[0177] Therefore, the compound of formula I (where R) 1 Compounds with hydrocarbon groups, such as Me, are effective antibacterial agents.

[0178] Furthermore, these tests demonstrate that multiple functionalities provide effective antibacterial effects. For example, at least urea or thiourea groups can be used as linking groups. 3 The group has been proven to be effective at least for substituted or unsubstituted alkyl or aryl groups. 2 The group has been shown to be effective for at least substituted or unsubstituted alkyl or aryl groups.

[0179] Antimicrobial test—carboxylic acid derivatives Hydrolyzed compounds (where R=H): Figure 2 and Figure 3 The carboxylic acid derivatives (1-H to 5-H and 7-H to 12-H) of the MAA compounds shown (where R=H) have been tested against Escherichia coli using the same protocol described above to determine their antibiotic performance.

[0180] In the attached diagram Figure 7 The colony-forming units of *E. coli* observed by plate counting (per 50 µL of solution) after incubation at 37°C on HBHI plates with the corresponding MAA 1H to 5H and 7H to 12H for 24 h are shown. No colonies were observed where no strips were provided.

[0181] It can be seen that no *E. coli* colonies were observed when using compounds 2-H to 7-H, 10-H, or 12-H. Only trace amounts of *E. coli* were observed when using compounds 1-H, 8-H, and 9-H. All compounds were more effective than the control sample in reducing the number of *E. coli* colonies.

[0182] Therefore, the compound of formula I (where R) 1 H) is an effective antibacterial agent.

[0183] Antimicrobial test—enantiomer As described above, the test for Staphylococcus aureus [SA, Gram-positive] is as follows: Figure 2 and Figure 3 The L-enantiomers and D-enantiomers of compound 3 are shown (where R = Me).

[0184] In the attached diagram Figure 8 The colony-forming units (per 50 µL of solution) observed by plate counting after incubation with each enantiomer of compound 3 for 24 h are shown.

[0185] It can be seen that the number of SA colonies observed in the presence of each enantiomer was similar to that of each other and was significantly lower than that observed in the control.

[0186] Therefore, the enantiomers of the selected compounds appear to have limited effect on the antimicrobial activity of the compounds.

[0187] Human cell compatibility The cytotoxicity of compounds 1 to 5 and 7 to 12, as well as the control (no compound), to Caco-2 human cells was determined using the AlamarBlue assay. Each compound was dispersed in PBS at 2 mg / mL. Caco-2 human cells were grown in 96-well microplates for 24 h. Then, each compound (at 2 mg / mL) was added to the wells containing the cells, and the cells were grown for another 24 h. The PBS and compounds were then removed, AlamarBlue was added, and the cells were incubated for another 2 h. Fluorescence was monitored to determine cell viability levels.

[0188] In the attached diagram Figure 9 The results of this cytotoxicity study are shown.

[0189] Compared with the control, compounds 1 to 5 and 7 to 12 did not show significant cytotoxicity levels.

[0190] Therefore, it was found that all the compounds tested were substantially compatible with human cells.

[0191] Antibacterial data for compounds 101 to 118 Antibacterial studies were conducted on compounds 101 to 118 against Staphylococcus aureus (SA) and Escherichia coli (EC). The functional groups of compounds 101 to 118 are listed in the table below.

[0192] In each case, X represents O.

[0193] A small suspension of bacterial species was taken from frozen bacteria (-80°C) using a cell scraper. This bacterial species suspension was then resuspended in a vial containing 1 mL of Dulbecco's phosphate-buffered saline (DPBS). The optical density of the bacteria was measured at 600 nm, and for various bacteria, 0 was obtained for Staphylococcus aureus (SA). 2 CFU, and obtained 10 against Escherichia coli (EC). 4 CFU (Optimal Colony Counting Conditions). Following this, stock solutions of various compounds in DBPS (4 mg / mL) were added to the bacterial solution, and the solution was kept in contact with the bacteria at 37°C for 4 hours. After 4 hours of incubation, 20 µL aliquots were plated onto prepared HBHI agar plates using a cell spreader. The plates were then held in the incubator to allow bacterial colonies to grow over 24 hours. Bacterial colonies were counted to quantify the effectiveness of the material.

[0194] In the attached diagram Figure 10 The results of studies on the antibacterial activity of compounds 101 to 118 are shown, with a graph presenting the percentage of viable cells remaining in each test relative to the control.

[0195] All tyrosine derivatives were found to exhibit antibacterial properties against SA and / or EC.

[0196] Compounds 103, 106, and 108 yielded the best results. Among these compounds, R... 2 This indicates an aromatic group (phenyl) with an electron-withdrawing group (nitro or chlorine in these examples) at the para or meta position.

[0197] XR 1 =OMe compounds exhibit high activity (e.g., compounds 103, 104, 105, 106, 107, 108, 109, and 117), while L=urea (i.e., -NHCONH-) compounds (e.g., compounds 103, 104, 105, 106, 107, 108, 109, 117, and 118) also exhibit high activity.

[0198] Where R 3 =Me compound 117 also exhibits high antibacterial activity.

[0199] Variants of compound 103 (where the ester has been hydrolyzed to form a carboxylic acid (XR)) 1 =OH, compound 118), also showed effectiveness. This compound is water-soluble and can form a gel.

[0200] Variant of compound 103—of which XR1 It is O-tert-butyl (compound 110), where R 2 Aryl groups with a nitro group at the ortho position (compound 111), or where L is an amide (compound 115) – all showed reduced antimicrobial effects. For derivatives of compound 109, namely compound 112: R 1 =tert-butyl; and compound 114:L=amide, the same situation was observed. However, these compounds are still effective to some extent. Compounds where L represents thiourea (compound 113) showed a lower antibacterial effect.

[0201] Cytotoxicity data for compounds 101 to 118 To test toxicity, the AlamarBlue™ assay was performed. The assay was performed on CaCo-2 cells. A single 50 µL aliquot of the frozen cell line (1 mL vial) was transferred to 20 mL of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (P / S). After thawing the cells in the medium, they were transferred to a T 75 cell culture flask (CCF). The flask was then incubated for 4–5 days for cell growth, with the CCF lid loosely closed to allow respiration. The cells were first washed with 15 mL of PBS, then 3 mL of trypsin was added and the trypsin was incubated at 37°C for 10–15 minutes in the flask to lyse the cells. The cells were then centrifuged in 50 mL Falcon tubes at 1500 rpm for 5 minutes. Cells were deposited at the bottom of the flask, and the culture medium (supernatant) was discarded. These cells were then dispersed in 1 mL of culture medium and transferred to another T 75 CCF. 14 mL of culture medium was added to this CCF to bring the total volume to 15 mL. A 96-well plate was taken, and 7.75 µL of cells / culture medium was transferred to each well. Next, 100 µL of culture medium (15 mg / mL) was added to each well, and the plate was incubated overnight. On the second day, the culture medium was removed, and compounds 101 to 118, dispersed in 200 µL of culture medium, were added to each well. After 24 hours of incubation, the culture medium was removed, and 100 µL of alamarBlue™ solution (220 µL alamarBlue in 2.2 mL of culture medium) was added. TMThe 96-well plate was then wrapped in aluminum foil to prevent light exposure and incubated for 2 hours. The solution consisting of alamarBlue™ solution was then partially transferred to a new 96-well plate and read using a multimode microplate reader.

[0202] The results of this study are shown in the accompanying figures. Figure 11 In this study, each of compounds 101 to 118 exhibited significant biocompatibility.

[0203] Antibacterial and cytotoxic data of compounds 201 to 248 The antibacterial activity of compounds 201 to 248 was determined following the procedure described above for compounds 101 to 118. Compounds 201 to 248 are described in the table below: In each case, X represents O. * indicates that it combines with the adjacent nitrogen of the urea group to form a five-membered ring, as in proline.

[0204] Preliminary antibacterial studies involved tyrosine derivatives 201 to 209 targeting four bacterial strains. The antibacterial properties of the samples targeted Staphylococcus aureus (Staphylococcus aureus). Staphylococcus aureus SA), Klebsiella pneumoniae ( Klebsiella pneumoniae KP), Moraxella catarrhalis (K ...) Moraxhella catarrhalis / *M. catarrhalis* and *Escherichia coli* (E. coli). First, a small suspension of bacterial species was taken from frozen bacteria (-80°C) using a cell scraper. This bacterial species suspension was then resuspended in vials containing 1 mL of Dulbecco's phosphate-buffered saline (DPBS). The optical density (OD) of the bacteria was measured at 600 nm, and different values ​​were optimized after multiple trials for various bacteria. The optimized OD at 600 nm was approximately 0.05 for a bacterial suspension diluted 10⁻⁵ for *Staphylococcus aureus* (SA). 2 It is diluted 10 times and is effective against Moraxella catarrhalis (Mx), Escherichia coli (E. coli), and Klebsiella pneumoniae (KP). 4The stock solution of CMP (4 mg / mL) dispersed in DBPS was then added to the bacterial solution, and the solution was kept in contact with the bacteria at 37°C for 4 hours. After 4 hours of incubation, 20 µL aliquots were plated onto prepared HBHI agar plates using a cell spreader. The plates were then kept in the incubator to allow bacterial colonies to grow over 24 hours. The bacterial colonies were counted to quantify the effectiveness of the material.

[0205] The results are shown in the attached figure. Figure 12a As shown. Specifically, Figure 12a Preliminary studies demonstrate the antibacterial activity of tyrosine-based MAA against *Escherichia coli*, *Klebsiella pneumoniae*, *Moraxella catarrhalis*, and *Staphylococcus aureus*. The MAA was incubated in PBS at a concentration of 4 mg / mL at 37°C for 24 h, then plated onto suitable culture media and incubated at 37°C for another 24 h. Colony-forming units were then counted. While all tyrosine derivatives exhibited antibacterial properties, compounds 202, 203, and 206 showed the greatest versatility.

[0206] To test the potential solubility effect in PBS, the compound was incubated at 60°C for one week, filtered, and the antimicrobial activity of the solvent PBS was examined. The results are shown in the attached figure. Figure 12b As shown. Specifically, Figure 12b The results of the leaching test are shown. Although limited activity was demonstrated, the feasibility of solubilizing the compound was proven.

[0207] To test toxicity, an AlamarBlue assay was performed. The assay was performed on CaCo-2 cells. 50 µL of the frozen cell line (1 mL vial) was aspirated once into 20 mL of Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin (P / S). After thawing the cells in the medium, they were transferred to a T 75 cell culture flask (CCF). The flask was then incubated for 4–5 days for cell growth, with the CCF lid loosely closed to allow respiration. The cells were first washed with 15 mL of PBS, then 3 mL of trypsin was added and the trypsin was incubated at 37°C for 10–15 minutes in the flask to lyse the cells. The cells were then centrifuged in 50 mL Falcon tubes at 1500 rpm for 5 minutes. Cells were deposited at the bottom of the flask, and the culture medium (supernatant) was discarded. These cells were then dispersed in 1 mL of culture medium and transferred to another T 75 CCF. 14 mL of culture medium was added to this CCF to bring the total volume to 15 mL. A 96-well plate was taken, and 7.75 µL of cells / culture medium was transferred to each well. Next, 100 µL of culture medium (15 mg / mL) was added to each well, and the plate was incubated overnight. On the second day, the culture medium was removed, and wells 1 through 9, dispersed in 200 µL of culture medium, were added to each well. After 24 hours of incubation, the culture medium was removed, and 100 µL of AlamarBlue solution (220 µL of alarm blue in 2.2 mL of culture medium) was added. The 96-well plate was then wrapped in aluminum foil to prevent light exposure and incubated for 2 hours. The solution consisting of AlamarBlue solution was then partially transferred to a new 96-well plate and read using a multimode microplate reader.

[0208] In the attached diagram Figure 12c The results of this study are presented. Specifically, Figure 12c The results show that the compounds were non-cytotoxic to Caco-2 human cells (72 h) using the AlamarBlue assay procedure. In each case (a to c), the error bars were calculated as the average error from 5 rounds, and each compound showed biocompatibility of over 80%.

[0209] To broaden the range of compounds tested, similar biocompatibility screening was performed on compounds 201 through 248. All compounds showed biocompatibility exceeding 75%. Compound 211 exhibited the lowest biocompatibility (77%). Compound 211 was the only compound present in a liquid rather than solid state.

[0210] Most of compounds 201 to 248 were tested for both SA and EC using the same conditions as described above in this subsection.

[0211] Compounds 202 to 210, 212 to 217, 219 to 221, 224 to 231, 233 to 236, 239, 241 and 243 to 248 exhibited good antimicrobial effects, wherein 50% or less of at least one of the bacteria remained after the testing period.

[0212] Compounds 202 to 209, 214, 217, 219 to 221, 225, 230, 233, 234, 244 and 247 exhibited excellent antimicrobial effects, wherein 20% or less of at least one of the bacteria remained after the testing period.

[0213] Compounds 203 to 206, 208 to 209, 220, 225 to 229 and 247 exhibited particularly excellent antimicrobial effects, with 20% or less of each bacterium remaining after the testing period.

[0214] In the attached diagram Figure 13 The results of this study are presented. Specifically, Figure 13 The antibacterial activity of most MAA 201 to 248 against Escherichia coli and Staphylococcus aureus was shown, with MAA at a concentration of 4 mg / mL in PBS, incubated at 37°C for 24 h, then plated onto suitable medium and incubated at 37°C for another 24 h, followed by counting of colony-forming units.

[0215] It should be noted that the amide bonds in compounds 214, 215 and 218 significantly reduce the effectiveness of the parent urea derivative against these two pathogens.

[0216] To investigate the efficacy of the compounds against higher concentrations of pathogens and their effects on vitreous formation, the three most potent compounds, 203, 206 (tyrosine-based) and 228 (alanine-based), were cast onto vitreous slides (equivalent to 16 mg / mL) and placed in higher concentrations of EC and SA (10⁸ CFU / mL and 10⁷ CFU / mL, respectively), with CFU counts monitored over 24 h.

[0217] The results of this study are shown in the attached figures. Figure 14 As shown, within 24 h, the CFU of both bacteria decreased significantly for each compound. After 24 h, no bacteria were observed in the presence of any of the three compounds.

[0218] The effectiveness of compound 203 against pathogens highlighted by the WHO, particularly against various MRSA and VRSA pathogens, was determined. The bacterial strains tested included SH1000, Newman, MRSA252, TW20, E-MRSA15, JDK6159, Mu3, Mu50, SH1000-128, and LAC-128.

[0219] In the attached diagram Figure 15 Bacterial survival rates of colonies after exposure to control (initial, 0 h), control (no exposure to the compounds of the present invention for 18 h), and the present invention (exposure to compound 203 for 18 h) are shown. In each case, no significant increase in bacterial survival rate was observed between the initial control and the control without exposure to said compound for 18 h. However, after exposure to compound 203 for 18 h, the bacterial survival rates of these challenging strains remained (without significant difference) or decreased. Indeed, the growth rate of each of the strains was slowed.

[0220] It was also found that the glassy film of compound 203 cast on the slide was effective, showing a significant reduction in bacterial colony counts against strain LAC-128 compared to the bacterial control alone and the bacterial control without compound 203 on the slide.

Claims

1. An article comprising a compound of formula I: Formula I, in: R 1 It represents H, or an optional substituted C1-C12 hydrocarbon group, or a water-soluble functional group; R 2 Indicates C1 or an optional higher hydrocarbon group that has been substituted; R 3 Indicates H or an optional substituted C1-12 hydrocarbon group; X represents O, NH, S, or PH; and L represents a linking group, and The article said article includes: a) A substrate and a surface layer, wherein the surface layer comprises the compound; and / or b) The compound dispersed in the adhesive.

2. The article of claim 1, wherein the article of claim 1 is selected from the list of: health care devices, medical devices, display devices, imaging devices, packaging, agricultural facilities, air treatment and / or treatment components, water treatment and / or treatment components, and food and / or beverage preparations.

3. The article of claim 2, wherein the article is an article of a medical device, packaging, touch screen, lens, light shield, or health care facility.

4. A composition comprising a compound of formula I and a carrier and / or a 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 of: detergent compositions, disinfectant compositions, food and / or beverage preservatives, and building materials.

6. The composition according to claim 4 or claim 5, wherein the composition further comprises water, surfactant, pigment, colorant, binder / polymer, oil, preservative, curing agent, fragrance, emollient, bleaching agent, filler, blocking agent, thickener, humectant, dihydroxyacetone, siloxane and / or tetrachlorohydroxyaluminum zirconium (GLY).

7. Non-therapeutic use of compounds of formula I or combinations thereof as antimicrobial agents.

8. A non-treatment method comprising contacting an article, water, soil and / or rock with a compound of formula I or a combination thereof.

9. A compound of formula I, said compound of formula I, used in the prevention or treatment of microbial infections.

10. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding claims, wherein R 2 This indicates the optional substituted C1-C50 alkyl and / or aryl groups.

11. The article, composition, non-therapeutic use, non-treatment method, or compound used according to claim 10, wherein R 2 This indicates that the C1-C12 hydrocarbon groups are substituted.

12. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding claims, wherein R 2 Optionally substituted with one or more groups selected from the list of the following: -NO2, -O-, halogens (e.g., -F, -Cl and -Br), -CN, -OH, CO2H, CO2R 1 And -N(H)C(O)N(H)-.

13. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding claims, wherein R 3 This indicates the optional substituted C1-12 alkyl and / or aryl groups.

14. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding claims, wherein R 3 Optionally, it may be substituted with one to four groups selected from the list of the following groups: -OH, -NH2, -CO2H, -CONH2, and -B(OH)2.

15. The article, composition, non-therapeutic use, non-therapeutic method, or compound used according to any of the preceding claims, wherein X represents O or NH.

16. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding claims, wherein R 1 It represents H or an unsubstituted C1-C4 hydrocarbon group.

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

18. The article, composition, non-therapeutic use, non-therapeutic method, or compound used according to any one of claims 1 to 9 or 12 to 17, wherein formula I is represented by formula III: Formula III, in: R 1 R 3 X and L are each defined independently as for equation I. R 4 and R 5 Each independently represents an optional substituted C1-C12 hydrocarbon group, and n is 1 or greater.

19. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding claims, wherein: -R 1 Indicates H or an optional substituted C1-C8 hydrocarbon group; -R 2 Indicates the optional substituted C1-C50 hydrocarbon group; -R 3 Represents H or optionally substituted C1-12 aryl and / or alkyl groups; - Any substituents are selected from the following list: thioethers, hydroxyl groups, ethers, nitro groups, nitrile groups, and halogens; -X indicates O, NH, or S; and -L contains or represents one or more groups selected from the list of the following: amides, esters, carbamates, carbonates, carboxylic anhydrides, thioureas, and ureas.

20. The article, composition, non-therapeutic use, non-treatment method, or compound used according to claim 19, wherein: -R 1 Indicates H or an unsubstituted C1-C2 hydrocarbon group; -R 2 This indicates a C1-C42 alkyl or aryl group that is optionally substituted by one to four groups selected from the list consisting of -NO2, -O-, halogen and -CN; -R 3 This indicates a C1-8 alkyl and / or aryl group that is optionally substituted by two or fewer groups selected from the list of groups consisting of -OH and -NH2; -X indicates O; and -L indicates a thiourea group or a urea group.

21. The article, composition, non-therapeutic use, non-treatment method, or compound used according to claim 20, wherein: -R 1 Indicates an H or methyl group; -R 2 It represents an unsubstituted C6-12 aryl group, or a C4-12 aryl group substituted with one to three groups selected from the list of -NO2, halogen and -CN in one or both of the meta and / or para positions; -R 3 This indicates a C7 aryl group or a C1 alkyl group that is optionally substituted with a -OH group; -X indicates O; and -L indicates urea.

22. The article, composition, non-therapeutic use, non-treatment method, or compound used according to claim 21, wherein: -R 1 Indicates an H or methyl group; -R 2 This indicates an unsubstituted phenyl group, or a phenyl group substituted in one or more of the meta and / or para positions by one or more groups selected from the list consisting of -NO2 and / or Cl; -R 3 This indicates -CH2Ph ​​or methyl, which may be optionally substituted with a -OH group; -X indicates O; and -L indicates urea.

23. The article, composition, non-therapeutic use, non-treatment method, or compound used according to claim 19, wherein said compound has one of the following structures: 。 24. The article, composition, non-therapeutic use, non-treatment method, or compound used according to claim 19, wherein said compound is functionalized as defined in the following table: 。 25. The article, composition, non-therapeutic use, non-treatment method, or compound used according to claim 19, wherein said compound is functionalized as defined in the following table: 。 26. The article, composition, non-therapeutic use, non-treatment method, or compound used according to any of the preceding claims, wherein the compound has the following stereochemistry: 。 27. A compound of formula I, said compound of formula I, used as a drug.

28. A compound of formula I, wherein the compound of formula I is not represented by formula II: Formula II.

29. The compound according to claim 28, wherein the compound is represented by one of the following structures: ， The condition is that the compound of formula I is not represented by formula II.

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