Phytochemical antibiotic conjugates as inhibitors of staphylococcus bacteria

Abstract

The present application relates to the use of sulfadiazine-phytochemical compounds of Formula I and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, and composition thereof for the treatment of a Staphylococcus bacterial infection or a disease, disorder or condition arising from a Staphylococcus bacterial infection. Formula (I)

Description

TITLE: PHYTOCHEMICAL ANTIBIOTIC CONJUGATES AS INHIBITORS OF STAPHYLOCOCCUS BACTERIA RELATED APPLICATIONS

[0001] The present application claims the benefit of priority of co-pending United States provisional patent application no. 63 / 745,972 filed on January 16, 2025, the contents of which are incorporated herein by reference in their entirety.FIELD

[0002] The present application relates to treatments for bacterial infections. More particularly, the application relates to the use of a sulfadiazine-phytochemical conjugates, such as compounds of Formula I as defined herein, for treatment of a Staphylococcus bacterial infection or a disease, disorder or condition arising from a Staphylococcus bacterial infection.BACKGROUND

[0003] Staphylococcus are a genus of Gram-positive bacteria commonly found on the skin of human and animals. Although most Staphylococcal infections are mild to moderate, deeper body infections caused by Staphylococcal species, such as coagulase-positive S. aureus and coagulase-negative S. epidermidis, can be severe and even life-threatening [1], Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common pathogens for healthcare-associated infections and resistant to penicillins and cephalosporins [2], MRSA infection is usually treated with vancomycin, trimethoprim-sulfamethoxazole and linezolid, however, resistance towards these drugs has emerged in recent years [3-5], Furthermore, S. aureus has been identified to be the common mastitis-causing pathogen in Canadian dairy farms [6], A recent study showed that the global occurrence of S. aureus is 29.07% in milk samples (MRSA: 6.52%) and 42.81% in cheese samples (MRSA: 1.69%) [7], S. epidermidis is another major pathogen for healthcare-associated infections and can lead to severe bloodstream, peritoneal and CNS infections [8], S. aureus and S. epidermidis have also been identified to be the predominant pathogens in human mastitis [9], Thus, developing novel antimicrobial agents to combat Staphylococcal infections and resistances is of high importance to both human and animal health.

[0004] As a major threat to human and animal health, antimicrobial resistance (AMR) has attracted a global attention and many counties have tightened the control on antibiotic usage [10, 11], In the meantime, various types of new antimicrobial compounds and therapeutic strategies have been developed. Based on the observation that AMR can be delayed / prevented by co-administration of synergistic antibiotics [12, 13], antibioticsconjugated with bioactive molecules such as antibodies and peptides have been investigated [14, 15],

[0005] Phytochemicals have been observed to possess antimicrobial functions [16, 17], Some combinations of antibiotics and phytochemicals have been investigated including phytochemical conjugates. For example, the antibiotic-phytochemical conjugate, sulfamethoxazole-gallatehas shown inhibitory activity against susceptible Streptococcus and Enterococcus bacterial strains with minimum inhibitory concentrations (MICs) around 1200 pg / mL and a multidrug-resistance Enterococcus faecalis clinical isolate

[0018] , Additional sulfamethoxazole-phytochemical conjugates have been shown to exhibit antimicrobial activities towards six tested strains of Gram-positive bacteria and one tested strain of Gramnegative bacteria

[0019] , For example, sulfamethoxazole-eugenol and sulfamethoxazole-caffeate showed relatively good inhibition of S. aureus and S. epidermidis with MICs of 125-250 pg / mL.

[0006] Jayaraman P. et al., (Drug Design, Development and Therapy, 2013, 7:449-475) describe the in silico design of various phytochemical-antibiotic drug conjugates as multitarget inhibitors of Pseudomonas aeruginosa enzymes. Protocatechuic acid and gallic acidsulfadiazine compounds were designed. However no compounds were actually prepared and tested.

[0007] There remains a need to develop new antimicrobial agents.SUMMARY

[0008] It has been shown herein that sulfadiazine-phytochemical compounds of the application conjugate provide surprisingly improved inhibitory activity and selectivity towards Staphylococcus bacteria /

[0009] Accordingly, the present application includes a compound of Formula I:R2R3IIL< Y R4rr5and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, whereinR1, R2, R4and R5are independently selected from H, OH, halo, NO2, CN, CO2H, C1-6alkyl, OC1-6alkyl, CO2C1-6alkyl, NH2, NH(C1-6alkyl) and N(C1-6alkyl)(C1-6alkyl);R3is selected from OH, halo, NO2, CN, CO2H, CHO, SO3H, Ci_6alkyl, C2.6alkenyl, OCi.6alkyl, NH2, NH(Ci.6alkyl), N(Ci.6alkyl)(Ci.6alkyl), CO2Ci.6alkyl, Ci.6alkyleneCO2H, Ci.6alkenyenelCO2H, Ci-6alkyleneCO2Ci-6alkyl, Ci-6alkenyleneCO2Ci-6alkyl, C1-6alkyleneCHO, Ci.6alkenyleneCHO, Ci-6alkyleneSO3H and Ci.6alkenyleneSO3H;L1is a linker group having the formula, Z1-(CH2)m-(Z2)n,Z1is selected from O, NR6, NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O, NR6C(O)NR6, OC(O)NR6and NR6C(O)O,Z2is selected from O, NR7, OC(O), C(O)O, OC(O)O, OC(O)NR7and NR7C(O)O,R6and R7are independently selected from H and Ci-4alkyl;m is selected from 0, 1, 2, 3 and 4, andn is selected from 0 and 1,provided m is not 0 when n is 1; andZ1is not NR6when Z2is O.

[0010] The application further includes a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, and a pharmaceutically acceptable carrier.

[0011] The application also includes a method of treating or preventing a Staphylococcus bacterial infection comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, to a subject in need thereof.

[0012] The application also includes a method reating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, to a subject in need thereof.

[0013] In an embodiment, the present application comprises, consists or consists essentially of the stated features, elements, components, groups, integers, and / or steps.

[0014] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the description as a whole.DRAWINGS

[0015] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0016] Figure 1 shows the structural comparison of exemplary sulfadiazine-eugenol compound 1-1 and exemplary sulfadiazine-protocatechuic acid compound I-2 methotrexate (MTX).DETAILED DESCRIPTIONI. Definitions

[0017] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0018] All features disclosed in the specification, including the claims, abstract, and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise.

[0019] The term “compound(s) of the application” or “conjugate(s) of the application” as used herein refers to a compound of Formula I and the like and includes pharmaceutically acceptable salts, solvates and / or prodrugs thereof as well as all stereoisomers and regioisomers.

[0020] The term “composition(s) of the application” or “composition(s) of the present application” and the like as used herein refers to a composition, such a pharmaceutical composition, comprising a compound of the application.

[0021] As used in this application and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "include" and "includes") or "containing" (and any form of containing, such as "contain" and "contains"), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0022] The term “consisting” and its derivatives as used herein are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0023] The term “consisting essentially of’, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers, and / or steps.

[0024] The term “suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, the identity of the molecule(s) to be transformed and / or the specific use for the compound, but the selection would be well within the skill of a person trained in the art. All process / method steps described herein are to be conducted under conditions sufficient to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0025] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0026] As used in this application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including “a compound” should be understood to present certain aspects with compound or two or more additional compounds.

[0027] In embodiments comprising an “additional” or “second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0028] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present. The term “and / or” with respect to pharmaceutically acceptable salts and / or solvates thereof means that the compounds of the application exist as individual salts and hydrates, as well as a combination of, for example, a solvate of a salt of a compound of the application.

[0029] The term “bacterial infection” as used herein refers to an invasion of cells or bodily tissues by a foreign undesirable bacteria.

[0030] The term “Staphylococcus bacterial infection” as used herein refers to a bacterial infection wherein the bacteria is from the genus Staphylococcus.

[0031] The term “phytochemical” as used herein refers to a biologically active compound produced by plants.

[0032] The term “antibiotic” as used herein refers to an antimicrobial drug used in the treatment and prevention of bacterial infections.

[0033] The term “sulfadiazine” as used herein refers to a compound having the chemical name: 4-amino-N-pyrimidin-2-ylbenzenesulfonamide, and having the chemical formula:

[0034] The term “eugenol” as used herein refers to a compound having the chemical name: 2-methoxy-4-(prop-2-en-1-yl)phenol, and having the chemical formula:

[0035] The term “protocatechuic acid” as used herein refers to a compound having the chemical name: 3,4-dihydroxybenzoic acid, and having the chemical formula:

[0036] The term “linker group” as used herein refers to any molecular structure that joins two or more other molecular structures together.

[0037] The term “alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix “Cni-n2”. For example, the term C-Moalkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. All alkyl groups are optionally fluorosubstituted, unless otherwise indicated.

[0038] The term “alkenyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2”. For example, the term C2-ealkenyl means an alkenyl grouphaving 2, 3, 4, 5 or 6 carbon atoms and at least one double bond. All alkenyl groups are optionally fluorosubstituted, unless otherwise indicated.

[0039] The term “alkylene”, whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2”. For example, the term O-ealkylene means an alkylene group having 1, 2, 3, 4, 5 or 6 carbon atoms. All alkylene groups are optionally fluorosubstituted, unless otherwise indicated.

[0040] The term “alkenylene” as used herein, whether it is used alone or as part of another group, means a straight or branched chain, unsaturated alkylene group, that is, an unsaturated carbon chain that contains substituents on two of its ends and at least one double bond. The number of carbon atoms that are possible in the referenced alkenylene group are indicated by the prefix “Cni-n2”. For example, the term C2-6alkenylene means an alkenylene group having 2, 3, 4, 5 or 6 carbon atoms. All alkenylene groups are optionally fluorosubstituted, unless otherwise indicated.

[0041] The terms “halo” or “halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.

[0042] The term “conjugate” as used herein refers to two molecules joined together via a covalent linkage, either directly or via a linker group.

[0043] The expression “disease, disorder or condition arising from a bacterial infection” as used herein refers to any disease, disorder or condition that is directly or indirectly caused by the presence of a bacterial infection in a subject.

[0044] The term “subject” as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus the methods of the present application are applicable to both human therapy and veterinary applications.

[0045] When used, for example, with respect to the methods of treatment, uses, compositions and kits of the application, a subject, for example a subject “in need thereof’ is a subject who has been diagnosed with, is suspected of having, may come in to contact with, and / or was previously treated for a bacterial infection or a disease, disorder or condition arising from a bacterial infection.

[0046] The term “pharmaceutical composition” as used herein refers to a composition of matter for pharmaceutical use.

[0047] The term “pharmaceutically acceptable” means compatible with the treatment of subjects.

[0048] The term “pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.

[0049] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with, the treatment of subjects.

[0050] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0051] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0052] The term “solvate” as used herein means a compound, or a salt of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice.

[0053] The term “prodrug” as used herein means a compound, or salt and / or solvate of a compound, that, after administration, is converted into an active drug.

[0054] The term “parenteral” as used herein means taken into the body or administered in a manner other than through the gastrointestinal tract.

[0055] The term “administered” as used herein means administration of an effective amount of a compound, including a compound of the application, to a cell either in cell culture or in a subject.

[0056] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount effective, at dosages and for periods of time necessary to achieve a desired result. For example, in the context of treating a bacterial infection, or a disease, disorder or condition arising from a bacterial infection, an effective amount of a compound is an amount that, for example, reduces the bacterial infection compared to the bacterial infection without administration of the compound. By “reducing the infection”, it is meant, for example, reducing the amount of the infectious agent in the subject and / or reducing the symptoms of the infection

[0057] The terms “to treat”, “treating” and “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, diminishment of extent of bacterial infection, stabilization (i.e. not worsening) of the state of the bacterial infection, preventing spread of the bacterial infection, delay or slowing of infection progression, amelioration or palliation of the bacterial infectious state, diminishment of the reoccurrence of bacterial infection, diminishment, stabilization, alleviation or amelioration of one or more diseases, disorders or conditions arising from the bacterial infection, diminishment of thereoccurrence of one or more diseases, disorders or conditions arising from the bacterial infection, and remission of the bacterial infection and / or one or more symptoms or conditions arising from the bacterial infection, whether partial or total, whether detectable or undetectable. “To treat”, “treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “To treat”, “treating” and “treatment” as used herein also include prophylactic treatment. For example, a subject with an early bacterial infection is treated to prevent progression, or alternatively a subject in remission is treated to prevent recurrence.

[0058] “Palliating” an infection, disease, disorder and / or condition means that the extent and / or undesirable clinical manifestations of an infection, disease, disorder and / or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to not treating the infection, disease, disorder and / or condition.

[0059] The term “prevention” or “prophylaxis” and the like as used herein refers to a reduction in the risk or probability of a subject becoming afflicted with a bacterial infection and / or a disease, disorder and / or condition arising from a bacterial infection or manifesting a symptom associated with a bacterial infection and / or a disease, disorder and / or condition arising from a bacterial infection.II. Compounds of the application

[0060] New sulfadiazine-phytochemical conjugates have been designed and developed and their inhibitory activity against various strains of bacteria has been investigated. Exemplary sulfadiazine-phytochemical conjugates such as sulfadiazine-eugenol and sulfadiazine-protocatechuic acid were prepared and the antibacterial activity of the exemplary novel conjugates was evaluated, for example, against a panel of six Gram-positive and four Gramnegative bacteria. Surprisingly, it was found that the exemplary sulfadiazine-phytochemical conjugates exhibited extremely high potency and unexpected selectivity towards Staphylococcus bacteria such as S. aureus and S. epidermidis. In vitro activities of the exemplary conjugates were found to be comparable or even better than that of the FDA-approved silver sulfadiazine or to the phytochemical alone. This inhibitory activity did not extend to other Gram-positive strains such as those from the Streptococcus genus and in most cases the Enterococcus genus or to the Gram negative bacteria strains such as those from the Pseudomonas, Mannheimia and Escherichia coli genuses.

[0061] Therefore, the present application also includes a compound of Formula I:and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, whereinR1, R2, R4and R5are independently selected from H, OH, halo, NO2, CN, CO2H, Ci_6alkyl, OC1-ealkyl, CO2Ci.6alkyl, NH2, NH(Ci.6alkyl) and N(Ci.6alkyl)(Ci.6alkyl);R3is selected from OH, halo, NO2, CN, CO2H, CHO, SO3H, Ci_6alkyl, C2.6alkenyl, OCi.6alkyl, NH2, NH(Ci.6alkyl), N(Ci.6alkyl)(Ci.6alkyl), CO2Ci.6alkyl, Ci.6alkyleneCO2H, Ci.6alkenyenelCO2H, Ci-6alkyleneCO2Ci-6alkyl, Ci-6alkenyleneCO2Ci-6alkyl, C1-6alkyleneCHO, C1-6alkenyleneCHO, C1-6alkyleneSO3H and C1-6alkenyleneSO3H;L1is a linker group having the formula, Z1-(CH2)m-(Z2)n;Z1is selected from O, NR6, NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O, NR6C(O)NR6, OC(O)NR6and NR6C(O)O;Z2is selected from O, NR7, OC(O), C(O)O, OC(O)O, OC(O)NR7and NR7C(O)O;R6and R7are independently selected from H and Ci_4alkyl;m is selected from 0, 1, 2, 3 and 4; andn is selected from 0 and 1,provided m is not 0 when n is 1; andZ1is not NR6when Z2is O.

[0062] In some embodiments, R1, R2, R4and R5are independently selected from H, OH, halo, N02, CN, CO2H, Ci-4alkyl, OCi.4alkyl, CO2Ci.4alkyl, NH2, NH(Ci.4alkyl) and N(Ci.4alkyl)(Ci.4alkyl). In some embodiments, R1, R2, R4and R5are independently selected from H, OH, halo, N02, CN, CO2H, Ci-3alkyl, OCi.3alkyl, CO2Ci.3alkyl, NH2, NH(Ci.3alkyl) and N(Ci.3alkyl)(Ci.3alkyl). In some embodiments, R1, R2, R4and R5are independently selected from H, OH, halo, N02, CN, CO2H, Ci-2alkyl, OCi-2alkyl, CO2Ci-2alkyl, NH2, NH(Ci-2alkyl) and N(Ci-2alkyl)(Ci-2alkyl). In some embodiments, R1, R2, R4and R5are independently selected from H, OH, F, Cl, Br, I, N02, CN, CO2H, Ci.2alkyl, OCi.2alkyl, CO2Ci.2alkyl, NH2, NH(Ci.2alkyl) and N(Ci.2alkyl)(Ci.2alkyl). In some embodiments, R1, R2, R4and R5are independently selected from H, OH, F, Cl, Br, I, N02, CN, CO2H, OCH3, OCH2CH3, CO2CH3, CO2CH2CH3, NH2, NH(CH3), NH(CH2CH3), N(CH2CH3)(CH3), N(CH3)2and N(CH2CH3)2. In some embodiments, R1, R2, R4and R5are independently selected from H, OH, F, Cl, Br, I, NO2, CN, CO2H, OCH3, OCH2CH3, CO2CH3, and CO2CH2CH3. In some embodiments, R1, R2, R4and R5are independently selected from H, OH, F, Cl, CO2H, OCH3, CO2CH3. In some embodiments, R1, R2, R4and R5are independently selected from H, OH, OCH3, and CO2H.

[0063] In some embodiments, one or two of R1, R2, R4and R5are independently selected from OH, F, Cl, Br, I, NO2, CN, CO2H, Ci-2alkyl, OCi-2alkyl, CO2Ci-2alkyl, NH2, NH(Ci-2alkyl) and N(Ci-2alkyl)(Ci_2alkyl). In some embodiments, one ortwo of R1, R2, R4and R5are independently selected from OH, F, Cl, Br, I, NO2, CN, CO2H, Ci-2alkyl, OCi-2alkyl, and CO2Ci.2alkyl. In some embodiments, one or two of R1, R2, R4and R5are independently selected from F, Cl, Br, I, NO2, CN, CO2H, CH3, CH2CH3, OCH3, OCH2CH3, CO2CH3, and CO2CH2CH3. In some embodiments, one or two of R1, R2, R4and R5are independently selected from F, Cl, Br, I, CO2H, OCH3, OCH2CH3and CO2CH3.

[0064] In some embodiments, one ortwo of R1, R2, R4and R5are selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCi.2alkyl, CO2Ci.2alkyl, NH2, NH(Ci.2alkyl) and N(Ci.2alkyl)(Ci.2alkyl) and the remaining of R1, R2, R4and R5are selected from H, F, Cl, OH, Ci-2alkyl and OCi-2alkyl. In some embodiments, one or two of R1, R2, R4and R5are selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCH3, OCH2CH3, CO2CH3, CO2CH2CH3, NH2, NH(CH3), NH(CH2CH3), N(CH2CH3)(CH3), N(CH3)2and N(CH2CH3)2and the remaining of R1, R2, R4and R5are selected from H, F, Cl, CH3. CH2CH3, OCH3and OCH2CH3In some embodiments, one or two of R1, R2, R4and R5are selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCH3, OCH2CH3, CO2CH3, and CO2CH2CH3, and the remaining of R1, R2, R4and R5are selected from H, F, Cl, CH3. CH2CH3and OCH3. In some embodiments, one or two of R1, R2, R4and R5are selected from OH, F, Cl, CO2H, OCH3, CO2CH3, and the remaining of R1, R2, R4and R5are selected from H, OH and CH3. In some embodiments, one or two of R1, R2, R4and R5are selected from OH, OCH3, and CO2H and the remaining of R1, R2, R4and R5are selected from H and CH3. In some embodiments, one or two of R1, R2, R4and R5are selected from OH and OCH3and the remaining of R1, R2, R4and R5are selected from H and CH3.

[0065] In some embodiments, one of R1and R5is selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCi.2alkyl, CO2Ci-2alkyl, NH2, NH(Ci-2alkyl) and N(Ci-2alkyl)(Ci-2alkyl) and the other of R1and R5is selected from H, OH, Ci_2alkyl, and OCi.2alkyl. In some embodiments, one of R1and R5is selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCH3, OCH2CH3, CO2CH3, CO2CH2CH3, NH2, NH(CH3), NH(CH2CH3), N(CH2CH3)(CH3), N(CH3)2and N(CH2CH3)2and the other of R1and R5is selected from H, OH, CH3, CH2CH3, OCH3, and OCH2CH3. In some embodiments, one of R1and R5is selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCH3, OCH2CH3, CO2CH3, and CO2CH2CH3and the other of R1and R5is selected from H, OH, CH3, CH2CH3, OCH3, and OCH2CH3. In some embodiments, one of R1and R5is selected from OH,F, Cl, CO2H, OCH3, CO2CH3and the other of R1and R5is selected from H, OH and OCH3. In some embodiments, one of R1and R5is selected from OH, OCH3, and CO2H and the other of R1and R5is selected from H, OH and OCH3. In some embodiments, one of R1and R5is selected from OH and OCH3, and the other of R1and R5is selected from H, OH and OCH3.

[0066] In some embodiments, R2and R4are independently selected from H, F, Cl, OH, C1-2alkyl and OC1-2alkyl. In some embodiments, R2and R4are independently selected from H, F, Cl, CH3, CH2CH3, OCH3and OCH2CH3. In some embodiments, R2and R4are independently selected from H, F, Cl, CH3, CH2CH3and OCH3. In some embodiments, R2and R4are independently selected from selected from H, OH and CH3. In some embodiments, R2and R4are independently selected from H and CH3. In some embodiments, R2and R4are both H.

[0067] In some embodiments, one of R1and R5is selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCi.2alkyl, CO2Ci-2alkyl, NH2, NH(Ci-2alkyl) and N(Ci-2alkyl)(Ci-2alkyl) and the other of R1and R5is selected from H, OH, Ci_2alkyl and OCi.2alkyl and R2and R4are independently selected from H, F, Cl, OH, Ci_2alkyl and OCi.2alkyl. In some embodiments, one of R1and R5is selected from OH, F, Cl, CO2H, OCH3, CO2CH3and the other of R1and R5is selected from H, OH and OCH3and R2and R4are independently selected from selected from H, OH and CH3. In some embodiments, one of R1and R5is selected from OH and OCH3, and the other of R1and R5is selected from H, OH and OCH3and R2and R4are independently selected from H and CH3. In some embodiments, one of R1and R5is selected from OH and OCH3, and the other of R1and R5is H and R2and R4are both H.

[0068] In some embodiments, R3is selected from OH, halo, NO2, CN, CO2H, CHO, SO3H, C1-4alkyl, C2.4alkenyl, OCi.4alkyl, NH2, NH(Ci.4alkyl), N(Ci_4alkyl)(Ci_4alkyl), CO2Ci.4alkyl, C1-4alkyleneCO2H, Ci.4alkenyleneCO2H, Ci.4alkyleneCO2Ci.4alkyl, Ci.4alkenyleneCO2Ci.4alkyl, C1-6alkyleneCHO, Ci.4alkenyleneCHO, Ci.4alkyleneSO3H and Ci.4alkenyleneSO3H. In some embodiments, R3is selected from OH, F, Cl, Br, I, NO2, CN, CO2H, CHO, SO3H, Ci_4alkyl, C2.4alkenyl, OC1-4alkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), CO2C1-4alkyl, C1-4alkylCO2H, C1-4alkenyleneCO2H, C1-4alkyleneCO2C1-4alkyl, C1-4alkenyleneCO2C1-4alkyl, C1-4alkyleneCHO, C1-4alkenyleneCHO, C1-4alkyleneSO3H and C1-4alkenyleneSO3H.

[0069] In some embodiments, R3is selected from OH, F, Cl, Br, I, NO2, CO2H, CHO, SO3H, C2-4alkenyl, OC1-4alkyl, NH2, NH(C1-4alkyl), N(C1-4alkyl)(C1-4alkyl), CO2C1-4alkyl, C1-4alkyleneCO2H, C1-4alkenyleneCO2H, C1-4alkyleneCO2C1-4alkyl, C1-4alkenyleneCO2C1-4alkyl, C1-4alkyleneCHO, C1-4alkenyleneCHO, C1-4alkyleneSO3H and C1-4alkenyleneSO3H. In some embodiments, R3is selected from OH, F, Cl, NO2, CO2H, CHO, SO3H, C2-4alkenyl, OC1-4alkyl, NH2, NH(C1-2alkyl), N(C1-2alkyl)(C1-2alkyl), CO2C1-2alkyl, C1-4alkyleneCO2H, C1-4alkenyleneCO2H, C1-4alkyleneCO2C1-2alkyl, C1-4alkenyleneCO2C1-2alkyl, C1-4alkyleneCHO, C1-4alkenylCHO, C1-4alkyleneSO3H and C1-4alkenyleneSO3H. In some embodiments, R3is selected from OH, F, Cl, NO2, CO2H, CHO, SO3H, C2-4alkenyl, OC1-4alkyl, CO2C1-2alkyl, C1-4alkylCO2H, C1-4alkenyleneCO2H, C1-4alkyleneCO2C1-2alkyl, C1-4alkenyleneCO2C1-2alkyl, C1-4alkyleneCHO, C1-4alkenyleneCHO, C1-4alkyleneSO3H and C1-4alkenyleneSO3H. In some embodiments, R3is selected from OH, NO2, CO2H, CHO, SO3H, C2-4alkenyl, OC1-4alkyl, CO2C1-2alkyl, C1-4alkyleneCO2H, C1-4alkenyleneCO2H, C1-4alkyleneCO2C1-2alkyl, C1-4alkenyleneCO2C1-2alkyl, C1-4alkyleneCHO, C1-4alkenyleneCHO, C1-4alkyleneSO3H and C1-4alkenyleneSO3H. In some embodiments, R3is selected from OH, CO2H, CHO, SO3H, C2-4alkenyl, OC1-4alkyl, CO2C1-2alkyl, C1-4alkenyleneCO2H, C1-4alkenyleneCHO and C1-4alkenyleneSO3H. In some embodiments, R3is selected from OH, CO2H, CHO, SO3H, CH2CH=CH2, OC1-3alkyl, CO2C1-2alkyl, CH=CHCO2H, CH=CHCHO and CH=CHSO3H. In some embodiments, R3is selected from CO2H, CHO, SO3H, CO2CH3, CH2CH=CH2, CH=CHCO2H, CH=CHCHO and CH=CHSO3H. In some embodiments, R3is selected from CO2H, CO2CH3and CH2CH=CH2. In some embodiments, R3is selected from CO2H and CH2CH=CH2.

[0070] In some embodiments, Z1is selected from NR6, NR6C(O), OC(O), OC(O)O, NR6C(O)NR6, and NR6C(O)O. In some embodiments, Z1is selected from NR6, NR6C(O), OC(O), NR6C(O)NR6and NR6C(O)O. In some embodiments, Z1is selected from NR6and NR6C(O). In some embodiments, Z1is NR6C(O).

[0071] In some embodiments, Z2is selected from O, NR7, OC(O), C(O)O, OC(O)O and OC(O)NR7. In some embodiments, Z2is selected from O, NR7, C(O)O, and OC(O)O. In some embodiments, Z2is O.

[0072] In some embodiments, m is selected from 0, 1, 2 and 3. In some embodiments, m is selected from 0, 1 and 2. In some embodiments, m is selected from 1, 2 and 3. In some embodiments, m is selected from 0 and 1. In some embodiments, m is selected from 1 and 2. In some embodiments, m is 3. In some embodiments, m is 2. In some embodiments, m is 1. In some embodiments, m is 0.

[0073] In some embodiments, n is 1. In some embodiments, n is 0.

[0074] In some embodiments, m and n are both 0 and Z1is selected from NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O NR6C(O), C(O)NR6, NR6C(O)NR6, OC(O)NR6and NR6C(O)O. In some embodiments, m and n are both 0 and Z1is NR6C(O)NR6. In some embodiments, m and n are both 0 and L1is Z1.

[0075] In some embodiments, m is selected from 1 and 2, n is 0, and Z1is selected from NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O NR6C(O), C(O)NR6, NR6C(O)NR6, OC(O)NR6and NR6C(O)O. In some embodiments, m is selected from 1 and 2, n is 0, and Z1is NR6C(O)NR6.

[0076] In some embodiments, n is 1, m is selected from 1, 2, 3 and 4, Z1is selected from O, NR6, NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O, NR6C(O)NR6, OC(O)NR6and NR6C(O)O and Z2is selected from O, NR7and C(O)O. In some embodiments, n is 1, m is selected from 1 and 2, Z1is selected from O, NR6, NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O, NR6C(O)NR6, OC(O)NR6and NR6C(O)O and Z2is selected from O, NR7and C(O)O. In some embodiments, n is 1, m is selected from 1 and 2, Z1is selected from NR6, NR6C(O), OC(O), OC(O)O, NR6C(O)NR6, and NR6C(O)O and Z2is selected from O, NR7and C(O)O. In some embodiments, n is 1, m is selected from 1 and 2, Z1is NR6C(O) and Z2is O.

[0077] In some embodiments, L1is selected from NR6C(O)(CH2)mO, OC(O)(CH2)mO, NR6C(O)NR6(CH2)m, NR6C(O)NR6, OC(O)(CH2)mNR7, NR6(CH2)mC(O)O and OC(O)(CH2)mNR7. In some embodiments, L1is selected from NR6C(O)CH2O, OC(O)CH2O, NR6C(O)NR6CH2, NR6C(O)NR6, OC(O)CH2NR7, NR6CH2C(O)O and OC(O)CH2NR7.

[0078] In some embodiments, L1is NR6C(O)(CH2)mO. In some embodiments, m is 1 and L1is NR6C(O)CH2O.

[0079] In some embodiments, R6and R7are independently selected from H and C1-3alkyl. In some embodiments, R6and R7are independently selected from H and Ci_2alkyl. In some embodiments, R6and R7are independently selected from H, CH3and CH2CH3. In some embodiments, R6and R7are independently selected from H and CH3. In some embodiments, R6and R7are both H.

[0080] In some embodiments, the compound of Formula I is a compound of Formula la:and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,wherein R1, R2, R3, R4, R5and R6are as defined for Formula I including embodiments thereof.

[0081] In some embodiments, R2and R4are both H. In some embodiments, the compound of Formula I is a compound of Formula lb:R3HNhKsoAo(lb)and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,wherein R1, R3and R5are as defined for Formula I including embodiments thereof.

[0082] In some embodiments, the compound of Formula I is a compound of Formula Ic:and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,wherein R1, R3and R5are as defined for Formula I including embodiments thereof.

[0083] In some embodiments, in the compounds of Formula lb and Ic, R1and R5are independently selected from H, OH, CO2H, OCi.6alkyl and CO2C1-6alkyl. In some embodiments, in the compounds of Formula lb and Ic, one of R1and R5is selected from OH, CO2H and OC1-6alkyl, and the other of R1and R5is selected from H, OH and OC1-6alkyl.

[0084] In some embodiments, in the compounds of Formula lb and Ic, R1and R5are independently selected from H, OH, CO2H, OCH3and CO2CH3. In some embodiments, in the compounds of Formula lb and Ic, one of R1and R5is selected from OH, CO2H and OCH3, and the other of R1and R5is selected from H, OH and OCH3. In some embodiments, in the compounds of Formula lb and Ic, one of R1and R5is selected from OH and OCH3, and the other of R1and R5is selected from H, OH and OCH3.

[0085] In some embodiments, in the compounds of Formula la, lb and Ic, R3is selected from OH, CO2H, CHO, SO3H, C2-4alkenyl, OC1-4alkyl, C1-4alkenyleneCO2H, C1-4alkenyleneCHO and C1-4alkenylSO3H. In some embodiments, in the compounds of Formula la, lb and Ic, R3is selected from OH, CO2H, CHO, SO3H, CH2CH=CH2, OCi.3alkyl, CH=CHCO2H, CH=CHCHO and CH=CHSO3H. In some embodiments, in the compounds of Formula la, lb and Ic, R3is selected from CO2H, CHO, SO3H, CH2CH=CH2, CH=CHCO2H, CH=CHCHO and CH=CHSO3H. In some embodiments, in the compounds of Formula la, lb and Ic, R3is selected from CO2H and CH2CH=CH2

[0086] In some embodiments, the compound of Formula I is in the form of the free acid or a pharmaceutically acceptable basic addition salt of the free acid.

[0087] In some embodiments, the compounds of Formula I are selected from:CompoundStructure CHEMICAL NAMEI. D.2-(4-allyl-2-methoxyphenoxy)-N-HT H (4-(N-(pyrimidin-2- 1-1<N^N1\ 11 o II o yl)sulfamoyl)phenyl)acetamide;and(J A0 3-hydroxy-4-(2-oxo-2-((4-(N- (pyrimidin-2- I -2 H \ ||OMH r IT ii0yl)sulfamoyl)phenyl)amino)ethoxy) / N N 0 benzoic acidQ Aomethyl 3-hydroxy-4-(2-oxo-2-((4- (N-(pyrimidin-2- I-3 H r II °H1\ If Ti ° yl)sulfamoyl)phenyl)amino)ethoxy)<N N O benzoateQ Aor a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0088] In an embodiment the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt may be made by a person skilled in the art (see, for example, S. M. Berge, et al., " Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0089] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p-toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. In an embodiment, the mono- or di-acid salts are formed, and such salts exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceuticallyacceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0090] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. The selection of the appropriate salt may be useful, for example, so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

[0091] Solvates of compounds of the application include, for example, those made with solvents that are pharmaceutically acceptable. Examples of such solvents include water (resulting solvate is called a hydrate) and ethanol and the like. Suitable solvents are physiologically tolerable at the dosage administered.

[0092] In embodiments of the present application, the compounds described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having an alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.

[0093] The compounds of the present application may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0094] The compounds of the present application may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.

[0095] The compounds of the present application may further be radiolabeled and accordingly all radiolabeled versions of the compounds of the application are included within the scope of the present application. The compounds of the application also include those in which one or more radioactive atoms are incorporated within their structure.III. Compositions of the Application

[0096] The compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.

[0097] In some embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.

[0098] The compounds of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a compound of the application is administered by oral, inhalation, parenteral, buccal, sublingual, nasal, rectal, vaginal, patch, pump, minipump, topical or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 -20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.

[0099] Parenteral administration includes systemic delivery routes other than the gastrointestinal (Gl) tract, and includes, for example intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.

[0100] In some embodiments, a compound of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, corn starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). In embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release ortimed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. Timed-release compositions are formulated, for example as liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried corn starch.

[0101] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents are added. Such liquid preparations for oral administration are prepared by conventional meanswith pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); nonaqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0102] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.

[0103] In some embodiments, a compound of the application is administered parenterally. For example, solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are delivered, for example, by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiment, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzalkonium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.

[0104] In some embodiments, a compound of the application is formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection are, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contain formulating agents such as suspending, stabilizing and / or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0105] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. For intranasal administration oradministration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which, for example, take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator are, for example, formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. The aerosol dosage forms can also take the form of a pump-atomizer.

[0106] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein a compound of the application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0107] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.

[0108] In some embodiments a compound of the application is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example,polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.

[0109] The compounds of the application are particularly amenable to administration with the air of nano-carrier systems, such as liposomes, micelles, nanoparticles, nanoemulsions, lipidic nano-systems and the like (see for example, Bhat, M. et al. Chem. and Phys, of Lipids, 2021, 236, 105053). Accordingly the present application includes a composition comprising one or more compounds of the application and one or more components of a nanocarrier system.

[0110] In some embodiments, compounds of the application may be coupled with viral, non-viral or other vectors. Viral vectors may include retrovirus, lentivirus, adenovirus, herpesvirus, poxvirus, alphavirus, vaccinia virus or adeno-associated viruses. Non-viral vectors may include nanoparticles, cationic lipids, cationic polymers, metallic nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. Nanoparticles may include silica, lipid, carbohydrate, or other pharmaceutically acceptable polymers

[0111] A compound of the application including pharmaceutically acceptable salts and / or solvates thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.

[0112] In some embodiments, the compounds of the application including pharmaceutically acceptable salts and / or solvates thereof are used are administered in a composition comprising an additional therapeutic agent. Therefore the present application also includes a pharmaceutical composition comprising one of more compounds of the application, or pharmaceutically acceptable salts and / or solvates thereof and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients. In someembodiments, the additional therapeutic agent is another known agent useful for treatment a disease, disorder or condition arising from a Staphylococcus bacterial infection.

[0113] In the above, the term "a compound" also includes embodiments wherein one or more compounds are referenced. Likewise, the term “compounds of the application” also includes embodiments wherein only one compound is referenced.III. Treatment methods and uses of the application

[0114] The compounds of the application have been shown to exhibit extremely high inhibitory activity and unexpected selectivity towards Staphylococcus bacteria such as S. aureus and S. epidermidis.

[0115] Accordingly, the present application also includes a method of treating or preventing a Staphylococcus bacterial infection comprising administering an effective amount of a compound of the application to a subject in need thereof.

[0116] Also included in the present application is a use of a compound of the application to treat or prevent a Staphylococcus bacterial infection. Further, included is a use of a compound of the application to prepare (optionally, manufacture) a medicament to treat or prevent a Staphylococcus bacterial infection. Further included is a compound of the application for use to treat or prevent a Staphylococcus bacterial infection.

[0117] The present application includes a method of treating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection comprising administering an effective amount of a compound of the application to a subject in need thereof.

[0118] Also included in the present application is a use of a compound of the application to treat or prevent a disease, disorder or condition arising from a Staphylococcus bacterial infection. Further, included is a use of a compound of the application to prepare a medicament to treat or prevent a disease, disorder or condition arising from a Staphylococcus bacterial infection. Further included is a compound of the application for use to treat or prevent a disease, disorder or condition arising from a Staphylococcus bacterial infection.

[0119] In some embodiments, the Staphylococcus bacteria are any of the known grampositive bacteria classified under this genus.

[0120] In some embodiments, the Staphylococcus bacterial infection is an infection of at least one bacterium belonging to the genus Staphylococcus. In some embodiments, the Staphylococcus bacterium is selected from S. argenteus, S. arlettae, S. agnetis, S. aureus, S. auricularis, S. borealis, S. Caeli, S. capitis, S. caprae, S. carnosus, S. caseolyticus, S. chromogenes, S. cohnii, S. cornubiensis, S. condiment, S. debuckii, S. delphini, S. devriesei,S. edaphicus, S. epidermidis, S. equorum, S. felis, S. fleurettii, S. gallinarum, S. haemolyticus, S. hominis, S. hyicus, S. intermedius, S. jettensis, S. kloosii, S. leei, S. lentus, S. lugdunensis, S. lutrae, S. lyticans, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S. petrasii, S. pettenkoferi, S. piscifermentans, S. pseudintermedius, S. pseudolugdunensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. schweitzeri, S. sciuri, S. simiae, S. simulans, S. singaporensis, S. stepanovicii, S. succinus, S. vitulinus, S. warned, S. xylosus and S. Westin species. In some embodiments, the Staphylococcus bacterium is selected from S. aureus and S. epidermidis species.

[0121] In further embodiments, the present application also includes a method of treating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection comprising administering a therapeutically effective amount of a compound of the application in combination with another known agent useful for treating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection to a subject in need thereof. The present application also includes a use of a compound of the application in combination with a known agent useful for treating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection, and a compound of the application for treating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection.

[0122] In some embodiments, the compound of Formula I, and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, is present in the composition in an amount effective to treat a Staphylococcus bacterial infection in a subject in need thereof.

[0123] In an embodiment, effective amounts vary according to factors such as the disease state, age, sex and / or weight of the subject. In a further embodiment, the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. In an embodiment, the effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom.

[0124] In an embodiment, the compounds of the application are administered at least once a week. However, in another embodiment, the compounds are administered to the subject from about one time per two weeks, three weeks or one month. In another embodiment, the compounds are administered about one time per week to about once daily. In another embodiment, the compounds are administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease,disorder or condition, the age of the subject, the concentration and / or the activity of the compounds of the application, and / or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration is required. For example, the compounds are administered to the subject in an amount and for duration sufficient to treat the subject.

[0125] In an embodiment, the subject is a mammal. In another embodiment, the subject is human. In an embodiment, the subject is a non-human animal. In an embodiment, the subject is canine. In an embodiment, the subject is feline. In an embodiment, the subject is bovine. Accordingly, the compounds, methods and uses of the present application are directed to both human and veterinary diseases, disorders and conditions.

[0126] In some embodiments, the “subject in need thereof’ is a subject having the disease, disorder or condition to be treated. In some embodiments, the “subject in need thereof” is a subject who has been diagnosed with and / or has been treated Staphylococcus bacterial infection and / or a disease, disorder or condition arising from a Staphylococcus bacterial infection.

[0127] Compounds of the application are either used alone or in combination with other known agents useful treating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection. When used in combination with other agents useful in treating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection, it is an embodiment that a compound of the application is administered contemporaneously with those agents. As used herein, “contemporaneous administration” of two substances to a subject means providing each of the two substances so that they are both active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a non-contemporaneous fashion. In an embodiment, a compound of the present application is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present applicationprovides a single unit dosage form comprising a compound of the application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0128] Treatment methods comprise administering to a subject one or more compounds of the application, and optionally consists of a single administration, or alternatively comprises a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the infection, disease, disorder or condition, the age of the subject, the dosage of the compound of the application, the activity of one or more compounds of the application, or a combination thereof.

[0129] In an embodiment, the compound of the application is administered or used as soon as possible after exposure to the bacteria. In an embodiment, the compound of the application is administered or used until treatment of the bacterial infection, disease disorder or condition is achieved. For example, until complete elimination of the bacteria is achieved, or until the number of bacteria has been reduced to the point where the subject’s defenses are no longer overwhelmed and can kill any remaining bacteria.

[0130] The dosage of a compound of the application varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. In some embodiments, a compound of the application is administered initially in a suitable dosage that is adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of the compound of the application from about 0.01 pg / cc to about 1000 pg / cc, or about 0.1 pg / cc to about 100 pg / cc. As a representative example, oral dosages of one or more compounds of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day. For parenteral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg will be administered. For oral administration, a representative amount is from about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg or about 0.1 mg / kg to about 1 mg / kg. For administration in suppository form, a representative amount is from about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg.

[0131] In some embodiments of the application, compositions are formulated for oral administration and the compound of the application are suitably in the form of tablets containing0.1, 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient (one or more compounds of the application) per tablet. In some embodiments of the application the compound of the application is administered in a single daily, weekly or monthly dose or the total daily dose is divided into two, three or four daily doses.

[0132] In an embodiment, the dosage of the compound of the application is equal to or less than the dosage of the known dosage of the phytochemical acid and / or sulfadiazine when used alone. Such dosages are known to or readily determined by those skilled in the art.III. Methods of preparing compounds of Formula I

[0133] Compounds of the present application can be prepared by various synthetic processes. The choice of particular structural features and / or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula I is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art. In the Schemes below showing the preparation of compounds of the application, all variables are as defined in Formula I, unless otherwise stated,

[0134] The one or more compounds of the application generally can be prepared according to the processes illustrated in the Schemes below. A person skilled in the art would appreciate that many of the reactions depicted in the Schemes below would be sensitive to oxygen and water and would know to perform the reaction under an anhydrous, inert atmosphere if needed. Reaction temperatures and times are presented for illustrative purposes only and may be varied to optimize yield as would be understood by a person skilled in the art.

[0135] In an embodiment, the compounds of Formula I are prepared as shown in Scheme 1.Scheme 1

[0136] Therefore, sulfadiazine or a suitable sulfadiazine derivative compound of Formula A is coupled with an appropriate bifunctional compound of Formula B in the presence of a suitable base such as triethylamine and in a suitable solvent such as dimethylformamide (DMF) to provide the sulfadiazine-linker compound of Formula C. The sulfadiazine-linker compound of Formula C is then coupled with a compound of Formula D the presence of a suitable base in a suitable solvent such as DMF and followed by deprotection if necessary to provide the compound of Formula I. FGi, FG2, FG3and FG4are independently suitable functional groups, wherein FGi is a suitable functional group that reacts with a complementary function group, FG2, and FG3is a suitable functional group that reacts with a complementary function group, FG4. and FGi, FG2, FG3and FG4are selected such that they react to form a covalent bond / further functional group to produce the linker L1of the compound of Formula I. In an exemplary embodiment, FGi is NH2, FG2is C(O)Cl, FG3is Cl and FG4is OH.

[0137] A person skilled in the art would appreciate that, in an alternate method for the preparation of the compound of Formula I, an appropriate bifunctional compound of Formula B may be first reacted with an appropriate compound of Formula D, and then coupled with sulfadiazine or suitable sulfadiazine derivative compound of Formula A, to provide the compound of Formula I.

[0138] The formation of a desired compound salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction or any other suitable method.

[0139] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0140] One skilled in the art will recognize that where a reaction step of the present application is carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

[0141] Prodrugs of the compounds of Formula I, or salts and / or solvates thereof, may be prepared, for example, by acylating available hydroxy or amino groups using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine). Similarly, available carboxylic acid groups may be converted to ester groups using known chemistry, for example, by activation in the presence of base and reaction with suitable groups containing a nucleophile. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0142] The formation of solvates will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a “hydrate”. The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.

[0143] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis", T. W. Green, P. G. M. Wuts, Wiley-lnterscience, New York, (1999).

[0144] It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediateor final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations -A Guide to Functional Group Preparations” R. C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or, “Organic Synthesis", Smith, McGraw Hill, (1994).

[0145] Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.

[0146] The products of the processes of the application may be isolated according to known methods, for example, the compounds may be isolated by evaporation of the solvent, by filtration, centrifugation, chromatography or other suitable method.

[0147] Amide bond forming conditions comprise any known method for the coupling of carboxylic acids and amines that is compatible with the intermediates and products shown in the above Schemes or that may be used to prepare a compound of the application. Known methods to prepare amides by the coupling of carboxylic acids and amines comprise use of either a coupling reagent or by prior conversion of the carboxylic acid into an activated derivative. Coupling reagents include, but are not limited to, any of the known peptide coupling reagents, such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), dicyclohexylcarbodiimide (DCC) diisopropylcarbodiimide (DIC), hexafluorophosphate benzotriazole tetramethyl uranium (HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), O-(1 / - / -6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), benzotriazol- 1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP) and propanephosphonic acid anhydride.

[0148] The following non-limiting examples are illustrative of the present application. As is apparent to those skilled in the art, many of the details of the examples may be changed while still practicing the methods, compositions and kits described herein.NUMBERED EMBODIMENTS OF THE APPLICATION

[0149] 1. A compound of Formula I:and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, whereinR1, R2, R4and R5are independently selected from H, OH, halo, NO2, CN, CO2H, C1-6alkyl, OC1-6alkyl, CO2Ci.6alkyl, NH2, NH(Ci.6alkyl) and N(Ci.6alkyl)(Ci.6alkyl);R3is selected from OH, halo, NO2, CN, CO2H, CHO, SO3H, Ci-ealkyl, C2.6alkenyl, OCi-ealkyl, NH2, NH(Ci.6alkyl), N(Ci.6alkyl)(Ci.6alkyl), CO2Ci.6alkyl, Ci.6alkyleneCO2H, Ci.6alkenyenelCO2H, Ci-6alkyleneCO2Ci-6alkyl, Ci-6alkenyleneCO2Ci-6alkyl, Ci-ealkyleneCHO, Ci. ealkenyleneCHO, Ci-ealkyleneSOsH and Ci-salkenyleneSOsH;L1is a linker group having the formula, Z1-(CH2)m-(Z2)n;Z1is selected from O, NR6, NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O, NR6C(O)NR6, OC(O)NR6and NR6C(O)O;Z2is selected from O, NR7, OC(O), C(O)O, OC(O)O, OC(O)NR7and NR7C(O)O;R6and R7are independently selected from H and Ci.4alkyl;m is selected from 0, 1, 2, 3 and 4; andn is selected from 0 and 1,provided m is not 0 when n is 1; andZ1is not NR6when Z2is O.

[0150] 2. The compound of embodiment 1, wherein R1, R2, R4and R5are independently selected from H, OH, halo, NO2, CN, CO2H, C1-4alkyl, OC1-4alkyl, CO2Ci.4alkyl, NH2, NH(Ci.4alkyl) and N(Ci-4alkyl)(Ci-4alkyl).

[0151] 3. The compound of embodiment 2, wherein R1, R2, R4and R5are independently selected from H, OH, halo, NO2, CN, CO2H, Ci_2alkyl, OCi-2alkyl, CO2Ci.2alkyl, NH2, NH(Ci.2alkyl) and N(Ci.2alkyl)(Ci.2alkyl).

[0152] 4. The compound of embodiment 3, wherein R1, R2, R4and R5are independently selected from H, OH, F, Cl, Br, I, NO2, CN, CO2H, OCH3, OCH2CH3, CO2CH3, and CO2CH2CH3.

[0153] 5. The compound of embodiment 4, wherein R1, R2, R4and R5are independently selected from H, OH, F, Cl, CO2H, OCH3, CO2CH3.

[0154] 6. The compound of embodiment 5, wherein R1, R2, R4and R5are independently selected from H, OH, OCH3, and CO2H.

[0155] 7. The compound of embodiment 1, wherein one or two of R1, R2, R4and R5are independently selected from OH, F, Cl, Br, I, NO2, CN, CO2H, Ci-2alkyl, OCi-2alkyl, CO2Ci.2alkyl, NH2, NH(Ci.2alkyl) and N(Ci.2alkyl)(Ci.2alkyl).

[0156] 8. The compound of embodiment 7, wherein one or two of R1, R2, R4and R5are independently selected from F, Cl, Br, I, CO2H, OCH3, OCH2CH3and CO2CH3.

[0157] 9. The compound of embodiment 8, wherein one or two of R1, R2, R4and R5are selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCi-2alkyl, CO2Ci-2alkyl, NH2, NH(Ci-2alkyl) and N(Ci_2alkyl)(Ci_2alkyl) and the remaining of R1, R2, R4and R5are selected from H, F, Cl, OH, Ci_2alkyl and OCi.2alkyl.

[0158] 10. The compound of embodiment 9, wherein one or two of R1, R2, R4and R5are selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCH3, OCH2CH3, CO2CH3, and CO2CH2CH3, and the remaining of R1, R2, R4and R5are selected from H, F, Cl, CH3. CH2CH3and OCH3.

[0159] 11. The compound of embodiment 10, wherein one or two of R1, R2, R4and R5are selected from OH, OCH3, and CO2H and the remaining of R1, R2, R4and R5are selected from H and CH3.

[0160] 12. The compound of embodiment 1, wherein one of R1and R5is selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCi.2alkyl, CO2Ci.2alkyl, NH2, NH(Ci.2alkyl) and N(Ci.2alkyl) (Ci-2alkyl) and the other of R1and R5is selected from H, OH, Ci-2alkyl, and OCi-2alkyl.

[0161] 13. The compound of embodiment 12, wherein one of R1and R5is selected from OH, F, Cl, CO2H, OCH3, CO2CH3and the other of R1and R5is selected from H, OH and OCH3.

[0162] 14. The compound of embodiment 13, wherein one of R1and R5is selected from OH and OCH3, and the other of R1and R5is selected from H, OH and OCH3.

[0163] 15. The compound of any one of embodiments 1, 12 and 13, wherein R2and R4are independently selected from H, F, Cl, OH, Ci.2alkyl and OCi.2alkyl.

[0164] 16. The compound of embodiment 15, R2and R4are both H.

[0165] 17. The compound of any one of embodiments 1 to 16, wherein R3is selected from OH, halo, NO2, CN, CO2H, CHO, SO3H, Ci.4alkyl, C2.4alkenyl, OCi-4alkyl, NH2, NH(Ci.4alkyl), N(Ci.4alkyl)(Ci.4alkyl), CO2Ci.4alkyl, Ci.4alkyleneCO2H, Ci.4alkenyleneCO2H, Ci-4alkyleneCO2Ci.4alkyl, Ci.4alkenyleneCO2Ci.4alkyl, C1-4alkyleneCHO, C1-4alkenyleneCHO, C1-4alkyleneSO3H and Ci.4alkenyleneSO3H.

[0166] 18. The compound of embodiment 17, wherein R3is selected from OH, F, Cl, Br, I, NO2, CO2H, CHO, SO3H, C2.4alkenyl, OCi-4alkyl, NH2, NH(Ci-4alkyl), N(Ci-4alkyl)(Ci-4alkyl), CO2Ci.4alkyl, Ci.4alkyleneCO2H, Ci.4alkenyleneCO2H, Ci.4alkyleneCO2Ci.4alkyl, Ci-4alkenyleneCO2Ci.4alkyl, Ci.4alkyleneCHO, Ci.4alkenyleneCHO, Ci.4alkyleneSO3H and Ci.4alkenyleneSO3H.

[0167] 19. The compound of embodiment 18, wherein R3is selected from OH, F, Cl, NO2, CO2H, CHO, SO3H, C2.4alkenyl, OCi-4alkyl, CO2Ci.2alkyl, Ci.4alkylCO2H, Ci-4alkenyleneCO2H, Ci.4alkyleneCO2Ci.2alkyl, Ci.4alkenyleneCO2Ci.2alkyl, Ci.4alkyleneCHO, Ci-4alkenyleneCHO, Ci.4alkyleneSO3H and Ci.4alkenyleneSO3H.

[0168] 20. The compound of embodiment 19, wherein R3is selected from OH, CO2H, CHO, SO3H, C2.4alkenyl, OCi-4alkyl, CO2Ci.2alkyl, Ci.4alkenyleneCO2H, Ci-4alkenyleneCHO and Ci.4alkenylSO3H.

[0169] 21. The compound of embodiment 20, wherein R3is selected from OH, CO2H, CHO, SO3H, CH2CH=CH2, OCi-3alkyl, CO2Ci-2alkyl, CH=CHCO2H, CH=CHCHO and CH=CHSO3H.

[0170] 22. The compound of embodiment 21, wherein R3is selected from CO2H and CH2CH=CH2

[0171] 23. The compound of any one of embodiments 1 to 22, wherein Z1is selected from NR6, NR6C(O), OC(O), NR6(CO)NR6and NR6C(O)O.

[0172] 24. The compound of embodiment 23, wherein Z1is and NR6C(O).

[0173] 25. The compound of any one of embodiments 1 to 24, wherein Z2is selected from O, NR7, OC(O), C(O)O, OC(O)O and OC(O)NR7.

[0174] 26. The compound of embodiment 25, wherein Z2is O.

[0175] 27. The compound of any one of embodiments 1 to 22, wherein m and n are both 0 and Z1is selected from NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O NR6C(O), C(O)NR6, NR6(CO)NR6, OC(O)NR6and NR6C(O)O.

[0176] 28. The compound of embodiment 27, wherein m and n are both 0 and Z1is NR6(CO)NR6.

[0177] 29. The compound of any one of embodiments 1 to 22, wherein m is selected from 1 and 2, n is 0, and Z1is selected from NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O NR6C(O), C(O)NR6, NR6(CO)NR6, OC(O)NR6and NR6C(O)O.

[0178] 30. The compound of embodiment 29, wherein m is selected from 1 and 2, n is 0, and Z1is NR6(CO)NR6.

[0179] 31. The compound of any one of embodiments 1 to 22, wherein n is 1, m is selected from 1, 2, 3 and 4, Z1is selected from O, NR6, NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O, NR6C(O)NR6, OC(O)NR6and NR6C(O)O and Z2is selected from O, NR7and C(O)O.

[0180] 32. The compound of embodiment 31, wherein n is 1, m is selected from 1 and 2, Z1is NR6C(O) and Z2is O.

[0181] 33. The compound of any one of embodiments 1 to 22, wherein L1is selected from NR6C(O)(CH2)mO, OC(O)(CH2)mO, NR6C(O)NR6(CH2)m, NR6C(O)NR6, OC(O)(CH2)mNR7, NR6(CH2)mC(O)O and OC(O)(CH2)mNR7.

[0182] 34. The compound of any one of embodiments 1 to 22, wherein L1is selected from NR6C(O)CH2O, OC(O)CH2O, NR6C(O)NR6CH2, NR6C(O)NR6, OC(O)CH2NR7, NR6CH2C(O)O and OC(O)CH2NR7.

[0183] 35. The compound of any one of embodiments 1 to 22, wherein L1is NR6C(O)(CH2)mO.

[0184] 36. The compound of embodiment 35, wherein L1is NR6C(O)CH2O.

[0185] 37. The compound of any one of embodiments 1 to 36, wherein R6and R7are independently selected from H and Ci_2alkyl.

[0186] 38. The compound of embodiment 37, wherein R6and R7are independently selected from H and CH3.

[0187] 39. The compound of embodiment 1, wherein the compound of Formula I is a compound of Formula la:and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,wherein R1, R2, R3, R4, R5and R6are as defined in any one of embodiments 1 to 38.

[0188] 40. The compound of embodiment 1, wherein the compound of Formula I is a compound of Formula lb:(lb)and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,wherein R1, R3and R5are as defined in any one of embodiments are as defined in any one of embodiments 1 to 38.

[0189] 41. The compound of embodiment 1, wherein the compound of Formula I is a compound of Formula Ic:and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,wherein R1, R3and R5are as defined in any one of embodiments are as defined in any one of embodiments 1 to 38.

[0190] 42. The compound of embodiment 1, wherein the compound of Formula I is selected from:CompoundStructure CHEMICAL NAMEI. D.2-(4-allyl-2-methoxyphenoxy)-N-Hr il (4-(N-(pyrimidin-2- 1-1 / N^N1\ II O II ° yl)sulfamoyl)phenyl)acetamide;andQ A0 3-hydroxy-4-(2-oxo-2-((4-(N- HH0VArA0H (pyrimidin-2- I -2yl)sulfamoyl)phenyl)amino)ethoxy / N N O jbenzoic acidQ AoHO. / methyl 3-hydroxy-4-(2-oxo-2-((4- H ||0(N-(pyrimidin-2- I-31A \ U Il O II ° yl)sulfamoyl)phenyl)amino)ethoxy jbenzoateQ Aor a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

[0191] 43. A pharmaceutical composition comprising a compound of any one of embodiments 1 to 42 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, and a pharmaceutically acceptable carrier.

[0192] 44. A method of treating or preventing a Staphylococcus bacterial infection comprising administering an effective amount of a compound of any one of embodiments 1 to 42 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, to a subject in need thereof.

[0193] 45. A method of treating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection comprising administering an effective amount of a compound of any one of embodiments 1 to 42 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, to a subject in need thereof.

[0194] 46. The method of embodiment 44 or 45, wherein the Staphylococcus bacteria are any of the known gram-positive bacteria classified under the genus Staphylococcus.

[0195] 47. The method of embodiment 44 or 45, wherein the Staphylococcus bacterial infection is an infection of at least one bacterium belonging to the genus Staphylococcus. In some embodiments, the Staphylococcus bacterium is selected from S. argenteus, S. arlettae, S. agnetis, S. aureus, S. auricularis, S. borealis, S. Caeli, S. capitis, S. caprae, S. carnosus, S. caseolyticus, S. chromogenes, S. cohnii, S. cornubiensis, S.condiment, S. debuckii, S. delphini, S. devriesei, S. edaphicus, S. epidermidis, S. equorum, S. felis, S. fleurettii, S. gallinarum, S. haemolyticus, S. hominis, S. hyicus, S. intermedius, S. jettensis, S. kloosii, S. leei, S. lentus, S. lugdunensis, S. lutrae, S. lyticans, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S. petrasii, S. pettenkoferi, S. piscifermentans, S. pseudintermedius, S. pseudolugdunensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. schweitzeri, S. sciuri, S. simiae, S. simulans, S. singaporensis, S. stepanovicii, S. succinus, S. vitulinus, S. warned, S. xylosus and S. Westin species.

[0196] 48. The method of embodiment 47, wherein the Staphylococcus bacterium is selected from S. aureus and S. epidermidis species.EXAMPLESA. Chemical synthesis of sulfadiazine-phytochemical conjugatesGeneral Materials

[0197] Chemicals used in the study were purchased from Sigma-Aldrich Canada (Oakville, ON, Canada).Example 1: Preparation of sulfadiazine-eugenol conjugate (1-1)Step 1: Preparation of N-chloroacetyl-sulfadiazine, 2-chloro-N-(4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)acetamide (3)

[0198] Chloroacetyl chloride (2, 0.16 mL, 2.0 mmol) and triethylamine (Et3N, 0.42 mL, 3.0 mmol) was gradually added into a solution of sulfadiazine (1, 500 mg, 2.0 mmol) in dimethylformamide (DMF, 5 mL) at 5 °C and reaction mixture was stirred for 12 h. Reaction progression was monitored using thin-layer chromatography (TLC, CH2CI2-MeOH, 20:3) under a UV lamp. Upon completion, the reaction mixture was poured into H2O and extracted with ethyl acetate (50 mL). The organic layer was then washed with H2O (50 mL), dried with Na2SO4and concentrated to give the N-chloroacetyl-sulfadiazine derivative, 2-chloro-N-(4-(N- (pyrimidin-2-yl)sulfamoyl)phenyl)acetamide (3, light brown solid, 510 mg, 78%).Step 2: Preparation of sulfadiazine-eugenol conjugate, 1-1

[0199] Eugenol (4, 0.19 mL, 1.22 mmol) was gradually added to a solution of N-chloroacetyl-sulfadiazine (3, 200 mg, 0.61 mmol) in DMF (3 mL) at 80 °C in the presence of K2CO3(442 mg, 3.05 mmol). The reaction mixture was stirred for 12 h. Reaction progression was also monitored using TLC (DCM-MeOH, 20:3) under a UV lamp. Upon completion, the reaction mixture was filtered through a Celite-545 bed (500 mg) and washed with MeOH (15 mL). Solvents were removed under reduced pressure using a rotatory evaporator and coevaporated with toluene (2x20 mL) to produce sulfadiazine-eugenol conjugate 1-1, 2-(4-allyl-2-methoxyphenoxy)-N-(4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)acetamide (1-1; brown solid, 200 mg, 72%).

[0200] 1H NMR (DMSO-d6, 700 MHz): δ 6.82-6.34 (m, 10 H, Aromatic H), 5.76-5.69 (m, 1H, CH=CH2), 4.85-4.75 (m, 4 H, CH2=CH, CH2), 3.51 (s, 3H, OCH3); ESI-MS [M+1]+: 455.1389Example 2: Preparation of sulfadiazine-protocatechuic acid conjugate (I-2) and sulfadiazine-protocatechuic methyl ester conjugate I-3

[0201] Methyl 3,4-dihydroxybenzoate (6; 160 mg, 0.95 mmol) was gradually added to a solution of N-chloroacetyl-sulfadiazine (3, 320 mg, 0.97 mmol) in DMF (3 mL) at room temperature in presence of K2CO3(134 mg, 0.97 mmol). The reaction mixture was stirred for 12 h. Reaction progression was monitored using TLC (DCM-MeOH, 7:1) under a UV lamp. Upon completion, the reaction mixture was filtered through Celite-545 bed (500 mg) and washed with MeOH (15 mL). Solvents were removed under reduced pressure using a rotatoryevaporator and co-evaporated with toluene (2x20 mL) to give 1-3 (0.38 g, 85%). 1-3 was then treated with 1.0 M NaOH at room temperature for 12 h followed by purification of the crude product over SiO2using Toluene-EtOAc (1:4) as the eluant to generate the sulfadiazine-protocatechuic acid conjugate, 2-oxo-2-((4-(N-(pyrimidin-2-yl)sulfamoyl)phenyl)amino)ethyl3,4-dihydroxybenzoate (I-2; brown solid, 325 mg, 88%).

[0202] 1H NMR of I-2 (DMSO-d6, 700 MHz): δ 8.11 (br s, 1 H, COOH), 7.02-6.98 (m, 4 H, Aromatic H), 6.52-6.50 (m, 2 H, Aromatic H), 5.93-5.80 (m, 4 H, Aromatic H), 3.66 (s, 2 H, CH2); ESI-MS [M+1]+: 445.0818B. BiologyGeneral MaterialsBacterial strains, culture media and chemicals

[0203] Streptococcus dysgalactiae 43078, Streptococcus uberis 19436, Enterococcus faecium 700221, Enterococcus faecalis 29212, Staphylococcus aureus 29213, Staphylococcus epidermidis 12228, Pseudomonas aeruginosa 27853, Pasteurella multocida 43137, Mannheimia haemolytica 29702 and Escherichia coli 25422 were purchased from the American Type Culture Collection (Manassas, VA, USA). Cell culture media for each bacterium were purchased from Cedarlane Labs (Burlington, ON, Canada).Example 3: Minimum Inhibitory Concentration (MIC) measurementMIC was determined for each exemplary conjugate against a panel of six Gram-positive (Streptococcus dysgalactiae, Streptococcus uberis, Enterococcus faecium, Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis) and four Gram-negative bacteria (Pseudomonas aeruginosa, Pasteurella multocida, Mannheimia haemolytica and Escherichia coli) using apreviously published protocol

[0019] , The measurement was carried out in triplicate.Results and discussion

[0204] New antibiotic-phytochemical conjugates, e.g., sulfadiazine-eugenol (1-1) and sulfadiazine-protocatechuic acid (I-2) were synthesized.

[0205] In vitro antibacterial activity of exemplary sulfadiazine-eugenol(l-l) and sulfadiazine-protocatechuic acid (1-2) conjugates were evaluated against a panel of six Grampositive (Streptococcus dysgalactiae, Streptococcus uberis, Enterococcus faecium, Enterococcus faecalis, Staphylococcus aureus and Staphylococcus epidermidis) and four Gram-negative bacteria (Pseudomonas aeruginosa, Pasteurella multocida, Mannheimia haemolytica and Escherichia coli) using a published protocol

[0019] , Similar to the previouslyinvestigated sulfamethoxazole-phytochemical conjugates, the sulfadiazine-phytochemical conjugates were also more active towards Gram-positive bacteria (Table 1).Table 1. Antimicrobial activity (MIC: pg / mL) of exemplary compounds of the application against six Gram-positive and four Gram-negative bacteria.1-1 I-2Gram-positive bacteriaStreptococcus dysgalactiae 500 500Streptococcus uberis 1000 500Enterococcus faecium 2000 1000Enterococcus faecalis 125 2000Staphylococcus aureus 31 16-31Staphylococcus epidermidis 63 16Gram-negative bacteriaPseudomonas aeruginosa 2000 1000Pasteurella multocida 250 125Mannheimia haemolytica 2000 250Escherichia coli >2000 2000

[0206] However, as can be seen from Table 1, the exemplary conjugates 1-1 and I-2 also showed potent inhibitory activity against Pasteurella multocida (gram negative) with respective minimum inhibitory concentration (MIC) of 250 pg / mL and 125 pg / mL. For the Gram-positive bacteria, the exemplary sulfadiazine-eugenol, 1-1, and sulfadiazine-protocatechuic acid, I-2, conjugates were less effective towards Streptococcal and Enterococcal species (except sulfadiazine-eugenol, 1-1, against Enterococcus faecalis, MIC: 125 pg / mL) but surprisingly demonstrated extremely strong activity towards Staphylococcal species compared to the previously investigated sulfamethoxazole-phytochemical conjugates and to the individual compounds (e.g. sulfadiazine, eugenol and protocatechuic acid [20, 21, 22, 23, 23A, 23B, 23C). MIC of the exemplary sulfadiazine-eugenol conjugate, 1-1, was 31 pg / mL against S. aureus and 63 pg / mL against S. epidermidis, and MIC of the exemplary sulfadiazine-protocatechuic acid conjugate, I-2 was 16-31 pg / mL against S. aureus and 16 pg / mL against S. epidermidis (Table 1). This suggests that the new exemplary sulfadiazine-phytochemical conjugates, 1-1 and I-2, have comparable or even better in vitro antibacterial activity than the FDA-approved drug, silver sulfadiazine, which exhibited an in vitro MIC of 16-120 pg / mL against MRSA strains and 25-50 pg / mL against S. epidermidis strains [24, 25], Thus, it is concluded the new sulfadiazine-phytochemical conjugates, have been obtained that are highly active and selective towards Staphylococcal species.Example 4: Pilot pharmacokinetic study

[0207] A pilot pharmacokinetic study was carried out for exemplary sulfadiazineeugenol conjugate (1-1) at two different doses (50 and 100 mg / kg formulated in 0.5% CMC in deionezed water) in male CD-1 mice (IUCAC approval number: I037). Briefly, the mice were allowed to acclimate to the test facility for at least 2 days prior to study start. Blood samples (~ 35 pL / each sample) was collected via tail vein snip in accordance with test facility standard operating procedures at 0.25, 0.5, 1, 2, 4, 8 and 24 h after oral administration (gavage) of the conjugate compound. Concentration of the conjugate in the blood samples was measured by quantitative LC-MS in reference to a calibration curve.Results and Discussion

[0208] To get an understanding of the pharmacological function of the conjugates, a pilot pharmacokinetic study of exemplary sulfadiazine-eugenol conjugate, 1-1, in male CD-1 mice was carried out. Blood samples were collected at ~35 pL (15 pL plasma) from the murine tail vein at 0.25, 0.5, 1, 2, 4, 8 and 24 h after oral administration of the compound (doses: 50 and 100 mg / kg). Concentration of the conjugate in the blood samples was measured using quantitative liquid chromatography-mass spectrometry (LC-MS). However, at either oral dose, compound in the blood samples could not be detected, suggesting that the exemplary sulfadiazine-eugenol conjugate, 1-1 is possibly fast-metabolized or has high plasma protein binding potential. Furthermore, toxicity (such as behavior change and sleepiness) of the conjugate, 1-1, to the CD-1 mice was not observed. Fast metabolism may be beneficial for dairy and beef farmers and industries as residual antibiotic in milk and beef has been a major concern from customers.Example 5: Functional mechanism: potential targets in bacteria

[0209] Combination therapy of antibiotics and bioactive molecules (especially inhibitors of a particular resistance mechanism) has been widely used to improve therapeutic outcome and delay / prevent development of AMR [27-29], Advantage of this multi-target therapeutic strategy includes achieving synergistic effect on killing bacteria, eliminating evolutionary advantage of resistant strains and imposing selection inversion [30, 31], However, one challenge of this therapy is that drugs in the combination therapy may have different pharmacokinetic profiles, rendering decreased therapeutic efficacy. Thus, chemical conjugation of synergistic antibiotics and bioactive molecules (including their respectivepharmacophores) has been proposed to take advantage of both multi-target function and uniform pharmacokinetic property [18, 19, 32, 33],

[0210] To understand functional mechanism of the exemplary sulfadiazine-eugenol, I- 1, and sulfadiazine-protocatechuic acid, I-2, conjugates, their potential targets in bacteria have been identified. Sulfadiazine is a competitive inhibitor of dihydrofolate synthetase and inhibits folic acid synthesis

[0034] , It is also used in combination with trimethoprim, an inhibitor of dihydrofolate reductase

[0035] , Some structural similarity was observed between the exemplary conjugates, 1-1 and I-2, and trimethoprim although they are much bigger in size. The exemplary conjugates, 1-1 and I-2, were further compared with methotrexate (MTX), a structural analogue of trimethoprim and an inhibitor of human dihydrofolate reductase used to treat diseases such as cancer and rheumatoid arthritis [36, 37], As shown in Figure 1, the exemplary conjugates, 1-1 and l-2,are highly structurally homologous to MTX and, without being bound by theory, may occupy similar 3-dimentional space, although each molecule maintains certain flexibility due to the linker region. Human and bacterial dihydrofolate reductases share a relatively high structural homology (for example, sequence homology is 57% between human and Streptococcus uberis dihydrofolate reductases), and Escherichia coli dihydrofolate reductase is a known bacterial target for MTX

[0038] , Thus, MTX has been shown to be effective against different species of bacteria [39, 40] and exhibit sever systemic toxicity upon co-administration with sulfamethoxazole / trimethoprim

[0041] , Thus, without being bound by theory, it may be inferred that bacterial dihydrofolate reductase may also be a target for the two conjugates. The antibacterial function of eugenol includes damaging cytoplasmic membrane

[0042] , inhibiting protease, histidine carboxylase and amylase [43, 44], inhibiting membrane-bound ATPase

[0045] , producing reactive oxygen species (ROS)

[0046] , inhibiting expression of virulence factors [47, 48], inhibiting bacterial metabolism

[0049] , and inhibiting bacterial migration and invasion [48, 49], As for protocatechuic acid, its antibacterial function includes damaging cell membrane

[0050] , lowering intracellular pH and ATP level

[0050] , causing leakage of potassium ions

[0050] , inhibiting biofilm formation

[0051] , damaging bacterial cell wall

[0052] , increasing intracellular ROS level [52, 53], and inhibiting ATPase, pyruvate kinase and succinate dehydrogenase [52, 54], In Table 2 is provided a summary of potential targets and functional mechanism for the exemplary conjugates, 1-1 and I-2, implying that their antimicrobial activity is highly likely via multiple targets..Table 2. Potential targets and functional mechanism of exemplary compounds in bacteria.1-1 I-21. Inhibiting dihydrofolate synthetase 1. Inhibiting dihydrofolate synthetase2. Inhibiting dihydrofolate reductase 2. Inhibiting dihydrofolate reductase3. Damaging cytoplasmic membrane 3. Damaging cell membrane 4. Inhibiting protease, histidine 4. Lowering intracellular pH and ATP carboxylase and amylase level 5. Inhibiting membrane-bound ATPase 5. Causing leakage of potassium ions 6. Producing reactive oxygen species 6. Inhibiting biofilm formation (ROS) 7. Damaging bacterial cell wall 7. Inhibiting expression of virulence 8. Increasing intracellular ROS level factors 9. Inhibiting ATPase, pyruvate kinase 8. Inhibiting bacterial metabolism and succinate dehydrogenase 9. Inhibiting bacterial migration and invasion

[0211] While the present application has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

[0212] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.FULL CITATIONS FOR DOCUMENTS REFERRED TO IN THE SPECIFICATION

[0213] A number of publications are cited herein. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0214] 1. Tong SY, Davis JS, Eichenberger E, Holland TL, Fowler VG Jr. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev. 2015; 28(3): 603-661.

[0215] 2. Peacock SJ, Paterson GK. Mechanisms of Methicillin Resistance in Staphylococcus aureus. Annu Rev Biochem. 2015; 84: 577-601.

[0216] 3. Cong Y, Yang S, Rao X. Vancomycin resistant Staphylococcus aureus infections: A review of case updating and clinical features. J Adv Res. 2019; 21: 169-176.

[0217] 4. Carrel M, Smith M, Shi Q, Hasegawa S, Clore GS, Perencevich EN, Goto M. Antimicrobial Resistance Patterns of Outpatient Staphylococcus aureus Isolates. JAMA Netw Open. 2024; 7(6): e2417199.

[0218] 5. Youenou B, Martins Simoes P, Tristan A, Farfour E, Beauruelle C, Kolenda C, Ranc AG, Vandenesch F, Laurent F, Dupieux C. Linezolid resistance: detection of the cfr(B) gene in French clinical MRSA strains. J Antimicrob Chemother. 2023; 78(2): 445-449.

[0219] 6. Olde Riekerink RG, Barkema HW, Kelton DF, Scholl DT. Incidence rate of clinical mastitis on Canadian dairy farms. J Dairy Sci. 2008; 91(4): 1366-1377.

[0220] 7. Gajewska J, Zakrzewski A, Chaj^cka-Wierzchowska W, Zadernowska A. Meta-analysis of the global occurrence of S. aureus in raw cattle milk and artisanal cheeses. Food Control. 2023; 147: 109603.

[0221] 8. Azimi T, Mirzadeh M, Sabour S, Nasser A, Fallah F, Pourmand MR. Coagulase-negative staphylococci (CoNS) meningitis: a narrative review of the literature from 2000 to 2020. New Microbes New Infect. 2020; 37: 100755.

[0222] 9. Angelopoulou A, Field D, Ryan CA, Stanton C, Hill C, Ross RP. The microbiology and treatment of human mastitis. Med Microbiol Immunol. 2018; 207(2): 83-94.

[0223] 10. Van Boeckel TP, Brower C, Gilbert M, Grenfell BT, Levin SA, Robinson TP, Teillant A, Laxminarayan R. Global trends in antimicrobial use in food animals. Proc Natl Acad Sci USA. 2015; 112(18): 5649-5654.

[0224] 11. Watkins RR, Bonomo RA. The Ongoing Threat of Antimicrobial Resistance. Infect Dis Clin North Am. 2020; 34(4): xiii-xiv.

[0225] 12. Basavegowda N, Baek KH. Combination Strategies of Different Antimicrobials: An Efficient and Alternative Tool for Pathogen Inactivation. Biomedicines.2022;10(9): 2219.

[0226] 13. Xu X, Xu L, Yuan G, Wang Y, Qu Y, Zhou M. Synergistic combination of two antimicrobial agents closing each other's mutant selection windows to prevent antimicrobial resistance. Sci Rep. 2018; 8(1): 7237.

[0227] 14. Cavaco M, Castanho MARB, Neves V. The Use of Antibody-Antibiotic Conjugates to Fight Bacterial Infections. Front Microbiol. 2022; 13: 835677.

[0228] 15. Svenningsen SW, Frederiksen RF, Counil C, Ficker M, Leisner JJ, Christensen JB. Synthesis and Antimicrobial Properties of a Ciprofloxacin and PAMAM-dendrimer Conjugate. Molecules. 2020; 25(6): 1389.

[0229] 16. Biharee A, Sharma A, Kumar A, Jaitak V. Antimicrobial flavonoids as a potential substitute for overcoming antimicrobial resistance. Fitoterapia. 2020; 146: 104720.

[0230] 17. Barbosa F, Pinto E, Kijjoa A, Pinto M, Sousa E. Targeting antimicrobial drug resistance with marine natural products. Int J Antimicrob Agents. 2020; 56(1): 106005.

[0231] 18. Rajamanickam K, Yang J, Sakharkar MK. A Novel Antimicrobial- Phytochemical Conjugate With Antimicrobial Activity Against Streptococcus uberis, Enterococcus faecium, and Enterococcus faecalis. Front Pharmacol. 2019; 10: 1405.

[0232] 19. Yang J, Kaul-Ghanekar R, Sakharkar MK. Chemical synthesis and antimicrobial activity evaluation of four novel sulfamethoxazole-phytochemical conjugates. Results Chem. 2024; 7: 101235.

[0233] 20. Kratky M, Dzurkova M, Janousek J, Konecna K, Trejtnar F, Stolafikova J, Vinsova J. Sulfadiazine Salicylaldehyde-Based Schiff Bases: Synthesis, Antimicrobial Activity and Cytotoxicity. Molecules. 2017; 22(9): 1573.

[0234] 21. Ueda Y, Miyazaki M, Mashima K, Takagi S, Hara S, Kamimura H, Jimi S. The Effects of Silver Sulfadiazine on Methicillin-Resistant Staphylococcus aureus Biofilms. Microorganisms. 2020; 8(10): 1551.

[0235] 22. Yadav MK, Chae SW, Im GJ, Chung JW, Song JJ. Eugenol: a phytocompound effective against methicillin-resistant and methicillin-sensitive Staphylococcus aureus clinical strain biofilms. PLoS One. 2015; 10(3): e0119564.

[0236] 23. Fifere A, Turin-Moleavin I A, Rosea I. Does Protocatechuic Acid Affect the Activity of Commonly Used Antibiotics and Antifungals? Life (Basel). 2022; 12(7): 1010.

[0237] 23A. Chai, B, Jiang W, Hu M, Wu Y, Si H, In vitro synergistic interactions of Protocatechuic acid and Chlorogenic acid in combination with antibiotics against animal pathogens, Synergy 9 (2019) 100055.

[0238] 23B. Jayaraman P. Sakharkar M, Lim CS, Tang TH, Sakharkar K, Activity and interactions of antibiotic and phytochemical combinations against Pseudomonas aeruginosa in vitro, Int. J. Biol. Sci. 2010, 6(6):556-568.

[0239] 23C. Rajamanickam K, Yang J, Sakharkar MK. Phytochemicals as alternatives to antibiotics against major pathogens involved in bovine respiratory disease (BRD) and bovine mastitis (BM). Bioinformation 15(1): 32-35 (2019).

[0240] 24. Carr HS, Wlodkowski TJ, Rosenkranz HS. Silver sulfadiazine: in vitro antibacterial activity. Antimicrob Agents Chemother. 1973; 4(5): 585-587.

[0241] 25. Maple PA, Hamilton-Miller JM, Brumfitt W. Comparison of the in-vitro activities of the topical antimicrobials azelaic acid, nitrofurazone, silver sulphadiazine and mupirocin against methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother. 1992; 29(6): 661-668.

[0242] 26. Yang J, Hediyal TA, Chidambaram SB, Kaul-Ghanekar R, Sakharkar MK. Benzyl isothiocyanate as an alternative to antibiotics? a comparative in vivo study using Pseudomonas aeruginosa infection as a model. PLoS One. 2024; 19(5): e0303490.

[0243] 27. Si Z, Pethe K, Chan-Park MB. Chemical Basis of Combination Therapy to Combat Antibiotic Resistance. JACS Au. 2023; 3(2): 276-292.

[0244] 28. Tamma PD, Cosgrove SE, Maragakis LL. Combination therapy for treatment of infections with gram-negative bacteria. Clin Microbiol Rev. 2012; 25(3): 450-470.

[0245] 29. Rybak MJ, McGrath BJ. Combination antimicrobial therapy for bacterial infections. Guidelines for the clinician. Drugs. 1996; 52(3): 390-405.

[0246] 30. Baym M, Stone LK, Kishony R. Multidrug evolutionary strategies to reverse antibiotic resistance. Science. 2016; 351(6268): aad3292.

[0247] 31. Coates ARM, Hu Y, Holt J, Yeh P. Antibiotic combination therapy against resistant bacterial infections: synergy, rejuvenation and resistance reduction. Expert Rev Anti Infect Ther. 2020; 18(1): 5-15.

[0248] 32. Caradec T, Anoz-Carbonell E, Petrov R, Billamboz M, Antraygues K, Cantrelle FX, Boll E, Beury D, Hot D, Drobecq H, Trivelli X, Hartkoorn RC. A Novel NaturalSiderophore Antibiotic Conjugate Reveals a Chemical Approach to Macromolecule Coupling. ACS Cent Sci. 2023; 9(11): 2138-2149.

[0249] 33. Yamauchi R, Kawano K, Yamaoka Y, Taniguchi A, Yano Y, Takasu K, Matsuzaki K. Development of Antimicrobial Peptide-Antibiotic Conjugates to Improve the Outer Membrane Permeability of Antibiotics Against Gram-Negative Bacteria. ACS Infect Dis. 2022; 8(11): 2339-2347.

[0250] 34. McCullough JL, Maren TH. Inhibition of dihydropteroate synthetase from Escherichia coli by sulfones and sulfonamides. Antimicrob Agents Chemother. 1973; 3(6): 665-669.

[0251] 35. Burchall JJ, Hitchings GH. Inhibitor binding analysis of dihydrofolate reductases from various species. Mol Pharmacol. 1965; 1(2): 126-136.

[0252] 36. Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer. 1978; 41(1): 36-51.

[0253] 37. Braun J, Rau R. An update on methotrexate. Curr Opin Rheumatol. 2009; 21(3): 216-223.

[0254] 38. Matthews DA, Alden RA, Bolin JT, Freer ST, Hamlin R, Xuong N, Kraut J, Poe M, Williams M, Hoogsteen K. Dihydrofolate reductase: x-ray structure of the binary complex with methotrexate. Science. 1977; 197(4302): 452-425.

[0255] 39. Metcalfe D, Hughes WT. Effects of methotrexate on group A beta hemolytic streptococci and streptococcal infection. Cancer. 1972; 30(2): 588-593.

[0256] 40. Maier L, Pruteanu M, Kuhn M, Zeller G, Telzerow A, Anderson EE, Brochado AR, Fernandez KC, Dose H, Mori H, Patil KR, Bork P, Typas A. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018; 555(7698): 623-628.

[0257] 41. Cudmore J, Seftel M, Sisler J, Zarychanski R. Methotrexate and trimethoprim-sulfamethoxazole: toxicity from this combination continues to occur. Can Fam Physician. 2014; 60(1): 53-56.

[0258] 42. Ulanowska M, Olas B. Biological Properties and Prospects for the Application of Eugenol-A Review. Int J Mol Sci. 2021; 22(7): 3671.

[0259] 43. Marchese A, Barbieri R, Coppo E, Orhan IE, Daglia M, Nabavi SF, Izadi M, Abdollahi M, Nabavi SM, Ajami M. Antimicrobial activity of eugenol and essential oils containing eugenol: A mechanistic viewpoint. Crit Rev Microbiol. 2017; 43(6): 668-689.

[0260] 44. Devi KP, Nisha SA, Sakthivel R, Pandian SK. Eugenol (an essential oil of clove) acts as an antibacterial agent against Salmonella typhi by disrupting the cellular membrane. J Ethnopharmacol. 2010; 130(1): 107-115.

[0261] 45. Gill AO, Holley RA. Inhibition of membrane bound ATPases of Escherichia coli and Listeria monocytogenes by plant oil aromatics. Int J Food Microbiol. 2006; 111(2): 170-174.

[0262] 46. Hyldgaard M, Mygind T, Meyer RL. Essential oils in food preservation: mode of action, synergies, and interactions with food matrix components. Front Microbiol. 2012; 3: 12.

[0263] 47. Hu Q, Zhou M, Wei S. Progress on the Antimicrobial Activity Research of Clove Oil and Eugenol in the Food Antisepsis Field. J Food Sci. 2018; 83(6): 1476-1483.

[0264] 48. Baskaran SA, Kollanoor-Johny A, Nair MS, Venkitanarayanan K. Efficacy of Plant-Derived Antimicrobials in Controlling Enterohemorrhagic Escherichia coli Virulence In Vitro. J Food Prot. 2016; 79(11): 1965-1970.

[0265] 49. Upadhyaya I, Upadhyay A, Kollanoor-Johny A, Darre MJ, Venkitanarayanan K. Effect of plant derived antimicrobials on Salmonella enteritidis adhesion to and invasion of primary chicken oviduct epithelial cells in vitro and virulence gene expression. Int J Mol Sci.2013; 14(5): 10608-10625.

[0266] 50. Wu M, Tian L, Fu J, Liao S, Li H, Gai Z, Gong G. Antibacterial mechanism of Protocatechuic acid against Yersinia enterocolitica and its application in pork. Food Control.2022; 133, Part A: 108573.

[0267] 51. Gao C, Tian L, Lu J, Gong G. A Novel Bioactive Antimicrobial Film Based on Polyvinyl Alcohol-Protocatechuic Acid: Mechanism and Characterization of Biofilm Inhibition and its Application in Pork Preservation. Food Bioprocess Technol. 2024; 17: 3319–3332.

[0268] 52. Cai J, Sun L, Wang Q. Antibacterial activity and mechanism of Protocatechuic acid against bacterial canker of tomato fruits caused by Clavibacter michiganensis subsp. Michiganensis. 2024; 60: 104437.

[0269] 53. Ajiboye TO, Habibu RS, Saidu K, Haliru FZ, Ajiboye HO, Aliyu NO, Ibitoye OB, Uwazie JN, Muritala HF, Bello SA, Yusuf II, Mohammed AO. Involvement of oxidative stress in protocatechuic acid-mediated bacterial lethality. Microbiologyopen. 2017; 6(4): e00472.

[0270] 54. Hao J, Lei Y, Gan Z, Zhao W, Shi J, Jia C, Sun A. Synergetic Inactivation Mechanism of Protocatechuic Acid and High Hydrostatic Pressure against Escherichia coli O157: H7. Foods. 2021; 10(12): 3053.

Claims

CLAIMS:

1. A compound of Formula I:and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof, whereinR1, R2, R4and R5are independently selected from H, OH, halo, NO2, CN, CO2H, Ci_6alkyl, OC1-ealkyl, CO2Ci.6alkyl, NH2, NH(Ci.6alkyl) and N(Ci.6alkyl)(Ci.6alkyl);R3is selected from OH, halo, NO2, CN, CO2H, CHO, SO3H, Ci_6alkyl, C2.6alkenyl, OCi.6alkyl, NH2, NH(Ci.6alkyl), N(Ci.6alkyl)(Ci.6alkyl), CO2Ci.6alkyl, Ci.6alkyleneCO2H, Ci.6alkenyenelCO2H, Ci-6alkyleneCO2Ci-6alkyl, Ci-6alkenyleneCO2Ci-6alkyl, Ci-6alkyleneCHO, Ci.6alkenyleneCHO, Ci-6alkyleneSO3H and Ci.6alkenyleneSO3H;L1is a linker group having the formula, Z1-(CH2)m-(Z2)n;Z1is selected from O, NR6, NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O, NR6C(O)NR6, OC(O)NR6and NR6C(O)O;Z2is selected from O, NR7, OC(O), C(O)O, OC(O)O, OC(O)NR7and NR7C(O)O;R6and R7are independently selected from H and Ci_4alkyl;m is selected from 0, 1, 2, 3 and 4; andn is selected from 0 and 1,provided m is not 0 when n is 1; andZ1is not NR6when Z2is O.

2. The compound of claim 1, wherein R1, R2, R4and R5are independently selected from H, OH, halo, N02, CN, CO2H, Ci.4alkyl, OCi.4alkyl, CO2Ci.4alkyl, NH2, NH(Ci.4alkyl) and N(Ci.4alkyl)(Ci.4alkyl).

3. The compound of claim 2, wherein R1, R2, R4and R5are independently selected from H, OH, F, Cl, Br, I, N02, CN, CO2H, OCH3, OCH2CH3, CO2CH3, and CO2CH2CH3.

4. The compound of claim 2, wherein one or two of R1, R2, R4and R5are selected from OH, F, Cl, Br, I, N02, CN, CO2H, OCi-2alkyl, CO2Ci-2alkyl, NH2, NH(Ci-2alkyl) and N(Ci-2alkyl)(Ci-2alkyl) and the remaining of R1, R2, R4and R5are selected from H, F, Cl, OH, Ci.2alkyl and OCi.2alkyl.

5. The compound of claim 1, wherein one of R1and R5is selected from OH, F, Cl, Br, I, NO2, CN, CO2H, OCi.2alkyl, CO2Ci.2alkyl, NH2, NH(Ci.2alkyl) and N(Ci.2alkyl)(Ci.2alkyl) and the other of R1and R5is selected from H, OH, Ci_2alkyl, and OCi.2alkyl.

6. The compound of claim 5, wherein one of R1and R5is selected from OH and OCH3, and the other of R1and R5is selected from H, OH and OCH3.

7. The compound of any one of claims 1 to 6, wherein R3is selected from OH, halo, NO2, CN, CO2H, CHO, SO3H, Ci-4alkyl, C2.4alkenyl, OCi.4alkyl, NH2, NH(Ci.4alkyl), N(Ci.4alkyl)(Ci.4alkyl), CO2Ci.4alkyl, Ci.4alkyleneCO2H, Ci.4alkenyleneCO2H, Ci.4alkyleneCO2Ci.4alkyl, C1-4alkenyleneCO2Ci.4alkyl, C1-6alkyleneCHO, Ci.4alkenyleneCHO, Ci.4alkyleneSO3H and C1-4alkenyleneSO3H.

8. The compound of claim 7, wherein R3is selected from OH, F, Cl, NO2, CO2H, CHO, SO3H, C2.4alkenyl, OCi.4alkyl, CO2Ci.2alkyl, Ci.4alkylCO2H, Ci.4alkenyleneCO2H, C1-4alkyleneCO2Ci-2alkyl, Ci-4alkenyleneCO2Ci-2alkyl, Ci.4alkyleneCHO, Ci.4alkenyleneCHO, C1-4alkyleneSO3H and Ci.4alkenyleneSO3H.

9. The compound of claim 8, wherein R3is selected from OH, CO2H, CHO, SO3H, CH2CH=CH2, OCi-3alkyl, CO2Ci-2alkyl, CH=CHCO2H, CH=CHCHO and CH=CHSO3H.

10. The compound of any one of claims 1 to 9, wherein Z1is selected from NR6, NR6C(O), OC(O), NR6(CO)NR6and NR6C(O)O and Z2is selected from O, NR7, OC(O), C(O)O, OC(O)O and OC(O)NR7.

11. The compound of any one of claims 1 to 9, wherein m and n are both 0 and Z1is selected from NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O NR6C(O), C(O)NR6, NR6(CO)NR6, OC(O)NR6and NR6C(O)O; orwherein m is selected from 1 and 2, n is 0, and Z1is selected from NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O NR6C(O), C(O)NR6, NR6(CO)NR6, OC(O)NR6and NR6C(O)O; or wherein n is 1, m is selected from 1, 2, 3 and 4, Z1is selected from O, NR6, NR6C(O), C(O)NR6, OC(O), C(O)O, OC(O)O, NR6C(O)NR6, OC(O)NR6and NR6C(O)O and Z2is selected from O, NR7and C(O)O, andR6and R7are independently selected from H and Ci-2alkyl.

12. The compound of any one of claims 1 to 9, wherein L1is selected from NR6C(O)(CH2)mO, OC(O)(CH2)mO, NR6C(O)NR6(CH2)m, NR6C(O)NR6, OC(O)(CH2)mNR7, NR6(CH2)mC(O)O and OC(O)(CH2)mNR7.

13. The compound of any one of claims 1 to 10, wherein L1is NR6C(O)(CH2)mO, or wherein L1is NR6C(O)CH2O.

14. The compound of claim 1, wherein the compound of Formula I is a compound of Formula lb:L1TH [ R5N o / XOand / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,wherein R1, R3and R5are as defined in any one of claims 1 to 13.

15. The compound of claim 1, wherein the compound of Formula I is a compound of Formula Ic:Rl6NxY o yO R5and / or a pharmaceutically acceptable salt, prodrug and / or solvate thereof,wherein R1, R3and R5are as defined in any one of claims 1 to 13.

16. The compound of claim 1, wherein the compound of Formula I is selected from:CompoundStructure CHEMICAL NAMEI. D.2-(4-allyl-2-methoxyphenoxy)-N- HN (4-(N-(pyrimidin-2- nO0yl)sulfamoyl)phenyl)acetamide;andHO. 3-hydroxy-4-(2-oxo-2-((4-(N- H (pyrimidin-2- n ° yl)sulfamoyl)phenyl)amino)etho o xy)benzoic acidCompoundStructure CHEMICAL NAMEI. D.0methyl 3-hydroxy-4-(2-oxo-2- H r n ° ((4-(N-(pyrimidin-2- I-31yl)sulfamoyl)phenyl)amino)etho 1 II II 0AYAAJ o xy)benzoate(J Aor a pharmaceutically acceptable salt, solvate and / or prodrug thereof.

17. A pharmaceutical composition comprising a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof, and a pharmaceutically acceptable carrier.

18. A method of treating or preventing a Staphylococcus bacterial infection, or of treating or preventing a disease, disorder or condition arising from a Staphylococcus bacterial infection comprising administering an effective amount of a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt, solvate and / or prodrug thereof or the pharmaceutical composition of claim 17, to a subject in need thereof.

19. The method of claim 18, wherein the Staphylococcus bacterial infection is an infection of at least one bacterium belonging to the genus Staphylococcus and the Staphylococcus bacterium is selected from S. argenteus, S. arlettae, S. agnetis, S. aureus, S. auricularis, S. borealis, S. Caeli, S. capitis, S. caprae, S. carnosus, S. caseolyticus, S. chromogenes, S. cohnii, S. cornubiensis, S. condiment, S. debuckii, S. delphini, S. devriesei, S. edaphicus, S. epidermidis, S. equorum, S. fells, S. fleurettii, S. gallinarum, S. haemolyticus, S. hominis, S. hyicus, S. intermedius, S. jettensis, S. kloosii, S. leei, S. lentus, S. lugdunensis, S. lutrae, S. lyticans, S. massiliensis, S. microti, S. muscae, S. nepalensis, S. pasteuri, S. petrasii, S. pettenkoferi, S. piscifermentans, S. pseudintermedius, S. pseudolugdunensis, S. pulvereri, S. rostri, S. saccharolyticus, S. saprophyticus, S. schleiferi, S. schweitzeri, S. sciuri, S. simiae, S. simulans, S. singaporensis, S. stepanovicii, S. succinus, S. vitulinus, S. warneri, S. xylosus and S. Westin species.

20. The method of claim 19, wherein the Staphylococcus bacterium is selected from S. aureus and S. epidermidis species.

Images