Antimicrobial conjugated oligoelectrolytes as broad-spectrum antibiotics

Abstract

Compositions and methods of making and using thereof are provided with a specific antimicrobial activity toward Gram-positive and Gram-negative bacteria and / or low levels of toxicity toward mammalian cells. The compositions include water-soluble molecules characterized by a hydrophobic interior fragment and side groups containing basic ionizable functionalities that may be positively charged under physiological conditions. A class of these molecules is provided with structural variations that can impact the antimicrobial activity and toxicity to mammalian cells.

Description

ANTIMICROBIAL CONJUGATED OLIGOELECTROLYTES AS BROAD-SPECTRUM ANTIBIOTICS INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application No.63 / 498,480, filed April 26, 2023, which is incorporated by reference in its entirety. STATEMENT OF GOVERNMENT INTEREST

[0002] This invention was made with government support under W911NF-19-2- 0026 and W911NF-19-D-0001 awarded by the United State Army Research Office. The government has certain rights in the invention. BACKGROUND Field

[0003] This application relates to antimicrobial conjugated oligoelectrolytes (COEs), and their use for treating infections caused by Gram-negative and / or Gram-positive bacteria. Description

[0004] Human health has benefited from the development of antimicrobial prophylaxis and therapeutics. For example, the first antibiotic, penicillin, was introduced in 1940. However, Abraham and coworkers found cultures of staphylococci developed resistance after continuous subculture in the presence of penicillin. Methicillin was introduced in 1959 to overcome increasing bacterial resistance to not only penicillin, but also streptomycin, tetracycline and erythromycin. Unfortunately, 18 strains of S. aureus were reported to exhibit resistance to methicillin within two years. In attempts to solve this problem, new antibiotics continued to be developed, including vancomycin, which constitutes a last resort for treating methicillin-resistant S. aureus infections. However, a vancomycin-resistant strain of S. aureus was also reported in 2002.

[0005] The ability of microbes to develop antimicrobial resistance (AMR) underlies the emergence of drug-resistant strains which cause infections that are increasingly difficult totreat, resulting in increased hospitalization times, poor patient outcomes, and significant negative economic implications. It is estimated that a failure to address the antibiotic resistance crisis would result in as many as 10 million annual deaths and a reduction in global GDP of $100 trillion. Additionally, the threat of acquiring drug-resistant infections can impact many modern medical practices (e.g., surgery, dialysis, and organ transplants), universally reducing quality of life.

[0006] The so-called ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) comprise a group of Gram-positive and Gram-negative bacteria that have been identified as particularly urgent threats for their ability to develop antimicrobial resistance and cause life-threating infections. The emergence of multidrug resistant (MDR) strains now poses a threat to the sustainable use of antibiotics to treat serious infections. This problem is compounded by the sparse clinical pipeline and the poor coverage of these few potential new antibiotics over the greatest unmet medical needs. Discovery and development of new antibiotics, ideally those with novel chemical scaffolds and those which act by novel mechanisms of action, is among the greatest scientific challenges of our time. SUMMARY

[0007] The following embodiments and aspects thereof are described and illustrated in conjunction with compositions and methods which are meant to be exemplary and illustrative, not limiting in scope.

[0008] Some embodiments described herein relate to a antimicrobial COEs, or a pharmaceutically acceptable salt thereof, described herein.

[0009] Other embodiments described herein relate to a method of treating, reducing the severity of and / or slowing the progression of a bacterial infection in a mammalian subject that can include administering an effective amount of an antimicrobial COE, or pharmaceutically acceptable salt thereof, described herein.

[0010] Other features and advantages of the application will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, various features of embodiments of the application.DETAILED DESCRIPTION

[0011] All references cited herein, including all of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and / or listed in the Application Data Sheet, are incorporated by reference in their entirety, unless indicated otherwise. It is not an admission that any of the aforementioned documents are prior art or relevant to the present application, or that any publication specifically or implicitly referenced is prior art.

[0012] Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Singleton et al., Dictionary of Microbiology and Molecular Biology 3rded., Revised, J. Wiley & Sons (New York, NY 2006); March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 7thed., J. Wiley & Sons (New York, NY 2013); and Sambrook and Russel, Molecular Cloning: A Laboratory Manual 4thed., Cold Spring Harbor Laboratory Press (Cold Spring Harbor, NY 2012), provide one skilled in the art with a general guide to many of the terms used in the present application. For references on how to prepare antibodies, see D. Lane, Antibodies: A Laboratory Manual 2nded. (Cold Spring Harbor Press, Cold Spring Harbor NY, 2013); Kohler and Milstein, (1976) Eur. J. Immunol. 6: 511; Queen et al. U. S. Patent No. 5,585,089; and Riechmann et al., Nature 332: 323 (1988); U.S. Pat. No.4,946,778; Bird, Science 242:423-42 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85: 5879-5883 (1988); Ward et al., Nature 334:544-54 (1989); Tomlinson I. and Holliger P. (2000) Methods Enzymol, 326, 461-479; Holliger P. (2005) Nat. Biotechnol. Sep;23(9):1126-36).

[0013] One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present application. Indeed, the present application is in no way limited to the methods and materials described. For purposes of the present application, the following terms are defined below.

[0014] Unless otherwise indicated, the term “alkyl” means a straight chain and / or branched hydrocarbon having from 1 to 20 (e.g., 1 to 10 or 1 to 4) carbon atoms, i.e., C1-C20 (including any integer number of carbon atoms between 1 and 20). Alkyl moieties having from 1 to 4 carbons are referred to as “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4- dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl and dodecyl.

[0015] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s).3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0016] As used herein, “cycloalkyl(alkyl)” refer to a cycloalkyl group connected, as a substituent, via an alkylene group. The alkylene and cycloalkyl group of an cycloalkyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to, cyclopropyl–CH2–, cyclobutyl–CH2–, cyclopentyl–CH2–, cyclohexyl–CH2–, cyclopropyl–CH2CH2–, cyclobutyl– CH2CH2–, cyclopentyl–CH2CH2–, cyclohexyl–CH2CH2–, cyclopropyl–CH2CH2CH2–, cyclobutyl–CH2CH2CH2–, cyclopentyl–CH2CH2CH2–, cyclohexyl–CH2CH2CH2–, cyclopropyl– CH2CH2CH2CH2–, cyclobutyl–CH2CH2CH2CH2–, cyclopentyl–CH2CH2CH2CH2– and cyclohexyl–CH2CH2CH2CH2–.

[0017] Unless otherwise indicated, the term “alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, which is saturated or unsaturated (i.e., contains one or more double and / or triple bonds), and having from one to twenty carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. In some embodiments, the alkylene chain can have 1, 2, 3 or 4 carbons atoms. The alkylene chain is attached via a single or double bond.

[0018] As used herein, the ʌ (pi) system of a molecule is used as understood by those skilled in the art. The (pi) system of a molecule is formed by the interaction of unhybridized p atomic orbitals on atoms that have sp2- and sp-hybridization. The interaction that results in ʌ bonding takes place between p orbitals that are adjacent by virtue of a ı bond joining the atoms and takes the form of side-to-side overlap of p orbitals.

[0019] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched or a stereoisomeric mixture. In addition, it isunderstood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0020] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0021] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half- life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0022] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol or the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0023] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0024] Unless otherwise indicated, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. Suitable pharmaceutically acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,Nƍ- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitable non-toxic acids include, but are not limited to, inorganic and organic acids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic, succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxic acids include hydrochloric, hydrobromic, phosphoric, sulfuric, and methanesulfonic acids. Examples of specific salts thus include hydrochloride and mesylate salts. Others are well known in the art. See, e.g., Remington’s Pharmaceutical Sciences (18th ed., Mack Publishing, Easton Pa.: 1990) and Remington: The Science and Practice of Pharmacy (19th ed., Mack Publishing, Easton Pa.: 1995).

[0025] Unless otherwise indicated, the term “protecting group” or “protective group,” when used to refer to part of a molecule subjected to a chemical reaction, means a chemical moiety that is not reactive under the conditions of that chemical reaction, and which may be removed to provide a moiety that is reactive under those conditions. Protecting groups are well known in the art. See, e.g., Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis (3rded., John Wiley & Sons: 1999); Larock, R. C., Comprehensive Organic Transformations (2nded., John Wiley & Sons: 1999).

[0026] Various embodiments of the present application are described above in the Detailed Description. While these descriptions directly describe the embodiments, it is understood that those skilled in the art may conceive modifications and / or variations to the specific embodiments shown and described herein. Any such modifications or variations that fall withinthe purview of this description are intended to be included therein as well. Unless specifically noted, it is the intention of the inventors that the words and phrases in the specification and claims be given the ordinary and accustomed meanings to those of ordinary skill in the applicable art(s).

[0027] The present description is not intended to be exhaustive nor limit the present application to the precise form disclosed and many modifications and variations are possible in the light of the above teachings. The embodiments described serve to explain the principles of the present application and its practical application and to enable others skilled in the art to utilize the present application in various embodiments and with various modifications as are suited to the particular use contemplated. Therefore, it is intended that the present application not be limited to the particular embodiments disclosed herein. Rather the various embodiments are meant to be illustrative and descriptive.

[0028] While particular embodiments of the present application have been shown and described, it will be obvious to those skilled in the art that, based upon the teachings herein, changes and modifications may be made without departing from this application and its broader aspects and, therefore, the appended claims are to encompass within their scope all such changes and modifications as are within the true spirit and scope of this application. It will be understood by those within the art that, in general, terms used herein are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.).

[0029] As used herein the term “comprising” or “comprises” is used in reference to compositions, methods, and respective component(s) thereof, that are useful to an embodiment, yet open to the inclusion of unspecified elements, whether useful or not. Although the open-ended term “comprising,” as a synonym of terms such as including, containing, or having, is used herein, the present application, or embodiments thereof, may alternatively be described using alternative terms such as “consisting of” or “consisting essentially of.”

[0030] Therefore, it is an objective of the present application to provide compositions with an antimicrobial activity at a dosage range that is nontoxic to mammalian cells.

[0031] It is another objective of the present application to provide a method of treating bacterial infection in a mammalian subject, such as a subject that requires treatment for a bacterialinfection, wherein the bacterial infection has developed resistance to typical drug treatment strategies.

[0032] Conjugated oligoelectrolytes (COEs) are a class of molecules that have been studied in bioelectrochemical systems, such as microbial fuel cells and electrobiosynthesis platforms. More recently, certain COE scaffolds have been studied in the context of their antimicrobial properties.

[0033] Antimicrobial COEs, along with pharmaceutically acceptable salts thereof, (such as a compound of Formula (I)) described herein and their modifications are provided to increase activity towards bacteria and / or reduce their toxicity towards mammalian cells. In various embodiments, modulating the hydrophobic / hydrophilic content can enhance the selectivity of the antimicrobial COEs In some embodiments, the antimicrobial COEs (along with pharmaceutically acceptable salts thereof) described herein can exhibit significant antimicrobial efficacy against both Gram-negative and Gram-positive bacteria, while displaying minimal toxicity toward HepG2 cells, relative to all COE variations reported previously. Compounds Embodiment 1

[0034] A compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein: R1A, R2A, R3Aand R4Acan be independently selected from hydrogen, an unsubstituted C1-4alkyl and an unsubstituted C3-6cycloalkyl; R1Bcan be hydrogen or an unsubstituted C1-4alkyl; and R1Ccan be an unsubstituted C1-4alkyl, an unsubstituted C3-6cycloalkyl and an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4 alkyl); or R1Band R1Ccan be taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7-membered ring; R2Bcan be hydrogen or an unsubstituted C1-4 alkyl; and R2Ccan be an unsubstituted C1-4 alkyl, an unsubstituted C3-6cycloalkyl and an unsubstituted C3-6cycloalkyl(an unsubstituted C1-4alkyl); or R2Band R2Ccan be taken together along with each atom to which R2Band R2Care attached to form a 5-, 6-, or 7- membered ring; R3Bcan be hydrogen or an unsubstituted C1-4 alkyl; and R3Ccan be an unsubstituted C1-4 alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4 alkyl); or R3Band R3Ccan be taken together along with each atom to which R3Band R3Care attached to form a 5-, 6-, or 7-membered ring; R4Bcan be hydrogen or an unsubstituted C1-4alkyl; R4Ccan be an unsubstituted C1-4alkyl, an unsubstituted C3-6cycloalkyl and an unsubstituted C3-6cycloalkyl(an unsubstituted C1-4alkyl); or R4Band R4Ccan be taken together along with each atom to which R4Band R4Care attached to form a 5-, 6-, or 7-membered ring; R5A, R5B, R5Cand R5Dcan be independently selected from hydrogen and halogen; and R6A, R6B, R6Cand R6Dcan be independently selected from hydrogen and halogen. Embodiment 2

[0035] The compound of Embodiment 1, wherein R1Acan be hydrogen. Embodiment 3

[0036] The compound of Embodiment 1, wherein R1Acan be an unsubstituted C1-4alkyl. Embodiment 4

[0037] The compound of Embodiment 1, wherein R1Acan be an unsubstituted C3-6 cycloalkyl. Embodiment 5

[0038] The compound of any one of Embodiments 2-4, wherein R1Bcan be hydrogen. Embodiment 6

[0039] The compound of any one of Embodiments 2-4, wherein R1Bcan be an unsubstituted C1-4alkyl. Embodiment 7

[0040] The compound of any one of Embodiments 2-6, wherein R1Ccan be an unsubstituted C1-4 alkyl. Embodiment 8

[0041] The compound of any one of Embodiments 2-6, wherein R1Ccan be an unsubstituted C3-6cycloalkyl.Embodiment 9

[0042] The compound of any one of Embodiments 2-6, wherein R1Ccan be an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4 alkyl). Embodiment 10

[0043] The compound of any one of Embodiments 2-4, wherein R1Band R1Ccan be taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7- membered ring. Embodiment 11

[0044] The compound of any one of Embodiments 1-10, wherein R2Acan be hydrogen. Embodiment 12

[0045] The compound of any one of Embodiments 1-10, wherein R2Acan be an unsubstituted C1-4 alkyl. Embodiment 13

[0046] The compound of any one of Embodiments 1-10, wherein R2Acan be an unsubstituted C3-6cycloalkyl. Embodiment 14

[0047] The compound of any one of Embodiments 11-13, wherein R2Bcan be hydrogen. Embodiment 15

[0048] The compound of any one of Embodiments 11-13, wherein R2Bcan be an unsubstituted C1-4 alkyl. Embodiment 16

[0049] The compound of any one of Embodiments 11-15, wherein R2Ccan be an unsubstituted C1-4alkyl. Embodiment 17

[0050] The compound of any one of Embodiments 11-15, wherein R2Ccan be an unsubstituted C3-6 cycloalkyl. Embodiment 18

[0051] The compound of any one of Embodiments 11-15, wherein R2Ccan be an unsubstituted C3-6cycloalkyl(an unsubstituted C1-4alkyl).Embodiment 19

[0052] The compound of any one of Embodiments 11-13, wherein R2Band R2Ccan be taken together along with each atom to which R2Band R2Care attached to form a 5-, 6-, or 7- membered ring. Embodiment 20

[0053] The compound of any one of Embodiments 1-19, wherein R3Acan be hydrogen. Embodiment 21

[0054] The compound of any one of Embodiments 1-19, wherein R3Acan be an unsubstituted C1-4alkyl. Embodiment 22

[0055] The compound of any one of Embodiments 1-19, wherein R3Acan be an unsubstituted C3-6 cycloalkyl. Embodiment 23

[0056] The compound of any one of Embodiments 20-22, wherein R3Bcan be hydrogen. Embodiment 24

[0057] The compound of any one of Embodiments 20-22, wherein R3Bcan be an unsubstituted C1-4 alkyl. Embodiment 25

[0058] The compound of any one of Embodiments 20-24, wherein R2Ccan be an unsubstituted C1-4 alkyl. Embodiment 26

[0059] The compound of any one of Embodiments 20-24, wherein R3Ccan be an unsubstituted C3-6cycloalkyl. Embodiment 27

[0060] The compound of any one of Embodiments 20-24, wherein R3Ccan be an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4 alkyl). Embodiment 28

[0061] The compound of any one of Embodiments 20-22, wherein R3Band R3Ccan be taken together along with each atom to which R3Band R3Care attached to form a 5-, 6-, or 7- membered ring.Embodiment 29

[0062] The compound of any one of Embodiments 1-28, wherein R4Acan be hydrogen. Embodiment 30

[0063] The compound of any one of Embodiments 1-28, wherein R4Acan be an unsubstituted C1-4 alkyl. Embodiment 31

[0064] The compound of any one of Embodiments 1-28, wherein R4Acan be an unsubstituted C3-6cycloalkyl. Embodiment 32

[0065] The compound of any one of Embodiments 29-31, wherein R4Bcan be hydrogen. Embodiment 33

[0066] The compound of any one of Embodiments 29-31, wherein R4Bcan be an unsubstituted C1-4alkyl. Embodiment 34

[0067] The compound of any one of Embodiments 29-33, wherein R4Ccan be an unsubstituted C1-4alkyl. Embodiment 35

[0068] The compound of any one of Embodiments 29-33, wherein R4Ccan be an unsubstituted C3-6 cycloalkyl. Embodiment 36

[0069] The compound of any one of Embodiments 29-33, wherein R4Ccan be an unsubstituted C3-6cycloalkyl(an unsubstituted C1-4alkyl). Embodiment 37

[0070] The compound of any one of Embodiments 29-31, wherein R4Band R4Ccan be taken together along with each atom to which R4Band R4Care attached to form a 5-, 6-, or 7- membered ring.

[0071] In some embodiments, an unsubstituted C1-4 alkyl can be selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. In some embodiments, an unsubstituted C3-6cycloalkyl can be an unsubstituted monocyclic C3-6cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl) or an unsubstituted bicyclic C5-6cycloalkyl.In some embodiments, an unsubstituted C3-6cycloalkyl(an unsubstituted C1-4alkyl). For example, the unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4 alkyl) can be an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C1-4 alkyl), such as an unsubstituted monocyclic C3-6 cycloalkyl(CH2)–, an unsubstituted monocyclic C3-6 cycloalkyl(CH2CH2)–, an unsubstituted monocyclic C3-6 cycloalkyl(CH2CH2CH2)– and an unsubstituted monocyclic C3-6 cycloalkyl(CH2CH2CH2CH2)–. In some embodiments, the 5-, 6-, or 7-membered ring formed by taking together two “R” groups (such as R1Band R1C, R2Band R2C, R3Band R3Cand R4Band R4C), can include one nitrogen. In some embodiments, the 5-, 6-, or 7-membered ring formed by taking together two “R” groups (such as R1Band R1C, R2Band R2C, R3Band R3Cand R4Band R4C), can include an additional heteroatom, for example, an additional nitrogen, oxygen or sulfur. Embodiment 38

[0072] The compound of any one of Embodiments 1-37, R5Acan be hydrogen. Embodiment 39

[0073] The compound of any one of Embodiments 1-37, R5Acan be halogen. For example, R5Acan be fluoro, chloro or bromo. Embodiment 40

[0074] The compound of any one of Embodiments 1-39, R5Bcan be hydrogen. Embodiment 41

[0075] The compound of any one of Embodiments 1-39, R5Bcan be halogen, such as fluoro, chloro or bromo. Embodiment 42

[0076] The compound of any one of Embodiments 1-41, R5Ccan be hydrogen. Embodiment 43

[0077] The compound of any one of Embodiments 1-41, R5Ccan be halogen. For example, R5Ccan be fluoro, chloro or bromo. Embodiment 44

[0078] The compound of any one of Embodiments 1-43, R5Dcan be hydrogen. Embodiment 45

[0079] The compound of any one of Embodiments 1-43, R5Dcan be halogen, for example, fluoro, chloro or bromo.Embodiment 46

[0080] The compound of any one of Embodiments 1-45, R6Acan be hydrogen. Embodiment 47

[0081] The compound of any one of Embodiments 1-45, R6Acan be halogen. For example, R6Acan be fluoro, chloro or bromo. Embodiment 48

[0082] The compound of any one of Embodiments 1-47, R6Bcan be hydrogen. Embodiment 49

[0083] The compound of any one of Embodiments 1-47, R6Bcan be halogen, such as fluoro, chloro or bromo. Embodiment 50

[0084] The compound of any one of Embodiments 1-49, R6Ccan be hydrogen. Embodiment 51

[0085] The compound of any one of Embodiments 1-49, R6Ccan be halogen, for example, fluoro, chloro or bromo. Embodiment 52

[0086] The compound of any one of Embodiments 1-51, R6Dcan be hydrogen. Embodiment 53

[0087] The compound of any one of Embodiments 1-51, R6Dcan be halogen. For example, R6Dcan be fluoro, chloro or bromo.

[0088] In some embodiments, R1A, R2A, R3Aand R4Acan be each the same. In some embodiments, R1B, R2B, R3Band R4Bcan be each the same. In some embodiments, R1C, R2C, R3Cand R4Ccan be each the same.

[0089] In some embodiments, R1A, R2A, R3Aand R4Acan be each hydrogen; R1B, R2B, R3Band R4Bcan be each hydrogen; and R1C, R2C, R3Cand R4Ccan be each an unsubstituted C3-6cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In other embodiments, R1A, R2A, R3Aand R4Acan be each hydrogen; R1B, R2B, R3Band R4Bcan be each an unsubstituted C1-4 alkyl; and R1C, R2C, R3Cand R4Ccan be each an unsubstituted C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In still other embodiments, R1A, R2A, R3Aand R4Acan be each hydrogen; R1B, R2B, R3Band R4Bcan be each an unsubstituted C1-4alkyl; and R1C, R2C, R3Cand R4Ccan be each an unsubstituted C3-6cycloalkyl. In yet still other embodiments, R1A,R2A, R3Aand R4Acan be each hydrogen; R1B, R2B, R3Band R4Bcan be each an unsubstituted C1-4alkyl; and R1C, R2C, R3Cand R4Ccan be each an unsubstituted C1-4 alkyl. In some embodiments, R1A, R2A, R3Aand R4Acan be each hydrogen; R1B, R2B, R3Band R4Bcan be each hydrogen; and R1C, R2C, R3Cand R4Ccan be each an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4 alkyl), such as an unsubstituted C3-6 cycloalkyl–CH2–. In some embodiments, R1A, R2A, R3Aand R4Acan be each hydrogen; R1B, R2B, R3Band R4Bcan be each an unsubstituted C3-6cycloalkyl; and R1C, R2C, R3Cand R4Ccan be each, an unsubstituted C3-6cycloalkyl. In other embodiments, R1A, R2A, R3Aand R4Acan be each hydrogen; R1Band R1Ccan be taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7-membered ring; R2Band R2Ccan be taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7-membered ring; R3Band R3Ccan be taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7-membered ring; and R4Band R4Ccan be taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7-membered ring.

[0090] In some embodiments, R6A, R6B, R6Cand R6Dcan be each hydrogen. In other embodiments, R6Aand R6Dcan be each halogen; and R6Band R6Ccan be hydrogen. In still other embodiments, R6A, R6B, R6Cand R6Dcan be each halogen. In some embodiments, including those of this paragraph, R5A, R5B, R5Cand R5Dcan be each hydrogen. In other embodiments, including those of this paragraph, R5Band R5Ccan be each halogen; and R5Aand R5Dcan be hydrogen. In still other embodiments, including those of this paragraph, R5A, R5B, R5Cand R5Dcan be each halogen. In some embodiments, R5A, R5B, R5Cand R5Dcan be each the same; R6A, R6B, R6Cand R6Dcan be each the same; and R5A, R5B, R5Cand R5Dcan be different from R6A, R6B, R6Cand R6D.Embodiment 54

[0091] The compound of Embodiment 1 can be selected from:,,, or a pharmaceutically acceptable salt of any of the foregoing. Embodiment 55

[0092] A pharmaceutical composition comprising an effective amount of a compound of any one of Embodiments 1-54, or a pharmaceutically acceptable salt thereof, and excipient. Embodiment 56

[0093] A method for treating a bacterial infection in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Embodiments 1- 54, or a pharmaceutically acceptable salt thereof. Embodiment 57

[0094] The method of Embodiment 56, wherein the bacterial infection is due to a Gram-negative bacteria. Embodiment 58

[0095] The method of Embodiment 56, wherein the bacterial infection is due to a Gram-positive bacteria. Embodiment 59

[0096] The method of Embodiment 56, wherein the bacterial infection is due to a bacteria selected from the group consisting of Salmonella enterica Typhimurium, E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, methicillin-resistant S. aureus, methicillin-sensitive S. aureus, E. faecium, A. baumannii, E. cloacae, S. epidermidis, K. aerogenes, S. flexneri, Y. pseudotuberculosis, Nontuberculous Mycobacteria (NTM); Mycobacterium tuberculosis; N. gonorrhoeae, and S. pneumoniae.

[0097] In some embodiments, a compound of Formula (I) cannot be, or a pharmaceutically acceptable salt thereof.

[0098] Some advantages of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to known COEs (such as known quaternary ammonium COEs) include, but are not limited to, increased activity against one or more bacterial strains, reduced cytotoxicity, and / or increased water solubility. In some embodiments, varying the hydrophobicity of a compound of Formula (I) (along with pharmaceutically acceptable salts thereof) described herein can reduce cytotoxicity. For example, a less hydrophobic compound of Formula (I) (along with pharmaceutically acceptable salts thereof) described herein can result in reduced cytotoxicity. Furthermore, this modification to hydrophobicity may have positive, negative, or no impact on activity towards Gram-negative and / or Gram-positive bacteria.

[0099] In various embodiments, one or more of compounds described herein (along with pharmaceutically acceptable salts thereof) have a high affinity towards cell membranes, especially bacterial cell membranes. For example, at least 50%, 60% or 70% of the compounds of Formula (I) (along with pharmaceutically acceptable salts thereof) are taken up by or adsorbed to cells following incubation for 30 minutes, 1 hour, 1.5 hour, 2 hours or longer, given that the compounds are not at a concentration that oversaturates the cell culture medium or cells.

[0100] In various embodiments, one or more compounds described herein (along with pharmaceutically acceptable salts thereof) having a high affinity towards cells are also readily soluble in water or an aqueous medium. For example, the solubility of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 500, 1,000, or 10,000 μg / mL in water.Methods of Preparation

[0101] Compounds of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt of any of the foregoing, can be synthesized using standard synthetic techniques known to those skilled in the art, wherein Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt of any of the foregoing, are as provided in the section entitled “Compounds.” For example, compounds of the present disclosure can be synthesized using appropriately modified synthetic procedures set forth in the general synthetic schemes detailed below and in the examples.

[0102] To this end, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in the suitable field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation(s) necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed. In general, starting components may be obtained from sources such as Sigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. or synthesized according to sources known to those skilled in the art (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley, December 2000)).

[0103] General Synthetic Scheme A provides a representative synthesis for compounds of Formula (I), or a pharmaceutically acceptable salt thereof, described herein. General Synthetic Scheme AFor R5A-5D= halogen or an unsubstituted C1-4alkylAll compounds of Formula (I)

[0104] General Synthetic Scheme A provides methods for obtaining compounds of Formula (I) along with pharmaceutically acceptable salts thereof. In General Synthetic Scheme A, PG1represents a protecting group. It will be appreciated by those skilled in the art that in the processes for preparing the compounds described herein, the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include, but are not limited to, hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include, but are not limited to, trialkylsilyl or diarylalkylsilyl (for example, t- butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, methoxymethyl (“MOM”), and the like). Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl ("Boc"), benzyloxycarbonyl, and the like. Protecting groups are optionally added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin. It should be also appreciated that various alternative strategies for preparation of compounds described herein (compounds of Formula (I), or a pharmaceutically acceptable salt thereof) are available to those of ordinary skill in the art, wherein Formula (I), or a pharmaceutically acceptable salt thereof, are as provided inthe section entitled “Compounds.” For example, other compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can be prepared according to analogous methods using the appropriate starting material, wherein Formula (I), or a pharmaceutically acceptable salt thereof, are as provided in the section entitled “Compounds.”

[0105] It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of this disclosure may not possess pharmacological activity as such, they may be administered to a mammal and thereafter metabolized in the body to form compounds of the disclosure which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Prodrugs of compounds of this disclosure are included within the scope of embodiments of the disclosure.

[0106] The examples and preparations provided below further illustrate and exemplify the compounds of the present application, methods of preparing such compounds and methods for evaluating biological activity. Methods of Using

[0107] A method of treating, reducing the severity of and / or slowing the progression of a bacterial infection in a mammalian subject is provided that can include administering an effective amount of one, two, three, four, or more compounds of Formula (I) to a mammalian subject. In various embodiments, the effective amount of a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be non-toxic to the normal tissue or cells of a mammalian subject. In various embodiments, the mammalian subject can be a human. In various embodiments, a compound of Formula (I) can have activity against one or more bacteria, such as Salmonella enterica Typhimurium (ST) (ATCC 14028); E. coli (EC) (ATCC 25922); Pseudomonas aeruginosa (PA) (ATCC 27853); Klebsiella pneumoniae (KPN) (ATCC 700603); S. aureus (SA) (ATCC 29213); Enterococcus faecium; Acinetobacter baumannii; Enterobacter cloacae; Staphylococcus epidermidis; Klebsiella aerogenes; Shigella flexneri; Yersinia pseudotuberculosis; Nontuberculous Mycobacteria (NTM); Mycobacterium avium complex, Mycobacterium abscessus, Mycobacterium tuberculosis; Neisseria gonorrhoeae; and Streptococcus pneumoniae.

[0108] In various embodiments, the methods described herein can treat, reduce the severity of and / or slow the progression of one or more bacterial infections including but not limitedto bacterial skin infections (e.g., Cellulitis, Folliculitis, Impetigo, Boils); foodborne illness such as nausea, vomiting, diarrhea, fever, chills and abdominal pain; sexually transmitted diseases such as chlamydia, gonorrhea, syphilis, bacterial vaginosis; and other bacterial infections such as bacterial meningitis, otitis media, urinary tract infection, and respiratory tract infections (e.g., sore throat, bronchitis, sinusitis).

[0109] In various embodiments, the method of treating, reducing the severity of and / or slowing the progression of a bacterial infection in a mammalian subject can have a specific efficacy towards Gram-negative, Gram-positive, or both, yet maintains the viability of normal mammalian cells of at least 70%, 80%, 90%, 95% or greater.

[0110] In some embodiments, an effective amount of a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the methods and / or compositions described herein may be in the range of about 0.001-0.01 mg / kg / day, 0.01- 0.05 mg / kg / day, 0.05-0.1 mg / kg / day, 0.1-0.2 mg / kg / day, 0.2-0.3 mg / kg / day, 0.3-0.4 mg / kg / day, 0.4-0.5 mg / kg / day, 0.5-1 mg / kg / day, 1-5 mg / kg / day, 5-10 mg / kg / day, 10-20 mg / kg / day, 20-30 mg / kg / day, 30-40 mg / kg / day, 40-50 mg / kg / day, 50-60 mg / kg / day, 60-70 mg / kg / day, 70-80 mg / kg / day, 80-90 mg / kg / day, 90-100 mg / kg / day, 100-200 mg / kg / day, 200-300 mg / kg / day, 300- 400 mg / kg / day, 400-500 mg / kg / day, 500-600 mg / kg / day, 600-700 mg / kg / day, 700-800 mg / kg / day, 800-900 mg / kg / day, 900-1000 mg / kg / day, 1000-1100 mg / kg / day, 1100-1200 mg / kg / day, 1200-1300 mg / kg / day, 1300-1400 mg / kg / day, 1400-1500 mg / kg / day, 1500-1600 mg / kg / day, 1600-1700 mg / kg / day, 1700-1800 mg / kg / day, 1800-1900 mg / kg / day, or 1900-2000 mg / kg / day.

[0111] In other embodiments, an effective amount of a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the methods and / or compositions descried herein may be in the range of about 1-10 mg / kg / week, 10-30 mg / kg / week, 30-50 mg / kg / week, 50-100 mg / kg / week, 100-200 mg / kg / week, 200-300 mg / kg / week, 300-400 mg / kg / week, 400-500 mg / kg / week, 500-600 mg / kg / week, 600-700 mg / kg / week, 700-800 mg / kg / week, 800-900 mg / kg / week, 900-1000 mg / kg / week, 1000-1100 mg / kg / week, 1100-1200 mg / kg / week, 1200-1300 mg / kg / week, 1300-1400 mg / kg / week, 1400- 1500 mg / kg / week, 1500-1600 mg / kg / week, 1600-1700 mg / kg / week, 1700-1800 mg / kg / week, 1800-1900 mg / kg / week or 1900-2000 mg / kg / week.

[0112] In various embodiments, the methods described herein can treat, reduce the severity of and / or slow the progression of one or more bacterial infections including but not limited to bacterial skin infections (e.g., Cellulitis, Folliculitis, Impetigo, Boils); foodborne illness such as nausea, vomiting, diarrhea, fever, chills and abdominal pain; sexually transmitted diseases such as chlamydia, gonorrhea, syphilis, bacterial vaginosis; and other bacterial infections such as bacterial meningitis, otitis media, urinary tract infection and respiratory tract infections (e.g., sore throat, bronchitis, sinusitis).

[0113] In various embodiments, the mammalian subjects in the methods described herein may have developed antibiotic resistance, where bacteria are no longer sensitive to an antibiotic medication such as one or more of Vancomycin, Ceftobiprole, Ceftaroline, Clindamycin, Dalbavancin, Daptomycin, Fusidic acid, Linezolid, Mupirocin (topical), Oritavancin, Tedizolid, Telavancin, Tigecycline, Aminoglycosides, Carbapenems, Ceftazidime, Cefepime, Ceftobiprole, Ceftolozane / tazobactam, Fluoroquinolones, Piperacillin / tazobactam, Ticarcillin / clavulanic acid, Linezolid, Streptogramins, Tigecycline and Daptomycin.

[0114] In some embodiments, the method described herein further can include administering an antibiotic medication in addition to a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), which may be simultaneously, concurrently, or sequentially administered. Exemplary antibiotic medication includes Vancomycin, Ceftobiprole, Ceftaroline, Clindamycin, Dalbavancin, Daptomycin, Fusidic acid, Linezolid, Mupirocin (topical), Oritavancin, Tedizolid, Telavancin, Tigecycline, Aminoglycosides, Carbapenems, Ceftazidime, Cefepime, Ceftobiprole, Ceftolozane / tazobactam, Fluoroquinolones, Piperacillin / tazobactam, Ticarcillin / clavulanic acid, Linezolid, Streptogramins, Tigecycline and Daptomycin. Pharmaceutical Compositions

[0115] Various embodiments, described herein are directed to a pharmaceutical composition for treatment of bacterial infection in a mammalian subject. The pharmaceutical composition can include an effective amount of a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient.

[0116] The pharmaceutical compositions can contain any pharmaceutically acceptable excipient. “Pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. Examples of excipients include but are not limited to starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, wetting agents, emulsifiers, coloring agents, release agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, antioxidants, plasticizers, gelling agents, thickeners, hardeners, setting agents, suspending agents, surfactants, humectants, carriers, stabilizers, and combinations thereof.

[0117] In various embodiments, the pharmaceutical compositions may be formulated for delivery via any route of administration. “Route of administration” may refer to any administration pathway known in the art, including but not limited to aerosol, nasal, oral, transmucosal, transdermal, parenteral or enteral. “Parenteral” refers to a route of administration that is generally associated with injection, including intraorbital, infusion, intraarterial, intracapsular, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intraspinal, intrasternal, intrathecal, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous, transmucosal, or transtracheal. Via the parenteral route, the compositions may be in the form of solutions or suspensions for infusion or for injection, or as lyophilized powders. Via the enteral route, the pharmaceutical compositions can be in the form of tablets, gel capsules, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid vesicles or polymer vesicles allowing controlled release. Typically, the compositions can be administered by oral consumption or by injection. Methods for these administrations are known to one skilled in the art.

[0118] The pharmaceutical compositions can contain any pharmaceutically acceptable carrier. “Pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue, organ, or portion of the body to another tissue, organ, or portion of the body. For example, the carrier may be a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, or a combination thereof. Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of theformulation. It must also be suitable for use in contact with any tissues or organs with which it may come in contact, meaning that it must not carry a risk of toxicity, irritation, allergic response, immunogenicity, or any other complication that excessively outweighs its therapeutic benefits.

[0119] Another drug delivery system, as a suitable pharmaceutical carrier for a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof), is sustained released or increased circulatory half-life vehicles such as the liposome. Methods of preparing liposome delivery systems are provided in Gabizon et al., Cancer Research (1982) 42:4734; Cafiso, Biochem Biophys Acta (1981) 649:129; and Szoka, Ann Rev Biophys Eng (1980) 9:467. Other drug delivery systems are known in the art and are described in, e.g., Poznansky et al., DRUG DELIVERY SYSTEMS (R. L. Juliano, ed., Oxford, N.Y.1980), pp.253- 315; M. L. Poznansky, Pharm Revs (1984) 36:277.

[0120] The pharmaceutical compositions can also be encapsulated, tableted or prepared in an emulsion or syrup for oral administration. Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition. Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water. Solid carriers include starch, lactose, calcium sulfate, dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

[0121] The pharmaceutical preparations can be made following the conventional techniques of pharmacy involving milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation can be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly p.o. or filled into a soft gelatin capsule.

[0122] After the liquid pharmaceutical composition is prepared, it may be lyophilized to prevent degradation and to preserve sterility. Methods for lyophilizing liquid compositions are known to those of ordinary skill in the art. Just prior to use, the composition may be reconstituted with a sterile diluent (Ringer's solution, distilled water, or sterile saline, for example) which may include additional ingredients. Upon reconstitution, the composition can be administered to subjects using those methods that are known to those skilled in the art.

[0123] The pharmaceutical compositions may be delivered in a therapeutically effective amount. The precise therapeutically effective amount can be the amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given subject. This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the therapeutic compound (including activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), the nature of the pharmaceutically acceptable carrier or carriers in the formulation, and the route of administration. One skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount through routine experimentation, for instance, by monitoring a subject’s response to administration of a compound and adjusting the dosage accordingly. For additional guidance, see Remington: The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000). EXAMPLES

[0124] The following examples are provided to better illustrate the embodiments described herein and are not to be interpreted as limiting the scope of the present application. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the present application. One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the present application.

[0125] It is to be also understood that these examples are not meant to limit the methods used to test the compound(s), and that various modifications to an example described herein (e.g. use of additional cell types, use of different strains of the same cell type, or alternative methods) are well known to those of ordinary skill in the art. Further, the data presented herein is not intended to be comprehensive, but rather serve to demonstrate, by way of example, features of the present application.Synthesis of tert-butyl (3-chloropropyl)carbamate

[0126] In a round-bottomed flask equipped with a magnetic stir bar and a dropping funnel, 3-chloropropylamine HCl (5 g, 1 eq.) and triethylamine (11 mL, 2.1 eq.) was suspended in 30 mL of DCM. The suspension was cooled down to 0 °C by an ice bath. A solution of Boc2O (9.2 g, 1.1 eq.) in 25 mL DCM was added to the dropping funnel and was added to the reaction flask dropwise. Then, the mixture was allowed to warm up to room temperature and stirred overnight. The crude reaction was diluted in DCM and washed with water and brine. Combined organic layers were dried over Na2SO4and evaporated under reduced pressure. The product was purified by a silica gel column chromatography (20% EA / hexanes) to obtain the target compound as a clear oil (97%).1H NMR (500 MHz, CDCl3): į (ppm) 4.64 (s, 1H), 3.59 (t, J = 6 Hz, 2H), 3.26-3.30 (m, 2H), 1.95-1.98 (m, 2H), 1.44 (s, 9H). Synthesis of 3,5-bis(N-Boc-3-aminopropoxy)benzaldehyde

[0127] In a flame-dried round bottom flask equipped with a stir bar, 3,5- dihydroxybenzaldehyde (650 mg, 1 eq.), tert-butyl (3-chloropropyl)carbamate (2 g, 2.3 eq.), and K2CO3(1.5 g, 2.5 eq.) were added under inert atmosphere followed by an addition of 20 mL dry DMF. The resulting suspension was stirred under inert atmosphere at 100 °C for 5 hours. After cooling down to room temperature, the mixture was diluted in DCM, washed with 1 M LiCl, water and brine. The combined organics were dried over Na2SO4, and the solvents were evaporated using a rotary evaporator. The crude reaction was purified by a silica gel column chromatography (40% EA / hexanes) to obtain the target compound as a clear viscous liquid (95%).1H NMR (500 MHz, CDCl3): į (ppm) 9.89 (s, 1H), 6.99 (d, J = 2.5 Hz, 2H), 6.69 (t, J = 2.5 Hz, 1H), 4.71 (s, 2H), 4.05 (t, J = 6 Hz, 4H), 3.31–3.35 (m, 4H), 1.97–2.02 (m, 4H), 1.44 (s, 18H).Synthesis of tert-butyl (3-chloropropyl)(methyl)carbamate

[0128] To a flame dried flask was added tert-butyl (3-chloropropyl)carbamate (800 mg, 1 eq.) and 25 mL of anhydrous THF under inert atmosphere. Methyl iodide (707 mg, 1.2 eq.) was added via syringe. While stirring the mixture, sodium hydride (182 mg, 1.1 eq., 60 wt%) was added slowly. The resulting suspension was maintained at room temperature and allowed to stir for an additional 12 hours. The mixture was concentrated to ~5 mL by rotary evaporation before partioning between ethyl acetate and brine. The organic layer was collected and the aqueous layer was extracted with three additional portions of ethyl acetate. The combined organic layers were dried over Na2SO4and solvents were evaporated by rotary evaporation. The pure product was afforded by silica gel column chromatography (8% EA / hexanes) to obtain tert-butyl (3- chloropropyl)(methyl)carbamate as a clear liquid (80%).1H NMR (500 MHz, CDCl3): į (ppm) 3.56 (t, J = 6.5 Hz, 2H), 3.37 (t, J = 6.8 Hz, 2H), 2.88 (s, 3H), 2.05-1.97 (m, 2H), 1.47 (s, 9H). Synthesis of 3,5-bis(N-Boc-N-methyl-3-aminopropoxy)benzaldehyde

[0129] In a flame-dried round bottom flask equipped with a stir bar, 3,5- dihydroxybenzaldehyde (124 mg, 1 eq.), tert-butyl (3-chloropropyl)carbamate (428 mg, 2.2 eq.), and K2CO3 (309 mg, 2.5 eq.) were added under inert atmosphere followed by an addition of 10 mL dry DMF. The resulting suspension was stirred under inert atmosphere at 100 °C for 5 hours. After cooling down to room temperature, the mixture was diluted in DCM, washed with 1 M LiCl, water and brine. The combined organics were dried over Na2SO4 and solvents were evaporated using a rotary evaporator. The crude reaction was purified by a silica gel column chromatography (30% EA / hexanes) to obtain tert-butyl (3-chloropropyl)(methyl)carbamate as a clear viscous liquid (82%).1H NMR (400 MHz, CDCl3): į (ppm) 9.90 (s, 1H), 7.00 (d, J = 2.3 Hz, 2H), 6.70 (t, J = 2.3 Hz, 1H), 4.03 (t, J = 6.1 Hz, 4H), 3.43 (t, J = 6.9 Hz, 4H), 2.89 (s, 6H), 2.03 (p, J = 6.5 Hz, 4H), 1.45 (s, 18H).General procedure for the Horner-Wadsworth-Emmons reactions

[0130] A flame-dried round-bottomed flask equipped with a magnetic stir bar was added tetraethyl (1,4-phenylenebis(methylene))bis(phosphonate) (1 eq) and a benzaldehyde intermediate (1.95 eq.) in dry THF under inert atmosphere. After cooling the solution down in an ice bath, a solution of NaOtBu in dry THF (2.1 eq.) was slowly added to the mixture via a syringe. The reaction was warmed up to room temperature and was stirred overnight. Then, the mixture was diluted in DCM, washed with water and brine. Combined organic layers were dried over Na2SO4. Volatile solvents were removed using a rotary evaporator. The crude reaction was recrystallized in DCM / hexanes to obtain a pure product. Compound 1 Boc

[0131] Yield: 85%.1H NMR (500 MHz, CDCl3): į (ppm) 7.49 (s, 4H), 7.06 (d, J = 16 Hz, 2H), 7.01 (d, J = 16.5 Hz, 2H), 6.67 (d, J = 2 Hz, 4H), 6.38 (t, J = 2 Hz, 2H), 4.76 (s, 3H), 4.05 (t, J = 5.5 Hz, 8H), 3.32–3.36 (m, 8H), 1.97–2.01 (m, 8H), 1.45 (s, 36H). Compound 2 Boc

[0132] Yield: 90%.1H NMR (500 MHz, CDCl3): į (ppm) 7.51 (s, 2H), 7.12-7.01 (m, 2H), 6.68 (d, J = 2.2 Hz, 2H), 6.40 (t, J = 2.2 Hz, 1H), 4.02 (t, J = 6.1 Hz, 4H), 3.44 (t, J = 6.8 Hz, 4H), 2.91 (s, 6H), 2.04 (q, J = 7.8, 7.0 Hz, 4H), 1.48 (s, 36H). General procedure for Boc deprotection reactions

[0133] A dry reaction vessel containing compound 1 Boc or 2 Boc was added dry chloroform to dissolve the starting material. After that, HCl (g) was periodically bubbled into the solution at room temperature while stirring. During the course of the reaction, small amounts of MeOH was added over time to help dissolve precipitates. After 5 hours, the reaction was dried under reduced pressure to yield the corresponding amine HCl salt with a quantitative yield. Compound 1 HCl

[0134] 1H NMR (500 MHz, CD3OD): į (ppm) 7.56 (s, 4H), 7.18 (d, J = 16.5 Hz, 2H), 7.12 (d, J = 16.5 Hz, 2H), 6.81 (d, J = 2 Hz, 4H), 6.51 (t, J = 2 Hz, 2H), 4.17 (t, J = 5.5 Hz, 8H), 3.18 (t, J = 7.5 Hz, 8H), 2.15–2.20 (m, 8H). Compound 2 HCl

[0135] 1H NMR (500 MHz, CD3OD): į (ppm) 7.56 (s, 4H), 7.18 (d, J = 16.5 Hz, 2H), 7.12 (d, J = 16.5 Hz, 2H), 6.82 (d, J = 2 Hz, 4H), 6.52 (t, J = 2 Hz, 2H), 4.17 (t, J = 6 Hz, 8H), 3.25 (t, J = 7 Hz, 8H), 2.76 (s, 12H), 2.18–2.23 (m, 8H). General procedure for the preparation of amine intermediates from an alkyl iodide

[0136] To a dry 1 Dr vail was added 1,4-bis((E)-3,5-bis(3-iodopropoxy)styryl)benzene (1 eq.) and 1 mL of dry DMF under inert atmosphere. 40 equivalents of the appropriate primary amine was added quickly via syringe while stirring rapidly. After 12 hours at room temperature, the solution was added to ~3 mL 2M HCl in diethyl ether. The precipitate was collected by centrifugation and washed with two additional portions of diethyl ether. The solid was dissolved in water and partitioned between DCM and 2M NaOH. The organic layer was collected. The aqueous layer was extracted with an additional five portions of DCM. The organic layers were combined, dried over Na2SO4 and concentrated to afford a green, highly-viscous oil. No further purification was necessary. The synthesis of (1,4-bis((E)-3,5-bis(3-iodopropoxy)styryl)benzene) has been described previously (See Limwongyut et al.. Chem. Sci. (2020) 11(31):8138-8144). Compound 3

[0137] Yield: 97%.1H NMR (500 MHz, CDCl3): į (ppm) 7.51 (s, 4H), 7.11–7.03 (m, 4H), 6.69 (d, J = 2.2 Hz, 4H), 6.42 (t, J = 2.2 Hz, 2H), 4.08 (t, J = 6.2 Hz, 8H), 2.92 (t, J = 6.9 Hz, 8H), 2.17 (tt, J = 6.7, 3.6 Hz, 4H), 2.00 (p, J = 6.5 Hz, 8H), 0.47 (td, J = 6.5, 4.3 Hz, 8H), 0.40- 0.34 (m, 8H).Compound 4

[0138] Yield: 98%.1H NMR (500 MHz, CDCl3): į (ppm) 7.51 (s, 4H), 7.11–7.03 (m, 4H), 6.69 (d, J = 2.2 Hz, 4H), 6.42 (t, J = 2.2 Hz, 2H), 4.09 (t, J = 6.2 Hz, 8H), 2.83 (t, J = 6.9 Hz, 8H), 2.66-2.60 (m, 8H), 2.01 (p, J = 6.5 Hz, 8H), 1.55 (dt, J = 14.5, 7.4 Hz, 8H), 0.95 (t, J = 7.4 Hz, 12H). General procedure for the syntheses of imidate salts Procedure A

[0139] In a dry microwave reaction tube with a magnetic stir bar was added 2 mL of dry MeOH under inert atmosphere. MeOH was bubbled with HCl (g) for 30 minutes at room temperature. After saturating MeOH with HCl, nitrile (1 g) was added to the reaction vessel. The reaction vessel was then sealed and stirred at room temperature for 5 hours. Removal of volatile compounds from the reaction under high vacuum yielded the corresponding imidate salt. Procedure B

[0140] An amide was added to a flame-dried round bottomed flask equipped with a stir bar and was dissolved in anhydrous diethyl ether before cooling to 0 °C. Methyl triflate was then slowly added to the solution via a syringe. The mixture was allowed to stir at room temperature overnight. Dry K2CO3powder was then added, and the suspension was stirred for 30 minutes. The mixture was filtered and added to HCl in ether (2 M). The mixture was then centrifuged, andthe supernatant was discarded. The resulting oil was dried under high vacuum to obtain the corresponding imidate salt as an oil. Compound a

[0141] Yield: 65%.1H NMR (500 MHz, CD3CN): į (ppm) 4.16 (s, 3H), 2.70 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H). Compound b

[0142] Yield: 80%.1H NMR (500 MHz, CD3CN): į (ppm) 12.26 (s, 1H), 10.62 (s, 1H), 4.08 (s, 3H), 2.28–2.33 (m, 1H), 1.19–1.28 (m, 4H). Compound c

[0143] Yield: 70%.1H NMR (500 MHz, CD3CN): į (ppm) 12.20 (s, 1H), 11.22 (s, 1H), 4.19 (s, 3H), 2.58 (d, J = 7 Hz, 2H), 1.07–1.13 (m, 1H), 0.50–0.60 (m, 2H), 0.33–0.36 (m, 2H). Compound d

[0144] Yield: 68%.1H NMR (500 MHz, CD3CN): į (ppm) 4.17 (s, 1H), 3.13 (d, J = 4.3 Hz, 1H), 2.30 (s, 1H).Compound e

[0145] Yield: 63%.1H NMR (500 MHz, CD3CN): į (ppm) 4.26 (s, 3H), 3.84-3.77 (m, 2H), 2.92-2.86 (m, 2H), 2.25 (dq, J = 8.8, 7.7 Hz, 2H). Compound f

[0146] Yield: 62%.1H NMR (500 MHz, CD3CN): į (ppm) 4.18 (s, 3H), 2.94 (tt, J = 7.4, 3.8 Hz, 1H), 2.46 (s, 3H), 1.15-1.10 (m, 3H), 0.98 (tdd, J = 7.2, 2.0, 0.9 Hz, 3H). General procedure for the syntheses of amidine compounds

[0147] If the amine intermediate is a HCl salt, neutralize the amine HCl by basic water extractions or treatments with Amberlyst A21 resin to obtain a free base form and evaporate solvents to complete dryness before use.

[0148] In a flame-dried 1-Dram vial, amine intermediate (18 mg) was dissolved in 0.4 mL of dry DMF under inert atmosphere. Meanwhile, in another 1-Dram vial, imidate HCl salt was neutralized with 2 M aqueous K2CO3and extracted with chloroform. After the extraction, 0.2 mL of chloroform (containing 10 eq. of imidate) was transferred to the reaction vial. Acetic acid (4 eq.) was slowly added to the mixture. The reaction was stirred at 40 °C for 1 day. The crude reaction was poured into Et2O containing additional equivalent of acetic acid to precipitate the product. The crude product was centrifuged and washed with Et2O and dried under vacuum. The crude product was dissolved in a minimal water and was purified by a reverse-phase silica gel column chromatography using a flash chromatography system (Gradient: water to 40% acetonitrile in water with 0.1% acetic acid as an additive). Purified fractions were combined and lyophilized to obtain pure product as white solid.Compound 1a

[0149] Yield: 91%.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.60 (s, 4H), 7.26 (d, J = 16.5 Hz, 2H), 7.17 (d, J = 16 Hz, 2H), 6.79 (s, 4H), 6.44 (d, J = 2.5 Hz, 2H), 4.08 (t, J = 6.5 Hz, 8H), 3.36 (t, J = 7 Hz, 8H), 2.38-2.43 (m, 8H), 1.96-2.00 (m, 8H), 1.67 (s, 12H), 1.14 (t, J = 8 Hz, 12H). Formula A

[0150] Yield: 92%.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.60 (s, 4H), 7.27 (d, J = 16.5 Hz, 2H), 7.18 (d, J = 16.5 Hz, 2H), 6.80 (s, 4H), 6.44 (s, 2H), 4.08 (t, J = 6.5 Hz, 8H), 3.39 (t, J = 7 Hz, 8H), 1.96-2.02 (m, 8H), 1.93-1.94 (m, 4H), 1.69 (s, 12H), 1.04-1.11 (m, 8H), 0.97- 1.03 (m, 8H).Formula G

[0151] Yield: 86%.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.60 (s, 4H), 7.27 (d, J = 16.5 Hz, 2H), 7.18 (d, J = 16.5 Hz, 2H), 6.80 (s, 4H), 6.44 (s, 2H), 4.10 (t, J = 6 Hz, 8H), 3.42 (t, J = 7 Hz, 8H), 2.33 (d, J = 7.5 Hz, 8H), 1.98-2.04 (m, 8H), 1.71 (s, 9H), 1.06-1.10 (m, 4H), 0.43- 0.47 (m, 8H), 0.27-0.31 (m, 8H). Formula H

[0152] Yield: 82%.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.60 (s, 4H), 7.27 (d, J = 16.5 Hz, 2H), 7.18 (d, J = 16 Hz, 2H), 6.79 (s, 4H), 6.43 (s, 2H), 4.07 (t, J = 6.5 Hz, 8H), 3.36- 3.44 (m, 8H), 2.79-2.86 (m, 12H), 2.15 (s, 12H), 1.99 (t, J = 6 Hz, 8H), 1.70 (s, 12H). Formula J

[0153] Yield: quant.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.62 (s, 4H), 7.30 (d, J = 16 Hz, 2H), 7.20 (d, J = 17 Hz, 2H), 6.82 (s, 4H), 6.46 (s, 2H), 4.09–4.10 (m, 8H), 3.50-3.54 (m, 8H), 3.39-3.42 (m, 8H), 2.73-2.75 (m, 8H), 1.97-2.01 (m, 16H), 1.74 (s, 6H). Formula K

[0154] Yield: quant.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.60 (s, 4H), 7.26 (d, J = 16.5 Hz, 2H), 7.18 (d, J = 16 Hz, 2H), 6.79 (s, 4H), 6.43 (s, 2H), 4.06 (t, J = 6 Hz, 8H), 3.23- 3.51 (m, 8H), 2.62 (m, 4H), 2.19 (s, 12H), 1.96 (m, 8H), 1.70 (s, 12H), 0.71 (m, 8H), 0.57 (m, 8H). Formula D

[0155] Yield: quant.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.56 (s, 4H), 7.22 (d, J = 16 Hz, 2H), 7.14 (d, J = 16 Hz, 2H), 6.76 (s, 4H), 6.38 (d, J = 2.5 Hz, 2H), 4.02 (t, J = 5.5 Hz, 8H), 3.58 (t, J = 7 Hz, 8H), 3.04 (s, 12H), 2.45-2.50 (m, 8H), 1.97-2.01 (m, 8H), 1.64 (s, 12H), 1.08 (t, J = 6 Hz, 12H).Formula B

[0156] Yield: quant.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.61 (s, 4H), 7.28 (d, J = 16.5 Hz, 2H), 7.19 (d, J = 16 Hz, 2H), 6.80 (d, J = 2 Hz, 4H), 6.44 (t, J = 2 Hz, 2H), 4.08 (t, J = 6 Hz, 8H), 3.75 (t, J = 7.5 Hz, 8H), 3.13 (s, 12H), 2.02–2.08 (m, 8H), 1.90-1.96 (m, 4H), 1.70 (s, 9H), 0.96-0.98 (m, 8H), 0.91-0.95 (m, 8H). Formula E

[0157] Yield: quant.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.61 (s, 4H), 7.27 (d, J = 16.5 Hz, 2H), 7.20 (d, J = 16.5 Hz, 2H), 6.80 (d, J = 2 Hz, 4H), 6.44 (s, 2H), 4.07 (t, J = 6 Hz, 8H), 3.60 (t, J = 7 Hz, 8H), 2.76-2.79 (m, 4H), 2.57–2.62 (m, 8H), 2.02-2.06 (m, 8H), 1.71 (s, 12H), 1.11 7.5 Hz, 12H), 0.93-0.97 (m, 8H), 0.78–0.82 (m, 8H).Formula F

[0158] Yield: quant.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.61 (s, 4H), 7.27 (d, J = 16.5 Hz, 2H), 7.19 (d, J = 16.5 Hz, 2H), 6.80 (d, J = 2H, 4H), 6.44 (t, J = 2.5 Hz, 2H), 4.07 (t, J = 6 Hz, 8H), 3.57 (t, J = 7.5 Hz, 8H), 3.35 (t, J = 8 Hz, 8H), 2.502.54 (m, 8H), 2.00-2.05 (m, 8H), 1.68 (s, 12H), 1.55-1.60 (m, 8H), 1.13 (t, J = 7.5 Hz, 12H), 0.88 (t, J = 7.5 Hz, 12H). Formula C

[0159] Yield: quant.1H NMR (500 MHz, DMSO-d6): į (ppm) 7.61 (s, 4H), 7.28 (d, J = 16.5 Hz, 2H), 7.20 (d, J = 16.5 Hz, 2H), 6.81 (d, J = 2.5 Hz, 4H), 6.44 (t, J = 2.5 Hz, 2H), 4.09 (t, J = 6 Hz, 8H), 3.70 (t, J = 7.5 Hz, 8H), 3.48 (t, J = 8 Hz, 8H), 2.03–2.08 (m, 8H), 1.94-1.99 (m, 4H), 1.72 (s, 9H), 1.57-1.65 (m, 8H), 1.02-1.05 (m, 8H), 0.95-1.00 (m, 8H), 0.89 (t, J = 7.5 Hz, 12H).ņormula L

[0160] Each of the following1H NMR information is for Formula L.

[0161] Intermediate A:1H NMR (500 MHz, CDCl3): G (ppm) 9.91 (s, 1H), 7.21 (d, J = 2.3 Hz, 2H), 6.98 (t, J = 2.3 Hz, 1H), 5.21 (s, 4H), 3.49 (s, 6H).

[0162] Intermediate B:1H NMR (500 MHz, CDCl3): G (ppm) 10.35 (s, 2H), 8.16 (s, 2H).

[0163] Intermediate C:1H NMR (500 MHz, DMSO-d6): G (ppm) 7.64 (s, 2H), 5.55 (t, J = 5.5 Hz, 2H), 4.48 (d, J = 5.4 Hz, 4H).

[0164] Intermediate D:1H NMR (500 MHz, CDCl3): G (ppm) 7.98 (s, 2H), 4.70 (s, 4H).

[0165] Intermediate E:1H NMR (500 MHz, CDCl3): G (ppm) 7.64 (d, J = 2.1 Hz, 2H), 4.12-4.01 (m, 8H), 3.32 (d, J = 20.7 Hz, 4H), 1.27 (t, J = 7.1 Hz, 12H).

[0166] Intermediate F:1H NMR (500 MHz, CDCl3): G (ppm) 7.85 (s, 2H), 7.32 (d, J = 16.2 Hz, 2H), 6.98 (d, J = 16.1 Hz, 2H), 6.90 (d, J = 2.2 Hz, 4H), 6.72 (t, J = 2.2 Hz, 2H), 5.20 (s, 8H), 3.51 (s, 12H).

[0167] Intermediate G:1H NMR (500 MHz, DMSO-d6): G (ppm) 9.37 (s, 4H), 8.13 (s, 2H), 7.26 (d, J = 16.1 Hz, 2H), 7.15 (d, J = 16.1 Hz, 2H), 6.48 (d, J = 2.2 Hz, 4H), 6.20 (t, J = 2.1 Hz, 2H).

[0168] Intermediate H:1H NMR (500 MHz, CDCl3): G (ppm) 7.85 (s, 2H), 7.32 (d, J = 16.1 Hz, 2H), 6.96 (d, J = 16.1 Hz, 2H), 6.69 (d, J = 2.2 Hz, 4H), 6.42 (t, J = 2.2 Hz, 2H), 4.75 (s, 4H), 4.05 (t, J = 6.0 Hz, 8H), 3.34 (d, J = 6.5 Hz, 8H), 2.00 (p, J = 6.4 Hz, 8H), 1.45 (s, 36H).

[0169] Intermediate J:1H NMR (500 MHz, CD3OD): G (ppm) 8.01 (s, 2H), 7.38 (d, J = 16.2 Hz, 2H), 7.17 (d, J = 16.1 Hz, 2H), 6.83 (d, J = 2.2 Hz, 4H), 6.57 (t, J = 2.1 Hz, 2H), 4.17 (t, J = 5.8 Hz, 8H), 3.18 (t, J = 7.3 Hz, 8H), 2.70 (s, 12H), 2.17 (p, J = 6.2 Hz, 8H).

[0170] Formula L:1H NMR (500 MHz, CD3OD): G (ppm) 9.11 (s, 4H), 8.50 (s, 4H), 8.37 (s, 4H), 8.01 (s, 2H), 7.36 (d, J = 16.2 Hz, 2H), 7.16 (d, J = 16.1 Hz, 2H), 6.80 (d, J = 2.1 Hz, 4H), 6.54 (t, J = 2.2 Hz, 2H), 4.13 (t, J = 5.8 Hz, 8H), 3.51 (q, J = 6.6 Hz, 8H), 2.70 (s, 12H), 2.15 (p, J = 6.4 Hz, 8H), 1.88 (ddd, J = 13.1, 8.6, 5.1 Hz, 4H), 1.25-1.04 (m, 16H). Formula M

[0171] Each of the following1H NMR information is for Formula M.

[0172] Intermediate A:1H NMR (500 MHz, CDCl3): G (ppm)10.39 (s, 1H), 7.27 (d, J = 2.8 Hz, 1H), 7.10 (d, J = 2.8 Hz, 1H), 5.27 (s, 2H), 5.19 (s, 2H), 3.54 (s, 3H), 3.47 (s, 3H).

[0173] Intermediate B:1H NMR (500 MHz, CDCl3): G (ppm) 7.57-7.52 (m, 6H), 7.08 (d, J = 2.7 Hz, 2H), 7.02 (d, J = 16.1 Hz, 2H), 6.82 (d, J = 2.6 Hz, 2H), 5.25 (s, 4H), 5.21 (s, 4H), 3.54 (s, 6H), 3.51 (s, 6H).

[0174] Intermediate C:1H NMR (500 MHz, CD3OD): G (ppm) 7.56 (s, 4H), 7.51 (d, J = 16.1 Hz, 2H), 7.02 (d, J = 16.1 Hz, 2H), 6.72 (d, J = 2.7 Hz, 2H), 6.38 (d, J = 2.6 Hz, 2H).

[0175] Intermediate D:1H NMR (500 MHz, CDCl3): G (ppm) 7.57 (s, 4H), 7.54 (d, J = 16.1 Hz, 2H), 7.02 (d, J = 16.1 Hz, 2H), 6.84 (d, J = 2.6 Hz, 2H), 6.42 (d, J = 2.6 Hz, 2H), 5.33 (s, 2H), 4.73 (s, 2H), 4.10-4.06 (m, 8H), 3.44-3.30 (m, 8H), 2.09-1.97 (m, 8H), 1.45 (s, 36H).

[0176] Intermediate E:NMR (500 MHz, CDCl3): G (ppm) 7.61 (s, 4H), 7.57 (d, J = 16.1 Hz, 2H), 7.18 (d, J = 16.2 Hz, 2H), 7.03 (d, J = 2.7 Hz, 2H), 6.67 (d, J = 2.6 Hz, 2H), 4.22 (td, J = 5.7, 2.6 Hz, 8H), 3.26 (t, J = 7.2 Hz, 4H), 3.20 (t, J = 7.2 Hz, 4H), 2.70 (s, 12H), 2.27-2.16 (m, 8H).

[0177] Formula M:1H NMR (500 MHz, CD3OD): G (ppm) 7.61 (s, 4H), 7.58 (d, J = 16.1 Hz, 2H), 7.17 (d, J = 16.1 Hz, 2H), 7.00 (d, J = 2.6 Hz, 2H), 6.63 (d, J = 2.6 Hz, 2H), 4.17 (q, J = 5.2 Hz, 8H), 3.56 (t, J = 6.9 Hz, 4H), 3.51 (t, J = 6.9 Hz, 4H), 2.23-2.11 (m, 8H), 1.89 (s, 12H), 1.86 (dt, J = 8.3, 5.1 Hz, 4H), 1.23-1.09 (m, 16H). Formula N

[0178] Each of the following1H NMR information is for Formula N.

[0179] Intermediate A:1H NMR (500 MHz, CDCl3): G (ppm) 7.88 (s, 2H), 4.42 (q, J = 7.2 Hz, 4H), 1.41 (t, J = 7.1 Hz, 6H).

[0180] Intermediate B:1H NMR (500 MHz, DMSO-d6): G (ppm) 7.50 (s, 2H), 5.51 (t, J = 5.6 Hz, 2H), 4.53 (d, J = 5.4 Hz, 4H).

[0181] Intermediate C:1H NMR (500 MHz, CDCl3): G (ppm) 7.48 (s, 2H), 4.50 (s, 4H).

[0182] Intermediate D:1H NMR (500 MHz, CDCl3): G (ppm) 7.46 (d, J = 2.2 Hz, 2H), 4.07 (p, J = 7.2 Hz, 8H), 3.29 (d, J = 20.7 Hz, 4H), 1.27 (t, J = 7.0 Hz, 12H).

[0183] Intermediate E:1H NMR (500 MHz, CDCl3): G (ppm) 7.68 (s, 2H), 7.36 (d, J = 16.1 Hz, 2H), 7.00 (d, J = 16.1 Hz, 2H), 6.69 (d, J = 2.2 Hz, 4H), 6.42 (t, J = 2.2 Hz, 2H), 4.77 (bs, 4H), 4.05 (t, J = 6.0 Hz, 8H), 3.34 (q, J = 6.3 Hz, 8H), 2.00 (p, J = 6.1 Hz, 8H), 1.45 (s, 36H).

[0184] Intermediate F:1H NMR (500 MHz, DMSO-d6): G (ppm) 8.00 (s, 2H), 7.80 (bs, 12H), 7.42 (d, J = 16.2 Hz, 2H), 7.35 (d, J = 16.3 Hz, 2H), 6.83 (d, J = 2.2 Hz, 4H), 6.53 (t, J = 2.2 Hz, 2H), 4.10 (t, J = 6.1 Hz, 8H), 2.98 (q, J = 6.6 Hz, 8H), 2.36 (s, 12H), 2.03 (p, J = 6.5 Hz, 8H).

[0185] Formula N:1H NMR (500 MHz, CD3OD): G (ppm) 9.12 (s, 4H), 8.51 (s, 4H), 8.38 (s, 4H), 7.87 (s, 2H), 7.42 (d, J = 16.2 Hz, 2H), 7.22 (d, J = 16.2 Hz, 2H), 6.81 (d, J = 2.2 Hz, 4H), 6.54 (t, J = 2.2 Hz, 2H), 4.13 (t, J = 5.8 Hz, 8H), 3.51 (q, J = 6.6 Hz, 8H), 2.69 (s, 12H), 2.15 (p, J = 6.4 Hz, 8H), 1.87 (ddd, J = 13.3, 8.6, 5.0 Hz, 4H), 1.22-1.10 (m, 16H).Formula O

[0186] Each of the following1H NMR information is for Formula O.

[0187] Intermediate A:1H NMR (500 MHz, CDCl3): G (ppm) 6.77 (d, J = 2.7 Hz, 1H), 6.46 (d, J = 2.7 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H).

[0188] Intermediate B:1H NMR (500 MHz, CDCl3): G (ppm) 10.50 (s, 1H), 7.01 (d, J = 2.9 Hz, 1H), 6.73 (d, J = 2.9 Hz, 1H), 3.91 (s, 3H), 3.84 (s, 3H).

[0189] Intermediate C:1H NMR (500 MHz, CDCl3): G (ppm) 7.62-7.55 (m, 6H), 7.07 (d, J = 16.2 Hz, 2H), 6.83 (d, J = 2.7 Hz, 2H), 6.47 (d, J = 2.6 Hz, 2H), 3.90 (s, 6H), 3.88 (s, 6H).

[0190] Intermediate D:1H NMR (500 MHz, CD3OD): G (ppm) 7.56 (s, 4H), 7.52 (d, J = 16.2 Hz, 2H), 7.06 (d, J = 16.2 Hz, 2H), 6.72 (d, J = 2.7 Hz, 2H), 6.37 (d, J = 2.7 Hz, 2H).

[0191] Intermediate E:1H NMR (500 MHz, CDCl3): G (ppm) 7.58-7.53 (m, 6H), 7.05 (d, J = 16.2 Hz, 2H), 6.83 (d, J = 2.6 Hz, 2H), 6.44 (d, J = 2.7 Hz, 2H), 5.28 (s, 2H), 4.75 (s, 2H), 4.13-4.02 (m, 8H), 3.43-3.30 (m, 8H), 2.10-1.95 (m, 8H), 1.45 (s, 36H).

[0192] Intermediate F:1H NMR (500 MHz, DMSO-d6): G (ppm) 7.79 (s, 12H), 7.67 (s, 4H), 7.50 (d, J = 16.2 Hz, 2H), 7.37 (d, J = 16.2 Hz, 2H), 7.06 (d, J = 2.6 Hz, 2H), 6.69 (d, J = 2.6 Hz, 2H), 4.16 (q, J = 6.4 Hz, 8H), 3.00 (q, J = 7.2 Hz, 8H), 2.34 (s, 12H), 2.05 (q, J = 6.9 Hz, 8H).

[0193] Formula O:1H NMR (500 MHz, CD3OD): G (ppm) 9.13 (s, 4H), 8.51 (s, 4H), 8.37 (s, 4H), 7.62 (s, 4H), 7.58 (d, J = 16.3 Hz, 2H), 7.22 (d, J = 16.2 Hz, 2H), 7.00 (d, J = 2.6 Hz, 2H), 6.67 (d, J = 2.6 Hz, 2H), 4.18 (t, J = 5.8 Hz, 8H), 3.59-3.48 (m, 8H), 2.70 (s, 12H), 2.23-2.11 (m, 8H), 1.88 (td, J = 8.5, 3.6 Hz, 4H), 1.23-1.09 (m, 16H). Formula P

[0194] Each of the following1H NMR information is for Formula P.

[0195] Intermediate A:1H NMR (500 MHz, CDCl3): G (ppm) 7.34 (s, 1H), 6.52 (s, 1H), 3.90 (s, 6H).

[0196] Intermediate B:1H NMR (500 MHz, CDCl3): G (ppm) 10.45 (s, 1H), 6.71 (s, 1H), 3.95 (s, 6H).

[0197] Intermediate C:1H NMR (500 MHz, CDCl3): G (ppm) 7.56 (s, 4H), 7.13 (d, J = 3.7 Hz, 4H), 6.53 (s, 2H), 3.94 (s, 12H).

[0198] Intermediate D:1H NMR (500 MHz, CD3OD): G (ppm) 7.58 (s, 4H), 7.16 (d, J = 16.6 Hz, 2H), 7.07 (d, J = 16.6 Hz, 2H), 6.54 (s, 2H).

[0199] Intermediate E:1H NMR (500 MHz, CDCl3): G (ppm) 7.57 (s, 4H), 7.11 (d, J = 3.2 Hz, 4H), 6.53 (s, 2H), 5.18 (s, 4H), 4.11 (t, J = 5.7 Hz, 8H), 3.39 (q, J = 6.2 Hz, 8H), 2.05 (p, J = 5.8 Hz, 8H), 1.44 (s, 36H).

[0200] Intermediate F:1H NMR (500 MHz, DMSO-d6): G (ppm) 7.82 (t, J = 5.8 Hz, 12H), 7.66 (s, 4H), 7.18 (d, J = 16.6 Hz, 2H), 7.02 (d, J = 16.6 Hz, 2H), 6.95 (s, 2H), 4.24 (t, J = 6.0 Hz, 8H), 3.01 (h, J = 6.0 Hz, 8H), 2.36 (s, 12H), 2.07 (p, J = 6.4 Hz, 8H).

[0201] Formula P:1H NMR (500 MHz, CD3OD): G (ppm) d 9.15 (s, 4H), 8.52 (s, 4H), 8.39 (s, 4H), 7.60 (s, 4H), 7.19 (d, J = 16.6 Hz, 2H), 7.08 (d, J = 16.6 Hz, 2H), 6.89 (s, 2H), 4.27 (t, J = 5.7 Hz, 8H), 3.56 (q, J = 6.5 Hz, 8H), 2.70 (s, 12H), 2.22 (p, J = 6.4 Hz, 8H), 1.88 (ddd, J = 13.3, 8.5, 5.1 Hz, 4H), 1.23 – 1.11 (m, 16H). Formula Q

[0202] Each of the following1H NMR information is for Formula Q.

[0203] Intermediate A:1H NMR (500 MHz, CDCl3): G (ppm) 6.87 (dd, J = 10.5, 8.8 Hz, 1H), 6.39 (dd, J = 7.2, 2.9 Hz, 1H), 6.36 (ddd, J = 8.7, 3.6, 2.9 Hz, 1H), 0.99 (s, 9H), 0.97 (s, 9H), 0.18 (d, J = 1.0 Hz, 6H), 0.17 (s, 6H).

[0204] Intermediate B:1H NMR (500 MHz, CDCl3): G (ppm) 10.28 (s, 1H), 6.86 (dd, J = 4.5, 3.0 Hz, 1H), 6.65 (dd, J = 7.2, 3.0 Hz, 1H), 1.01 (s, 9H), 0.97 (s, 9H), 0.22 (d, J = 1.0 Hz, 6H), 0.19 (s, 6H).

[0205] Intermediate C:1H NMR (500 MHz, CDCl3): G (ppm) 7.52 (s, 4H), 7.22 (d, J = 16.4 Hz, 2H), 7.07 (d, J = 16.4 Hz, 2H), 6.65 (dd, J = 5.2, 2.9 Hz, 2H), 6.33 (dd, J = 7.0, 2.8 Hz, 2H), 1.01 (s, 18H), 1.00 (s, 18H), 0.21 (s, 24H).

[0206] Intermediate D:1H NMR (400 MHz, CD3OD): G (ppm) 7.54 (s, 4H), 7.24 (d, J = 16.4 Hz, 2H), 7.12 (d, J = 16.4 Hz, 2H), 6.54 (dd, J = 5.1, 2.9 Hz, 2H), 6.32 (dd, J = 7.2, 2.9 Hz, 2H).

[0207] Intermediate E:1H NMR (500 MHz, CDCl3): G (ppm) 7.53 (s, 4H), 7.29 (s, 2H), 7.12 (d, J = 16.4 Hz, 2H), 6.67 (dd, J = 5.0, 2.8 Hz, 2H), 6.46 (dd, J = 6.8, 2.8 Hz, 2H), 4.88 (s, 2H), 4.74 (s, 2H), 4.08 (t, J = 6.0 Hz, 4H), 4.03 (t, J = 6.0 Hz, 4H), 3.35 (t, J = 5.6 Hz, 8H), 2.01 (dt, J = 17.2, 6.3 Hz, 8H), 1.45 (s, 36H).

[0208] Intermediate F:1H NMR (500 MHz, DMSO-d6): G (ppm) 7.81 (s, 12H), 7.65 (s, 4H), 7.38 (d, J = 16.5 Hz, 2H), 7.29 (d, J = 16.5 Hz, 2H), 6.93 (dd, J = 5.2, 2.8 Hz, 2H), 6.70(dd, J = 7.0, 2.8 Hz, 2H), 4.13 (dt, J = 12.7, 6.1 Hz, 8H), 2.98 (s, 8H), 2.36 (s, 12H), 2.04 (h, J = 6.2 Hz, 8H).

[0209] Formula Q:1H NMR (500 MHz, CD3OD): G (ppm) 9.11 (d, J = 7.5 Hz, 4H), 8.52 (s, 4H), 8.38 (d, J = 7.8 Hz, 4H), 7.59 (s, 4H), 7.32 (d, J = 16.5 Hz, 2H), 7.26 (d, J = 16.5 Hz, 2H), 6.85 (dd, J = 5.0, 2.8 Hz, 2H), 6.67 (dd, J = 6.9, 2.8 Hz, 2H), 4.17 (t, J = 5.8 Hz, 4H), 4.13 (t, J = 5.8 Hz, 4H), 3.51 (p, J = 6.1 Hz, 8H), 2.70 (s, 11H), 2.22 – 2.10 (m, 8H), 1.88 (dq, J = 8.3, 4.1 Hz, 4H), 1.23 – 1.10 (m, 16H). Formula R

[0210] Each of the following1H NMR information is for Formula R.

[0211] Intermediate A:1H NMR (400 MHz, CDCl3): G (ppm) 7.41 (d, J = 16.7 Hz, 2H), 7.04 (d, J = 16.6 Hz, 2H), 6.69 (d, J = 2.2 Hz, 4H), 6.44 (t, J = 2.2 Hz, 2H), 4.75 (s, 3H), 4.05 (t, J = 5.9 Hz, 8H), 3.40-3.30 (m, 8H), 2.00 (p, J = 6.4 Hz, 8H), 1.45 (s, 36H).

[0212] Intermediate B:1H NMR (400 MHz, CD3OD): G (ppm) 7.47 (d, J = 16.7 Hz, 2H), 7.15 (d, J = 16.7 Hz, 2H), 6.84 (d, J = 2.2 Hz, 4H), 6.60 (t, J = 2.2 Hz, 2H), 4.17 (t, J = 5.8 Hz, 8H), 3.18 (t, J = 7.3 Hz, 8H), 2.70 (s, 12H), 2.21-2.08 (m, 8H).

[0213] Formula R:1H NMR (400 MHz, CD3OD): G (ppm) 9.13 (s, 3H), 8.52 (s, 3H), 8.38 (s, 3H), 7.47 (d, J = 16.6 Hz, 2H), 7.15 (d, J = 16.7 Hz, 2H), 6.82 (d, J = 2.2 Hz, 4H), 6.57 (t, J = 2.2 Hz, 2H), 4.13 (t, J = 5.8 Hz, 8H), 3.50 (q, J = 6.8 Hz, 8H), 2.69 (s, 12H), 2.14 (p, J = 6.3 Hz, 8H), 1.86 (ddd, J = 13.3, 8.4, 5.1 Hz, 4H), 1.24-1.08 (m, 16H). Susceptibility Test

[0214] The minimum inhibitory concentration (MIC) was determined according to the Clinical and Laboratory Standards Institute (CLSI) guidelines by broth dilution. Bacteria were cultured in an appropriate medium (such as Cation-Adjusted Muller Hinton Broth) for 6-12 hours and diluted into same medium containing 2-fold serial dilutions of antibiotics. MIC values were derived after 14-20 hour incubation, and were the result of at least 3 independent determinations. The MIC study included Gram-negative strains Salmonella enterica Typhimurium (ST) ATCC 14028, E. coli (EC) ATCC 25922, Pseudomonas aeruginosa (PA) ATCC 27853, and Klebsiella pneumoniae (KPN) ATCC 700603 and Gram-positive strain S. aureus (SA) ATCC 259213. Cytotoxicity

[0215] Cellular cytotoxicity was assessed using an MTT viability assay. HepG2 (ATCC HB-8065) cells were seeded at 1×104cells / well in 96 well plates over night at 37 °C in DMEM supplemented with 10% FBS before use. Compounds were serially diluted with 2-fold dilution in culture media to afford a concentration ranging from 8 to 1024 ^g / mL. After 24h incubation, 10μL of a 5 mg / mL solution of MTT was added to each well. After incubation for 2- 4 h, upon discard of previous media, 100 ^L of DMSO as solubilizing solution was added to each well, and absorbance at 570 nm were measured on a plate reader. Percent viability was determined by dividing background-corrected absorbance measurements by background correctedmeasurements for untreated cells. The lowest concentration for which percent viability was less than 50% was deemed the cytotoxicity IC50.

[0216] Table 1 shows MIC results, cytotoxicity, and RP-HPLC retention times for different COEs. The MIC and cytotoxicity results for previously-described quaternary ammonium COEs COE2-3C, COE2-3C-C4butyl, and COE2-3C-C4hexyl are consistent with previous data (See Limwongyut et al., Chem. Sci. (2020) 11(31):8138-8144). TABLE 1

[0217] As shown herein, compounds of Formula (I) have biology activity against Gram-positive and Gram-negative bacteria, varying degrees of cytotoxicity, and varying hydrophobicity. Specific comparisons between compounds of Formula (I) can be made to highlight impacts, both expected and unexpected, of chemical structure on activity and safety. For example, previously-described COE2-3C-C4butyl and Formula C have similar hydrophobicity and cytotoxicity, however, unexpectedly Formula C is more active against all tested bacterial strains. Formula C and Formula K have different cytotoxicity and hydrophobicity, however, unexpectedly identical activities against all tested bacterial strains. Formula K and Formula A have similar hydrophobicity and cytotoxicity, however, unexpectedly Formula A is more active against alltested bacterial strains. Formula A has similar cytotoxicity and an intermediate hydrophobicity between COE2-3C and COE2-3C-C4butyl, however, unexpectedly has considerably higher activity against all tested bacterial strains. Taken together, these observations serve to illustrate a hydrophobicity / cytotoxicity correlation and the high activity of compounds described by Formula (I) (including pharmaceutically acceptable salts thereof) that could not have been predicted.

[0218] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. The various embodiments described above can be combined to provide further embodiments. These and other changes can be made to the embodiments in light of the above-detailed description. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the present disclosure. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:wherein: R1A, R2A, R3Aand R4Aare independently selected from the group consisting of hydrogen, an unsubstituted C1-4alkyl and an unsubstituted C3-6cycloalkyl; R1Bis hydrogen or an unsubstituted C1-4 alkyl; and R1Cis an unsubstituted C1-4 alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4 alkyl); or R1Band R1Care taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7-membered ring; R2Bis hydrogen or an unsubstituted C1-4 alkyl; and R2Cis an unsubstituted C1-4 alkyl, an unsubstituted C3-6cycloalkyl and an unsubstituted C3-6cycloalkyl(an unsubstituted C1-4alkyl); or R2Band R2Care taken together along with each atom to which R2Band R2Care attached to form a 5-, 6-, or 7-membered ring; R3Bis hydrogen or an unsubstituted C1-4alkyl; and R3Cis an unsubstituted C1-4alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4 alkyl); or R3Band R3Care taken together along with each atom to which R3Band R3Care attached to form a 5-, 6-, or 7-membered ring; R4Bis hydrogen or an unsubstituted C1-4 alkyl; and R4Cis an unsubstituted C1-4 alkyl, an unsubstituted C3-6cycloalkyl and an unsubstituted C3-6cycloalkyl(an unsubstituted C1-4alkyl); or R4Band R4Care taken together along with each atom to which R4Band R4Care attached to form a 5-, 6-, or 7-membered ring;R5A, R5B, R5Cand R5Dare independently selected from the group consisting of hydrogen and halogen; and R6A, R6B, R6Cand R6Dare independently selected from the group consisting of hydrogen and halogen.

2. The compound of Claim 1, wherein R1Ais hydrogen.

3. The compound of Claim 1, wherein R1Ais an unsubstituted C1-4alkyl.

4. The compound of Claim 1, wherein R1Ais an unsubstituted C3-6cycloalkyl.

5. The compound of any one of Claims 2-4, wherein R1Bis hydrogen.

6. The compound of any one of Claims 2-4, wherein R1Bis an unsubstituted C1-4alkyl.

7. The compound of any one of Claims 2-6, wherein R1Cis an unsubstituted C1-4 alkyl.

8. The compound of any one of Claims 2-6, wherein R1Cis an unsubstituted C3-6 cycloalkyl.

9. The compound of any one of Claims 2-6, wherein R1Cis an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4alkyl).

10. The compound of any one of Claims 2-4, wherein R1Band R1Care taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7-membered ring.

11. The compound of any one of Claims 1-10, wherein R2Ais hydrogen.

12. The compound of any one of Claims 1-10, wherein R2Ais an unsubstituted C1-4 alkyl.

13. The compound of any one of Claims 1-10, wherein R2Ais an unsubstituted C3-6 cycloalkyl.

14. The compound of any one of Claims 11-13, wherein R2Bis hydrogen.

15. The compound of any one of Claims 11-13, wherein R2Bis an unsubstituted C1-4alkyl.

16. The compound of any one of Claims 11-15, wherein R2Cis an unsubstituted C1-4alkyl.

17. The compound of any one of Claims 11-15, wherein R2Cis an unsubstituted C3-6 cycloalkyl.

18. The compound of any one of Claims 11-15, wherein R2Cis an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4alkyl).

19. The compound of any one of Claims 11-13, wherein R2Band R2Care taken together along with each atom to which R2Band R2Care attached to form a 5-, 6-, or 7-membered ring.

20. The compound of any one of Claims 1-19, wherein R3Ais hydrogen.

21. The compound of any one of Claims 1-19, wherein R3Ais an unsubstituted C1-4 alkyl.

22. The compound of any one of Claims 1-19, wherein R3Ais an unsubstituted C3-6cycloalkyl.

23. The compound of any one of Claims 20-22, wherein R3Bis hydrogen.

24. The compound of any one of Claims 20-22, wherein R3Bis an unsubstituted C1-4alkyl.

25. The compound of any one of Claims 20-24, wherein R2Cis an unsubstituted C1-4 alkyl.

26. The compound of any one of Claims 20-24, wherein R3Cis an unsubstituted C3-6 cycloalkyl.

27. The compound of any one of Claims 20-24, wherein R3Cis an unsubstituted C3-6cycloalkyl(an unsubstituted C1-4alkyl).

28. The compound of any one of Claims 20-22, wherein R3Band R3Care taken together along with each atom to which R3Band R3Care attached to form a 5-, 6-, or 7-membered ring.

29. The compound of any one of Claims 1-28, wherein R4Ais hydrogen.

30. The compound of any one of Claims 1-28, wherein R4Ais an unsubstituted C1-4 alkyl.

31. The compound of any one of Claims 1-28, wherein R4Ais an unsubstituted C3-6cycloalkyl.

32. The compound of any one of Claims 29-31, wherein R4Bis hydrogen.

33. The compound of any one of Claims 29-31, wherein R4Bis an unsubstituted C1-4alkyl.

34. The compound of any one of Claims 29-33, wherein R4Cis an unsubstituted C1-4 alkyl.

35. The compound of any one of Claims 29-33, wherein R4Cis an unsubstituted C3-6 cycloalkyl.

36. The compound of any one of Claims 29-33, wherein R4Cis an unsubstituted C3-6cycloalkyl(an unsubstituted C1-4 alkyl).

37. The compound of any one of Claims 29-31, wherein R4Band R4Care taken together along with each atom to which R4Band R4Care attached to form a 5-, 6-, or 7-membered ring.

38. The compound of any one of Claims 1-37, wherein R5Ais hydrogen.

39. The compound of any one of Claims 1-37, wherein R5Ais halogen.

40. The compound of any one of Claims 1-39, wherein R5Bis hydrogen.

41. The compound of any one of Claims 1-39, wherein R5Bis halogen.

42. The compound of any one of Claims 1-41, wherein R5Cis hydrogen.

43. The compound of any one of Claims 1-41, wherein R5Cis halogen.

44. The compound of any one of Claims 1-43, wherein R5Dis hydrogen.

45. The compound of any one of Claims 1-43, wherein R5Dis halogen.

46. The compound of any one of Claims 1-45, wherein R6Ais hydrogen.

47. The compound of any one of Claims 1-45, wherein R6Ais halogen.

48. The compound of any one of Claims 1-47, wherein R6Bis hydrogen.

49. The compound of any one of Claims 1-47, wherein R6Bis halogen.

50. The compound of any one of Claims 1-49, wherein R6Cis hydrogen.

51. The compound of any one of Claims 1-49, wherein R6Cis halogen.

52. The compound of any one of Claims 1-51, wherein R6Dis hydrogen.

53. The compound of any one of Claims 1-51, wherein R6Dis halogen.

54. The compound of Claim 1 is selected from the group consisting of:, or a pharmaceutically acceptable salt of any of the foregoing.

55. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-54, or a pharmaceutically acceptable salt thereof, and excipient.

56. A method for treating a bacterial infection in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-54, or a pharmaceutically acceptable salt thereof.

57. The method of Claim 56, wherein the bacterial infection is due to a Gram-negative bacteria.

58. The method of Claim 56, wherein the bacterial infection is due to a Gram-positive bacteria.

59. The method of Claim 56, wherein the bacterial infection is due to a bacteria selected from the group consisting of Salmonella enterica Typhimurium, E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, methicillin-resistant. aureus, methicillin-sensitive S. aureus, E. faecium, A. baumannii, E. cloacae, S. epidermidis, K. aerogenes, S. flexneri, Y. pseudotuberculosis, Nontuberculous Mycobacteria (NTM); Mycobacterium avium complex; Mycobacterium abscessus; Mycobacterium tuberculosis; N. gonorrhoeae, and S. pneumoniae.

60. The method of any one of Claims 56-59, wherein further comprising the use of an antibiotic.

61. The method of Claim 60, wherein the mechanism of action of the antibiotic is selected from the group consisting of inhibiting protein synthesis, inhibiting folic acid synthesis, inhibiting cell wall synthesis, inhibiting RNA synthesis, inhibiting DNA gyrase and / or cell division, inhibiting cell wall synthesis for gram-positive bacteria and disrupting out membrane of gram-negative bacteria.

62. The method of Claim 61, wherein the antibiotic is selected from the group consisting of chloramphenicol, sulfamethoxazole, ampicillin, penicillin, rifampin, ciprofloxacin, vancomycin and colistin.

63. The method of any one of Claims 56-62, wherein the bacterial infection has developed drug resistance to an antibiotics selected from the group consisting of vancomycin, ceftobiprole, ceftaroline, clindamycin, dalbavancin, daptomycin, fusidic acid, linezolid, mupirocin (topical), oritavancin, tedizolid, telavancin, tigecycline, aminoglycosides, carbapenems, ceftazidime, cefepime, ceftobiprole, ceftolozane or tazobactam, fluoroquinolones, piperacillin or tazobactam, ticarcillin or clavulanic acid, linezolid, streptogramins, tigecycline, and daptomycin.ANTIMICROBIAL CONJUGATED OLIGOELECTROLYTES AS BROAD-SPECTRUM ANTIBIOTICS ABSTRACT Compositions and methods of making and using thereof are provided with a specific antimicrobial activity toward Gram-positive and Gram-negative bacteria and / or low levels of toxicity toward mammalian cells. The compositions include water-soluble molecules characterized by a hydrophobic interior fragment and side groups containing basic ionizable functionalities that may be positively charged under physiological conditions. A class of these molecules is provided with structural variations that can impact the antimicrobial activity and toxicity to mammalian cells.WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:wherein:R1A, R2A, R3Aand R4Aare independently selected from the group consisting of hydrogen, an unsubstituted C1-4alkyl and an unsubstituted C3-6 cycloalkyl;R1Bis hydrogen or an unsubstituted C1-4alkyl; and R1Cis an unsubstituted C1-4alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4alkyl); or R1Band R1Care taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7-membered ring;R2Bis hydrogen or an unsubstituted C1-4alkyl; and R2Cis an unsubstituted C1-4alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4alkyl); or R2Band R2Care taken together along with each atom to which R2Band R2Care attached to form a 5-, 6-, or 7-membered ring;R3Bis hydrogen or an unsubstituted C1-4alkyl; and R3Cis an unsubstituted C1-4alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4alkyl); or R3Band R3Care taken together along with each atom to which R3Band R3Care attached to form a 5-, 6-, or 7-membered ring;R4Bis hydrogen or an unsubstituted C1-4alkyl; and R4Cis an unsubstituted C1-4alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4alkyl); or R4Band R4Care taken together along with each atom to which R4Band R4Care attached to form a 5-, 6-, or 7-membered ring;R5A, R5B, R5Dand R5Dare independently sdected from the group consisting of hydrogen and halogen; andR6A, R6B, R6Cand R6Dare independently sdected from the group consisting of hydrogen and halogen.

2. The compound of Claim 1, wherein R1Ais hydrogen.The compound of Claim 1, wherein R1Ais an unsubstituted C1-4alkylThe compound of Claim 1, wherein R1Ais an unsubstituted C1-4cycloalkyl.

5. The compound of any one of Claims 2-4, wherein R1Bis hydrogen.

6. The compound of any one of Claims 2-4, wherein R1Bis an unsubstituted C1-4alkyl7. The compound of any one of Claims 2-6, wherein R1Cis an unsubstituted C1-4alkyl8. The compound of any one of Claims 2-6, wherein R1Cis an unsubstituted C3-6cydoalkyl9. The compound of any one of Claims 2-6, wherein R1Cis an unsubstituted C3-6cydoalkyl(an unsubstituted C1-4alkyl).

10. The compound of any one of Claims 2-4, wherein R1Band R1Care taken together along with each atom to which R1Band R1Care attached to form a 5-, 6-, or 7-membered ring.

11. The compound of any one of Claims 1-10, wherein R2Ais hydrogen.

12. The compound of any one of Claims 1-10, wherein R2Ais an unsubstituted C1-4alkyl13. The compound of any one of Claims 1-10, wherein R2Ais an unsubstituted C3-6cycloalkyl.

14. The compound of any one of Claims 11-13, wherein R2Bis hydrogen.

15. The compound of any one of Claims 11-13, wherein R2Bis an unsubstituted C1-4alkyl16. The compound of any one of Claims 11-15, wherein R2Cis an unsubstituted C1-4alkyl17. The compound of any one of Claims 11-15, wherein R2Cis an unsubstituted C3-6cydoalkyl18. The compound of any one of Claims 11-15, wherein R2Cis an unsubstituted C3-6cydoalkyl(an unsubstituted C1-4alkyl).

19. The compound of any one of Claims 11-13, wherein R2Band R2Care taken together along with each atom to which R2Band R2Care attached to form a 5-, 6-, or 7-membered ring.

20. The compound of any one of Claims 1-19, wherein R3Ais hydrogen.

21. The compound of any one of Claims 1-19, wherein R3Ais an unsubstituted C1-4alkyl.

22. The compound of any one of Claims 1-19, wherein R3Ais an unsubstituted C3-6 cycloalkyl.

23. The compound of any one of Claims 20-22, wherein R3Bis hydrogen.

24. The compound of any one of Claims 20-22, wherein R3Bis an unsubstituted C1-4alkyl.

25. The compound of any one of Claims 20-24, wherein R2Cis an unsubstituted C1-4alkyl.

26. The compound of any one of Claims 20-24, wherein R3Cis an unsubstituted C3-6 cycloalkyl.

27. The compound of any one of Claims 20-24, wherein R3Cis an unsubstituted C3-6 cycloalkyl(an unsubstituted C1-4alkyl).

28. The compound of any one of Claims 20-22, wherein R3Band R3Care taken together along with each atom to which R3Band R3Care attached to form a 5-, 6-, or 7-membered ring.

29. The compound of any one of Claims 1-28, wherein R4Ais hydrogen.

30. The compound of any one of Claims 1-28, wherein R4Ais an unsubstituted C1-4alkyl.

31. The compound of any one of Claims 1-28, wherein R4Ais an unsubstituted C3-6 cycloalkyl.

32. The compound of any one of Claims 29-31, wherein R4Bis hydrogen.

33. The compound of any one of Claims 29-31, wherein R4Bis an unsubstituted C1-4alkyl.

34. The compound of any one of Claims 29-33, wherein R4Cis an unsubstituted C1-4alkyl.

35. The compound of any one of Claims 29-33, wherein R4Cis an unsubstituted C3-6 cycloalkyl.

36. The compound of any one of Claims 29-33, wherein R4Cis an unsubstituted C3-6 cycloalky l(an unsubstituted C1-4alkyl).

37. The compound of any one of Claims 29-31 , wherein R4Band R4Care taken together along with each atom to which R4Band R40are attached to form a 5-, 6-, or 7-membered ring.

38. The compound of any one of Claims 1-37, wherein R5Ais hydrogen.

39. The compound of any one of Claims 1-37, wherein R5Ais halogen.

40. The compound of any one of Claims 1-39, wherein R5Bis hydrogen.

41. The compound of any one of Claims 1-39, wherein R5Bis halogen.

42. The compound of any one of Claims 1-41, wherein R5Cis hydrogen.

43. The compound of any one of Claims 1-41, wherein R5Cis halogen.

44. The compound of any one of Claims 1-43, wherein R5Dis hydrogen.

45. The compound of any one of Claims 1-43, wherein R5Dis halogen.

46. The compound of any one of Claims 1-45, wherein R6Ais hydrogen.

47. The compound of any one of Claims 1-45, wherein R6Ais halogen.

48. The compound of any one of Claims 1-47, wherein R6Bis hydrogen.

49. The compound of any one of Claims 1-47, wherein R68is halogen.

50. The compound of any one of Claims 1-49, wherein R6Bis hydrogen.

51. The compound of any one of Claims 1-49, wherein R6Cxs halogen.

52. The compound of any one of Claims 1-51, wherein R6Dis hydrogen.

53. The compound of any one of Claims 1-51, wherein R6Dis halogen.

54. The compound of Claim 1 is selected from the group consisting of:or a pharmaceutically acceptable salt of any of the foregoing.

55. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-54, or a pharmaceutically acceptable salt thereof, and excipient.

56. A method for treating a bacterial infection in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-54, or a pharmaceutically acceptable salt thereof.

57. The method of Claim 56, wherein the bacterial infection is due to a Gram-negative bacteria.

58. The method of Claim 56, wherein the bacterial infection is due to a Gram-positive bacteria.

59. The method of Claim 56, wherein the bacterial infection is due to a bacteria selected from the group consisting of Salmonella enterica Typhimurium, E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, methicillin-resistant S. aureus, methicillin-sensitive S. aureus, E. faecium, A. baumannii, E. cloacae, S. epidermidis, K. aerogenes, S. flexneri, Y. pseudotuberculosis, Nontuberculous Mycobacteria (NTM); Mycobacterium avium complex; Mycobacterium abscessus; Mycobacterium tuberculosis; N. gonorrhoeae, and S. pneumoniae.

60. The method of any one of Claims 56-59, wherein further comprising the use of an antibiotic.

61. The method of Claim 60, wherein the mechanism of action of the antibiotic is selected from the group consisting of inhibiting protein synthesis, inhibiting folic acid synthesis, inhibiting cell wall synthesis, inhibiting RNA synthesis, inhibiting DNA gyrase and / or cell division, inhibiting cell wall synthesis for gram-positive bacteria and disrupting out membrane of gram-negative bacteria.

62. The method of Claim 61, wherein the antibiotic is selected from the group consisting of chloramphenicol, sulfamethoxazole, ampicillin, penicillin, rifampin, ciprofloxacin, vancomycin and colistin.

63. The method of any one of Claims 56-62, wherein the bacterial infection has developed drug resistance to an antibiotics selected from the group consisting of vancomycin, ceftobiprole, ceftaroline, clindamycin, dalbavancin, daptomycin, fusidic acid, linezolid, mupirocin (topical), oritavancin, tedizolid, telavancin, tigecycline, aminoglycosides, carbapenems, ceftazidime, cefepime, ceftobiprole, ceftolozane or tazobactam, fluoroquinolones, piperacillin or tazobactam, ticarcillin or clavulanic acid, linezolid, streptogramins, tigecycline, and daptomycin.

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