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WO2025049804A2 - Agents pour traitement contre des bactéries non réplicatives - Google Patents

Agents pour traitement contre des bactéries non réplicatives Download PDF

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Publication number
WO2025049804A2
WO2025049804A2 PCT/US2024/044515 US2024044515W WO2025049804A2 WO 2025049804 A2 WO2025049804 A2 WO 2025049804A2 US 2024044515 W US2024044515 W US 2024044515W WO 2025049804 A2 WO2025049804 A2 WO 2025049804A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
compound
hydrogen
further aspect
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/US2024/044515
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English (en)
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WO2025049804A3 (fr
Inventor
Richard E. Lee
Ying Zhao
Michael LaFleur
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Arietis Corp
St Jude Childrens Research Hospital
Original Assignee
Arietis Corp
St Jude Childrens Research Hospital
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Publication of WO2025049804A2 publication Critical patent/WO2025049804A2/fr
Publication of WO2025049804A3 publication Critical patent/WO2025049804A3/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/552—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • ESKAPE Enterococcus faecium, Staphyloccocus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas aeruginosa, and Escherichia coli
  • WHO World Health Organization
  • antibiotics may be chemically incompatible with one another when mixed.
  • One alternative to combination therapy is a dual hybrid antibiotic.
  • the underlying objective behind ligating two antibiotics together via metabolically stable tethers is to construct a singular heterodimeric entity with a fixed pharmacokinetic profile while retaining the antibacterial mechanisms of the constituent pharmacophores. Without wishing to be bound by theory, this could improve on-site targeting, impede bacterial efflux, sterically protect constituent pharmacophores from enzymatic degradation, and reduce toxicity when administered in-vivo (Pokrovskaya and Baasov (2010) J. Med. Chem.52(8): 2243-2254; Theuretzbacher (2020) Nat.
  • the invention in one aspect, relates to compounds useful as hybrid antibiotics, acting as both activators of the ClpP protease and inhibitors of RNA polymerase activity.
  • Also disclosed are methods of using the disclosed compounds in the treatment of infectious diseases such as, for example, biofilm-mediated diseases and infectious diseases due to prosthetic joint infections, intracellular bacteria, and Gram-positive bacteria e.g., Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus a
  • Also disclosed are compounds having a structure represented by a formula: , wherein Y is selected from R 80 and –NH–(Q)q–Ar 2 ; wherein q is selected from 0 and 1; wherein Q is selected from ⁇ CH2 ⁇ , ⁇ CH2CH2 ⁇ , ⁇ CH CH ⁇ , and ⁇ (cyclopropyl) ⁇ ; wherein R 80 is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, ⁇ (C1-C8 alkyl) ⁇ (C3-C8 cycloalkyl), ⁇ (C1-C8 alkyl) ⁇ (C3-C8 cycloalkenyl), ⁇ (C2-C8 alkenyl) ⁇ (C3-C8 cycloalkyl), and ⁇ (C2-C8 alkenyl) ⁇ (C3-C8 cycloalkenyl; wherein Ar 2 is selected from C6 aryl and C2- C9 hetero
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog; wherein each of R 1a , R 1b , and R 1c is independently
  • compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • methods for treating an infectious disease in a subject in need thereof in the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby treating the infectious disease in the subject.
  • methods for activating ClpP protease in a cell the method comprising contacting the cell with an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby activating ClpP protease in the cell.
  • Also disclosed are methods for activating ClpP protease in a subject the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby activating ClpP protease in the subject.
  • methods for inhibiting RNA polymerase activity in a cell the method comprising contacting the cell with an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby inhibiting RNA polymerase activity in the cell.
  • Also disclosed are methods for inhibiting RNA polymerase activity in a subject the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby enhancing RNA polymerase activity in the subject.
  • kits comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an antimicrobial agent; (b) instructions for treating an infectious disease; and (c) instructions for administering the compound in connection with treating a microbial infection.
  • kits comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an antimicrobial agent; (b) instructions for treating an infectious disease; and (c) instructions for administering the compound in connection with treating a microbial infection.
  • FIG.1 shows structure of compound 5192.
  • FIG.2A-F shows representative data for the mechanism of action of compound 5192.
  • FIG.3A and FIG.3B show representative data of stationary phase and intracellular killing.
  • FIG.4A-D shows representative data of the in vivo efficacy of compound 5192.
  • FIG.5 shows a representative graph illustrating the efficacy of compound 5192 in a peritonitis septicemia model in kidneys.
  • FIG.6 shows a representative graph illustrating the effects of compound 5192 in a thigh lesion MRSA model.
  • FIG.7 shows a representative graph illustrating the effects of compound 5192 and control antibiotics on MRSA counts in a foreign device biofilm model.
  • the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”
  • Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
  • an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
  • references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease or disorder.
  • the term “patient” includes human and veterinary subjects.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
  • the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.
  • subject also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.
  • the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.
  • the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject.
  • Such methods include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent.
  • a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition.
  • a preparation can be administered prophylactically; that is, administered for prevention of a disease or condition.
  • imaging refers to a procedure that can make detailed pictures of areas inside a human body. Imaging procedures use different forms of energy such as x-rays (high-energy radiation), ultrasound (high-energy sound waves), radio waves, and radioactive substances. Imaging procedures can be used to help diagnose disease, to plan treatment, or to determine how well treatment is working. Exemplary imaging procedures include, but are not limited to, computed tomography (CT), mammography, ultrasonography, magnetic resonance imaging (MRI), nuclear medicine tests, positron emission tomography (PET), PET/MRI, and PET/CT.
  • CT computed tomography
  • mammography mammography
  • ultrasonography magnetic resonance imaging
  • PET positron emission tomography
  • PET PET/MRI
  • PET/CT PET/CT
  • radioactive isotope and “radioisotope,” as used herein, refers to an isotope whose nuclei is unstable and, as such, the isotope can dissipate excess energy by spontaneously emitting radiation in the form of alpha, beta, and/or gamma rays.
  • radioisotopes include, but are not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 F, 35 S, 36 Cl, 82 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 I.
  • a subject in need of RONS imaging refers to a subject who has been diagnosed as having, or is otherwise suspected of having, a disorder or disease caused by or otherwise attributable to oxidative stress as detailed elsewhere herein.
  • a subject is suspected of having a disorder or disease caused by or exacerbated by oxidative stress (e.g., a subject in need of RONS imaging)
  • the subject can undergo an imaging procedure to assess whether they demonstrate an increased signal (e.g., an increased PET signal) in a region of interest. If the imaging procedure reveals that the subject does, indeed, have an increased signal in the region of interest, they would then be identified as being in need of therapeutic treatment.
  • the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration.
  • compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition. [0048]
  • “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject.
  • a dosage form can comprise a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques.
  • Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-
  • a dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.
  • kit means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.
  • instruction(s) means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.
  • therapeutic agent include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, an
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which
  • Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a polyester refers to one or more -OCH 2 CH 2 O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more -CO(CH 2 ) 8 CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen
  • the heteroatoms can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • aliphatic or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s- butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can be cyclic or acyclic.
  • the alkyl group can be branched or unbranched.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • a “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
  • alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine.
  • monohaloalkyl specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
  • polyhaloalkyl specifically refers to an alkyl group that is independently substituted with two or more halides, i.e.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
  • hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
  • alkyl is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like. [0061] This practice is also used for other groups described herein.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.”
  • a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like.
  • cycloalkyl is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, ⁇ NH2, (C1-C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, ether, halogen, ⁇ OH, C1-C4 hydroxyalkyl, ⁇ NO2, silyl, sulfo-oxo, ⁇ SH, and C1-C4 thioalkyl, as described herein.
  • polyalkylene group as used herein is a group having two or more CH2 groups linked to one another.
  • the polyalkylene group can be represented by the formula — (CH2)a—, where “a” is an integer of from 2 to 500.
  • alkoxy and alkoxyl as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA 1 where A 1 is alkyl or cycloalkyl as defined above.
  • Alkoxy also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA 1 —OA 2 or — OA 1 —(OA 2 )a—OA 3 , where “a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl, aryl, heteroaryl, aldehyde, ⁇ NH2, (C1- C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, carboxylic acid, ester, ether, halogen, ⁇ OH, C1-C4 hydroxyalkyl, ketone, azide, ⁇ NO2, silyl, sulfo-oxo, ⁇ SH, and C1-C4 thioalkyl, as described herein.
  • alkynyl as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond.
  • the alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • cycloalkynyl as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound.
  • cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
  • heterocycloalkynyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted.
  • the cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
  • aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference.
  • aromatic group is inclusive of both aryl and heteroaryl groups.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ⁇ NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • biasryl is a specific type of aryl group and is included in the definition of “aryl.”
  • the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon- carbon bond.
  • biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • aldehyde as used herein is represented by the formula —C(O)H.
  • amine or “amino” as used herein are represented by the formula — NA 1 A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a specific example of amino is ⁇ NH2.
  • alkylamino as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein.
  • dialkylamino as used herein is represented by the formula —N(-alkyl) 2 where alkyl is a described herein.
  • Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N- ethyl-N-propylamino group and the like.
  • carboxylic acid as used herein is represented by the formula —C(O)OH.
  • esteer as used herein is represented by the formula —OC(O)A 1 or — C(O)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polyester as used herein is represented by the formula —(A 1 O(O)C-A 2 -C(O)O)a— or —(A 1 O(O)C-A 2 -OC(O))a—, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
  • ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula —(A 1 O-A 2 O)a—, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500.
  • Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halo halogen
  • halide as used herein can be used interchangeably and refer to F, Cl, Br, or I.
  • isoptically- labeled halogens are also envisioned.
  • the isotopically labeled halogens also include the radioactive isotopes such as ⁇ 18 F, ⁇ 76 Br, ⁇ 123 I, and ⁇ 124 I.
  • the terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.
  • heteroalkyl refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroaryl group can be substituted or unsubstituted.
  • the heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • Heteroaryl groups can be monocyclic, or alternatively fused ring systems.
  • Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.
  • heterocycle or “heterocyclyl” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon.
  • Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4- tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including
  • heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl.
  • a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
  • a C5 heterocyclyl comprises a group, which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like.
  • bicyclic heterocycle or “bicyclic heterocyclyl” as used herein refers to a ring system in which at least one of the ring members is other than carbon.
  • Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring.
  • Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6- membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms.
  • Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H- pyrazolo[3,2-b]pyridin-3-yl.
  • heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
  • the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • hydroxy or “hydroxyl” as used herein is represented by the formula — OH.
  • ketone as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • Azide or “azido” as used herein is represented by the formula —N 3 .
  • nitro as used herein is represented by the formula —NO2.
  • nitrile or “cyano” as used herein is represented by the formula —CN or — C ⁇ N.
  • sil as used herein is represented by the formula —SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo is represented by the formulas —S(O)A 1 , — S(O) 2 A 1 , —OS(O) 2 A 1 , or —OS(O) 2 OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 S(O)2A 2 is represented by the formula A 1 S(O)2A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • thiol as used herein is represented by the formula —SH.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • Suitable monovalent substituents on R ⁇ are independently halogen, — (CH2)0–2R ⁇ , –(haloR ⁇ ), –(CH2)0–2OH, –(CH2)0–2OR ⁇ , –(CH2)0–2CH(OR ⁇ )2; -O(haloR ⁇ ), –CN, –N 3 , –(CH 2 ) 0–2 C(O)R ⁇ , –(CH 2 ) 0–2 C(O)OH, –(CH 2 ) 0–2 C(O)OR ⁇ , –(CH 2 ) 0–2 SR ⁇ , –(CH 2 ) 0–2 SH, –(CH2)0–2NH2, –(CH2)0–2NHR ⁇ , –(CH2)0–2NR ⁇ 2,
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2)2–3O–, wherein each independent occurrence of R * is selected from hydrogen, C 1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R * include halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R ⁇ , –NR ⁇ 2, –C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH2C(O)R ⁇ , – S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , –C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above,
  • Suitable substituents on the aliphatic group of R ⁇ are independently halogen, – R ⁇ , -(haloR ⁇ ), –OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH2, –NHR ⁇ , –NR ⁇ 2, or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • the term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
  • suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
  • the terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions.
  • hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).
  • organic residue defines a carbon containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove.
  • Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like.
  • organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
  • Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.
  • a very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared.
  • a 2,4-thiazolidinedione radical in a particular compound has the structure: , regardless of whether thiazolidinedione is used to prepare the compound.
  • the radical for example an alkyl
  • the number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
  • Organic radicals contain one or more carbon atoms.
  • An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms.
  • an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
  • Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
  • an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2- naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di- substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
  • Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together.
  • examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals.
  • the inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical.
  • Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
  • Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture.
  • Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers.
  • the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included.
  • stereoisomers For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*).
  • bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • bonds to the chiral carbon when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically- labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl, respectively.
  • Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the compounds described in the invention can be present as a solvate.
  • the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
  • the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • a hydrate which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • the invention includes all such possible solvates.
  • co-crystal means a physical association of two or more molecules which owe their stability through non-covalent interaction.
  • One or more components of this molecular complex provide a stable framework in the crystalline lattice.
  • the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g.
  • pyrazoles can exist in two tautomeric forms, N 1 - unsubstituted, 3-A 3 and N 1 -unsubstituted, 5-A 3 as shown below. Unless stated to the contrary, the invention includes all such possible tautomers.
  • chemical substances form solids, which are present in different states of order which are termed polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.
  • a structure of a compound can be represented by a formula: , which is understood to be equivalent to a formula: , wherein n is typically an integer. That is, R n is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n(a) is halogen, then R n(b) is not necessarily halogen in that instance.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • A-D a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention.
  • compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.
  • B. COMPOUNDS [00121]
  • the invention relates to compounds useful as activators of the ClpP protease.
  • the compounds of the invention are useful as inhibitors for RNA polymerase activity in cells.
  • the compounds of the invention are useful in the treatment of infectious disease, including infectious disease associated with bacterial infections, and other diseases in which activation of the ClpP protease can have therapeutic benefit, as further described herein.
  • infectious disease including infectious disease associated with bacterial infections, and other diseases in which activation of the ClpP protease can have therapeutic benefit, as further described herein.
  • each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1.
  • STRUCTURE [00123] In one aspect, disclosed are compounds having a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a
  • compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is selected from ⁇ O ⁇ , ⁇ N(
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula:
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , wherein L is a linker selected from C1-C8 alkyl and ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl), or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula:
  • the residue of the rifamycin analog has a structure represented by a formula selected from: ,
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof. [00135] In various aspects, the compound has a structure represented by a formula:
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the residue of the rifamycin analog has a structure represented by a formula selected from: ,
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt thereof.
  • the residue of the rifamycin analog has a structure represented by a formula selected from:
  • the compound has a structure represented by a formula:
  • the compound is selected from:
  • the compound is selected from: ,
  • X is ⁇ CH(CH3) ⁇ . In an even further aspect, X is ⁇ CH2 ⁇ . d. Y GROUPS [00152] In one aspect, Y is selected from R 80 and –NH–(Q)q–Ar 2 . In a further aspect, Y is selected from R 80 and –NH–Q–Ar 2 . In a still further aspect, Y is selected from R 80 and – NHAr 2 . [00153] In various aspects, Y is selected from R 80 and a structure represented by a formula: . [00154] In various aspects, Y is R 80 . [00155] In various aspects, Y is a structure represented by a formula: . e.
  • R 1b is hydrogen and each of R 1a and R 1c is independently selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.
  • R 1b is hydrogen and each of R 1a and R 1c is independently selected from ⁇ F, ⁇ Cl, methyl, ethyl, n-propyl, isopropyl, ⁇ CF3, ⁇ CHF2, ⁇ CH2F, ⁇ CH2CF3, ⁇ CH2CHF2, ⁇ CH2CH2F, ⁇ CH(F)CH3, ⁇ CH(CH3)CF3, ⁇ CH(CH3)CHF2, ⁇ CH(CH3)CH2F, ⁇ CH2CH2CF3, ⁇ CH2CH2CHF2, ⁇ CH2CH2CF3, ⁇ CH2CH(F)CH3, ⁇ CCl3, ⁇ CHCl2, ⁇ CH2Cl, ⁇ CH2CCl3, ⁇ CH2CHCl2, ⁇ CH2CH2Cl, ⁇ CH(Cl)CH3, ⁇ CH(CH3)CCl3, ⁇ CH(CH3)CHCl2, ⁇ CH(CH3)CH2Cl, ⁇ CH2CH2CCl3, ⁇ CH(CH3)CH2
  • R 1b is hydrogen and each of R 1a and R 1c is independently selected from ⁇ F, ⁇ Cl, methyl, ethyl, ⁇ CF3, ⁇ CHF2, ⁇ CH2F, ⁇ CH 2 CF 3 , ⁇ CH 2 CHF 2 , ⁇ CH 2 CH 2 F, ⁇ CCl 3 , ⁇ CHCl 2 , ⁇ CH 2 Cl, ⁇ CH 2 CCl 3 , ⁇ CH 2 CHCl 2 , ⁇ CH2CH2Cl, ⁇ CH(Cl)CH3, ⁇ OCH3, ⁇ OCH2CH3, ⁇ OCH(CH3)2, ⁇ OCF3, ⁇ OCHF2, ⁇ OCH2F, ⁇ OCH 2 CF 3 , ⁇ OCH 2 CHF 2 , ⁇ OCH 2 CH 2 F, ⁇ OCH(F)CH 3 , ⁇ OCCl 3 , ⁇ OCHCl 2 , ⁇ OCH 2 Cl, ⁇ OCH2CCl3, ⁇ OC
  • R 1b is hydrogen and each of R 1a and R 1c is independently selected from ⁇ F, ⁇ Cl, methyl, ⁇ CF 3 , ⁇ CHF2, ⁇ CH2F, ⁇ CCl3, ⁇ CHCl2, ⁇ CH2Cl, ⁇ OCH3, ⁇ OCF3, ⁇ OCHF2, ⁇ OCH2F, ⁇ OCCl3, ⁇ OCHCl 2 , and ⁇ OCH 2 Cl.
  • R 1b is hydrogen and each of R 1a and R 1c is independently selected from hydrogen, ⁇ F, ⁇ Cl and C1-C4 alkyl.
  • R 1b is hydrogen and each of R 1a and R 1c is independently selected from ⁇ F, ⁇ Cl, methyl, ethyl, n-propyl, and isopropyl.
  • R 1b is hydrogen and each of R 1a and R 1c is independently selected from ⁇ F, ⁇ Cl, methyl, and ethyl.
  • R 1b is hydrogen and each of R 1a and R 1c is independently selected from ⁇ F, ⁇ Cl, and methyl.
  • R 1b is hydrogen and each of R 1a and R 1c is independently selected from hydrogen, ⁇ F, and methyl.
  • each of R 2a and R 2b is independently selected from hydrogen, halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • each of R 2a and R 2b is independently selected from hydrogen, halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1- C4 aminoalkyl.
  • each of R 2a and R 2b is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, methyl, ethyl, n-propyl, isopropyl, ⁇ CF3, ⁇ CHF 2 , ⁇ CH 2 F, ⁇ CH 2 CF 3 , ⁇ CH 2 CHF 2 , ⁇ CH 2 CH 2 F, ⁇ CH(F)CH 3 , ⁇ CH(CH 3 )CF 3 , ⁇ CH(CH3)CHF2, ⁇ CH(CH3)CH2F, ⁇ CH2CH2CF3, ⁇ CH2CH2CHF2, ⁇ CH2CH2CF3, ⁇ CH 2 CH(F)CH 3 , ⁇ CCl 3 , ⁇ CHCl 2 , ⁇ CH 2 Cl, ⁇ CH 2 CCl 3 , ⁇ CH 2 CHCl 2 , ⁇ CH 2 CH 2 Cl, ⁇ CH(Cl)CH3, ⁇ CH(CH3)CC
  • each of R 2a and R 2b is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, methyl, ethyl, ⁇ CF3, ⁇ CHF2, ⁇ CH2F, ⁇ CH2CF3, ⁇ CH2CHF2, ⁇ CH2CH2F, ⁇ CH(F)CH3, ⁇ CCl3, ⁇ CHCl2, ⁇ CH2Cl, ⁇ CH2CCl3, ⁇ CH2CHCl2, ⁇ CH2CH2Cl, ⁇ CH(Cl)CH3, ⁇ OCH3, ⁇ OCH2CH3, ⁇ NHCH3, ⁇ NHCH2CH3, ⁇ N(CH3)2, ⁇ N(CH3)CH2CH3, ⁇ CH2NH2, and ⁇ CH2CH2NH2.
  • each of R 2a and R 2b is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, methyl, ⁇ CF3, ⁇ CHF2, ⁇ CH2F, ⁇ CCl3, ⁇ CHCl2, ⁇ CH2Cl, ⁇ OCH3, ⁇ NHCH3, ⁇ N(CH3)2, and CH2NH2.
  • each of R 2a and R 2b is independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • each of R 2a and R 2b is independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 2a and R 2b is independently selected from ⁇ F, ⁇ Cl, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, methyl, ethyl, n-propyl, isopropyl, ⁇ CF 3 , ⁇ CHF 2 , ⁇ CH 2 F, ⁇ CH2CF3, ⁇ CH2CHF2, ⁇ CH2CH2F, ⁇ CH(F)CH3, ⁇ CH(CH3)CF3, ⁇ CH(CH3)CHF2, ⁇ CH(CH 3 )CH 2 F, ⁇ CH 2 CH 2 CF 3 , ⁇ CH 2 CH 2 CHF 2 , ⁇ CH 2 CH 2 CF 3 , ⁇ CH 2 CH(F)CH 3 , ⁇ CCl 3 , ⁇ CHCl2, ⁇ CH2Cl, ⁇ CH2CCl3, ⁇ CH2CHCl2, ⁇ CH2CH2Cl, ⁇ CH(Cl)CH3, ⁇ CH(CH3)CCl3,
  • each of R 2a and R 2b is independently selected from ⁇ F, ⁇ Cl, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, methyl, ethyl, ⁇ CF3, ⁇ CHF2, ⁇ CH2F, ⁇ CH2CF3, ⁇ CH2CHF2, ⁇ CH2CH2F, ⁇ CH(F)CH3, ⁇ CCl3, ⁇ CHCl2, ⁇ CH2Cl, ⁇ CH2CCl3, ⁇ CH2CHCl2, ⁇ CH2CH2Cl, ⁇ CH(Cl)CH3, ⁇ OCH3, ⁇ OCH2CH3, ⁇ NHCH3, ⁇ NHCH2CH3, ⁇ N(CH3)2, ⁇ N(CH3)CH2CH3, ⁇ CH2NH2, and ⁇ CH2CH2NH2.
  • each of R 2a and R 2b is independently selected from ⁇ F, ⁇ Cl, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, methyl, ⁇ CF3, ⁇ CHF2, ⁇ CH2F, ⁇ CCl3, ⁇ CHCl2, ⁇ CH2Cl, ⁇ OCH3, ⁇ NHCH3, ⁇ N(CH3)2, and CH2NH2.
  • each of R 2a and R 2b is independently selected from hydrogen, halogen, and C1-C6 alkyl.
  • each of R 2a and R 2b is independently selected from hydrogen, halogen, and C1-C4 alkyl.
  • each of R 2a and R 2b is independently selected from hydrogen, halogen, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, each of R 2a and R 2b is independently selected from hydrogen, halogen, methyl, and ethyl. In an even further aspect, each of R 2a and R 2b is independently selected from hydrogen, halogen, and ethyl. In a still further aspect, each of R 2a and R 2b is independently selected from hydrogen, halogen, and methyl. [00166] In various aspects, each of R 2a and R 2b is independently selected from hydrogen, ⁇ F, ⁇ Cl, and C1-C6 alkyl.
  • each of R 2a and R 2b is independently selected from hydrogen, ⁇ F, ⁇ Cl, and C1-C4 alkyl. In a still further aspect, each of R 2a and R 2b is independently selected from hydrogen, ⁇ F, ⁇ Cl, methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, each of R 2a and R 2b is independently selected from hydrogen, ⁇ F, ⁇ Cl, methyl, and ethyl. In an even further aspect, each of R 2a and R 2b is independently selected from hydrogen, ⁇ F, ⁇ Cl, and ethyl.
  • each of R 2a and R 2b is independently selected from hydrogen, ⁇ F, ⁇ Cl, and methyl.
  • each of R 2a and R 2b is independently selected from halogen and C1-C6 alkyl.
  • each of R 2a and R 2b is independently selected from halogen and C1-C4 alkyl.
  • each of R 2a and R 2b is independently selected from halogen, methyl, ethyl, n-propyl, and isopropyl.
  • each of R 2a and R 2b is independently selected from halogen, methyl, and ethyl.
  • each of R 2a and R 2b is independently selected from halogen and ethyl. In a still further aspect, each of R 2a and R 2b is independently selected from halogen and methyl. [00168] In various aspects, each of R 2a and R 2b is independently selected from ⁇ F and methyl. [00169] In various aspects, each of R 2a and R 2b is hydrogen. g. R 3 G ROUPS [00170] In one aspect, R 3 is selected from hydrogen, ⁇ OH, ⁇ OC(O) ⁇ L ⁇ R 21 , ⁇ NH 2 , ⁇ NH ⁇ L ⁇ R 21 , ⁇ L ⁇ C(O) ⁇ R 21 , and NHC(O) ⁇ L ⁇ R 21 .
  • R 3 is selected from hydrogen, ⁇ OH, ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NH2, ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ O ⁇
  • R 3 is selected from hydrogen, ⁇ OH, ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NH2, ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 3 is selected from hydrogen, ⁇ OH, ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH 2 , ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 .
  • R 3 is selected from ⁇ OH, ⁇ OC(O) ⁇ L ⁇ R 21 , ⁇ NH2, ⁇ NH ⁇ L ⁇ R 21 , ⁇ L ⁇ C(O) ⁇ R 21 , and NHC(O) ⁇ L ⁇ R 21 .
  • R 3 is selected from ⁇ OH, ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NH2, ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ O ⁇ (
  • R 3 is selected from ⁇ OH, ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NH2, ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 3 is selected from ⁇ OH, ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH2, ⁇ NH ⁇ (C1- C8 alkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 . [00172] In various aspects, R 3 is selected from ⁇ OH and ⁇ OC(O) ⁇ L ⁇ R 21 .
  • R 3 is selected from ⁇ OH, ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , and ⁇ OC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 3 is selected from ⁇ OH, ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , and ⁇ OC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 3 is selected from ⁇ OH, and ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 . [00173] In various aspects, R 3 is selected from ⁇ NH 2 , ⁇ NH ⁇ L ⁇ R 21 , ⁇ L ⁇ C(O) ⁇ R 21 , and NHC(O) ⁇ L ⁇ R 21 .
  • R 3 is selected from ⁇ NH2, ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 3 is selected from ⁇ NH 2 , ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1- C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 3 is selected from ⁇ NH2, ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 .
  • R 3 is selected from hydrogen, ⁇ OH, and ⁇ NH2. In a further aspect, R 3 is selected from hydrogen and ⁇ OH. In a still further aspect, R 3 is selected from hydrogen and ⁇ NH2. [00175] In various aspects, R 3 is selected from ⁇ OH and ⁇ NH2. In a further aspect, R 3 is ⁇ OH. In a still further aspect, R 3 is ⁇ NH2. [00176] In various aspects, R 3 is selected from ⁇ OC(O) ⁇ L ⁇ R 21 , ⁇ NH ⁇ L ⁇ R 21 , ⁇ L ⁇ C(O) ⁇ R 21 , and NHC(O) ⁇ L ⁇ R 21 .
  • R 3 is selected from ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 3 is selected from ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ OC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 , ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 3 is selected from ⁇ OC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ NH ⁇ (C1-C8 alkyl) ⁇ R 21 , and ⁇ NHC(O) ⁇ (C1-C8 alkyl) ⁇ R 21 . [00177] In various aspects, R 3 is selected from ⁇ OC(O) ⁇ L ⁇ R 21 ⁇ L ⁇ C(O) ⁇ R 21 , and ⁇ NHC(O) ⁇ L ⁇ R 21 . In a further aspect, R 3 is selected from ⁇ OC(O) ⁇ L ⁇ R 21 and NHC(O) ⁇ L ⁇ R 21 .
  • R 3 is selected from ⁇ L ⁇ C(O) ⁇ R 21 and NHC(O) ⁇ L ⁇ R 21 . In yet a further aspect, R 3 is selected from ⁇ OC(O) ⁇ L ⁇ R 21 and NHC(O) ⁇ L ⁇ R 21 . In an even further aspect, R 3 is ⁇ OC(O) ⁇ L ⁇ R 21 . In an even still further aspect, R 3 is ⁇ L ⁇ C(O) ⁇ R 21 . In yet an even further aspect, R 3 is ⁇ NHC(O) ⁇ L ⁇ R 21 . [00178] In various aspects, R 3 is selected from ⁇ L ⁇ C(O) ⁇ R 21 and NHC(O) ⁇ L ⁇ R 21 .
  • R 3 is ⁇ L ⁇ C(O) ⁇ R 21 . In a still further aspect, R 3 is NHC(O) ⁇ L ⁇ R 21 . h. R 4 G ROUPS [00179] In one aspect, R 4 is selected from hydrogen, C1-C4 alkyl, ⁇ OH, and ⁇ CH 2 OH. In a further aspect, R 4 is selected from hydrogen and ⁇ OH. In a still further aspect, R 4 is selected from hydrogen and ⁇ CH 2 OH. [00180] In various aspects, R 4 is selected from ⁇ OH and ⁇ CH2OH. In a further aspect, R 4 is ⁇ OH. In a still further aspect, R 4 is ⁇ CH 2 OH.
  • R 4 is selected from hydrogen and C1-C4 alkyl. In a further aspect, R 4 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a still further aspect, R 4 is selected from hydrogen, methyl and ethyl. In yet a further aspect, R 4 is selected from hydrogen and methyl. [00182] In various aspects, R 4 is a C1-C4 alkyl. In a further aspect, R 4 is selected from methyl, ethyl, propyl, and isopropyl. In a still further aspect, R 4 is selected from methyl and ethyl. In yet a further aspect, R 4 is methyl.
  • R 4 is hydrogen. i. R 10 GROUPS [00184]
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 .
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , ⁇ C(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ C(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , and ⁇ C(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1- C4 alkyl) ⁇ R 21 .
  • R 10 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, ⁇ C(O)R 20 , ⁇ C(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ C(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , and ⁇ C(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 10 is selected from hydrogen, methyl, ethyl, ⁇ C(O)R 20 , ⁇ C(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , and ⁇ C(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 10 is selected from hydrogen, methyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ (C1-C8 alkyl) ⁇ R 21 .
  • R 10 is selected from hydrogen, C1-C4 alkyl, and ⁇ C(O)R 20 .
  • R 10 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and ⁇ C(O)R 20 . In a still further aspect, R 10 is selected from hydrogen, methyl, ethyl, and ⁇ C(O)R 20 . In yet a further aspect, R 10 is selected from hydrogen, methyl, and ⁇ C(O)R 20 . [00186] In various aspects, R 10 is ⁇ C(O) ⁇ L ⁇ R 21 .
  • R 10 is selected from ⁇ C(O) ⁇ (C1-C8 alkyl) ⁇ R 21 , ⁇ C(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 , and ⁇ C(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 10 is selected from ⁇ C(O) ⁇ (C1-C8 alkyl) ⁇ R 21 and ⁇ C(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 10 is ⁇ C(O) ⁇ (C1-C8 alkyl) ⁇ R 21 .
  • R 10 is ⁇ C(O) ⁇ (C1-C4 alkyl) ⁇ O ⁇ (C1-C4 alkyl) ⁇ R 21 .
  • R 10 is ⁇ C(O) ⁇ (C4-C7 cycloalkyl) ⁇ R 21 .
  • R 10 is selected from hydrogen and C1-C4 alkyl.
  • R 10 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl.
  • R 10 is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 10 is selected from hydrogen and ethyl. In an even further aspect, R 10 is selected from hydrogen and methyl. [00188] In various aspects, R 10 is C1-C4 alkyl. In a further aspect, R 10 is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 10 is selected from methyl and ethyl. In yet a further aspect, R 10 is ethyl. In an even further aspect, R 10 is methyl. [00189] In various aspects, R 10 is hydrogen. j.
  • R 20 is C1-C4 alkyl. In a further aspect, R 20 is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 20 is selected from methyl and ethyl. In yet a further aspect, R 20 is ethyl. In a still further aspect, R 20 is methyl. [00192] In various aspects, R 20 is Ar 1 . k. R 21 GROUPS [00193] In one aspect, R 21 is a residue of a rifamycin analog (e.g., a rifamycin analog minus a proton). In a further aspect, the residue of the rifamycin analog has a structure represented by a formula selected from:
  • the residue of the rifamycin analog has a structure represented by a formula selected from:
  • R 22 is selected from C1-C4 alkyl and C1-C4 alkoxy.
  • the residue of the rifamycin analog has a structure: .
  • the residue of the rifamycin analog has a structure:
  • the residue of the rifamycin analog has a structure: .
  • the residue of the rifamycin analog has a structure: .
  • the residue of the rifamycin analog has a structure:
  • R 22 is selected from C1-C4 alkyl and C1-C4 alkoxy.
  • R 22 is selected from methyl, ethyl, n-propyl, isopropyl, ⁇ OCH3, ⁇ OCH2CH3, ⁇ OCH(CH3)2, and ⁇ OCH2CH2CH3.
  • R 22 is selected from methyl, ethyl, ⁇ OCH3, and ⁇ OCH2CH3.
  • R 22 is selected from methyl and ⁇ OCH3.
  • R 22 is C1-C4 alkyl.
  • R 22 is selected from methyl, ethyl, n-propyl, and isopropyl. In a further aspect, R 22 is selected from methyl and ethyl. In a still further aspect, R 22 is methyl. [0003] In various aspects, R 22 is C1-C4 alkoxy. In a further aspect, R 22 is selected from ⁇ OCH3, ⁇ OCH2CH3, ⁇ OCH(CH3)2, and ⁇ OCH2CH2CH3. In a further aspect, R 22 is selected from ⁇ OCH 3 and ⁇ OCH 2 CH 3 . In a still further aspect, R 22 is ⁇ OCH 3 . m.
  • R 80 has a structure represented by a formula selected from: .
  • R 80 is a C1-C8 alkyl.
  • R 80 is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, neopentyl, isopentyl, sec-pentyl, tert- pentyl, 3,3-dimethylbutan-2-yl, or 2,3-dimethylbutan-2-yl.
  • R 80 is methyl, ethyl, propyl, isopropyl, tert-butyl, sec-butyl, isobutyl, or tert-butyl. In an even further aspect, R 80 is methyl, ethyl, propyl, or isopropyl. n.
  • Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 1 is C6 aryl substituted with 1 or 2 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 1 is C6 aryl monosubstituted with a group selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl. o.
  • Ar 2 is selected from C6 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is selected from C6 aryl and C2-C9 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is selected from C6 aryl and C2-C9 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is selected from C6 aryl and C2-C9 heteroaryl, and is monosubstituted with a group selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is selected from C6 aryl and C2-C9 heteroaryl, and is unsubstituted.
  • Ar 2 is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is C6 aryl substituted with 0 or 1 group selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is C6 aryl monosubstituted with a group selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is unsubstituted C6 aryl.
  • Ar 2 is C2-C9 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • C2-C9 heteroaryls include, but are not limited to, pyridinyl, pyrimidinyl, indolinyl, indolyl, oxazolyl, thiazolyl, isoxazolyl, and pyrazolyl.
  • Ar 2 is C2-C9 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is C2-C9 heteroaryl substituted with 0 or 1 group selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1- C6) dialkylamino, and C1-C6 aminoalkyl.
  • Ar 2 is C2-C9 heteroaryl monosubstituted with a group selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1- C6 aminoalkyl.
  • Ar 2 is unsubstituted C2-C9 heteroaryl.
  • Ar 2 is a structure represented by a formula: . 2. EXEMPLARY COMPOUNDS [00212]
  • a compound can be present as one or more of the following structures:
  • a compound can be present as one or more of the following structures:
  • compositions, kits, and uses can optionally be omitted from the disclosed invention.
  • pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses.
  • the pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like.
  • the compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein. [00220] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I-III, as described and exemplified below.
  • ROUTE I [00221]
  • the disclosed compounds can be prepared as shown below. S CHEME 1A .
  • compounds of type 1.12, and similar compounds can be prepared according to reaction Scheme 1B above.
  • compounds of type 1.9 can be prepared by a coupling reaction between an appropriate alcohol, e.g.1.7 as shown above, and an appropriate carboxylic acid, e.g., 1.8 as shown above.
  • Appropriate alcohols and appropriate carboxylic acids are commercially available or prepared by methods known to one of skill in the art.
  • the coupling reaction is carried out in the presence of an appropriate coupling agent, e.g., 2,4,6-trichlorobenzyl chloride, an appropriate activating agent, e.g., 4- dimethylaminopyridine (DMAP), and an appropriate base, e.g., triethylamine (TEA), in an appropriate solvent, e.g., diisopropylethylamine (DIPEA).
  • an appropriate coupling agent e.g., 2,4,6-trichlorobenzyl chloride
  • an appropriate activating agent e.g., 4- dimethylaminopyridine (DMAP)
  • an appropriate base e.g., triethylamine (TEA)
  • DIPEA diisopropylethylamine
  • the deprotection can be carried out in the presence of an appropriate deprotecting agent, e.g., hydrogen gas with 10% palladium on carbon, in an appropriate solvent, e.g., methanol.
  • an appropriate deprotecting agent e.g., hydrogen gas with 10% palladium on carbon
  • an appropriate solvent e.g., methanol.
  • Compounds of type 1.12 can be prepared by a condensation reaction between an appropriate amine, e.g., 1.10 as shown above, and an appropriate aldehyde, e.g., 1.11 as shown above. Appropriate aldehydes are commercially available or prepared by methods known to one of skill in the art.
  • the condensation reaction can be carried out in the presence of an appropriate acid, e.g., 2N acetic acid (AcOH), in an appropriate protic solvent, e.g., methanol.
  • compounds of type 2.12, and similar compounds can be prepared according to reaction Scheme 2B above.
  • compounds of type 1.9 can be prepared by a coupling reaction between an appropriate amine, e.g.2.7 as shown above, and an appropriate carboxylic acid, e.g., 2.8 as shown above.
  • Appropriate amines and appropriate carboxylic acids are commercially available or prepared by methods known to one of skill in the art.
  • the coupling reaction is carried out in the presence of an appropriate coupling agent, e.g., hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), and an appropriate base, e.g., N,N-diisopropylethylamine (DIEA), in an appropriate solvent, e.g., dimethylformamide (DMF).
  • an appropriate coupling agent e.g., hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU)
  • DIEA N,N-diisopropylethylamine
  • DMF dimethylformamide
  • Compounds of type 2.10 can be prepared by deprotection of an appropriate amine, e.g., 2.9 as shown above.
  • the deprotection can be carried out in the presence of an appropriate deprotecting agent, e.g., hydrogen gas with 10% palladium on carbon, in an appropriate solvent, e.g
  • Compounds of type 2.12 can be prepared by a condensation reaction between an appropriate amine, e.g., 2.10 as shown above, and an appropriate aldehyde, e.g., 2.11 as shown above.
  • Appropriate aldehydes are commercially available or prepared by methods known to one of skill in the art.
  • the condensation reaction can be carried out in the presence of an appropriate acid, e.g., 2N acetic acid (AcOH), in an appropriate protic solvent, e.g., methanol.
  • an appropriate acid e.g., 2N acetic acid (AcOH)
  • an appropriate protic solvent e.g., methanol.
  • compounds of type 3.10 can be prepared by a coupling reaction between an appropriate amine, e.g.3.8 as shown above, and an appropriate carboxylic acid, e.g., 3.9 as shown above.
  • Appropriate amines and appropriate carboxylic acids are commercially available or prepared by methods known to one of skill in the art.
  • the coupling reaction is carried out in the presence of an appropriate coupling agent, e.g., hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), and an appropriate base, e.g., N,N-diisopropylethylamine (DIEA), in an appropriate solvent, e.g., dimethylformamide (DMF).
  • an appropriate coupling agent e.g., hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU)
  • an appropriate base e.g., N,N-diisopropylethylamine
  • Compounds of type 3.13 can be prepared by a condensation reaction between an appropriate aldehyde, e.g., 3.11 as shown above, and an appropriate hydrazine, e.g., 3.12 as shown above.
  • Appropriate aldehydes and appropriate hydrazines are commercially available or prepared by methods known to one of skill in the art.
  • the condensation reaction can be carried out in the presence of an appropriate acid, e.g., 2N acetic acid (AcOH), in an appropriate protic solvent, e.g., methanol.
  • Compounds of type 3.14 can be prepared by click chemistry of an appropriate alkyne, e.g., 3.10 as shown above, and an appropriate azide, e.g., 3.13 as shown above.
  • the click chemistry reaction is carried out in the presence of an appropriate catalyst, e.g., copper sulfate, and an appropriate scavenger, e.g., sodium ascorbate, in an appropriate solvent, e.g., water in tetrahydrofuran, at an appropriate temperature, e.g., room temperature.
  • an appropriate catalyst e.g., copper sulfate
  • an appropriate scavenger e.g., sodium ascorbate
  • an appropriate solvent e.g., water in tetrahydrofuran
  • compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, useful in treating infectious diseases such as, for example, biofilm-mediated diseases and infectious diseases due to prosthetic joint infections, intracellular bacteria, and Gram-positive bacteria (e.g., Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermediu
  • infectious diseases such as, for example, biofilm-mediated diseases and infectious diseases due to
  • compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog; wherein each of R 1a , R 1b , and R 1c is independently
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog; wherein each of R 1a , R 1b , and R 1c is independently
  • the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration.
  • the compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients.
  • a pharmaceutical composition can be formulated for local or systemic administration, e.g., intravenous, topical, or oral administration.
  • the nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art.
  • the pharmaceutical composition is sterile or sterilizable.
  • the therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans.
  • Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol.
  • buffers for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer
  • amino acids for example, phosphate buffer, acetate buffer, and bicarbonate buffer
  • amino acids amino acids
  • urea amino acids
  • alcohols for example, ascorbic acid
  • phospholipids for example, polypeptides (for example, serum albumin)
  • EDTA sodium chloride
  • liposomes for example, mannitol, sorbitol, water, and glycerol.
  • a modulatory compound can be formulated in various ways, according to the corresponding route of administration
  • liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application.
  • Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.
  • the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants.
  • compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy. [00237]
  • the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention.
  • the compounds of the invention, or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques
  • a tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants.
  • Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • the instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.
  • Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices.
  • compositions can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods.
  • a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • compositions containing a compound of the invention, and/or pharmaceutically acceptable salts thereof can also be prepared in powder or liquid concentrate form.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactically effective amount.
  • the pharmaceutical composition is administered to a mammal.
  • the mammal is a human.
  • the human is a patient.
  • the pharmaceutical composition is used to treat an infectious disease.
  • infectious diseases include, but are not limited to, biofilm- mediated diseases (e.g., bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, an urinary tract infection (UTI), periodontitis, a wound infection, a diabetic foot ulcer, a catheter-associated bloodstream infection, an implant-associated infection, ventilator- associated pneumonia, osteomyelitis), infectious diseases due to a prosthetic joint infection, infectious diseases due to intracellular bacteria, infectious diseases due to a Gram-positive bacterial infection (e.g., methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, an enterococcal infection, a vancomycin-resistant enterococci (VRE) infection, anthrax, toxic shock).
  • biofilm- mediated diseases e.g., bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, an urinary tract infection (UTI), periodontitis, a wound
  • the pharmaceutical composition is used to treat an infectious disease due to a Gram-positive bacterial infection.
  • the Gram- positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp..
  • Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE).
  • the Gram-positive bacterial infection is due to a Gram- positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae.
  • a Gram- positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clos
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • PRSP penicillin-resistant Streptococcus pneumonia
  • compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.
  • E. METHODS OF TREATING AN INFECTIOUS DISEASE [00251] In one aspect, disclosed are methods for treating an infectious disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby treating the infectious disease in the subject.
  • X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkyla
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog; wherein each of R 1a , R 1b , and R 1c is independently
  • the compound has a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a r
  • the subject is a mammal. In a further aspect, the subject is a human.
  • the effective amount is a therapeutically effective amount. In a further aspect, the effective amount is a prophylactically effective amount.
  • the infectious disease is a biofilm-mediated disease.
  • biofilm-mediated diseases include, but are not limited to, bacterial endocarditis, bacteremia, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, a wound infection, a diabetic foot ulcer, a catheter-associated bloodstream infection, an implant-associated infection, ventilator-associated pneumonia, and osteomyelitis.
  • the infectious disease is due to a prosthetic joint infection.
  • the infectious disease is due to or complicated by the presence of intracellular bacteria.
  • the infectious disease is due to a Gram-positive bacterial infection.
  • Gram-positive bacterial infections include, but are not limited to, methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, an enterococcal infection, a vancomycin-resistant enterococci (VRE) infection, anthrax, and toxic shock.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSA methicillin-resistant Staphylococcus aureus
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp.
  • Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE).
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, and Streptococcus agalactiae.
  • a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clos
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • PRSP penicillin-resistant Streptococcus pneumonia
  • the compound kills intracellular pathogens such as, for example, S. aureus with a 2-log decrease in intracellular colony counts after 24 hours of exposure. In various further aspects, the compound kills intracellular pathogens such as, for example, S. aureus with a 1.5-log decrease in intracellular colony counts after 24 hours of exposure. In various further aspects, the compound kills intracellular pathogens such as, for example, S. aureus with a 1.0-log decrease in intracellular colony counts after 24 hours of exposure. In various further aspects, the compound kills intracellular pathogens such as, for example, S. aureus with a 2.5-log decrease in intracellular colony counts after 24 hours of exposure.
  • intracellular pathogens such as, for example, S. aureus with a 2-log decrease in intracellular colony counts after 24 hours of exposure. In various further aspects, the compound kills intracellular pathogens such as, for example, S. aureus with a 1.5-log decrease in intracellular colony counts after 24 hours of exposure. In various further
  • the subject has been diagnosed with a need for treatment of the infectious disease prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of the infectious disease.
  • the method further comprises administering to the subject an effective amount of an antibacterial agent.
  • antibacterial agents include, but are not limited to, amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin, demeclocycl
  • the compound and the antibacterial agent are administered simultaneously. In a further aspect, the compound and the antibacterial agent are administered sequentially. [00267] In various aspects, the compound and the antibacterial agent are co-formulated. In a further aspect, the compound and the antibacterial agent are co-administered. F. METHODS OF ACTIVATING CLPP PROTEASE IN CELLS [00268] In one aspect, disclosed are methods for activating ClpP proteasein a cell, the method comprising the step of contacting the cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt. Thus, in various aspects, disclosed are methods for activating ClpP proteasein a cell, the method comprising the step of contacting the cell with an effective amount of a compound having a structure represented by a formula:
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog; wherein each of R 1a , R 1b , and R
  • the compound has a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rif
  • the compound has a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog
  • the cell is a bacterial cell.
  • the cell is a Gram- positive bacterial cell.
  • the cell is a Gram-negative bacterial cell.
  • the cell is a fungus.
  • the cell has been isolated from a subject prior to the contacting step.
  • contacting the cell is via administration of the compound to a subject.
  • the cell is a bacterial cell, and is infecting a subject.
  • the subject has been diagnosed with a need for treatment of an infectious disease prior to the administering step.
  • the method further comprises the step of identifying a subject in need of activating ClpP protease prior to the administering step.
  • activating ClpP protease treats an infectious disease in a subject.
  • the subject has been diagnosed with a need for activating ClpP protease prior to the administering step.
  • the subject has been diagnosed with a need for treatment of a biofilm mediated disease prior to the administering step.
  • activating ClpP protease treats a biofilm-mediated disease in a subject.
  • the biofilm-mediated disease is due to a prosthetic joint infection.
  • the biofilm-mediated disease is due to a Gram-positive bacterial infection.
  • the method further comprises the step of identifying a subject in need of treatment of the biofilm mediated disease with a low potential for resistance development.
  • contacting the cell treats an infectious disease.
  • the infectious disease is selected from is selected from bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, and osteomyelitis.
  • the Gram-positive bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, and toxic shock.
  • MRSA methicillin-resistant Staphylococcus aureus
  • the Gram-positive bacterial infection is methicillin-resistant Staphylococcus aureus (MRSA).
  • MRSA methicillin-resistant Staphylococcus aureus
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp.
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani,
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • PRSP penicillin-resistant Streptococcus pneumonia
  • the method further comprises contacting the cell with an effective amount of an antibacterial agent.
  • the method further comprises contacting the cell with the compound and at least one antibacterial agent.
  • the compound and the antibacterial agent are administered simultaneously.
  • the compound and the antibacterial agent are co-formulated.
  • the compound and the antibacterial agent are administered sequentially.
  • the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin
  • RESULTS OF ACTIVATING CLPP PROTEASE IN A SUBJECT [00279]
  • X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialky
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog; wherein each of R 1a , R 1b , and R 1c is independently
  • the compound has a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a r
  • the compound administered is a product of a disclosed method of making a compound.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactically effective amount.
  • the subject is a mammal.
  • the subject is a human.
  • the subject has been diagnosed with a need for activating ClpP protease prior to the administering step.
  • the method further comprises the step of identifying a subject in need of activating ClpP protease prior to the administering step.
  • activating ClpP protease treats an infectious disease in a subject.
  • the subject has been diagnosed with a need for activating ClpP protease prior to the administering step.
  • activating ClpP protease treats a biofilm-mediated disease in a subject.
  • the biofilm-mediated disease is due to a prosthetic joint infection.
  • the biofilm-mediated disease is due to a Gram-positive bacterial infection.
  • the method further comprises the step of identifying a subject in need of treatment of the biofilm mediated disease.
  • activating ClpP protease in a subject treats an infectious disease.
  • the infectious disease is selected from is selected from bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, and osteomyelitis.
  • the Gram-positive bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, and toxic shock.
  • the Gram-positive bacterial infection is methicillin-resistant Staphylococcus aureus (MRSA).
  • MRSA methicillin-resistant Staphylococcus aureus
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp.
  • Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE).
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • Bacillus anthracis Bacillus cereus, Bacillus subtilis
  • Clostridium difficile Clostridium tetani
  • Clostridium botulinum
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • PRSP penicillin-resistant Streptococcus pneumonia
  • the method further comprises administering to the subject an effective amount of an antibacterial agent.
  • the method further comprises administering to the subject an effective amount of the compound and at least one antibacterial agent.
  • the compound and the antibacterial agent are administered simultaneously.
  • the compound and the antibacterial agent are co-formulated. In an even further aspect, wherein the compound and the antibacterial agent are administered sequentially.
  • the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin,
  • the administration in a substantially simultaneous manner comprises a single dose form containing a fixed ratio of the compound and the antibacterial agent.
  • the single dose form is a capsule or a tablet.
  • the single dose form is an ampule for a single intravenous administration.
  • the co-administration is administration in a substantially sequential manner.
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog; wherein each of R 1a , R 1b , and R
  • the compound has a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a r
  • compositions comprising an effective amount of a compound having a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein X is selected from ⁇ O ⁇ ,
  • the cell is a bacterial cell.
  • the cell is a Gram- positive bacterial cell.
  • the cell is a Gram-negative bacterial cell.
  • the cell is a fungus.
  • the cell has been isolated from a subject prior to the contacting step.
  • contacting the cell is via administration of the compound to a subject.
  • the cell is a bacterial cell, and is infecting a subject.
  • the subject has been diagnosed with a need for treatment of an infectious disease prior to the administering step.
  • the method further comprises the step of identifying a subject in need of inhibiting RNA polymerase activity prior to the administering step.
  • inhibiting RNA polymerase activity treats an infectious disease in a subject.
  • the subject has been diagnosed with a need for inhibiting RNA polymerase activity prior to the administering step.
  • the subject has been diagnosed with a need for treatment of a biofilm-mediated disease prior to the administering step.
  • inhibiting RNA polymerase activity treats a biofilm-mediated disease in a subject.
  • the biofilm-mediated disease is due to a prosthetic joint infection.
  • the biofilm-mediated disease is due to a Gram-positive bacterial infection.
  • the method further comprises the step of identifying a subject in need of treatment of the biofilm mediated disease.
  • contacting the cell treats an infectious disease.
  • the infectious disease is selected from is selected from bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, and osteomyelitis.
  • the Gram-positive bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, and toxic shock.
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • Bacillus anthracis Bacillus cereus, Bacillus subtilis
  • Clostridium difficile Clostridium tetani
  • Clostridium botulinum
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • PRSP penicillin-resistant Streptococcus pneumonia
  • the method further comprises contacting the cell with an effective amount of an antibacterial agent.
  • the method further comprises contacting the cell with the compound and at least one antibacterial agent.
  • the compound and the antibacterial agent are administered simultaneously.
  • the compound and the antibacterial agent are co-formulated.
  • the compound and the antibacterial agent are administered sequentially.
  • the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin
  • RNA polymerase activity in a subject comprising the step administering to the subject an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof, thereby inhibiting RNA polymerase activity in the subject.
  • RNA polymerase activity in a subject, comprising the step of administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkyla
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog; wherein each of R 1a , R 1b , and R 1c is independently
  • the compound has a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a r
  • the compound administered is a product of a disclosed method of making a compound.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactically effective amount.
  • the subject is a mammal.
  • the subject is a human.
  • the subject has been diagnosed with a need for inhibiting RNA polymerase activity prior to the administering step.
  • the method further comprises the step of identifying a subject in need of inhibiting RNA polymerase activity prior to the administering step.
  • inhibiting RNA polymerase activity treats an infectious disease in a subject.
  • the subject has been diagnosed with a need for inhibiting RNA polymerase activity prior to the administering step.
  • the subject has been diagnosed with a need for treatment of a biofilm-mediated disease prior to the administering step.
  • inhibiting RNA polymerase activity treats a biofilm-mediated disease in a subject.
  • the biofilm-mediated disease is due to a prosthetic joint infection.
  • the biofilm-mediated disease is due to a Gram-positive bacterial infection.
  • the method further comprises the step of identifying a subject in need of treatment of the biofilm mediated disease.
  • inhibiting RNA polymerase activity in a subject treats an infectious disease.
  • the infectious disease is selected from is selected from bacterial endocarditis, prostatitis, rhinosinusitis, otitis media, a urinary tract infection (UTI), periodontitis, and osteomyelitis.
  • the Gram-positive bacterial infection is selected from methicillin-resistant Staphylococcus aureus (MRSA), a streptococcal infection, and toxic shock.
  • the Gram-positive bacterial infection is methicillin-resistant Staphylococcus aureus (MRSA).
  • MRSA methicillin-resistant Staphylococcus aureus
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Streptococcus spp., Staphylococcus spp., Enterococcus spp., Clostridium spp., and Corynebacterium spp.
  • Enterococcus spp. is vancomycin-resistant Enterococcus spp. (VRE).
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • Bacillus anthracis Bacillus cereus, Bacillus subtilis
  • Clostridium difficile Clostridium tetani
  • Clostridium botulinum
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from Clostridium difficile, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, and Streptococcus pyogenes.
  • the Gram-positive bacterial infection is due to a Gram-positive bacteria selected from methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and penicillin-resistant Streptococcus pneumonia (PRSP).
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • PRSP penicillin-resistant Streptococcus pneumonia
  • the method further comprises administering to the subject an effective amount of an antibacterial agent.
  • the method further comprises administering to the subject an effective amount of the compound and at least one antibacterial agent.
  • the compound and the antibacterial agent are administered simultaneously.
  • the compound and the antibacterial agent are co-formulated. In an even further aspect, wherein the compound and the antibacterial agent are administered sequentially.
  • the antibacterial agent is selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine, cloxacillin, colistin, dalbavancin, dalfopristin, daptomycin
  • the administration in a substantially simultaneous manner comprises a single dose form containing a fixed ratio of the compound and the antibacterial agent.
  • the single dose form is a capsule or a tablet.
  • the single dose form is an ampule for a single intravenous administration.
  • the co-administration is administration in a substantially sequential manner.
  • the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone.
  • the other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound.
  • a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred.
  • the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent.
  • the compounds can be co-administered with an antibacterial agent.
  • the compounds can be co-administered with an antibacterial agent selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clofazimine,
  • the compounds can be administered in combination with one or more antibacterial agents, and salts thereof and combinations thereof.
  • the compounds can be administered in combination with an antibacterial agent selected from amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavulanic acid, clinafloxacin, clindamycin, clof
  • an antibacterial agent selected from amoxicillin, ampicillin
  • compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein, which are usually applied in the treatment of the above mentioned pathological conditions.
  • MANUFACTURE OF A MEDICAMENT [00320]
  • the invention relates to a method for the manufacture of a medicament comprising one or more disclosed compounds, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for treating an infectious disease.
  • the one or more compounds is a product of a disclosed method of making.
  • the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in treatment of an infectious disease, such as, for example, biofilm-mediated diseases and infectious diseases due to prosthetic joint infections, intracellular bacteria, and Gram-positive bacteria (e.g., Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphyloc
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time- frame.
  • dosage will depend upon a variety of factors including the condition of the animal, the body weight of the animal, as well as the severity and stage of the disease or disorder.
  • the invention relates methods for the manufacture of a medicament for enhancing the activity of ClpP protease (e.g., treatment of one or more infectious diseases) in mammals (e.g., humans) comprising combining one or more disclosed compounds, products, or compositions or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, with a pharmaceutically acceptable carrier.
  • the disclosed methods can be performed with the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed methods can be employed in connection with the disclosed methods of using. 2. USE OF COMPOUNDS AND COMPOSITIONS [00322] Also provided are uses of the disclosed compounds, compositions, and products.
  • the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt thereof for treating an infectious disease in a subject.
  • the compound used is a product of a disclosed method of making.
  • the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.
  • the use relates to a treatment of an infectious disease in a subject.
  • the use is characterized in that the subject is a human.
  • the use is characterized in that the infectious disease is a biofilm-mediated disease or an infectious disease due to a prosthetic joint infection, an intracellular bacteria, or a Gram-positive bacteria (e.g., Gram-positive bacteria selected from Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Strept
  • the use relates to the manufacture of a medicament for the treatment of a disease or disorder due to oxidative stress in a subject.
  • the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits.
  • the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for treating an infectious disease in a mammal.
  • the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disease or disorder due to oxidative stress in a mammal. 3.
  • the subject of the disclosed methods is a vertebrate, e.g., a mammal.
  • the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • the subject has been diagnosed with a need for treatment prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with a need for treatment of an infectious disease prior to the administering step. some aspects of the disclosed methods, the subject has been identified with a need for treatment prior to the administering step. In one aspect, a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere. a.
  • Toxicity and therapeutic efficacy of the agents and pharmaceutical compositions described herein can be determined by standard pharmaceutical procedures, using either cells in culture or experimental animals to determine the LD 50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50/ED50.
  • Data obtained from cell culture assays and further animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity, and with little or no adverse effect on a human's ability to hear.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (that is, the concentration of the test compound which achieves a half- maximal inhibition of symptoms) as determined in cell culture.
  • IC50 that is, the concentration of the test compound which achieves a half- maximal inhibition of symptoms
  • Exemplary dosage amounts of a differentiation agent are at least from about 0.01 to 3000 mg per day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day, or more.
  • the formulations and routes of administration can be tailored to the disease or disorder being treated, and for the specific human being treated.
  • a subject can receive a dose of the agent once or twice or more daily for one week, one month, six months, one year, or more.
  • the treatment can continue indefinitely, such as throughout the lifetime of the human.
  • Treatment can be administered at regular or irregular intervals (once every other day or twice per week), and the dosage and timing of the administration can be adjusted throughout the course of the treatment.
  • the dosage can remain constant over the course of the treatment regimen, or it can be decreased or increased over the course of the treatment.
  • the dosage facilitates an intended purpose for both prophylaxis and treatment without undesirable side effects, such as toxicity, irritation, or allergic response.
  • the dosage required to provide an effective amount of a formulation will vary depending on several factors, including the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy, if required, and the nature and scope of the desired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York, NY).
  • b. ROUTES OF ADMINISTRATION Also provided are routes of administering the disclosed compounds and compositions.
  • the compounds and compositions of the present invention can be administered by direct therapy using systemic administration and/or local administration.
  • the route of administration can be determined by a patient's health care provider or clinician, for example following an evaluation of the patient.
  • an individual patient's therapy may be customized, e.g., the type of agent used, the routes of administration, and the frequency of administration can be personalized.
  • therapy may be performed using a standard course of treatment, e.g., using pre-selected agents and pre-selected routes of administration and frequency of administration.
  • Systemic routes of administration can include, but are not limited to, parenteral routes of administration, e.g., intravenous injection, intramuscular injection, and intraperitoneal injection; enteral routes of administration e.g., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops (e.g., ear drops), syrups, suspensions and emulsions; rectal administration, e.g., a rectal suppository or enema; a vaginal suppository; a urethral suppository; transdermal routes of administration; and inhalation (e.g., nasal sprays).
  • parenteral routes of administration e.g., intravenous injection, intramuscular injection, and intraperitoneal injection
  • enteral routes of administration e.g., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops (e.g., ear drops), syrups, suspensions and emulsions
  • rectal administration
  • kits comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an antimicrobial agent; (b) instructions for treating an infectious disease; and (3) instructions for administering the compound in connection with treating an infectious disease.
  • kits comprising a compound having a structure represented by a formula:
  • R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog; wherein each of R 1a , R 1b , and R
  • the compound has a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of
  • the compound has a structure represented by a formula: , wherein X is selected from ⁇ O ⁇ , ⁇ N(R 10 ) ⁇ , and ⁇ CH(R 10 ) ⁇ ; wherein R 10 is selected from hydrogen, C1-C4 alkyl, ⁇ C(O)R 20 , and ⁇ C(O) ⁇ L ⁇ R 21 ; wherein L is a linker; wherein R 20 is selected from C1-C4 alkyl and Ar 1 ; wherein Ar 1 is C6 aryl substituted with 1, 2, or 3 groups independently selected from halogen, ⁇ NH2, ⁇ OH, ⁇ NO2, ⁇ CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, (C1-C6)(C1-C6) dialkylamino, and C1-C6 aminoalkyl; wherein R 21 is a residue of a rifamycin analog
  • the antimicrobial agent is selected from an antibacterial agent, an antiviral agent, an antifungal agent, and an antiparasitic agent.
  • the antimicrobial agent is an antibacterial agent.
  • antibacterial agents include, but are not limited to, amoxicillin, ampicillin, azithromycin, aztreonam, azlocillin, bacitracin, carbenicillin, cefaclor, cefadroxil, cefamandole, cefazolin, cephalexin, cefdinir, cefditorin, cefepime, cefixime, cefoperazone, cefotaxime, cefoxitin, cefpodoxime, cefprozil, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefuroxime, chloramphenicol, cilastin, ciprofloxacin, clarithromycin, clavula
  • the antimicrobial agent is an antiviral agent.
  • antiviral agents include, but are not limited to, acyclovir, oseltamivir, cidofovir, lamivudine, nitazoxanide, ribavirin, famciclovir, foscarnet, vidarabine, and fomibirsen.
  • the antimicrobial agent is an antifungal agent. Examples of antifungal agents include, but are not limited to, clotrimazole, econazole, micronazole, terbinafine, fluconazole, ketoconazole, nystatin, and amphotericin.
  • the antimicrobial agent is an antiparasitic agent.
  • antiparasitic agents include, but are not limited to, metronidazole, furazolidone, tinidazole, albendazole, pyrantel pamoate, ivermectin, chloroquine, quinine, mefloquine, primaquine, sulfadozine-pyrimethamine, doxycycline, atovaquone-proguanil, and artemetherlumefantrine.
  • the compound and the antimicrobial agent are co-packaged. In a further aspect, the compound and the antimicrobial agent are co-formulated.
  • kits can also comprise compounds and/or products co-packaged, co-formulated, and/or co-delivered with other components.
  • a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient.
  • the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using. K.
  • reaction mixture was stirred overnight, taken up with ethyl acetate (EtOAc), and then washed with saturated NaHCO3 solution and brine.
  • EtOAc ethyl acetate
  • the organic layer was dried over anhydrous Na 2 SO 4 and the solvent was removed under reduced pressure after filtration.
  • N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl, 0.29 g, 1.84 mmol) was added to a stirring solution of 5 (0.8 g, 2.154 mmol), (2S,4R)-1-Boc- 4-methylpyrrolidine-2-carboxylic acid (0.593g, 2.58 mmol) and DMAP (53 mg, 0.431 mmol) in dichloromethane (CH2Cl2) (20 mL) at 0 °C. The mixture was slowly warmed to room temperature, stirred overnight, diluted with EtOAc, and washed successively with 1 N HCl, saturated NaHCO3, and brine.
  • EDC.HCl 2S,4R)-1-Boc- 4-methylpyrrolidine-2-carboxylic acid
  • DMAP 53 mg, 0.431 mmol
  • 5557 was synthesized from 4206, 2-bromoacetic acid and 3 following the method described from 5556 as a blue solid; UPLC t R 1.30; HRMS (ESI) m/z: [M+H] + calcd for C91H109F3N12O221779.7809; found 1779.7872. qq. SYNTHESIS OF COMPOUND 5624
  • 5624 was synthesized from 4206, 5-bromopentanoic acid and 3 following the method described from 5556 as a blue solid; UPLC t R 1.16; HRMS (ESI) m/z: [M+H] + calcd for C94H115F3N12O221821.8279; found 1821.8315. rr. SYNTHESIS OF COMPOUND 5632
  • NARSA Network on Antimicrobial Resistance in Staphylococcus aureus
  • BEI Resources NIAID, NIH: Staphylococcus aureus subsp. aureus, Strain JE2, NR-46543 a (Fey, P. D. et al. (2013)mBio 4, e00537-00512); Staphylococcus aureus subsp. aureus, Strain JE2, Transposon Mutant NE912 (SAUSA300_0752), NR-47455 (Fey, P. D. et al.
  • MHB media was inoculated with single freshly streaked out colonies of S. aureus 33591, S. aureus JE2, or E. faecalis V583 and grown at 37 °C in a shaking incubator. Tryptic soy broth (TSB) was inoculated with single freshly streaked out colonies of S. pneumoniae 6303 and grown at 37 °C with 5% CO2 in a shaking incubator. All cultures were incubated for 18 hours.
  • TTB Tryptic soy broth
  • MHB Staphylococcus and Enterococcus
  • TSB Steptococcus
  • a titration of experimental compounds including ADEP4 as a positive control, was generated in DMSO (10 mM-0 mM) in an LDV ECHO plate (Labcyte001-12782).100 nL was transferred from this plate to the assay plate using an ECHO 655 acoustic liquid handler.
  • the assay plate was vortexed briefly, centrifuged at 500 rpm for one minute, and incubated at room temperature for a further four minutes.5 ⁇ l assay solution containing 50 mM Tris-base, 100 mM NaCl, 2 mM DTT, 0.01% triton X-100 and 2 ⁇ M casein-BODIPY pH 8.0 was added to the assay plate with a multidrop combi.
  • RNA POLYMERASE INHIBITION The S. aureus RNA polymerase (RNAP) inhibition assay kit (RPA-100KSE) was purchased from ProFoldin (Hudson, MA, USA). Reagents were prepared according to the manufacturer’s instructions. Additional buffer was made following the manufacturer's instructions.
  • RNAP S. aureus RNA polymerase
  • Kit-supplied buffer was used for the reaction incubation.
  • the laboratory-made buffer was used to dilute the fluorescence reagent. All drugs were freshly prepared for each replicate. Ten-fold serial dilutions of each drug were made in DMSO for rifampin, 4206, and 5192 or water for daptomycin. Three ⁇ L of each dilution was added to the reaction mix in duplicate. Fluorescence was measured according to the manufacturer’s instructions using the Biotek Cytation 5 plate reader with NexGen 5 software. The average percent inhibition for each data point was calculated. The percent inhibition was plotted against the log concentration of drug using GraphPad Prism and the IC50 was determined. f. RNA-SEQUENCING [00422] Treatment conditions. S. aureus subsp.
  • aureus 33591 and mutants having reduced susceptibility to rifampin (S. aureus 33591 rif R ) or 4206 (S. aureus 335914206 R ) were cultured in TSB shaking at 210 rpm at 37° C.
  • Five mL of mid-log cultures (OD6000.4- 0.6) were treated with 1/2 MIC of 4206 (0.125 ⁇ g mL -1 ), 5192 (0.5 ⁇ g mL -1 ), rifampin (0.004 ⁇ g mL -1 ), or equivalent vehicle control (DMSO) for 30 minutes shaking at 210 rpm at 37 °C.
  • RNAeasy Plus Mini Kit (Qiagen; Cat. No. 74134) was used to extract the RNA following the manufacturer’s instructions utilizing mechanical lysis for Gram-positive bacteria.
  • Libraries were prepared from ribosomal RNA-depleted total RNA using Illumina Stranded Total RNA Prep, ligation with Ribo-Zero Plus mRNA Library Prep Kit according to the manufacturer’s instructions (Illumina, PN 20037135). Libraries were analyzed for insert size distribution using the 2100 BioAnalyzer High Sensitivity kit (Agilent). Libraries were quantified using the Quant-iT PicoGreen ds DNA assay (ThermoFisher). Paired-end 100 cycle sequencing was performed on a NovaSeq X Plus (Illumina) at St. Jude Children's Research Hospital sequencing core at a depth of 10M reads/sample.
  • aureus genome (reference genome downloaded from ATCC website: https://genomes.atcc.org/genomes/bfa4253471534524) using STAR2.5.3a (Dobin, A. et al. (2013) Bioinformatics 29, 15-21) and aligned reads were counted using featureCounts (Liao, Y., et al., (2014) Bioinformatics 30, 923-930).
  • Transcripts aligned to non-coding RNA i.e. small RNA, tRNA, remaining ribosomal RNA
  • aureus 33591 stored at -80° C were used to start overnight cultures in TSB.
  • the overnight cultures were then diluted to an OD600 of 0.05 in 75 mL of TSB and grown to mid-exponential phase (OD600 0.7) at 37 ° C with shaking (225 rpm).
  • Fifteen mL of cells were transferred to 50 mL conical tubes containing 10 ⁇ L of vehicle control or DMSO-solubilized compound equaling a final concentration of 1 ⁇ 2 MIC. Cultures were then incubated for 30 minutes in a shaking incubator (225 rpm).
  • Bacterial cells were harvested by centrifugation for 5 minutes at 4,000 ⁇ rcf at 4 °C and resuspended in buffer containing ice-cold 20 mM TrisHCl, 200 mM NaCl, 0.5% CHAPs. Cell lysis was performed through mechanical lysis using the Bead Mill four homogenizer (Fisher Scientific, Atlanta GA) at maximum speed for 30 s followed by 5 min on ice for a total of 4 cycles.
  • Proteins in lysate were digested into peptides, desalted, and labeled with TMT reagents.
  • Reagents consisted of three groups: an amine-specific active ester group that reacts with free alpha N-termini of peptides and the epsilon amino groups of lysine residues, a balance group, and a reporter group.
  • the isobaric labels defined by a different distribution of isotopes (13C, 15N) between the reporter and balance groups, allowed each labeled peptide to coelute during chromatography and to ionize at the same mass-to-charge in MS scans. Labeled samples were mixed and further fractionated by neutral pH reverse phase liquid chromatography.
  • aureus 33591 at 2.0 ⁇ 10 8 CFU/mL diluted in F12-K+10%FBS media from a frozen research cell bank stock was added to each well.
  • the 24-well plates were centrifuged for 10 minutes at 2000 ⁇ g at room temperature in a swinging bucket centrifuge with plate adaptors. Plates were then incubated for 2 hours at 37 °C, 5% CO2 after which the media was replaced with 1 mL F12-K+10%FBS supplemented with 200 ⁇ g/mL gentamicin and warmed to 37°C; the plates were incubated for 1 hour at 37 °C, 5% CO2.
  • the media was replaced with 1 mL prewarmed F12-K+10%FBS supplemented with 50 ⁇ g/mL gentamicin.
  • DMSO, rifampin, vancomycin or 5192, 4206 were added at 2 ⁇ or 10 ⁇ MIC to each well in triplicate.
  • DMSO controls were harvested to determine the time 0 intracellular bacterial count. The remaining wells were harvested after incubation for 24 hours at 37 °C, 5% CO2. To harvest and count the intracellular bacteria, cells were washed times with 1 mL PBS. Cells were then incubated with 0.5 mL 0.1% triton-X100 for 5 minutes at 37 °C, 5% CO2 and lysed by pipetting up and down 10 times.
  • CYTOTOXICITY [00429] HepG2 or FaDu cells were grown in EMEM supplemented with 10% FBS. On the day of seeding, cells were trypsinized (0.25% trypsin-EDTA) from a 75 cm 2 flask and counted using AOPI Stain (Revity/Perkin Elmer) and the Cellometer M2 cell counter (Nexcelom).
  • Cells were seeded into a 384 well plate at 1 ⁇ 10 4 cells/50 ⁇ L/well for FaDu cells and at 5 ⁇ 10 3 cells/50 ⁇ L/well for HepG2 cells. After seeding, cells were incubated overnight at 37 °C, 5% CO2. Compounds were dissolved and diluted 2-fold 11 times in DMSO such that when 1 ⁇ L of each concentration was added to the seeded cells in duplicate, final concentrations were 200 ⁇ g/mL to 0.39 ⁇ g/mL with DMSO final concentrations of 2%. DMSO controls were also included. Plates were incubated for 24 hours at 37° C, 5% CO2.
  • the pellet was further washed twice with 10 volumes of PBS pH 7.4.
  • the RBC pellet was then resuspended in PBS.
  • a stock solution of 5192 prepared in DMSO and diluted in PBS at 20x and mixed with RBC suspension for 2 hours and incubated at 37 °C in a 96-well V-bottom plate.
  • DMSO and 1% Triton X-100 in PBS were used as controls. Plates were centrifuged for 5 min at 500 ⁇ g and 100 ⁇ l of the supernatant was removed and transferred to the wells of a clear flat-bottomed 96-well plate. Absorbance was measured at 540 nm.
  • MTD maximum tolerated dose
  • mice were monitored for signs of toxicity including body weight changes (>20% weight loss) for one week.
  • PK MOUSE AND RAT PHARMACOKINETICS
  • the mobile phase for 5192 and 4206 was 0.1% formic acid in acetonitrile, and 10 mM ammonium formate in water or 0.2% formic acid in water.
  • the mobile phase was 0.1% formic acid in acetonitrile and 0.1% formic acid in water.
  • 5192 showed a retention time of 1.24 min.4206 showed a retention time of 1 min at a flow rate of 0.7 mL/min.
  • Rifampin showed a retention time of 1.09 min at a flow rate of 0.6 mL/min.
  • Samples were analyzed by triple quad LC-MS/MS instrument in multiple reaction monitoring mode.
  • the calibration curve was linear across the range of 1-5000 ng/mL of all compounds in mouse plasma.
  • M OUSE M ODEL O F P ERITONEAL S EPTICEMIA [00436] S. aureus 33591 was streaked out on TSA with 5% sheeps blood and grown overnight at 37 ° C. A liquid culture was grown in a flask containing 50 mL of brain heart infusion (BHI) media which was inoculated from the plate. The flask was incubated at 37 °C, 180 rpm for 45 minutes to 1 hour. The antibiotics 5192, rifampin, and vancomycin were prepared in 40% DMSO, 60% PEG400.
  • mice Female Swiss Webster mice (22 to 25 g) were obtained from a commercial vendor and were randomly assigned into treatment groups of 5 and injected intraperitoneally (IP) with 4 ⁇ 10 8 CFU per mouse. At 1 hour post-infection (PI), a group of 5 mice (time 0) were euthanized, the kidneys were weighed, homogenized in 1 mL PBS as described below, and plated for colony counts.
  • IP intraperitoneally
  • mice were treated at 1 and 3 hours post infection with 5192, rifampin, 4206, rifampin + 4206, and vancomycin or an equivalent volume of vehicle administered IP.
  • Mice were euthanized 6- hours post infection and the kidneys were harvested, homogenized, and plated for colony counts. Counts normalized based on the kidney weight and were plotted using GraphPad Prism. Statistical analysis was performed using 1-way ANOVA and Tukey’s post-test. o. NEUTROPENIC THIGH-LESION MODEL [00437] Female Swiss Webster mice of 22 to 25 g were obtained from a commercial vendor and were randomly assigned into treatment groups of 5.
  • mice were injected IP with 150 and 100 mg/kg cyclophosphamide 4 and 1 day preceding the establishment of infection.
  • wildtype, rifampin resistant, and 4206 resistant S. aureus 33591 were streaked out on TSA with 5% sheep blood and grown overnight at 37 °C.
  • 50 mL of BHI media was inoculated with bacteria from the agar plate using a 5 mm sterile inoculation loop. The flask was incubated at 37°C, 180 rpm for 45 minutes to 1 hour.
  • the bacterial culture was added to 3 mL sterile saline to create a bacterial suspension of 2 ⁇ 10 6 CFU/mL.50 ⁇ L of this suspension was injected into the right thigh muscle of each mouse under isoflurane anesthesia.
  • some mice were euthanized to determine the infectious burden at the time of antibiotic treatment.
  • the thigh tissue was dissected, weighed, homogenized in 2 mL PBS.10-fold serial dilutions were made in PBS and plated for colony counts.
  • Antibiotics were administered by IP injection. In the 2-day model, mice were treated at 2, 6, 24, and 28 hours post infection and treatment groups were sacrificed 48 hours post-infection.
  • mice of 22 to 25 g obtained from a commercial vendor were randomly assigned into treatment groups. Surgery was performed to place the 2 catheter pieces in subcutaneous pockets under the dorsal skin on either side of the midline. Incisions were closed with wound clips and veterinary grade topical tissue glue. Twenty-four hours after implantation, control mice were euthanized, the catheters removed and placed in 1 mL of sterile PBS to determine the initial bacterial burden. Catheter pieces were sonicated for 10 minutes, serially diluted, and plated for colony counts. The remaining groups of mice were treated once daily for 7 days with 5192, rifampin, 4206, or daptomycin administered by IP injection.
  • mice were euthanized, the catheters pieces were removed, sonicated, serial diluted, and plated for colony counts with and without antibiotics to determine resistance. Counts were plotted and statistical significance was determined using 1-way ANOVA and Tukey’s post-test in GraphPad Prism. q. HOMOGENIZATION AND PLATING [00439]
  • Harvested tissues were placed in pre-weighed 7 mL homogenizing tubes preloaded with 2.8 mm ceramic beads containing 1 mL of PBS for peritonitis model and 2 mL for thigh model. The tubes were reweighed to obtain the weight of the tissue. The tubes were placed in the bead mill homogenizer (Bead Ruptor Elite, Omni International) and homogenized.
  • Kidneys were homogenized for 15 seconds at speed 4.2 m/s, thigh muscle were homogenized for 40 seconds at speed 4.2 m/s, and catheters were flushed and sonicated with a bath sonicator for 10 minutes. After homogenization or sonication, 100 ⁇ L of homogenate or sonicate was added in triplicate to row A of a 96 well plate. The remaining wells of the 96 well plate were filled with 90 ⁇ L of sterile PBS. Using an electronic multichannel pipette, 10 ⁇ L of homogenate in each column was transferred from row A to row B and mixed by pipetting up and down 3 times at max speed.
  • MIC minimal inhibitory concentrations
  • Table 4 shows the MICs of 5192, 4206, and rifampin against Staphylococcus, Streptococcus, and Enterococcus.
  • Table 5 shows the MICs of disclosed compounds against Staphylococcus, Streptococcus, and Enterococcus. TABLE 4. TABLE 5.
  • the proteolytic activity of 5192 was compared to ClpP activators ADEP4 and 4206 by generating dose- response curves using this assay.
  • the EC50 of 5192 was found to be 0.36 ⁇ 0.07 ⁇ M, which was very similar to ADEP4 and 4206 with EC 50 s of 0.3 ⁇ 0.06 and 0.23 ⁇ 0.03 ⁇ M, respectively (FIG.2A). These data indicate 5192 dysregulates ClpP, causing uncontrolled proteolysis to a similar extent as ADEP4 and 4206.
  • RNA polymerase RNA polymerase
  • S. aureus RNAP inhibition assay was performed.
  • the RNA polymerase assay is based on the measurement of RNA molecules synthesized by S. aureus RNA polymerase using a single strand DNA template that produces a fluorescent product, which can be measured in a plate reader.
  • the IC50 for rifampin and 5192 was 6.0 ⁇ 3.3 ⁇ M and 3.7 ⁇ 2.6 ⁇ M, respectively (FIG.2B).4206 and daptomycin were included as negative controls and no RNAP inhibition was detected.
  • these results, taken together with the ClpP-mediated proteolysis assay suggest that 5192 activates ClpP and inhibits RNAP in biochemical assays to a similar extent as its constituent rifampin and 4206 pharmacophores.
  • RNA sequencing and quantitative proteomics could provide unique insights into the compound’s overall mechanism of action.
  • Transcriptomic profiling was conducted by extracting RNA from MRSA ATCC 33591 cells exposed to 1 ⁇ 2 MIC of 5192 (0.5 ⁇ g mL -1 ), 4206 (0.5 ⁇ g mL -1 ), and rifampin (0.004 ⁇ g mL -1 ) for 30 minutes.
  • 5192 induced various members of the lac operon (lacE and lacF) and downregulated ESAT-6 secretion system, similar to 4206, and these genes were not affected by rifampin treatment (FIG.2C). Interestingly, 5192 displayed also a unique transcriptional profile with 252 DEG that were not found upon 4206 or rifampin exposure (FIG.2D). Addition RNA-seq experiments were conducted on rifampin resistant and 4206 resistant isogenic strains using a similar experimental design. These studies revealed 37 out of 67 DEG (55%) identified upon 5192 exposure overlapped with rifampin in the 4206 resistant background, while 10 out of 11 DEG (90%) overlapped with 4206 in the rifampin resistant background.
  • FIG.2A shows S. aureus RNA polymerase inhibition was measured using a commercially available kit. The percent inhibition calculated was calculated and IC50 was obtained using GraphPad Prism.
  • FIG.2B shows purified S.
  • FIG.2C shows RNAseq volcano plots of differentially expressed genes (DEGs; Log2FC >
  • FIG.2D shows Upset plot depicting overlapping DEGs across the three treatment groups.
  • FIG.2E shows Volcano plots of significantly dysregulated proteins (Log2FC >
  • FIG.2F shows upset plot showing overlapping proteins across treatment groups. d.
  • 5192, 4206, rifampin, and vancomycin were added to the cell culture at 2 ⁇ and 10 ⁇ the MIC for 24 hours. Then, the epithelial cells were lysed, and the surviving intracellular bacteria were plated for colony counts.5192 and 4206 were found to have statistically significant bactericidal activity against intracellular bacteria compared to the vehicle control as well as to rifampin or vancomycin at both concentrations tested (FIG.3B). Taken together, these studies indicate that 5192 causes rapid bactericidal activity against high-density and intracellular bacteria, which appear to be properties that are retained from the 4206 pharmacophore. 4.
  • the initial concentration (C0) was 271.2 ⁇ g/mL.5192 concentrations were quantifiable up to 24 hours resulting in calculated AUC 0–inf at 549.6 ⁇ g*hr/mL.
  • 4206 and rifampin demonstrated PK parameters that were considerably different compared to 5192 (Table 6).
  • C0 values were 12-15-fold lower for each antibiotic separately, and the calculated AUC0-inf were 180- and 3.6-fold lower for 4206 and rifampin, respectively.4206 exhibited a T1/2 of 0.45 hours and a high clearance value of 54.8 mL/min/kg, while rifampin had a long T1/2 of 6.2 hours and a low clearance value of 1 mL/min/kg.
  • aureus strain 33591 and isogenically selected and characterized UDEP compound 4206 resistant and rifampin resistant variants.
  • Antibiotics were administered 1 and 3 hours after infection by intraperitoneal injection. The kidneys from each mouse were harvested, weighed, homogenized, and plated on Mueller Hinton agar containing charcoal for colony counts 6 hours after the infectious dose was delivered. The colony counts were log transformed and plotted, along with the mean and standard deviation for each group. These results showing the efficacy of compound 5192 are shown in FIG.5.
  • Statistical significance was determined by one-way analysis of variance with Tukey's multiple-comparison test, using GraphPad Prism (GraphPad, La Jolla, CA), and P values of ⁇ 0.05 were considered significant.
  • aureus strain 33591 was injected intraperitoneally to establish the infection and mice were treated with antibiotics 1 hour later. At 6 hours post-infection, kidneys were homogenized and plated for colony counts. The bacterial burden in the kidneys following 10 or 20 mg/kg doses of 5192 were statistically significantly lower compared to 4206 (20 mg/kg) or a mouse adapted human dose of vancomycin (220 mg/kg).
  • NEUTROPENIC THIGH MODEL Female specific-pathogen-free Swiss Webster mice of 22 to 25 g were rendered neutropenic with cyclophosphamide. MRSA strain S. aureus ATCC 33591 was injected to the right thigh of each mouse at 1 ⁇ 10 5 CFU per thigh.
  • Antibiotics were administered by IP injection beginning 2 hours post infection over 2 days. After 48 hours, thighs were harvested, weighed, homogenized, and plated on Mueller Hinton agar containing charcoal for colony counts. The colony counts were log transformed and plotted in FIG.6, along with the mean and standard deviation for each group. Statistical significance was determined by one-way analysis of variance with Tukey's multiple-comparison test, using GraphPad Prism (GraphPad, La Jolla, CA), and P values of ⁇ 0.05 were considered significant. [00455] Next, the efficacy of 5192 was tested in the neutropenic thigh-lesion model of infection, which is highly translatable to antibiotic efficacy in clinical trials.
  • mice were rendered neutropenic with cyclophosphamide and 105 CFU of strain ATCC 33591 (MRSA) was introduced into the right thigh muscle of each mouse to form an abscess.
  • MRSA MRSA
  • Antibiotics were administered for 2 days beginning 2 hours after the infections were established. Mice were sacrificed, their thighs were harvested, homogenized, and plated for colony counts 48 hours later.5192 displayed considerable activity in the thigh model with statistically significant decreases in thigh burden detected for doses from 12.5 - 100 mg/kg (FIG.4B).
  • FIG.4B in the 2-day neutropenic thigh-lesion model, S.
  • aureus strain 33591 was injected into the right thigh muscle. Antibiotics were administered by IP injection starting 2 hours post-infection. After 48 hours, mice were euthanized and the infected thigh tissue was harvested, homogenized, serially diluted, and plated for colony counts. The activity of 5192 at 25 mg/kg after 2 days of dosing was similar to a mouse adapted human dose of vancomycin (220 mg/kg) and better than linezolid, an approved antibiotic that typically requires 3 days of dosing for efficacy in the thigh-lesion model. Rifampin and 4206 were included as controls and statistically significant decreases in bacterial burden were also observed for these antibiotics.
  • the neutropenic thigh-lesion model was established with rifampin and 4206 resistant derivatives of S. aureus strain 33591. Mice were treated with antibiotics starting 2-hour post-infection and equimolar concentrations of 5192 (50 mg/kg) and its constituents 4206 (25.12 mg/kg) and rifampin (24.2 mg/kg) were administered by IP injection. Mice were euthanized 24 hours later, and the bacterial burden was quantified.
  • the bar graph shows the average change in colony counts per gram tissue compared to each strain’s vehicle control. A solid color indicates wildtype S.
  • aureus strain 33591 with a checkered pattern and diagonal stripes indicating the rifampin resistant and 4206 resistant strain, respectively.
  • 4206 was not effective at its equimolar dose-level, while rifampin caused statistically significant decreases against the wildtype and 4206 resistant strains, but not in the rifampin resistant background.
  • Vancomycin was included as the positive control and it was effective against all three strains when dosed at the mouse adapted human equivalent of 220 mg/kg. The 50 mg/kg total daily dose of 5192 exhibited similar efficacy in the one- and two-day thigh models.
  • mice Female specific-pathogen-free Swiss Webster mice of 22 to 25 g were used. 8mm pieces of sterile catheters were soaked in a bacterial suspension containing 1 ⁇ 10 7 CFU/ml of S. aureus ATCC 33591 for 3-4hours in BHI media. Under isoflurane anesthesia, a 15mm 2 area was shaved on the midline of the back of each mouse and disinfected with betadine.10mm incisions were made on the back of each mouse and a 15mm subcutaneous tunnel created using blunt forceps. Catheter pieces were placed inside the tunnel and the incision was closed using a wound clip.
  • mice Post-surgery mice were monitored daily for wound and general health.24 hours post-surgery, antibiotics were delivered twice a day for 3 days by intraperitoneal or subcutaneous routes. On day 5, mice were euthanized, the catheters harvested and plated for colony counts after being sonicated in 1ml of PBS. The colony counts were log transformed and plotted in FIG.7, along with the mean and standard deviation for each group. Statistical significance was determined by one-way analysis of variance with Tukey's multiple-comparison test, using GraphPad Prism (GraphPad, La Jolla, CA), and P values of ⁇ 0.05 were considered significant.
  • Antibiotic treatments began 24 hours after implantation and some mice are euthanized at that time to determine the baseline infection level. The remaining mice were treated once daily for 7 days with 5192, rifampin, 4206, or daptomycin administered by IP injections. On day 9, the mice were euthanized, the catheters removed, placed in 1 ml of sterile PBS, sonicated, and plated for colony counts on agar plates with and without antibiotics.5192 dosed at 75 or 150 mg/kg eradicated catheter colony counts to below the limit of detection in 34 out of 35 catheters with no resistance detected (FIG.4D). With regard to FIG.4D, S.
  • aureus strain 33591 biofilms were grown on sterile catheter pieces and surgically implanted subcutaneously on the backs of the mice to establish the infection. Antibiotics were administered once a day for 7 days beginning 24 hours after surgery. Mice were euthanized 24 hours after the last dose and catheter colony counts were quantified on agar with and without antibiotics to determine resistance development. Open circles indicate resistance. Statistical significance was calculated using one-way ANOVA using GraphPad prism. Treatment with 4206 or rifampin resulted in statistically significant decreases in catheter counts but the effects were highly variable and resistance development detected in 8 of 16 catheters for 5192 and 13 of 22 catheters for rifampin.
  • FIG.4A-D * p-value ⁇ 0.5, *** p-value ⁇ 0.0005, **** p-value ⁇ 0.0001 compared to vehicle control;
  • 5192 engages both ClpP, the target of 4206, and RpoB, the target of rifampin by characterizing: 1) growth inhibition of each 4206- resistant and rifampin-resistant strains; 2) a low frequency of resistance ⁇ 10 -12 for S. aureus and other Gram-positive pathogen; and 3) transcriptomic and proteomic profiles highly overlapping with rifampin and 4206. It was also shown that the high-density and intracellular killing properties of 4206 and rifampin are retained in 5192. [00460] 5192 also displays excellent pharmacokinetics and safety, which are encouraging properties for future clinical development. The favorable half-life (2.5 hours in mice) indicates the sterically hindered ester linkage in 5192 is stable.
  • 5192 demonstrated excellent killing of biofilms in the implanted catheter model of infection and no resistance was detected, in contrast to rifampin, 4206, and daptomycin.5192 is active against all the major Gram-positive pathogens. Its unique dual- targeting mechanism of action and activity against biofilms and intracellular bacteria suggests it has the potential to reduce the unacceptably high level of mortality and morbidity caused by Gram-positive infections (Murray, C.J.L., et al. (2022) Lancet 399, 629-655; Kourtis, A. P. et al(2019)MMWR Morb Mortal Wkly Rep 68, 214-219; ContraFect Corporation. Form 10- K. United States Securities and Exchange Commission.
  • Staphylococcus aureus chronic and relapsing infections Evidence of a role for persister cells: An investigation of persister cells, their formation and their role in S. aureus disease. Bioessays 36, 991-996, doi:10.1002/bies.201400080 (2014).
  • Conlon, B. P. et al. Persister formation in Staphylococcus aureus is associated with ATP depletion. Nat Microbiol 1, doi:16051 [pii] [00464] 10.1038/nmicrobiol.2016.51 (2016).

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Abstract

Selon un aspect, l'invention concerne des composés utiles en tant qu'antibiotiques hybrides, agissant en tant qu'activateurs de la protéase ClpP et des inhibiteurs de l'activité de l'ARN polymérase. L'invention concerne également des procédés d'utilisation des composés décrits dans le traitement de maladies infectieuses telles que, par exemple, des maladies à médiation par biofilm et des maladies infectieuses dues à des infections de prothèse articulaire, des bactéries intracellulaires et des bactéries à Gram positif (par exemple, des bactéries à Gram positif choisies parmi Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Clostridium tetani, Clostridium botulinum, Clostridium perfringens, Corynebacterium diphtheriae, Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Listeria ivanovii, Micrococcus luteus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus hyicus, Staphylococcus intermedius, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae). Le présent abrégé est proposé à titre d'outil d'exploration à des fins de recherche dans cette technique particulière et n'est pas destiné à limiter la présente invention.
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