WO2016154051A1 - Polythérapie pour le traitement de maladies infectieuses - Google Patents

Polythérapie pour le traitement de maladies infectieuses Download PDF

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Publication number
WO2016154051A1
WO2016154051A1 PCT/US2016/023256 US2016023256W WO2016154051A1 WO 2016154051 A1 WO2016154051 A1 WO 2016154051A1 US 2016023256 W US2016023256 W US 2016023256W WO 2016154051 A1 WO2016154051 A1 WO 2016154051A1
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optionally substituted
pharmaceutical composition
certain embodiments
alkyl
compound
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PCT/US2016/023256
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English (en)
Inventor
Robert William HUIGENS, III
Yasmeen ABOUELHASSAN
Aaron GARRISON
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University Of Florida Research Foundation, Inc.
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Publication of WO2016154051A1 publication Critical patent/WO2016154051A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Infectious diseases are the third leading cause of death in developed countries and the second leading cause of death worldwide (see, e.g., World Health Organization (WHO) Geneva, World Health Report (2002); Nathan, Nature (2004) 431 :899).
  • the efficacy of many antibacterial drugs has been compromised by the emergence of drug resistant, pathogenic bacteria (see, e.g., National Nosocomial Infections Surveillance (NNIS) System, Am. J. Infect. Control (2004) 32:470).
  • NIS National Nosocomial Infections Surveillance
  • the Infectious Disease Society of America has recently outlined the deadly implications of a growing number of drug-resistant pathogens (see, e.g., Boucher et ah, J. Clin. Infect. Dis. (2009) 48: 1).
  • Methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE), and penicillin-resistant Streptococcus epidermis are especially worrisome in clinical settings.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococci
  • Streptococcus epidermis is especially worrisome in clinical settings.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococci
  • Streptococcus epidermis are especially worrisome in clinical settings.
  • MRSA Methicillin-resistant Staphylococcus aureus
  • VRE vancomycin-resistant Enterococci
  • Streptococcus epidermis penicillin-resistant Streptococcus epidermis
  • Biofilms are complex communities of microorganisms that are commonly found on a variety of substrates or surfaces that are moist or submerged (Musk et ah, Curr. Med. Chem., 2006, 13, 2163). Though primarily populated by bacteria, biofilms can also contain many different individual types of microorganisms, e.g., bacteria, archaea, protozoa, and algae. The formation of biofilms can be thought of as a developmental process in which a few free-swimming (planktonic) bacteria adhere to a solid surface and, in response to appropriate signals, initiate the formation of a complex sessile microcolony existing as a community of bacteria and other organisms.
  • planktonic planktonic
  • Bacteria within biofilms are usually embedded within a matrix, which can consist of protein, polysaccharide, nucleic acids, or combinations of these macromolecules.
  • the matrix is a critical feature of the biofilm that protects the inhabiting organisms from antiseptics, microbicides, and host cells. It has been estimated that bacteria within biofilms are upwards of 1,000-fold more resistant to conventional antibiotics (Rasmussen et al., Int. J. Med. Microbiol., 2006, 296, 149). Accordingly, there is a need for development of new therapies to treat infectious diseases such as bacterial infections and/or biofilm.
  • the large majority of the antibiotic arsenal hits relatively few bacterial targets (e.g., cell wall synthesis machinery, bacterial ribosomes, DNA gyrase/topoisomerase, RNA polymerase) (K. Lewis, Nat. Rev. Drug Discov. 2013, 12, 371- 387).
  • bacterial targets e.g., cell wall synthesis machinery, bacterial ribosomes, DNA gyrase/topoisomerase, RNA polymerase
  • the present invention provides compositions comprising a quinoline and a potentiating agent, wherein the potentiating agent comprises a catechol moiety.
  • the present invention provides compositions comprising a quinoline, a potentiating agent, wherein the potentiating agent comprises a catechol moiet and optionally a surfactant.
  • the provided composition can be used to incorporate into, coat, impregnate, flush, or rinse an object or material.
  • the composition is a cleaning composition.
  • the provided compositions can be useful for decontaminating, inhibiting growth, or preventing growth on surfaces where microorganisms form a biofilm ⁇ e.g., tubing).
  • the present invention provides pharmaceutical compositions comprising a quinoline, a potentiating agent, wherein the potentiating agent comprises a catechol moiety, and optionally a pharmaceutically acceptable excipient.
  • the quinoline is a halogenated quinoline (HQ), i.e., comprising at least one halogen substituent.
  • the quinoline comprises at least one -N0 2 substituent.
  • the quinoline is a halogenated quinoline comprising at least one -N0 2 substitutent.
  • the potentiating agent acts to promote the antibacterial "potentiation" of the quinoline.
  • the potentiating agent may lower the minimum inhibitory concentration (MIC) value of the quinoline and provide increased antibacterial activity in the combination therapy.
  • the potentiating agent is a phytochemical.
  • phytochemicals refer to chemical compounds that occur naturally in plants or are derived from plants.
  • the potentiating agent is gallic acid, caffeic acid, or tiron.
  • the potentiating agent is gallic acid.
  • the pharmaceutical composition further comprises a second antimicrobial agent such as an antibiotic.
  • the pharmaceutical composition further comprises a salt.
  • the salt is a metal (II) salt.
  • the quinoline is of Formula (I):
  • the quinoline is of Formula (II):
  • the quinoline is of Formula (III):
  • the quinoline is of Formula (IV):
  • the quinoline is of Formula (V):
  • the present invention provides a compound of Formula (C-1)
  • the present invention provides methods to treat and/or prevent an infectious disease comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the infectious disease is a bacterial infection.
  • the bacterial infection is a chronic bacterial infection.
  • the bacterial infection is a urinary tract infection, gastritis, respiratory tract infection (e.g., those seen in patients with cystic fibrosis), cystitis, pyelonephritis, osteomyelitis, bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones, bacterial endocarditis, ear infection, and sinus infection.
  • the bacterial infection is a Gram-negative bacterial infection.
  • the Gram-negative bacterium is A. baumannii or K. pneumonia.
  • the bacterial infection is a Gram-positive bacterial infection.
  • the Gram-positive bacterium is S. aureus or S. epidermidis.
  • the bacterium is an antibiotic-resistant strain.
  • the bacterium is methicillin-resistant Staphylococcus aureus (MRSA) or methicillin-resistant S. epidermidis (MRSE).
  • the bacterium is an antibiotic-susceptible strain.
  • the bacterium is susceptible to one or more antibiotics selected from the group consisting of beta-lactams, sulfonamides, aminoglycosides, tetracyclines, chloramphenicols, macrolides, glycopeptides, oxazolidinones, ansamycins, quinolones, streptogramins, and lipopeptides.
  • the subject having or susceptible to the infectious disease also contracts another disease or condition.
  • the subject is diagnosed with cystic fibrosis.
  • the infectious disease is a fungal infection. In certain embodiments, the infectious disease is a parasital infection. In certain embodiments, the infectious disease is a protozoan infection. In certain embodiments, the infectious disease is associated with the formation of a biofilm.
  • the present invention provides methods for killing a bacterium comprising contacting the bacterium with a pharmaceutical composition as described herein.
  • the present invention provides methods for inhibiting bacterial cell growth comprising contacting the bacterium with a pharmaceutical composition as described herein.
  • the present invention provides methods for inducing bacterial hypersusceptibility comprising contacting a bacterium with a pharmaceutical composition as described herein.
  • the present invention provides methods of preventing biofilm formation comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the present invention provides methods of eradicating a biofilm comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition as described herein.
  • the biofilm includes one or more microorganisms selected from the group consisting of bacteria, archaea, protozoa, fungi and algae.
  • the biofilm includes bacteria.
  • the present invention provides methods of treating and/or preventing biofilm formation comprising contacting an object with an effective amount of the pharmaceutical composition as described herein.
  • the provided method is useful in inhibiting and/or removing a biofilm on the surface of an object.
  • the biofilm is produced by an organism selected from the group consisting of bacteria, archaea, algae, fungi, and protozoa.
  • the biofilm is a bacterial biofilm.
  • the biofilm includes antibiotic- resistant bacteria.
  • the biofilm includes MRSA.
  • the quinoline in the provided pharmaceutical compositions may bind metal ions and thereby provide their antibacterial properties.
  • the quinoline in the provided pharmaceutical compositions binds iron and/or other metals (e.g. , aluminum, thallium, chromium, magnesium, calcium, strontium, nickel, manganese, cobalt, copper, zinc, silver, sodium, potassium, cadmium, mercury, lead, antimony, molybdenum, tungsten, a lanthanide (e.g. , cerium), or an actinide (e.g. , uranium)).
  • metals e.g. , aluminum, thallium, chromium, magnesium, calcium, strontium, nickel, manganese, cobalt, copper, zinc, silver, sodium, potassium, cadmium, mercury, lead, antimony, molybdenum, tungsten, a lanthanide (e.g. , cerium), or an actinide (e.g. , uran
  • the quinoline in the provided pharmaceutical compositions binds metal(II) ions.
  • the metal (II) ion(s) is/are Zn 2+ , Fe 2+ , and/or Cu 2+ .
  • the quinoline in the provided pharmaceutical compositions chelates Fe and one or more metals important for bacterial growth, e.g. K, Mg, Ca, Mn, Zn, Co, Cu, and Mo.
  • the invention provides a kit for treating and/or preventing an infectious disease.
  • the invention provides a kit for preventing formation of biofilms.
  • the invention provides a kit for eradicating biofilms.
  • the kit is to treat and/or prevent biofilm formation in a subject.
  • the kit is to treat and/or prevent biofilm formation on an object (e.g. surface).
  • the kit further comprises an antimicrobial agent (e.g. , antibiotics).
  • the inventive kits include a first container containing a therapeutically effective amount of a pharmaceutical composition as described herein, and instructions for administering the pharmaceutical composition to the subject to treat and/or prevent an infectious disease.
  • kits include a first container containing an effective amount of a composition as described herein, and instructions for using the composition to prevent and/or eradicate a biofilm.
  • the kit is a cleaning kit.
  • the kit further comprises a disinfectant.
  • a kit may also include multiple unit dosages, for example, for multiple days of treatment.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates plane polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof.
  • a mixture containing equal proportions of the enantiomers is called a "racemic mixture.”
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and
  • an isomer/enantiomer may, in some embodiments, be provided substantially free of the corresponding enantiomer, and may also be referred to as “optically enriched” or “enantiomerically enriched.” “Optically enriched” and
  • enantiomeric ally enriched means that a provided compound is made up of a significantly greater proportion of one enantiomer.
  • a compound of the present invention is made up of at least about 70% by weight of a preferred enantiomer.
  • a compound of the present invention is made up of at least about 80% by weight of a preferred enantiomer.
  • a compound of the present invention is made up of at least about 90% by weight of a preferred enantiomer.
  • the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer.
  • Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including chiral high pressure liquid
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the depicted structures that differ only in the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by 13 C or 14 C are within the scope of this invention.
  • Such compounds may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.
  • CiV is intended to encompass, Ci, C 2 , C 3 , C 4 , C5, C 6 , Ci_6, Ci_5, Ci ⁇ , Ci_ 3 , Ci_ 2 , C 2 _6, C 2 _5, C 2 ⁇ , C 2 _ 3 , C 3 _6, C 3 _5, C 3 ⁇ , C4_6, C 4 _5, and Cs_6.
  • purified refers to a compound useful in the present invention being free of other, dissimilar compounds with which the compound is normally associated in its natural state, so that the compound comprises at least 0.5%, 1%, 5%, 10%, 20%, 50%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9% of the mass, by weight, of a given sample or composition. In one embodiment, these terms refer to the compound comprising at least 95%, 98%, 99%, or 99.9% of the mass, by weight, of a given sample or composition.
  • R XI is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched
  • heteroaliphatic cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,
  • heteroaryloxy aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R XI groups taken together form a 5- to 6-membered heterocyclic ring.
  • acyl groups include aldehydes (-CHO), carboxylic acids (-C0 2 H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.
  • Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • aliphatic includes both saturated and unsaturated, nonaromatic, straight chain (i.e. , unbranched), branched, acyclic, and cyclic (i.e. , carbocyclic)
  • hydrocarbons which are optionally substituted with one or more functional groups.
  • aliphatic is intended herein to include, but is not limited to, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties.
  • alkyl includes straight, branched and cyclic alkyl groups.
  • An analogous convention applies to other generic terms such as “alkenyl”, “alkynyl”, and the like.
  • alkyl encompass both substituted and unsubstituted groups.
  • aliphatic is used to indicate those aliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
  • Aliphatic group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroarylthioxy acyloxy, and the like, each of which may or may not be further substituted).
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals derived from a hydrocarbon moiety containing between one and twenty carbon atoms by removal of a single hydrogen atom.
  • the alkyl group employed in the invention contains 1-20 carbon atoms.
  • the alkyl group employed contains 1-15 carbon atoms.
  • the alkyl group employed contains 1-10 carbon atoms.
  • the alkyl group employed contains 1-8 carbon atoms.
  • the alkyl group employed contains 1-5 carbon atoms.
  • alkyl radicals include, but are not limited to, methyl (e.g.
  • Alkyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • alkenyl denotes a monovalent group derived from a straight- or branched-chain hydrocarbon moiety having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • the alkenyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkenyl group employed in the invention contains 2-15 carbon atoms. In another embodiment, the alkenyl group employed contains 2-10 carbon atoms. In still other embodiments, the alkenyl group contains 2-8 carbon atoms. In yet other embodiments, the alkenyl group contains 2-5 carbons.
  • Alkenyl groups include, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten- 1-yl, and the like, which may bear one or more substituents.
  • Alkenyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • alkenyl group e stereochemistry is not specified (e.g.,
  • alkynyl refers to a monovalent group derived from a straight- or branched-chain hydrocarbon having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
  • the alkynyl group employed in the invention contains 2-20 carbon atoms. In some embodiments, the alkynyl group employed in the invention contains 2-15 carbon atoms. In another embodiment, the alkynyl group employed contains 2-10 carbon atoms. In still other embodiments, the alkynyl group contains 2-8 carbon atoms. In still other embodiments, the alkynyl group contains 2-5 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl
  • Alkynyl group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroaliphaticoxy alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • Exemplary carbon atom substituents include, but are not limited to, halogen, -
  • each instance of is, independently, selected from Cuo alkyl, Cuo perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, Ce-i 4 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered
  • heterocyclyl or 5-14 membered heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R cc is, independently, selected from hydrogen, Ci_io alkyl, Cuo perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, Ce-i 4 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from Ci_ 6 alkyl, Ci_6 perhaloalkyl, C 2 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io carbocyclyl, C 6 -io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R is, independently, selected from hydrogen, Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, Ce- ff
  • io aryl and 5-10 membered heteroaryl, or two R groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and
  • exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -N0 2 , -N 3 , -S0 2 H, -S0 3 H, -OH, -OR aa , -ON(R bb ) 2 ,
  • each instance of is, independently, selected from CM O alkyl, Ci_io perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, heteroCi_io alkyl, heteroC 2 _ioalkenyl, heteroC 2 _ioalkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring
  • each instance of R bb is, independently, selected from hydrogen, -OH, -OR aa ,
  • each instance of R cc is, independently, selected from hydrogen, Ci_io alkyl, Ci_io perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, heteroCi_io alkyl, heteroC 2 _io alkenyl, heteroC 2 _io alkynyl, C 3 _io carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;
  • each instance of R ee is, independently, selected from Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroCi_ 6 alkyl, heteroC 2 _ 6 alkenyl, heteroC 2 _ 6 alkynyl, C 3 _io
  • each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, Ci_ 6 alkyl, Ci_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, heteroCi_ 6 alkyl, heteroC 2 _ 6 alkenyl, heteroC 2 _ 6 alkynyl, C 3 _io carbocyclyl, 3-10 membered heterocyclyl, C 6 -io aryl and 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,
  • heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • amino refers to a group of the formula (-NH 2 ).
  • a "substituted amino” refers either to a mono-substituted amine (-NHR h ) of a disubstituted amine (-NR h 2 ), wherein the R h substituent is any substituent as described herein that results in the formation of a stable moiety (e.g., a suitable amino protecting group; aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, amino, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino,
  • heteroarylamino alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
  • the R h substituents of the disubstituted amino group(-NR h 2 ) form a 5- to 6-membered heterocyclic ring.
  • alkoxy refers to a "substituted hydroxyl" of the formula (-OR 1 ), wherein R 1 is an optionally substituted alkyl group as defined herein, and the oxygen moiety is directly attached to the parent molecule.
  • alkylthioxy refers to a "substituted thiol” of the formula (-SR r ), wherein R r is an optionally substituted alkyl group as defined herein, and the sulfur moiety is directly attached to the parent molecule.
  • alkylamino refers to a "substituted amino' Of the formula (-NR h 2 ), wherein R h is, independently, a hydrogen or an optionally substituted alkyl group as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
  • aryl refer to stable aromatic mono- or polycyclic ring system having 3-20 ring atoms, of which all the ring atoms are carbon, and which may be substituted or unsubstituted.
  • aryl refers to a mono, bi, or tricyclic C 4 -C 2 o aromatic ring system having one, two, or three aromatic rings which include, but not limited to, phenyl, biphenyl, naphthyl, and the like, which may bear one or more substituents.
  • Aryl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • arylalkyl refers to an aryl substituted alkyl group, wherein the terms “aryl” and “alkyl” are defined herein, and wherein the aryl group is attached to the alkyl group, which in turn is attached to the parent molecule.
  • exemplary arylalkyl groups are benzyl and phenethyl.
  • aryloxy refers to a "substituted hydroxyl" of the formula (-OR 1 ), wherein R 1 is an optionally substituted aryl group as defined herein, and the oxygen moiety is directly attached to the parent molecule.
  • arylamino refers to a "substituted amino' Of the formula (-NR h 2 ), wherein R h is, independently, a hydrogen or an optionally substituted aryl group as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
  • arylthioxy refers to a "substituted thiol” of the formula (-SR r ), wherein R r is an optionally substituted aryl group as defined herein, and the sulfur moiety is directly attached to the parent molecule.
  • halo and halogen refer to an atom selected from fluorine
  • heteroaliphatic refers to an aliphatic moiety, as defined herein, which includes both saturated and unsaturated, nonaromatic, straight chain (i.e. , unbranched), branched, acyclic, cyclic (i.e. , heterocyclic), or polycyclic hydrocarbons, which are optionally substituted with one or more functional groups, and that contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
  • heteroaliphatic moieties are substituted by independent replacement of one or more of the hydrogen atoms thereon with one or more substituents.
  • heteroaliphatic is intended herein to include, but is not limited to, heteroalkyl, heteroalkenyl, heteroalkynyl, heterocycloalkyl, heterocycloalkenyl, and heterocycloalkynyl moieties.
  • heteroaliphatic includes the terms
  • heteroalkyl “heteroalkenyl”, “heteroalkynyl”, and the like. Furthermore, the terms
  • heteroalkyl encompass both substituted and unsubstituted groups.
  • heteroaliphatic is used to indicate those heteroaliphatic groups (cyclic, acyclic, substituted, unsubstituted, branched or unbranched) having 1-20 carbon atoms.
  • Heteroaliphatic group substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroarylamino alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
  • heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • heteroalkyl refers to an alkyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
  • heteroalkenyl refers to an alkenyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
  • heteroalkynyl refers to an alkynyl moiety, as defined herein, which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms, e.g. , in place of carbon atoms.
  • heteroalkylamino refers to a "substituted amino" of the formula (-
  • R h is, independently, a hydrogen or an optionally substituted heteroalkyl group, as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
  • heteroalkyloxy refers to a "substituted hydroxyl" of the formula (-
  • R 1 is an optionally substituted heteroalkyl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
  • heteroalkylthioxy refers to a "substituted thiol" of the formula (-
  • R r is an optionally substituted heteroalkyl group, as defined herein, and the sulfur moiety is directly attached to the parent molecule.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C 3 _i 4 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms ("C 3 _io carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3 _ 8 carbocyclyl”).
  • carbocyclyl group has 3 to 7 ring carbon atoms (“C 3 _7 carbocyclyl”).
  • carbocyclyl group has 3 to 6 ring carbon atoms ("C 3 _6 carbocyclyl”). In some embodiments, carbocyclyl group has 4 to 6 ring carbon atoms ("C4_6 carbocyclyl”). In some embodiments, carbocyclyl group has 5 to 6 ring carbon atoms (“Cs_6 carbocyclyl”). In some embodiments, carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl”).
  • Exemplary C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _ 8 carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like.
  • Exemplary C 3 _io carbocyclyl groups include, without limitation, the
  • C 3 _ 8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C9), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds.
  • Carbocyclyl also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 _i 4 carbocyclyl.
  • the carbocyclyl group is a substituted C 3 _i 4 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C 3 _i 4 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms ("C 3 _io cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3 _ 8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3 _6 cycloalkyl").
  • a cycloalkyl group has 4 to 6 ring carbon atoms ("C 4 _6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“Cs_6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("Cs-io cycloalkyl”). Examples of Cs_6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C5).
  • C 3 _ 6 cycloalkyl groups include the aforementioned Cs_ 6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ).
  • C 3 _ 8 cycloalkyl groups include the aforementioned C 3 _6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ).
  • each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents.
  • the cycloalkyl group is an unsubstituted C 3 _i 4 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3 _i 4 cycloalkyl.
  • heterocyclic refers to a cyclic heteroaliphatic group.
  • a heterocyclic group refers to a non-aromatic, partially unsaturated or fully saturated, 3- to 12-membered ring system, which includes single rings of 3 to 8 atoms in size, and bi- and tri-cyclic ring systems which may include aromatic five- or six-membered aryl or heteroaryl groups fused to a non-aromatic ring.
  • These heterocyclic rings include those having from one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, in which the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • heterocyclic refers to a non-aromatic 5-, 6-, or 7-membered ring or polycyclic group wherein at least one ring atom is a heteroatom selected from O, S, and N (wherein the nitrogen and sulfur heteroatoms may be optionally oxidized), and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
  • Heterocyclyl groups include, but are not limited to, a bi- or tri-cyclic group, comprising fused five, six, or seven- membered rings having between one and three heteroatoms independently selected from the oxygen, sulfur, and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iii) the nitrogen heteroatom may optionally be quaternized, and (iv) any of the above heterocyclic rings may be fused to an aryl or heteroaryl ring.
  • heterocycles include azacyclopropanyl, azacyclobutanyl, 1,3-diazatidinyl, piperidinyl, piperazinyl, azocanyl, thiaranyl, thietanyl, tetrahydrothiophenyl, dithiolanyl, thiacyclohexanyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropuranyl, dioxanyl, oxathiolanyl, morpholinyl, thioxanyl, tetrahydronaphthyl, and the like, which may bear one or more substituents.
  • Substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g. , aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, sulfinyl, sulfonyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy,
  • heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • heteroaryl refer to stable aromatic mono- or polycyclic ring system having 3-20 ring atoms, of which one ring atom is selected from S, O, and N; zero, one, or two ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon, the radical being joined to the rest of the molecule via any of the ring atoms.
  • heteroaryls include, but are not limited to pyrrolyl, pyrazolyl, imidazolyl, pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyyrolizinyl, indolyl, quinolinyl, isoquinolinyl, benzoimidazolyl, indazolyl, quinolinyl, isoquinolinyl, quinolizinyl, cinnolinyl, quinazolynyl, phthalazinyl, naphthridinyl,
  • Heteroaryl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g.
  • heteroalkyloxy aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
  • heteroarylamino refers to a "substituted amino' Of the (-NR h 2 ), wherein R h is, independently, hydrogen or an optionally substituted heteroaryl group, as defined herein, and the nitrogen moiety is directly attached to the parent molecule.
  • heteroaryloxy refers to a "substituted hydroxyl" of the formula (-
  • R 1 is an optionally substituted heteroaryl group, as defined herein, and the oxygen moiety is directly attached to the parent molecule.
  • heteroarylthioxy refers to a "substituted thiol" of the formula (-
  • R r is an optionally substituted heteroaryl group, as defined herein, and the sulfur moiety is directly attached to the parent molecule.
  • hydroxy or "hydroxyl” refers to a group of the formula (-OH).
  • substituted hydroxyl refers to a group of the formula (-OR 1 ), wherein R 1 can be any substituent which results in a stable moiety (e.g., a suitable hydroxyl protecting group;
  • nitro refers to a group of the formula (-N0 2 ).
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms.
  • a "protecting group” is well known in the art and include those described in detail in Greene 's Protective Groups in Organic Synthesis, P. G. M. Wuts and T. W. Greene, 4 edition, Wiley-Interscience, 2006, the entirety of which is incorporated herein by reference.
  • Suitable “amino-protecting groups” include methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t- butyl-[9-(10,10-dioxo- 10,10, 10,10-tetrahydrothioxanthyl)] methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-l- methylethyl carbamate (Adpoc), l,
  • TLBOC 1 -methyl- l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)- l- methylethyl carbamate (i-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, i-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, i
  • tungsten)carbonyl] amine N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4- dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4- methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridinesulfenamide (Npys), /?-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4- methoxybenzene
  • the substituent present on an oxygen atom is an hydroxyl protecting group.
  • a "hydroxyl protecting group” (also referred to as an “oxygen protecting group”) is well known in the art and includes those described in detail in Greene (1999).
  • Suitable hydroxyl protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), i-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), /?-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), i-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2- chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3- bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-
  • DEIPS diethylisopropylsilyl
  • TDMS i-butyldimethylsilyl
  • TDPS t- butyldiphenylsilyl
  • tribenzylsilyl tri-/?-xylylsilyl, triphenylsilyl
  • DPMS diphenylmethylsilyl
  • TMPS i-butylmethoxyphenylsilyl
  • formate benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, /?-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, /?-phenylbenzoate, 2,4,6- trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,
  • protecting groups include methylene acetal, ethylidene acetal, 1-i-butylethylidene ketal, 1-phenylethylidene ketal, (4- methoxyphenyl)ethylidene acetal, 2,2,2-trichloroethylidene acetal, acetonide,
  • cyclopentylidene ketal cyclohexylidene ketal, cycloheptylidene ketal, benzylidene acetal, p- methoxybenzylidene acetal, 2,4-dimethoxybenzylidene ketal, 3,4-dimethoxybenzylidene acetal, 2-nitrobenzylidene acetal, methoxymethylene acetal, ethoxymethylene acetal, dimethoxymethylene ortho ester, 1-methoxyethylidene ortho ester, 1-ethoxyethylidine ortho ester, 1,2-dimethoxyethylidene ortho ester, a-methoxybenzylidene ortho ester, ⁇ - ⁇ N,N- dimethylamino)ethylidene derivative, a-(N,N'-dimethylamino)benzylidene derivative, 2- oxacyclopentylidene ortho ester, di
  • the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group").
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • a "counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality.
  • An anionic counterion may be monovalent (i.e., including one formal negative charge).
  • An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent.
  • Exemplary counterions include halide ions ⁇ e.g. , F , CF, Br , ⁇ ), N0 3 , C10 4 , OH , H 2 P0 4 , HC0 3 ⁇ HS0 4 , sulfonate ions (e.g.
  • exemplary counterions which may be multivalent include C0 3 , HP0 4 ,
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboxylate anions e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like
  • carboranes e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the
  • carbohydrate refers to an aldehydic or ketonic derivative of polyhydric alcohols.
  • Carbohydrates include compounds with relatively small molecules (e.g. , sugars) as well as macromolecular or polymeric substances (e.g. , starch, glycogen, and cellulose polysaccharides).
  • saccharide refers to monosaccharides, disaccharides, or polysaccharides. Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed to smaller carbohydrates.
  • monosaccharides can be represented by the general formula C y H 2y O y (e.g., C 6 Hi 2 0 6 (a hexose such as glucose)), wherein y is an integer equal to or greater than 3.
  • C y H 2y O y e.g., C 6 Hi 2 0 6 (a hexose such as glucose)
  • y is an integer equal to or greater than 3.
  • Certain polyhydric alcohols not represented by the general formula described above may also be considered monosaccharides.
  • deoxyribose is of the formula CsHio0 4 and is a monosaccharide.
  • Monosaccharides usually consist of five or six carbon atoms and are referred to as pentoses and hexoses, receptively.
  • the monosaccharide contains an aldehyde it is referred to as an aldose; and if it contains a ketone, it is referred to as a ketose.
  • Monosaccharides may also consist of three, four, or seven carbon atoms in an aldose or ketose form and are referred to as trioses, tetroses, and heptoses, respectively.
  • Glyceraldehyde and dihydroxyacetone are considered to be aldotriose and ketotriose sugars, respectively.
  • aldotetrose sugars include erythrose and threose
  • ketotetrose sugars include erythrulose.
  • Aldopentose sugars include ribose, arabinose, xylose, and lyxose; and ketopentose sugars include ribulose, arabulose, xylulose, and lyxulose.
  • aldohexose sugars include glucose (for example, dextrose), mannose, galactose, allose, altrose, talose, gulose, and idose; and ketohexose sugars include fructose, psicose, sorbose, and tagatose.
  • Ketoheptose sugars include sedoheptulose.
  • the aldohexose D-glucose for example, has the formula C 6 Hi206, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of the 16 (i.e. , 2 4 ) possible stereoisomers.
  • the assignment of D or L is made according to the orientation of the asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the right the molecule is a D sugar, otherwise it is an L sugar.
  • the aldehyde or ketone group of a straight- chain monosaccharide will react reversibly with a hydroxyl group on a different carbon atom to form a hemiacetal or hemiketal, forming a heterocyclic ring with an oxygen bridge between two carbon atoms. Rings with five and six atoms are called furanose and pyranose forms, respectively, and exist in equilibrium with the straight-chain form.
  • the carbon atom containing the carbonyl oxygen becomes a stereogenic center with two possible configurations: the oxygen atom may take a position either above or below the plane of the ring.
  • the resulting possible pair of stereoisomers is called anomers.
  • an a anomer the -OH substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the - CH 2 OH side branch.
  • the alternative form, in which the -C3 ⁇ 4OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane of the ring, is called a ⁇ anomer.
  • a carbohydrate including two or more joined monosaccharide units is called a disaccharide or polysaccharide (e.g. , a trisaccharide), respectively.
  • Exemplary disaccharides include sucrose, lactulose, lactose, maltose, isomaltose, trehalose, cellobiose, xylobiose, laminaribiose, gentiobiose, mannobiose, melibiose, nigerose, and rutinose.
  • Exemplary trisaccharides include, but are not limited to, isomaltotriose, nigerotriose, maltotriose, melezitose, maltotriulose, raffinose, and kestose.
  • carbohydrate also includes other natural or synthetic stereoisomers of the carbohydrates described herein.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid.
  • Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate
  • basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • acids which can be employed to form therapeutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid.
  • Basic addition salts refer to salts derived from appropriate bases, these salts including alkali metal, alkaline earth metal, and quaternary amine salts. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.
  • Basic addition salts can be prepared during the final isolation and purification of the compounds, often by reacting a carboxyl group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
  • the cations of therapeutically acceptable salts include lithium, sodium (by using, e.g. , NaOH), potassium (by using, e.g.
  • KOH potassium hydroxide
  • calcium by using, e.g. , Ca(OH) 2
  • magnesium by using, e.g. , Mg(OH) 2 and magnesium acetate
  • zinc by using, e.g. , Zn(OH) 2 and zinc acetate
  • aluminum as well as nontoxic quaternary amine cations such as ammonium
  • tetramethylammonium tetraethylammonium
  • methylamine dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N- methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N- dibenzylphenethylamine, 1-ephenamine, and N,N-dibenzylethylenediamine.
  • organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, choline hydroxide, hydroxyethyl morpholine, hydroxyethyl pyrrolidone, imidazole, n-methyl-d-glucamine, ⁇ , ⁇ '- dibenzylethylenediamine, N,A ⁇ -diethylethanolamine, N,A ⁇ -dimethylethanolamine, triethanolamine, and tromethamine.
  • Basic amino acids e.g. , 1-glycine and 1-arginine
  • amino acids which may be zwitterionic at neutral pH e.g. , betaine (N,N,N-trimethylglycine) are also contemplated.
  • tautomer refers to a particular isomer of a compound in which a hydrogen and double bond have changed position with respect to the other atoms of the molecule. For a pair of tautomers to exist there must be a mechanism for interconversion. Examples of tautomers include keto-enol forms, imine-enamine forms, amide-imino alcohol forms, amidine-aminidine forms, nitroso-oxime forms, thio ketone-enethiol forms, N-nitroso- hydroxyazo forms, nitro-acz-nitro forms, lactam-lactim forms, ketene-ynol forms, enamine- enamine forms, and pyridione-hydroxypyridine forms.
  • polymorphs refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
  • solvate refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding.
  • Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like.
  • the compounds of the invention may be prepared, e.g. , in crystalline form, and may be solvated.
  • Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid.
  • “Solvate” encompasses both solution-phase and isolable solvates.
  • Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is associated with water.
  • a hydrate of a compound may be represented, for example, by the general formula R xH 2 0, wherein R is the compound and wherein x is a number greater than 0.
  • a given compound may form more than one type of hydrates, including, e.g. , monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g. , hemihydrates (R 0.5H 2 O)), and polyhydrates (x is a number greater than 1, e.g. , dihydrates (R-2H 2 0) and hexahydrates (R-6H 2 0)).
  • the term "subject" refers to any animal.
  • the subject is a mammal.
  • the subject is a human (e.g., a man, a woman, or a child).
  • the human may be of either sex and may be at any stage of development.
  • the subject has been diagnosed with the condition or disease to be treated.
  • the subject is at risk of developing the condition or disease.
  • the subject is an experimental animal (e.g. , mouse, rat, rabbit, dog, pig, or primate).
  • the experimental animal may be genetically engineered.
  • the subject is a domesticated animal (e.g. , dog, cat, bird, horse, cow, goat, sheep).
  • administer refers to implanting, absorbing, ingesting, injecting, or inhaling an inventive compound, or a pharmaceutical composition thereof.
  • treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a "pathological condition” (e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
  • pathological condition e.g. , a disease, disorder, or condition, or one or more signs or symptoms thereof
  • treatment may be administered after one or more signs or symptoms have developed or have been observed.
  • treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • condition condition
  • disease and “disorder” are used interchangeably.
  • an "effective amount" of a compound of the present invention or a pharmaceutical composition thereof refers to an amount sufficient to elicit the desired biological response, i.e., treating the condition.
  • the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactically effective amount.
  • an effective amount is the amount of a compound described herein in a single dose.
  • an effective amount is the combined amounts of a compound described herein in multiple doses.
  • an effective amount is a cleaning-effective amount.
  • the "cleaning-effective" amount of the compound refers to an amount of the compound as described herein which is necessary to remove at least 10% of bacteria from a biofilm as determined by a reduction in numbers of bacteria within the biofilm when compared with a biofilm not exposed to the compound.
  • the effective amount is a prophylactically effective amount to prevent normal biofilm formation between normal cleaning times as determined by a statistically significant increase in the number of cells within a biofilm or upon a clean surface. Prevention of normal biofilm formation is determined by the ability to disperse a biofilm using surfactants and or detergents or other chemical treatments which will result in the removal of bacterial cells from a biofilm.
  • the treated biofilm must be shown to release 10% or more of its bacteria when compared with a similar biofilm that is not treated when both biofilms are exposed to surfactants and or detergents or other chemical treatments which will result in the removal of bacterial cells from a biofilm.
  • a "therapeutically effective amount" of a compound of the present invention or a pharmaceutical composition thereof is an amount sufficient to provide a therapeutic benefit in the treatment of a condition, e.g., iron overload, or to delay or minimize one or more symptoms associated with the condition.
  • a therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition.
  • the term "therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.
  • a therapeutically effective amount is an amount sufficient for chelating a metal described herein.
  • a therapeutically effective amount is an amount sufficient for treating a pathological condition described herein. In certain embodiments, a therapeutically effective amount is an amount sufficient for chelating a metal described herein and for treating a pathological condition described herein.
  • a prophylactically effective amount of a compound of the present invention is an amount sufficient to prevent a condition, e.g. , iron overload, or one or more symptoms associated with the condition or prevent its recurrence.
  • a prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
  • a prophylactically effective amount is an amount sufficient for chelating a metal described herein.
  • a prophylactically effective amount is an amount sufficient for preventing a pathological condition described herein. In certain embodiments, a prophylactically effective amount is an amount sufficient for chelating a metal described herein and for preventing a pathological condition described herein.
  • tissue sample refers to any sample including tissue samples
  • tissue samples such as tissue sections and needle biopsies of a tissue
  • cell samples e.g. , cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise).
  • biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g. , obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
  • “Chelation,” “chelating,” “sequestration,” or “sequestering” is the formation or presence of two or more separate coordinate bonds between a polydentate (multiple- bonded) compound and a single central atom.
  • the polydentate compound is typically an organic compound and referred to as a "chelator,” “chelant,” “chelating agent,”
  • the central atom is usually a metal atom or metal ion (e.g., a metal atom or metal ion described herein, such as iron (e.g., Fe(II)), Zn(II), and Cu (II), etc.).
  • the chelator may form a stable complex with the central atom through coordinate bonds, inactivating the central atom so that the central atom is less likely to react with other molecules or atoms.
  • antimicrobial refers to a compound or composition having a destructive killing action upon microbes or microorganisms.
  • microorganism refer to very minute, microscopic life forms or organisms, which may be either plant or animal, and which may include, but are not limited to, algae, bacteria, fungi, protozoae, and parasites.
  • biofilm formation refers to the attachment of microorganisms to surfaces and the subsequent development of multiple layers of cells.
  • the biofilm is bacterial biofilm.
  • fungicide refers to a compound or composition having either a fungicidal or fungistatic effect upon fungi contacted by the compound or comosition.
  • Figure 1 shows exemplary quinoline compounds useful in the present invention.
  • Figures 2 A to 2B show ( Figure 2A) Friedlander quinoline synthesis used to synthesize quinolines 8-11; and ( Figure 2B) structures of exemplified potentiating agents.
  • Figures 3A to 3D show ( Figure 3A) antibacterial potentiation of quinolin compounds 1, 21 and 22 with GA against S. aureus 29213; ( Figure 3B) biofilm eradication potentiation of quinoline compound 1 with Gallic Acid against MRSA-2; ( Figure 3C) Metal(II) cation potentiation with 5 against S. aureus 29213; and ( Figure 3D) kill curves for quinoline compound 1 and GA as single agents and in combination against S. aureus 29213.
  • Figure 4 shows a potentiation of antibacterial activity assay (determined by
  • Figure 5 shows kill kinetics for quinoline 1 against S. aureus 29213 to make final concentrations of 2x, 4x, and 16x MIC for quinoline 1.
  • Figure 6 shows kill kinetics for halogenated quinoline 1 against S. aureus
  • Figure 7 shows cytotoxicity results of exemplary quinoline compounds
  • S.I. selectivity index; IC50/MIC values to show antibacterial selectivity.
  • Figure 9 shows exemplary quinoline potentiation with gallic acid (GA) against methicillin-resistant S. aureus clinical isolates.
  • Figure 11 shows metal(II) cation (100 ⁇ ) potentiation studies with quinolines against Staphylococcus aureus ATCC 29213.
  • * partial reduction in turbidity at highest test concentrations.
  • Figure 12 shows gallic acid potentiation of antibacterial activity against S. aureus ATCC 29213.
  • Figure 13 shows additional gallic acid potentiation of antibacterial activity against S. aureus ATCC 29213.
  • Figure 14 shows caffeic acid potentiation of antibacterial activity against S. aureus ATCC 29213.
  • Figure 15 shows tiron potentiation of antibacterial activity against S. aureus
  • Figure 16 shows gallic acid potentiation of antibacterial activity against
  • Figure 17 shows gallic acid potentiation of antibacterial activity against
  • Figure 18 shows gallic acid potentiation of antibacterial activity against S. aureus BAA-1707 and gallic acid potentiation of antibacterial activity against SA-156 (MRS A).
  • Figure 19 shows gallic acid potentiation of antibacterial activity against S. epidermidis ATCC 12228 and gallic acid potentiation of antibacterial activity against S. epidermidis MRSE-1.
  • Figure 20 shows gallic acid potentiation of antibacterial activity against
  • Figure 21 shows gallic acid potentiation of antibacterial activity against
  • PAOl Pseudomonas aeruginosa
  • Figure 22 shows ZnCl 2 -mediated potentiation of antibacterial activity against
  • Figure 23 shows (NH 4 )Fe(S0 4 ) 2 -mediated potentiation of antibacterial activity against S. aureus ATCC 29213.
  • Figure 24 shows CuS0 4 -mediated potentiation of antibacterial activity against
  • Figure 25A shows evaluation of exemplary quinoline compounds in MRSA-2 biofilm dispersion assay
  • Figure 25B shows evaluation of exemplary quinoline compounds in S. epidermidis biofilm dispersion assay
  • Figure 25C shows dose-response curve for compound A2 against MRSA-2 biofilm.
  • Infectious diseases are caused by microbes such as bacteria, fungi, and parasites. These pathogenic micobes typically require one or more metals (e.g., iron, calcium, magnesium, strontium, potassium, sodium, chromium, copper, manganese, molybdenum, zinc, and tungsten) to sustain life.
  • metals e.g., iron, calcium, magnesium, strontium, potassium, sodium, chromium, copper, manganese, molybdenum, zinc, and tungsten
  • inventive pharmaceutical compositions comprising a quinoline compound, a potentiating agent, and optionally a pharmaceutically acceptable excipient, can be used in the treatment and/or prevention infectious diseases.
  • compositions may act as metal chelators to interrupt the bacterial growth. Further provided herein are methods of using the provided pharmaceutical compositions to prevent or treat infectious disease. Also provided herein are methods of using the provided pharmaceutical compositions to prevent or eradicate biofilms. Compositions and Kits
  • the invention also provides a composition comprising a quinoline and a potentiating agent.
  • the invention provides a pharmaceutical composition comprising a quinoline, a potentiating agent, and optionally a pharmaceutically acceptable excipient.
  • the quinoline is a
  • halogenated quinoline i.e. comprising at least one halogen substituent.
  • the quinoline comprises at least one N0 2 substituent.
  • the quinoline is a halogenated quinoline comprising at least one N0 2 substitutent.
  • the quinoline is a compound of any one of Formulae (I)-(V) as described herein, or a pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or polymorph thereof.
  • compositions comprising a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a compound of Formula (C-I), or a pharmaceutically acceptable salt thereof).
  • the potentiating agent acts to promote the antibacterial "potentiation" of the quinoline.
  • the potentiating agent may lower minimum inhibitory concentration (MIC) value of the quinoline and provide increased antibacterial activity in the combination therapy.
  • the potentiating agent is a phytochemical.
  • phytochemicals refer to chemical compounds that occur naturally in plants.
  • exemplary phytochemicals include, but are not limited to, alkaloids (e.g. caffeine, theobromine, or theophylline), anthocyanins (e.g. cyanidin or malvidin), carotenoids (e.g. beta-carotene, lutein, or lycopene), coumestans, flavan-3-ols, flavonoids (e.g.
  • hydroxytyrosol monoterpenes (e.g. geraniol, limonene, organosulfides, allicin, glutathione, indole-3-carbinol, isothiocyanates, or sulforaphane), damnacanthal, digoxin, phytic acid, phenolic acids (e.g. capsaicin, ellagic acid, gallic acid, rosmarinic acid, tannic acid), phytosterols, beta-sitosterol, saponins, stylbenes (e.g. pterostilbene, resveratrol),
  • monoterpenes e.g. geraniol, limonene, organosulfides, allicin, glutathione, indole-3-carbinol, isothiocyanates, or sulforaphane
  • damnacanthal digoxin
  • phytic acid phenolic acids (e.g. capsa
  • triterpenoids triterpenoids, ursolic acid, xanthophylls, astaxanthin, and beta-cryptoxanthin.
  • the potentiating agent comprises a catechol moiety.
  • a catechol moiety refers to an optionally substituted, 1,2-dihydroxybenzyl moiety of the formula: . it is understood that the catechol moiety also encompass derivatives of 1,2-dihydroxybenzyl.
  • the derivatives of 1,2-dihydroxybenzyl can include additional substituents on the phenyl ring and/or protecting groups on one or two of the hydroxyl groups.
  • R A , R B , and R C" are as defined herein.
  • the potentiating agent is gallic acid, caffeic acid, or tiron. In certain embodiments, the potentiating agent is gallic acid.
  • the potentiating agent is present at about 1/100 of its
  • the potentiating agent is present at about 1/60 of its MIC. In certain embodiments, the potentiating agent is at about 1/30 of its MIC. In certain
  • the potentiating agent is at about 1/20 of its MIC. In certain embodiments, the potentiating agent is at about 1/10 of its MIC. In certain embodiments, the potentiating agent is at about 1/8 of its MIC. In certain embodiments, the potentiating agent is at about 1/7 of its MIC. In certain embodiments, the potentiating agent is at about 1/6 of its MIC. In certain embodiments, the potentiating agent is at about 1/5 of its MIC. In certain embodiments, the potentiating agent is at about 1/4 of its MIC. In certain embodiments, the potentiating agent is at about 1/3 of its MIC. In certain embodiments, the potentiating agent is at about 1/2 of its MIC. In certain embodiments, the potentiating agent is at about 1/1 of its MIC.
  • the molar ratio of the quinoline to the potentiating agent is about 10 10 : 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 : 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 6 : 1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 5 :1 to about 1: 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10 4 : 1 to about 1: 1.
  • the molar ratio of the quinoline to the potentiating agent is about 10 : 1 to about 1 : 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 100: 1 to about 1 : 1. In certain embodiments, the molar ratio of the quinoline to the potentiating agent is about 10: 1 to about 1 : 1.
  • the quinoline is provided in an effective amount in the composition.
  • the combination of quinoline and the potentiating agent is provided in an effective amount in the composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactic ally effective amount.
  • the effective amount is a clean-effective amount.
  • the effective amount is to prevent biofilm formation.
  • the effective amount is to eradicate or remove biofilm formed.
  • the provided composition further comprises a surfactant.
  • the surfactant is selected from the group consisting of anionic, nonionic, amphoteric, biological surfactants, and mixtures thereof.
  • the provided composition further comprises one or more disinfecting agents.
  • Disinfecting agents can comprise alcohols (such as ethanol or isopropanol), aldehydes (such as glutaraldehyde), oxidizing agents (such as sodium hypochlorite, calcium hypochlorite, chloramine, hydrogen peroxide, iodine, peracetic acid, performic acid, potassium
  • a disinfectant can be a spray or a liquid.
  • a disinfectant can be concentrated or ready-to-use.
  • a disinfectant can be for commercial or household use.
  • a composition of the invention can also be incorporated into household disinfectants, laundry detergent, and household cleaning solutions.
  • the provided compositions can be useful for decontaminating, inhibiting growth, or preventing growth on surfaces where microorganisms form a biofilm (e.g. tubing). Therefore, in some embodiments, a method of the invention includes rinsing or decontaminating a surface by contacting the surface with a composition of the invention. Further, in some embodiments, a method of the invention includes inhibiting biofilm growth or preventing biofilm growth by incorporating, coating, impregnating, flusing, or rinsing an object with the provided composition. In some embodiments, a composition of the invention can be incorporated into a surface by coating or impregnating the surface of an object. [00127] In certain embodiments, the uinoline is of Formula (I):
  • each instance of R A is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to oxygen, or a sulfur protecting group when attached to sulfur;
  • each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a nitrogen protecting group, or two R groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; each instance of R is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
  • R 6 is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group.
  • R 1 is hydrogen. In certain embodiments, R 1 is halogen. In certain embodiments, R 1 is F. In certain embodiments, R 1 is CI. In certain embodiments, R 1 is Br. In certain embodiments, R 1 is I. In certain embodiments, R 1 is N0 2 . In certain embodiments, R 1 is optionally substituted alkyl. In certain embodiments, R 1 is optionally substituted Ci_ 6 alkyl. In certain embodiments, R 1 is unsubstituted C 1-6 alkyl. In certain embodiments, R 1 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 1 is substituted C 1-6 alkyl. In certain embodiments, R 1 is optionally substituted carbocyclyl. In certain embodiments, R 1 is optionally substituted cyclohexyl. In certain embodiments, R 1 is optionally substituted aryl. In certain
  • R 2 is hydrogen. In certain embodiments, R 2 is halogen. In certain embodiments, R 2 is F. In certain embodiments, R 2 is CI. In certain embodiments, R 2 is Br. In certain embodiments, R 2 is I. In certain embodiments, R 2 is N0 2 . In certain embodiments, R 2 is optionally substituted alkyl. In certain embodiments, R is optionally substituted C 1-6 alkyl. In certain embodiments,
  • R 2 is unsubstituted C 1-6 alkyl. In certain embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 2 is substituted Ci_ 6 alkyl. In certain embodiments, R 2 is optionally substituted carbocyclyl. In certain embodiments, R is optionally substituted cyclohexyl. In certain embodiments, R is optionally substituted aryl. In certain
  • R 2 is optionally substituted phenyl. In certain embodiments, R 2 is optionally substituted heterocyclyl. In certain embodiments, R is optionally substituted heteroaryl. In certain embodiments, R 2 is optionally substituted furanyl. In certain embodiments, R 2 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R 2 is -OR A , wherein R A is as defined herein. In certain embodiments, R is -OH.
  • R is of the Formula (i)
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR A , or -N(R B ) 2 ,
  • R A is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group;
  • each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
  • R is optionally substituted C 1-6 alkyl.
  • R 8 is unsubstituted Ci_ 6 alkyl.
  • R 8 is methyl or ethyl.
  • R 8 is optionally substituted phenyl.
  • R 8 is unsubstituted phenyl.
  • R 3 is hydrogen. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is F. In certain embodiments, R 3 is CI. In certain embodiments, R 3 is Br. In certain embodiments, R 3 is I. In certain embodiments, R 3 is N0 2 . In certain embodiments, R 3 is optionally substituted alkyl. In certain embodiments, R 1 is optionally substituted C 1-6 alkyl. In certain embodiments,
  • R 3 is unsubstituted Ci_ 6 alkyl. In certain embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 3 is substituted Ci_ 6 alkyl. In certain embodiments, R 3 is optionally substituted carbocyclyl. In certain embodiments, R is optionally substituted cyclohexyl. In certain embodiments, R is optionally substituted aryl. In certain
  • R 3 is optionally substituted phenyl. In certain embodiments, R 3 is optionally substituted heterocyclyl. In certain embodiments, R is optionally substituted heteroaryl. In certain embodiments, R 3 is optionally substituted furanyl. In certain embodiments, R 3 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R 3 is -OR A , wherein R A is as defined herein. In certain embodiments, R 3 is -OH. In certain embodiments, R 3 is -
  • R C is as defined herein.
  • R C is optionally substituted alkyl or optionally substituted phenyl.
  • R 4 is hydrogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 4 is F. In certain embodiments, R 4 is CI. In certain embodiments, R 4 is Br. In certain embodiments, R 4 is I. In certain embodiments, R 4 is N0 2 . In certain embodiments, R 4 is optionally substituted alkyl. In certain embodiments, R 1 is optionally substituted C 1-6 alkyl. In certain embodiments, R 4 is unsubstituted Ci_ 6 alkyl. In certain embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 4 is substituted Ci_ 6 alkyl. In certain embodiments, R 4 is optionally substituted carbocyclyl. In certain embodiments, R 4 is optionally substituted cyclohexyl. In certain embodiments, R 4 is optionally substituted aryl. In certain
  • R 4 is optionally substituted phenyl. In certain embodiments, R 4 is optionally substituted heterocyclyl. In certain embodiments, R 4 is optionally substituted heteroaryl. In certain embodiments, R 4 is optionally substituted furanyl. In certain embodiments, R 4 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R 4 is -OR A , wherein R A is as defined herein. In certain embodiments, R 4 is -OH. In certain embodiments, R 4 is -
  • R C is as defined herein.
  • R C is optionally substituted alkyl or optionally substituted phenyl.
  • R 5 is hydrogen. In certain embodiments, R 5 is halogen. In certain embodiments, R 5 is F. In certain embodiments, R 5 is CI. In certain embodiments, R 5 is Br. In certain embodiments, R 5 is I. In certain embodiments, R 5 is N0 2 . In certain embodiments, R 5 is optionally substituted alkyl. In certain embodiments, R 5 is optionally substituted C 1-6 alkyl. In certain embodiments, R 5 is unsubstituted C 1-6 alkyl. In certain embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments, R 5 is substituted Ci_ 6 alkyl. In certain embodiments, R 5 is optionally substituted carbocyclyl. In certain embodiments, R 5 is optionally substituted cyclohexyl. In certain embodiments, R 5 is optionally substituted aryl. In certain embodiments,
  • R 5 is optionally substituted phenyl. In certain embodiments, R 5 is optionally substituted heterocyclyl. In certain embodiments, R 5 is optionally substituted heteroaryl. In certain embodiments, R 5 is optionally substituted furanyl. In certain embodiments, R 5 is optionally substituted 2-furanyl or 3-furanyl. In certain embodiments, R 5 is -OR A , wherein R A is as defined herein. In certain embodiments, R 5 is -OH. In certain embodiments, R 5 is -
  • R C is as defined herein.
  • R C is optionally substituted alkyl or optionally substituted phenyl.
  • At least one of R 4 and R 5 is halogen. In certain embodiments, one of R 4 and R 5 is halogen. In certain embodiments, R 4 is halogen. In certain embodiments, R 5 is halogen. In certain embodiments, both R 4 and R 5 are halogen. In certain embodiments, at least one of R 1 , R2 , and R 3 is not hydrogen. In certain embodiments, one of
  • R 1 , R2 , and R 3 is not hydrogen. In certain embodiments, two of R 1 , R2 , and R 3 are not hydrogen. In certain embodiments, all R 1 , R2 , and R 3 are not hydrogen.
  • R 6 is hydrogen. In certain embodiments, R 6 is of the
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R is optionally substituted alkyl.
  • R 7 is optionally substituted Ci_ 6 alkyl.
  • R 7 is unsubstituted C 1-6 alkyl.
  • R is methyl, ethyl, n-propyl, or isopropyl.
  • R 7 is substituted C 1-6 alkyl. In certain embodiments, R 7 is optionally substituted carbocyclyl-alkyl. In certain embodiments, R is optionally substituted cyclopentyl-alkyl. In certain embodiments, R is optionally substituted cyclopentyl-(CH 2 )i_5- In certain embodiments, R is unsubstituted cyclopentyl-(CH 2 )i_5-. In certain embodiments,
  • R 7 is optionally substituted aryl. In certain embodiments, R 7 is optionally substituted phenyl.
  • R 7 is mono-substituted phenyl. In certain embodiments, R 7 is optionally substituted heteroaryl. In certain embodiments, R is optionally substituted monocyclic heteroaryl. In certain embodiments, R is optionally substituted 5-membered heteroaryl. In certain embodiments, R is optionally substituted furanyl. In certain embodiments, R is optionally substituted 2-furanyl or 3-furanyl.
  • the quinoline is of Formula (II):
  • the quinoline is of Formula (III):
  • the quinoline is of Formula (IV):
  • the quinoline is of Formula (V):
  • the quinoline is of any one of the compounds in Table
  • the quinoline is of any one of the compounds in Table
  • compositions or pharmaceutical compositions further comprise an additional therapeutically active agent.
  • additional therapeutically active agents include, but are not limited to, antibacterial agents (e.g. antibiotics), antiviral agents, fungicides, protozoacides, parasiticides, anesthetics, steroidal or non-steroidal anti-inflammatory agents, antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, pain-relieving agents, analgesics, anti-pyretics, hormones, prostaglandins, etc.
  • Therapeutically active agents include small organic molecules such as drug compounds (e.g. , compounds approved by the U.S. Food and Drug
  • the additional therapeutically active agent is an antimicrobial agent.
  • the additional therapeutically active agent is an antibacterial agent.
  • the antimicrobial agent is selected from the group consisting of biocides, fungicides, antibiotics, and mixtures thereof.
  • the antimicrobial agent is an antibiotic.
  • Exemplary antibacterial agents for uses in combination with a quinoline as described herein include, but are not limited to, (-)-Florfenicol, Acetylsulfisoxazole,
  • Cephalosporins e.g., 7- Aminocephalosporanic acid, 7-Aminodeacetoxycephalosporanic acid, Cefaclor, Cefadroxil, Cefamandole, Cefazolin, Cefepime, Cefixime, Cefmenoxime, Cefmetazole, Cefoperazone, Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefpirome, Cefpodoxime proxetil, Cefsulodin, Cefsulodin sodium, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefuroxime, Cephalexin, Cephaloridine, Cephalosporin C, Cephalothin, Cephalothin sodium, Cephapirin, Cephradine), Cetrimide Chelerythrine, Chlorhexidine, Cephalosporin C, Cephalothin, Cephalothin sodium, Cephapirin
  • Clarithromycin Clavulanic acid (e.g., Amoxicillin-clavulanic acid), Clindamycin, Co- Trimoxazole, Dichlorophene, Didecyldimethylammonium chloride, Dihydrostreptomycin, Enoxacin, Ethambutol, Fleroxacin, Furazolidone, Grepafloxacin hydrochloride,
  • the additional therapeutically active agent is a fungicide.
  • fungicides for uses in combination with a quinoline as described herein include, but are not limited to, (-)-Fumagillin, (-)-Metalaxyl, 1,2, 5-Fluorocytosine, Acrisorcin, Anilazine, Antifouling agents, Azoxystrobin, Benomyl, Bordeaux mixture, Captan, Carbendazim, Caspofungin acetate, Chlorothalonil, Clotrimazole, Dichlofluanid, Dinocap, Dodine, Fenhexamid, Fenpropimorph, Ferbam, Fluconazole, Fosetyl Al,
  • Griseofulvin Guanidines (e.g. Agmatine, Amiloride hydrochloride, Biguanides (e.g.
  • the additional therapeutically active agent is a protozoacide.
  • exemplary protozoacides for uses in combination with a quinoline as described herein include, but are not limited to, Amebicides, Antimalarials (e.g. Artemisinin,
  • Chloroquine e.g. Chloroquine phosphate
  • Mefloquine Mefloquine
  • Sulfadoxine Coccidiostats
  • Leishmanicides Trichomonacides
  • Trypanosomicides e.g. Eflornithine
  • the additional therapeutically active agent is an antibiotic.
  • antibiotics for uses in combination with a quinoline as described herein include, but are not limited to, Abamectin, Actinomycin (e.g. , Actinomycin A, Actinomycin C, Actinomycin D, Aurantin), Adriamycin, Alatrofloxacin mesylate, Amikacin sulfate, Aminosalicylic acid, Anthracyclines (e.g. , Aclarubicin, Adriamycin, Doxorubicin, Epirubicin, Idarubicin), Antimycin (e.g.
  • Cephalosporins e.g. , 7-Aminocephalosporanic acid, 7- Aminodeacetoxycephalosporanic acid, Cefaclor, Cefadroxil, Cefamandole, Cefazolin, Cefepime, Cefixime, Cefmenoxime, Cefmetazole, Cefoperazone, Cefotaxime, Cefotetan, Cefotiam, Cefoxitin, Cefpirome, Cefpodoxime proxetil, Cefsulodin, Cefsulodin sodium, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefuroxime, Cephalexin, Cephaloridine,
  • Cephalosporin C Cephalothin, Cephalothin sodium, Cephapirin, Cephradine
  • Ciprofloxacin Enrofloxacin
  • Clindamycin Colicin
  • Cyclosporin e.g. Cyclosporin A
  • Dalfopristin/quinupristin Daunorubicin
  • Neomycin sulfate e.g. 6-Aminopenicillanic acid, Amoxicillin (e.g. Amoxicillin- clavulanic acid), Ampicillin, Ampicillin sodium, Azlocillin, Carbenicillin, Cefoxitin, Cephaloridine, Cloxacillin, Dicloxacillin, Mecillinam, Methicillin, Mezlocillin, Nafcillin, Oxacillin, Penicillin G, Penicillin G potassium, Penicillin G procaine, Penicillin G sodium, Penicillin V, Piperacillin, Piperacillin-tazobactam, Sulbactam, Tazobactam, Ticarcillin), Phleomycin, Polymyxin (e.g., Colistin, Polymyxin B), Pyocin (e.g. Pyocin R), RPX 7009, Rapamycin, Ristocetin, Salinomycin, Sparfloxacin, Penicillin (e.g. 6-Aminopenicillanic acid,
  • Tetracyclines e.g. Achromycin V, Demeclocycline, Doxycycline, Doxycycline
  • compositions described herein can be prepared by any method known in the art of pharmacology.
  • preparatory methods include the steps of bringing the compound of the present invention (the "active ingredient") into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)
  • crospovidone sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers
  • colloidal clays e.g. , bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)
  • long chain amino acid derivatives e.g.
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. , carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
  • carrageenan cellulosic derivatives (e.g. , carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. , polyoxyethylene sorbitan monolaurate (Tween 20),
  • polyoxyethylene sorbitan Teween 60
  • polyoxyethylene sorbitan monooleate Teween 80
  • sorbitan monopalmitate Span 40
  • sorbitan monostearate Span 60
  • sorbitan tristearate Span 65
  • polyoxyethylene esters e.g. , polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol
  • sucrose fatty acid esters polyethylene glycol fatty acid esters (e.g. , CremophorTM), polyoxyethylene ethers, (e.g.
  • polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamerl88, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • Exemplary binding agents include starch (e.g. , cornstarch and starch paste), gelatin, sugars (e.g. , sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. , acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g. , citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g. , sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g. ,
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic sa
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include
  • liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g.
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer' s solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or di-glycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • 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 medium prior to use.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quatern
  • the dosage form may comprise buffering agents.
  • wetting agents such as, for example, cetyl alcohol and glycerol monostearate
  • absorbents such as kaolin and bentonite clay
  • lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.
  • the dosage form may comprise buffering agents.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.
  • the active ingredient can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g. , tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical are Suitable devices for use in delivering intradermal pharmaceutical
  • compositions described herein include short needle devices.
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin.
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.
  • Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical
  • compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation .
  • therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • compositions provided herein can be administered by any route, including enteral (e.g. , oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • enteral e.g. , oral
  • parenteral intravenous
  • intramuscular intra-arterial
  • intramedullary intrathecal
  • subcutaneous intraventricular
  • transdermal transdermal
  • interdermal interdermal
  • rectal intravaginal
  • topical as by powders, ointments, creams, and/or drops
  • mucosal
  • inventive pharmaceutical compositions may also be mixed with blood ex vivo, and the resulting mixture may be administered (e.g. , intravenously) to a subject.
  • administration e.g. , intravenously
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g. , its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g. , whether the subject is able to tolerate oral administration).
  • any two doses of the multiple doses include different or substantially the same amounts of a compound described herein.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day.
  • the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day.
  • the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell.
  • the duration between the first dose and last dose of the multiple doses is three months, six months, or one year.
  • the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.
  • a dose (e.g. , a single dose, or any dose of multiple doses) described herein includes independently between 0.1 ⁇ g and 1 ⁇ g, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of the quinoline and potentiating agent described herein.
  • a dose described herein includes independently between 1 mg and 3 mg, inclusive, of the quinoline and potentiating agent described herein.
  • a dose described herein includes independently between 3 mg and 10 mg, inclusive, of the quinoline and potentiating agent described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of the quinoline and potentiating agent described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of the quinoline and potentiating agent described herein.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a dose described herein is a dose for an adult human whose body weight is approximately 70 kg.
  • the pharmaceutical composition as described herein, can be administered in combination with one or more additional therapeutically active agents.
  • the pharmaceutical compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the pharmaceutical composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • the one or more additional therapeutically active agents are different from the compounds and compositions described herein.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • it is expected that additional therapeutically active agents in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • Exemplary additional therapeutically active agents include, but are not limited to, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressant agents, and a pain-relieving agent. Exemplary additional therapeutically active agents also include, but are not limited to, cytotoxic agents. Therapeutically active agents include small organic molecules such as drug compounds (e.g. , compounds approved by the U.S.
  • CFR Code of Federal Regulations
  • proteins proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.
  • CFR Code of Federal Regulations
  • the present invention provides a kit for treating or preventing an infectious disease in a subject, wherein the kit comprising: a container comprising the pharmaceutical composition as described herein; and instructions for administering the pharmaceutical composition to the subject.
  • the present invention provides a kit for preventing biofilm formation in a subject, wherein the kit comprising a container comprising the pharmaceutical composition as described herein; and instructions for administering the pharmaceutical composition to the subject.
  • the present invention provides a kit for treating biofilm formation on an object, wherein the kit comprising a container comprising the pharmaceutical composition as described herein; and instructions for applying the pharmaceutical
  • composition to the object composition to the object.
  • the present invention provides a kit for eradicating a biofilm, wherein the kit comprising a container comprising the pharmaceutical composition as described herein; and instructions for applying the pharmaceutical composition to the object.
  • the present invention provides a kit comprising: a container comprising a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof; and instructions for using the compound or pharmaceutical composition.
  • the kit is for treating or preventing an infectious disease in a subject.
  • the kit is for preventing biofilm formation in a subject.
  • the kit is for preventing biofilm formation on an object.
  • the kit is for reducing or eradicating biofilm in a subject.
  • the kit is for reducing or eradicating biofilm on an object.
  • the instructions are for administrating the compound or pharmaceutical composition in a subject.
  • the instructions are for applying the compound or pharmaceutical composition to an object.
  • kits provided may comprise a device, e.g., a vial, ampule, bottle, syringe, and/or dispenser, for administering or applying the pharmaceutical composition as described herein.
  • a device e.g., a vial, ampule, bottle, syringe, and/or dispenser, for administering or applying the pharmaceutical composition as described herein.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a
  • the pharmaceutical composition described herein provided in the first container and the second container are combined to form one unit dosage form.
  • Infectious diseases are typically caused by microbial pathogens (e.g., viruses, viroids, prions, microorganisms such as bacteria, nematodes such as roundworms and pinworms, arthropods such as ticks, mites, fleas, and lice, fungi such as ringworm, and parasites such as protozoa, multicellular parasites, or tapeworms) into the cells ("host cells") of a subject ("host").
  • the infectious disease is a bacterial infection.
  • the infectious disease is a mycobacterial infection.
  • the infectious disease is a viral infection.
  • the infectious disease is a parasitic infection.
  • the infectious disease is a multicellular-parasitic infection.
  • the infectious disease is a fungal infection.
  • the infectious disease is a protozoan infection.
  • inventive methods for preventing and/or treating an infectious disease comprise administering to a subject in need thereof a pharmaceutical composition comprising a quinoline, a potentiating agent, and optionally a pharmaceutically acceptable excipient.
  • the present invention provides methods for preventing an infectious disease comprising administering to a subject in need thereof a compound of Formula (C-I), or or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • the present invention provides methods for treating an infectious disease comprising administering to a subject in need thereof a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • the infectious disease is responsive to the chelation or sequestration of a metal.
  • the metal is a monovalent, divalent, tetravalent, pentavalent, or hexavalent metal.
  • the metal is a monovalent metal.
  • the metal is a divalent metal.
  • the metal is a trivalent metal.
  • the metal is aluminum, thallium, chromium, magnesium, calcium, strontium, nickel, manganese, cobalt, copper, zinc, silver, sodium, potassium, cadmium, mercury, lead, antimony, molybdenum, tungsten, a lanthanide (e.g.
  • the metal is iron (e.g. , Fe(II)). In certain embodiments, the metal is zinc (e.g. , Zn (II)). In certain embodiments, the metal is copper (e.g. Cu (II)).
  • the infectious disease being treated and/or prevented is a bacterial infection.
  • the bacterial infection being treated and/or prevented is a chronic bacterial infection.
  • a "chronic bacterial infection” is a bacterial infection that is of a long duration or frequent recurrence.
  • a chronic middle ear infection, or otitis media can occur when the Eustachian tube becomes blocked repeatedly due to allergies, multiple infections, ear trauma, or swelling of the adenoids.
  • the definition of "long duration" will depend upon the particular infection. For example, in the case of a chronic middle ear infection, it may last for weeks to months.
  • Exemplary chronic bacterial infections include, but are not limited to, urinary tract infection (most commonly caused by Escherichia coli and/or Staphylococcus saprophyticus), gastritis (most commonly caused by Helicobacter pylori), respiratory infection (such as those commonly afflicting patents with cystic fibrosis, most commonly caused by Pseudomonas aeuroginosa), cystitis (most commonly caused by Escherichia coli), pyelonephritis (most commonly caused by Proteus species, Escherichia coli and/or Pseudomonas sp), osteomyelitis (most commonly caused by Staphylococcus aureus, but also by Escherichia coli), bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones (can be caused by Proteus mirabilis), bacterial endocarditis, and sinus infection.
  • urinary tract infection most commonly caused by Escherichia
  • the bacterial infection is one or more infections selected from the group consisting of urinary tract infection, gastritis, respiratory infection, cystitis, pyelonephritis, osteomyelitis, bacteremia, skin infection, rosacea, acne, chronic wound infection, infectious kidney stones, bacterial endocarditis, and sinus infection.
  • the infectious diseases is pneumonia, urinary tract infection, complicated intra-abdominal infection, or complicated skin/skin structure infection.
  • the infectious diseases is nosocomial pneumonia, community- acquired pneumonia, urinary tract infection, complicated intra-abdominal infection, complicated skin/skin structure infection, infectious exacerbations of cystic fibrosis, sepsis, or melioidosis.
  • the bacterial infection is respiratory infection.
  • the bacterial infection is upper respiratory infection. In certain embodiments, the bacterial infection is pneumonia. In certain embodiments, the bacterial infection is bronchitis.
  • the bacterial infection is caused by a Gram positive bacteria.
  • Gram positive bacteria include, but are not limited to, Staphylococcus, Streptococcus, Micrococcus, Peptococcus, Peptostreptococcus, Enterococcus, Bacillus, Clostridium, Lactobacillus, Listeria, Erysipelothrix, Propionibacterium, Eubacterium, and Corynebacterium.
  • the Gram positive bacteria is a bacteria of the phylum Firmicutes.
  • the bacteria is a member of the phylum
  • Enterococci bacteria include, but are not limited to, E. avium, E.
  • the Enterococcus infection is an E. faecalis infection. In certain embodiments, the Enterococcus infection is an E. faecium infection. In certain embodiments, the bacteria is a member of the phylum Firmicutes and the genus
  • Staphylococcus i.e., the bacterial infection is a Staphylococcus infection.
  • Exemplary Staphylococci bacteria include, but are not limited to, S. arlettae, S. aureus, S. auricularis, S. capitis, S. caprae, S. carnous, S. chromogenes, S. cohii, S. condimenti, S. croceolyticus, S. delphini, S. devriesei, S. epidermis, S. equorum, S. felis, S. fluroettii, S. gallinarum, S.
  • the Staphylococcus infection is an S. aureus infection.
  • the Staphylococcus infection is an S. aureus infection.
  • Staphylococcus infection is an S. epidermis infection.
  • the bacterial infection is a Gram negative bacteria.
  • Exemplary Gram negative bacteria include, but are not limited to, Escherchia coli,
  • catarrhalis Citrobacter diversus, Enterobacter aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Salmonella typhimurium, Neisseria meningitidis, Serratia marcescens, Shigella sonnei, Neisseria gonorrhoeae, Acinetobacter baumannii, Salmonella enteriditis,
  • the Gram negative bacteria species is Pseudomonas. In certain embodiments, the Gram negative bacteria species is Pseudomonas aeruginosa. In certain embodiments, the Gram negative bacteria species is Acinetobacter baumannii.
  • the bacterial infection being treated and/or prevented is caused by an organism resistant to one or more antibiotics.
  • the bacterium is resistant to penicillin.
  • the bacterium is resistant to vancomycin (VR).
  • the bacterium is vancomycin- resistant E. faecalis.
  • bacterium is vancomycin-resistant E. faecium.
  • bacterium is vancomycin-resistant Staphylococcus aureus (VRSA).
  • bacterium is vancomycin-resistant Enterococci (VRE).
  • the bacterium is a methicillin-resistant (MR) strain.
  • the bacterium is methicillin-resistant S. aureus (MRSA).
  • the bacterium is methicillin-resistant Staphylococcus epidermidis (MRSE).
  • MRSE methicillin-resistant Staphylococcus epidermidis
  • the bacterium is penicillin-resistant Streptococcus pneumonia. In certain embodiments, the bacterium is quinolone-resistant Staphylococcus aureus (QRSA). In certain embodiments, the bacterium is multi-drug resistant Mycobacterium tuberculosis.
  • QRSA quinolone-resistant Staphylococcus aureus
  • the bacterium is susceptible to one or more antibiotics.
  • the gram-positive bacterium is susceptible to one or more antibiotics.
  • the gram- negative bacterium is susceptible to one or more antibiotics.
  • antibiotics include, but are not limited to beta-lactams, sulfonamides,
  • aminoglycosides aminoglycosides, tetracyclines, chloramphenicols, macrolides, glycopeptides,
  • the bacterium is susceptible to one or more antibiotics selected from the group consisting of beta-lactams, aminoglycosides, tetracyclines, and quinolones.
  • the gram-positive bacterium is susceptible to methicillin.
  • the gram-negative bacterium is susceptible to one or more antibiotics selected from the group consisting of tigecycline, amikacin, ampicillin, and sulbactam.
  • bacterial susceptibility also called bacterial sensitivity, refers to inhibition of a bacterial growth by an antimicrobial agent when the recommended dosage is used for the site of infection.
  • the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition as described herein.
  • the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • the present invention provides methods of inhibiting the formation of biofilms comprising administering to a subject in need thereof a
  • the biofilms are produced by one or more microorganisms selected from the group consisting of bacteria, archaea, protozoa, fungi and algae.
  • the biofilms are produced by bacteria.
  • the biofilms are produced by Gram-negative bacteria.
  • the biofilms are produced by microbial species such as S. epidermidis, E. faecalis, E. coli, P. mirabilis, P. aeruginosa, K. pneumoniae, S. aureus, S. viridans, K. oxytoca, S. saprophyticus, L. pneumophila,
  • biofilms are produced by Gram-positive bacteria.
  • a method for inhibiting bacterial cell growth comprising contacting bacteria with the pharmaceutical composition as described herein.
  • a method for inhibiting bacterial cell growth comprising contacting bacteria with a compound of Formula (C-I), or a
  • pharmaceutically acceptable salt solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a method for inducing bacterial hypersusceptibility comprising contacting a bacterium with the pharmaceutical composition as described herein.
  • a method for inducing bacterial hypersusceptibility comprising contacting a bacterium with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • Hypersusceptibility refers to a condition of abnormal susceptibility to poisons, infective agents, or agents that are entirely innocuous in the normal individual.
  • a method for preventing biofilm formation comprising contacting a subject with the pharmaceutical composition as described herein.
  • a method for preventing biofilm formation comprising contacting a subject with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • provided herein is a method for preventing biofilm formation comprising contacting an object with the pharmaceutical composition as described herein.
  • a method for preventing biofilm formation comprising contacting an object with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a method for eradicating biofilm comprising contacting the biofilm with the pharmaceutical composition as described herein.
  • a method for eradicating biofilm comprising contacting the biofilm with a compound of Formula (C-I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • a compound of Formula (C-I) or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, isotopically labeled derivative, or prodrug thereof (e.g., a pharmaceutically acceptable salt thereof), or a pharmaceutical composition thereof.
  • the bacterium/a is contacted with the pharmaceutical composition as described herein in vitro. In certain embodiments, the bacterium/a is contacted with the pharmaceutical composition as described herein in vivo. In certain embodiments, the bacterium is subsequently contacted with one or more biocides. In certain embodiments, the biocides are antimicrobials. In certain embodiments, the antimicrobials are antibiotics.
  • the compounds of Formulae (I)-(V) can be typically formulated in dosage unit form for ease of administration and uniformity of dosage.
  • the compounds of Formulae (C-I) can be typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily dosage of the compositions of the present invention will be decided by an attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient(s) employed; and like factors well known in the medical arts.
  • the compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents (e.g., antibiotics, anti-inflammatory agents).
  • additional therapeutically active agents e.g., antibiotics, anti-inflammatory agents
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • the subject administered the quinoline as provided herein or pharmaceutical composition is a mammal.
  • the subject is a human.
  • the subject is immunodeficient.
  • Immunodeficiency (or immune deficiency) is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent.
  • the subject is a patient diagnosed with cystic fibrosis.
  • the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat.
  • the subject is a companion animal such as a dog or cat.
  • the subject is a livestock animal such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is an experimental animal such as a rodent or non-human primate.
  • the present invention provides methods to treat or prevent biofilm formation comprising administering to a subject in need thereof a therapeutically effective amount of a compound capable of chelating a metal (e.g. , quninoline) or pharmaceutical composition thereof as described herein.
  • the provided method treats, cleans, or disinfects a wound by administering the compound or composition as described herein.
  • the wounds are chronic wounds, acute wounds, surgical wounds, surgical sites, second and third degree burns, stasis ulcers, tropic lesions, decubitus ulcers, severe cuts, or abrasions.
  • the present invention provides methods to treat or prevent biofilm formation comprising contacting an object with an effective amount of a compound capable of chelating a metal (e.g. , quinoline) or the composition as described herein.
  • the provided methods inhibit, reduce, or remove biofilms on an object.
  • the provided method is to inhibit or remove the biofilm on the surface of the object.
  • the surface is a hard, rigid surface.
  • the surface is selected from the group consisting of a drainpipe, glaze ceramic, porcelain, glass, metal, wood, chrome, plastic, vinyl, and formica.
  • the surface is a soft, flexible surface.
  • the surface is selected from the group consisting of shower curtains or liners, upholstery, laundry, and carpeting.
  • the surface is a food preparation surface, such as kitchen counters, cutting boards, sinks, stoves, refrigerator surfaces, or on sponges.
  • the surface is a bathroom surface such as toilets, sinks, bathtubs, showers, and drains.
  • the surface is a medical device surface.
  • the contacting of the compound or composition as described herein with the object is carried out by wiping, sponging, or soaking, or laundering means.
  • the provided method is used to prevent or eradicate biofilm as a dentifrice, a mouthwash, a compound for the treatment of dental caries, acne treatment, cleaning and disinfecting contact lenses, and medically implanted devices that are permanent such as an artificial heart valve or hip joint, and those that are not permanent such as indwelling catheters, pacemakers, surgical pins etc.
  • the provided method is used to prevent or remove biofilm in situations involving bacterial infection of a host, either human or animal, for example in a topical dressing for burn patients. An example of such a situation would be the infection by P. aeruginosa of superficial wounds such as are found in burn patients or in the lung of a cystic fibrosis patient.
  • the provided method can be used to control or prevent the development of biofilm in the process of manufacturing integrated circuits, circuit boards or other electronic or microelectronic devices.
  • the invention also provides quinoline compounds of
  • each of R , R , and R is independently hydrogen, halogen, optionally substituted Ci_6 alkyl, or optionally substituted acyl;
  • R is hydrogen, halogen, or -N0 2 ;
  • R 5E is hydrogen, halogen, or -N0 2 ;
  • R 6E is hydrogen, optionally substituted acyl, or an oxygen protecting group; and provided that R 4E is halogen or N0 2 .
  • R IE is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, or optionally substituted acyl. In certain embodiments, R IE hydrogen. In certain embodiments, R IE is halogen. In certain embodiments, R IE is F. In certain embodiments, R IE is CI. In certain embodiments, R IE is Br. In certain embodiments,
  • R IE is I. In certain embodiments, R IE is optionally substituted C 1-6 alkyl. In certain embodiments, R IE is unsubstituted C 1-6 alkyl. In certain embodiments, R IE is methyl, ethyl, i propyl, or isopropyl. In certain embodiments, R IE is substituted Ci_ 6 alkyl. In certain embodiments, R IE is optionally substituted acyl.
  • R 2E is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, or optionally substituted acyl. In certain embodiments, R 2E hydrogen. In certain embodiments, R 2E is halogen. In certain embodiments, R 2E is F. In certain embodiments, R 2E is CI. In certain embodiments, R 2E is Br. In certain embodiments,
  • R 2E is I. In certain embodiments, R 2E is optionally substituted C 1-6 alkyl. In certain embodiments, R 2E is unsubstituted C 1-6 alkyl. In certain embodiments, R 2E is methyl, ethyl, i propyl, or isopropyl. In certain embodiments, R 2E is substituted Ci_ 6 alkyl. In certain embodiments, R 2E is optionally substituted acyl.
  • R 2E is of the Formula (iii)
  • R is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR A , or -N(R B ) 2 ;
  • R A is hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or an oxygen protecting group; and each instance of R is independently hydrogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group.
  • R 8E is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -OR , or -N(R ) 2.
  • R is optionally substituted alkyl.
  • R 8E is optionally substituted C 1-6 alkyl.
  • R 8E is unsubstituted C 1-6 alkyl.
  • R 8E is methyl, ethyl, n- propyl, or isopropyl.
  • R 8E is optionally substituted carbocyclyl.
  • R 8E is optionally substituted cyclohexyl. In certain embodiments, R 8E is optionally substituted aryl. In certain embodiments, R 8E is optionally substituted phenyl. In certain embodiments, R 8E is optionally substituted heterocyclyl. In certain embodiments, R 8E is optionally substituted heteroaryl. In certain embodiments, R 8E is optionally substituted monocyclic heteroaryl. In certain embodiments, R 8E is optionally substituted 5-membered heteroaryl. In certain embodiments, R 8E is optionally substituted furanyl. In certain embodiments, R 8E is optionally substituted 2-furanyl or 3-furanyl.
  • R 3E is independently hydrogen, halogen, optionally substituted Ci_ 6 alkyl, or optionally substituted acyl. In certain embodiments, R 3E is hydrogen. In certain embodiments, R 3E is halogen. In certain embodiments, R 3E is F. In certain embodiments, R 3E is CI. In certain embodiments, R 3E is Br. In certain embodiments,
  • R 3E is I. In certain embodiments, R 3E is optionally substituted Ci_ 6 alkyl. In certain
  • R 3E is unsubstituted Ci_ 6 alkyl. In certain embodiments, R 3E is methyl, ethyl, n- propyl, or isopropyl. In certain embodiments, R 3E is substituted C 1-6 alkyl. In certain embodiments, R 3E is optionally substituted acyl.
  • R 4E is hydrogen, halogen, or -N0 2 . In certain embodiments, R 4E is hydrogen. In certain embodiments, R 4E is halogen. In certain
  • R 4E is F. In certain embodiments, R 4E is CI. In certain embodiments, R 4E is Br.
  • R 4E is I. In certain embodiments, R 4E is N0 2 .
  • R 5E is hydrogen, halogen, or -N0 2 . In certain embodiments, R 5E is hydrogen. In certain embodiments, R 5E is halogen. In certain
  • R 5E is F. In certain embodiments, R 5E is CI. In certain embodiments, R 5E is Br.
  • R 5E is I. In certain embodiments, R 5E is N0 2 .
  • R 6E is hydrogen, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, R 6E is hydrogen. In certain embodiments, R is optionally substituted acyl. In certain embodiments, R is an oxygen protecting group.
  • R 6E is Boc. In certain embodiments, R 6E is of the Formula (iv):
  • R 7E is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl.
  • R is optionally substituted alkyl.
  • R 7E is optionally substituted Ci_ 6 alkyl.
  • R 7E is unsubstituted C 1-6 alkyl.
  • R 7E is methyl, ethyl, n-propyl, or isopropyl.
  • R 7E is substituted C 1-6 alkyl. In certain embodiments, R 7E is optionally substituted carbocyclyl-alkyl. In certain embodiments, R 7E is optionally substituted
  • R is optionally substituted cyclopentyl-(CH 2 )i_5-
  • R is unsubstituted cyclopentyl-(CH 2 )i-5-. In certain embodiments,
  • R 7E is optionally substituted aryl. In certain embodiments, R 7E is optionally substituted phenyl.
  • R 7E is optionally substituted phenyl of the formula , wherein e is 0, 1, 2, 3, 4, or 5; R is independently selected from the group consisting of hydrogen, halogen, -CN, -N0 2 , -N 3 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted phenyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted alkoxy, an optionally substituted amino group, or optionally substituted acyl.
  • e is 0.
  • e is 1.
  • e is 2.
  • e is 3.
  • e is 4.
  • e is 5.
  • e is 1 and R is optionally substituted alkyl or optionally substituted alkoxy.
  • e is 1 and R is one of the group consisting of hydrogen, halogen, -CN, -N0 2 , -N 3 , optionally substitute
  • e is 2 or
  • e is 3 and R 7E is one of the formulae:
  • e is 5 and R is of the formula
  • R is optionally substituted alkyl.
  • R E is nts, R is one of the
  • R is optionally substituted heteroaryl. In certain embodiments, R is optionally substituted monocyclic heteroaryl. In certain embodiments,
  • R is optionally substituted 5-membered heteroaryl. In certain embodiments, R 7 /E E i ⁇ s optionally substituted furanyl. In certain embodiments, R is optionally substituted 2-furanyl or 3 -furanyl.
  • a provided compound is any compound in Table 1.
  • a provided compound is any one of the compounds shown in Table 1, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, isotopically labeled derivatives, and prodrugs thereof (e.g., compounds shown in Table 1, and pharmaceutically acceptable salts thereof).
  • MIC minimum inhibitory concentration
  • Staphylococcus aureus ATCC strains: 29213, BAA-1707; clinical isolates MRSA-1, MRSA-2, SA-156
  • Staphylococcus epidermidis ATCC 12228; clinical isolate MRSE-1
  • Acinetobacter baumannii ATCC strains: 19606, BAA-1794
  • Klebsiella pneumonia ATCC 13883
  • Pseudomonas aeruginosa PAOl
  • gallic acid combinations with conventional antibacterial agents including: ciprofloxacin (targets DNA gyrase/topoisomerase IV; inhibits DNA synthesis), methicillin (targets transpeptidase; inhibits cell wall synthesis), erythromycin (targets 50S subunit of ribosome; inhibits protein synthesis), tobramycin (targets 30S and 50S subunits of ribosome; inhibits protein synthesis) and vancomycin (targets pentapeptides; inhibits cell wall synthesis). None of these antibacterial agents were potentiated by GA. This result points to a unique antibacterial mechanism for quinoline compounds that differs from conventional antibiotics.
  • S. epidermidis Methicillin-susceptible ATCC 12228 strain was used in addition to a methicillin-resistant S. epidermidis (MRSE-1) clinical isolate. GA was found to have some antibacterial activities against these strains (MICs 469 and 625 ⁇ , respectively). About 250 ⁇ of GA was used in these potentiation assays (-1/2 MIC). The overall potentiation of exemplified quinoline compounds by GA was less dramatic against S. epidermidis (4- to 63- fold potentiation) compared to S. aureus, but 9 of 13 exemplified quinoline compounds (69%) tested in the panel were potentiated against both S. epidermidis strains.
  • the quinoline compounds-GA combination demonstrates good antibacterial activity for select exemplified quinoline compounds, including: 1 (MIC: >100 ⁇ ; MIC + GA: 9.38 ⁇ ), 4 (MIC: 25 ⁇ ; MIC + GA: 0.3 ⁇ ) and 5 (MIC: >100 ⁇ ; MIC + GA: 1.56 ⁇ ).
  • Ester quinoline compounds 20 and 21 also demonstrated GA potentiation similar to their free hydroxyl counterparts (20 with 4; 21 with 1), most likely through a prodrug esterase cleavage mechanism. These esters did provide slight increases in antibacterial potencies (with and without GA) compared to their corresponding hydroxyl quinoline compounds (1 and 4).
  • a panel of exemplified quinoline compounds in combination with GA were tested against the gram- negative pathogens P. aeruginosa (PAOl) and K. pneumoniae (ATCC 13883). No potentiation of antibacterial activity was observed with the exemplified quinoline compounds -GA combination against PAOl (MICs for all exemplified quinoline compounds > 100 ⁇ with and without GA). GA potentiation of some quinoline compounds were found against K. pneumoniae such as 1, 4, 5, 17 (nitroxoline), 20 and 21. Gallic Acid Potentiation of Halogenated Quinoline 1 in MRSA-2 Biofilm Eradication Assay:
  • a single colony grown on LB agar solid medium was amplified in 2 milliliters of tryptic soy broth (TSB) medium with 0.5% glucose to an OD 6 oo ⁇ 1-0.
  • the bacterial suspension was then diluted to -lxlO 6 CFUmL "1 in TSB with 0.5% glucose.
  • Sterile 96-well flat-bottomed polystyrene plates (0.1% gelatin coated overnight) were then filled with 100 ⁇ ⁇ of this bacterial suspension.
  • the microtiter plates were then covered and incubated for 24 hours at 37 °C.
  • test compound in 100 ⁇ ⁇ TSB 0.5% glucose were delivered into each well at concentrations ranging from 2 to 2,000 ⁇ (DMSO did not exceed 2% v/v in these assays).
  • Gallic acid i.e., potentiating agent
  • the plates were then covered with a lid, wrapped in saran wrap and incubated with test compounds for 24 hours at 37 °C.
  • biofilm eradication was determined accordingly (microtiter wells that were turbid resulted from live biofilm/bacterial growth while microtiter wells that had no turbidity resulted from completely eradicated biofilms).
  • Minimum Biofilm Eradication Concentration (MBEC) values were determined as the lowest concentration of a test compound that resulted in complete biofilm eradication.
  • 8-Hydroxyquinolines contain a metal binding motif which includes the phenolic oxygen and heterocyclic nitrogen atom of the quinoline ring which can chelate various metal(II) cations (V. Prachayasittikul, S. Prachayasittikul, S. Ruchirawat, V.
  • Zinc(II)-, iron(II)- and copper(II)-cations were added in potentiation assays in an analogous fashion to potentiating agents (i.e., gallic acid) in the potentiation protocol described above.
  • Metal(II)-cations used during these studies included: ZnCl 2 , (NH 4 ) 2 Fe(S0 4 ) 2 -6H 2 0 and CuS0 4 .
  • Zinc(II) chloride (at 100 ⁇ ; ⁇ l/7 MIC) was found to potentiate the antibacterial activities of quinoline compounds 4 and 5 by 21- and 83-fold, respectively.
  • 8-Hydroxyquinoline 18 and nitroxoline 17 do not possess any halogen atoms and were not potentiated by ZnCl 2 , but did follow iron(II) and copper(II) potentiation trends similar to the exemplified quinoline compounds.
  • CytoTox96 Promega G1780
  • HeLa cells were grown in Dulbecco's Modified Eagle Medium (DMEM; Gibco) supplemented with 10% Fetal Bovine Serum (FBS) at 37°C with 5% C0 2 .
  • FBS Fetal Bovine Serum
  • halogenated quinolines were then diluted by DMEM (10% FBS) at concentrations of 25, 50 and 100 ⁇ and added to HeLa cells.
  • Triton X-100 (at 2% v/v) was used as the positive control for maximum lactate dehydrogenate (LDH) activity in this assay (i.e., complete cell death) while "medium only" lanes served as negative control lanes (i.e., no cell death).
  • LDH lactate dehydrogenate
  • DMSO DMSO was used as our vehicle control. HeLa cells were treated with compounds for 24 hours and then 50 of the supernatant was transferred into a fresh 96-well plate where 50 ⁇ ⁇ of the reaction mixture was added to the 96-well plate and incubated at room temperature for 30 minutes. Finally, 50 ⁇ L ⁇ of the Stop Solution is added to the incubating plates and the absorbance was measured at 490 nm.
  • the exemplified quinolines were evaluated for their abilities to inhibit bacterial growth in microdilution MIC experiments head-to-head against bromophenazine 1 (positive control) using a panel of four clinically relevant pathogens: S. aureus ATCC 29213, S. epidermidis ATCC 12228, A. baumannii ATCC 19606 and P. aeruginosa PAOl/BAA-47.
  • This panel of pathogens included both gram-positive (S. aureus and S. epidermidis) and gram-negative (A. baumannii and P. aeruginosa) bacteria to determine the spectrum of activity of the exemplified quinolines.
  • these quinolines were evaluated against several S. aureus clinical isolates, including several methicillin-resistant S. aureus isolates and a S. epidermidis clinical isolate.
  • aureus strain ATCC 29213 was used to obtain MIC and IC 50 values from same biofilm inhibition experiment (assay optimized for biofilm formation).
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

La présente invention concerne des compositions comprenant une quinoléine, un agent de potentialisation, et éventuellement un support pharmaceutiquement acceptable, pour le traitement et/ou la prévention de maladies infectieuses. Les compositions selon l'invention peuvent également comprendre un autre agent thérapeutique (par exemple un antibiotique). Ces compositions peuvent être utiles dans le traitement et/ou la prévention d'infections bactériennes ainsi que pour l'inhibition et l'éradication de la formation d'un biofilm.
PCT/US2016/023256 2015-03-20 2016-03-18 Polythérapie pour le traitement de maladies infectieuses WO2016154051A1 (fr)

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WO2019118311A1 (fr) * 2017-12-13 2019-06-20 Merck Sharp & Dohme Corp. Compositions pharmaceutiques de tedizolid phosphate
CN110507660A (zh) * 2019-09-24 2019-11-29 吉林大学 五环三萜类化合物在制备细菌性溶血素抑制剂中的用途
CN112891334A (zh) * 2021-01-19 2021-06-04 浙江大学 咖啡酸类衍生物在制备治疗淋病药物中的应用
WO2021203028A1 (fr) * 2020-04-03 2021-10-07 Vertex Pharmaceuticals Incorporated Dérivés de 7-ou 8-hydroxy-isoquinoléine et de 7-ou 8-hydroxy-quinoléine en tant que modulateurs d'alpha-1-antitrypsine pour traiter une déficience en alpha-1-antitrypsine (aatd)
WO2022028321A1 (fr) * 2020-08-03 2022-02-10 江苏亚虹医药科技股份有限公司 Dérivé de nitroxoline, son procédé de préparation et son utilisation
WO2023023647A3 (fr) * 2021-08-19 2023-03-30 Haus Bioceuticals, Inc. Compositions et méthodes pour polythérapie antivirale bimodale
US11623924B2 (en) 2018-10-05 2023-04-11 Vertex Pharmaceuticals Incorporated Modulators of alpha-1 antitrypsin
WO2023232019A1 (fr) * 2022-05-31 2023-12-07 江苏亚虹医药科技股份有限公司 Dérivé de 7-cyano-8-hydroxyquinoléine, son procédé de préparation et son utilisation médicale
US11884672B2 (en) 2019-05-14 2024-01-30 Vertex Pharmaceuticals Incorporated Modulators of alpha-1 antitrypsin

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019118311A1 (fr) * 2017-12-13 2019-06-20 Merck Sharp & Dohme Corp. Compositions pharmaceutiques de tedizolid phosphate
US11452719B2 (en) 2017-12-13 2022-09-27 Merck Sharp & Dohme Llc Pharmaceutical compositions of tedizolid phosphate
US11623924B2 (en) 2018-10-05 2023-04-11 Vertex Pharmaceuticals Incorporated Modulators of alpha-1 antitrypsin
US11884672B2 (en) 2019-05-14 2024-01-30 Vertex Pharmaceuticals Incorporated Modulators of alpha-1 antitrypsin
CN110507660A (zh) * 2019-09-24 2019-11-29 吉林大学 五环三萜类化合物在制备细菌性溶血素抑制剂中的用途
WO2021203028A1 (fr) * 2020-04-03 2021-10-07 Vertex Pharmaceuticals Incorporated Dérivés de 7-ou 8-hydroxy-isoquinoléine et de 7-ou 8-hydroxy-quinoléine en tant que modulateurs d'alpha-1-antitrypsine pour traiter une déficience en alpha-1-antitrypsine (aatd)
WO2022028321A1 (fr) * 2020-08-03 2022-02-10 江苏亚虹医药科技股份有限公司 Dérivé de nitroxoline, son procédé de préparation et son utilisation
CN115867540A (zh) * 2020-08-03 2023-03-28 江苏亚虹医药科技股份有限公司 硝羟喹啉衍生物及其制备方法和用途
CN112891334A (zh) * 2021-01-19 2021-06-04 浙江大学 咖啡酸类衍生物在制备治疗淋病药物中的应用
CN112891334B (zh) * 2021-01-19 2022-05-03 浙江大学 咖啡酸类衍生物在制备治疗淋病药物中的应用
WO2023023647A3 (fr) * 2021-08-19 2023-03-30 Haus Bioceuticals, Inc. Compositions et méthodes pour polythérapie antivirale bimodale
WO2023232019A1 (fr) * 2022-05-31 2023-12-07 江苏亚虹医药科技股份有限公司 Dérivé de 7-cyano-8-hydroxyquinoléine, son procédé de préparation et son utilisation médicale

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