WO2013036766A1

WO2013036766A1 - Small molecule naphthoquinone- and phthalimide-based lipocations as anti-parasitic agents

Info

Publication number: WO2013036766A1
Application number: PCT/US2012/054159
Authority: WO
Inventors: Timothy E. Long
Original assignee: University Of Georgia Research Foundation, Inc.
Priority date: 2011-09-09
Filing date: 2012-09-07
Publication date: 2013-03-14

Abstract

Small molecule naphthoquinone- and phthalimide-based lipocations are provided, as well as methods for their use in treating or preventing anti-parasitic diseases, such as malaria, Chagas disease, and African Sleeping Sickness.

Description

Small Molecule Naphthoquinone- and Phthalimide-Based Lipocations as Anti-Parasitic Agents

CROSS-REFERENCE TO PRIORITY APPLICATIONS

This application claims priority to U.S. Provisional Application No. 61/532,872, filed September 9, 2011, which is incorporated herein by reference in its entirety.

BACKGROUND

The human pathogen Plasmodium falciparum, the main causative agent of malaria, is a deadly protozoan that is responsible for millions of deaths each year. The number of safe and effective drugs used to treat infections by parasites such as this is gravely limited. Ubiquinone antagonists are currently used to treat different parasitic diseases and some, such as atovaquone, have the ability to eradicate both liver and blood stages of the malaria parasite. A feature common to atovaquone and other mitochondrion-acting anti-malarial agents is a hydrophobic residue which enhances permeability in phospholipid bilayers.

SUMMARY

Provided herein are small molecule naphthoquinone- and phthalimide-based lipocations and their use in methods for treating or preventing parasitic diseases. A class of compounds described herein includes compounds of the following structure:

and pharmaceutically acceptable salts or prodrugs thereof. In these compounds, n is an integer from 1 to 15; and Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Optionally, n is 3, 5 or 9. Y can optionally be methyl, substituted or unsubstituted phenyl, benzyl, cyclohexyl, or n-butyl.

A class of compounds describ ounds of the following structure:

and pharmaceutically acceptable salts or prodrugs thereof. In these compounds, n is an integer from 1 to 15; Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Z is hydrogen or substituted or unsubstituted alkyl. Optionally, n is 2 or 10. Y can optionally be substituted or unsubstituted phenyl, benzyl, or cyclohexyl and Z can optionally be hydrogen.

A class of compounds described herein includes compounds of the following structure:

and pharmaceutically acceptable salts or prodrugs thereof. In these compounds, n is an integer from 1 to 15; Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Z is hydrogen or substituted or unsubstituted alkyl. Optionally, n is 1, 4, 5, 9, or 10. Y can optionally be methyl, substituted or unsubstituted phenyl, benzyl, cyclohexyl, or n-butyl. Optionally, Z can be hydrogen, methyl, hydroxyl, or acetoxy.

A class of compounds descr ounds of the following structure:

and pharmaceutically acceptable salts or prodrugs thereof. In these compounds, n is an integer from 1 to 15; Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Z is hydrogen, hydroxyl, acetoxy, alkoxy, or substituted or unsubstituted alkyl. Optionally, n is 1, 2, or 8. Y can optionally be substituted or unsubstituted phenyl. Optionally, Z can be acetoxy, hydroxyl, or methoxy.

and pharmaceutically acceptable salts or prodrugs thereof. In these compounds, n is an integer from 1 to 15; Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Z is hydrogen, hydroxyl, acetoxy, or substituted or unsubstituted alkyl. Optionally, n is 2 or 9. Y can optionally be substituted or unsubstituted phenyl. Optionally, Z is methyl.

and pharmaceutically acceptable salts or prodrugs thereof. In these compounds, n is an integer from 1 to 15; Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Z is hydrogen, hydroxyl, acetoxy, or substituted or unsubstituted alkyl. Optionally, n is 1. Y can optionally be substituted or unsubstituted phenyl. Optionally, Z is methyl.

and pharmaceutically acceptable salts or prodrugs thereof. In these compounds, n is an integer from 1 to 15;

Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Z is hydrogen, hydroxyl, acetoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. Optionally, n is 1, 4, or 8. Y can optionally be substituted or unsubstituted phenyl. Optionally, Z is hydrogen, methyl, cyclohexyl, benzyl, 4- chlorobenzyl, or 4-methoxyphenyl.

Further compounds described herein include compounds of the following structure:

Also provided herein are compositions comprising one or more of the compounds as described above and a pharmaceutically acceptable carrier.

Further provided herein are methods of treating or preventing a parasitic disease in a subject, comprising administering to the subject an effective amount of one or more compounds or compositions as described above. Optionally, the parasitic disease is a Plasmodium related disease (e.g., malaria) or a Trypanosoma related disease (e.g., Chagas disease or African Sleeping Sickness). Optionally the methods further include administering a second therapeutic agent (e.g., an anti-malarial agent) to the subject.

Also provided herein are methods of inhibiting a parasite, comprising contacting the parasite with an effective amount of one or more compounds or compositions as described above. The parasite can be selected from the group consisting of Plasmodium falciparum, Trypanosoma cruzi, and Trypanosoma brucei. Optionally, the contacting is performed in vivo. Optionally, the contacting is performed in vitro.

The details of one or more embodiments are set forth in the description below. Other features, objects, and advantages will be apparent from the description and from the claims.

DETAILED DESCRIPTION

Described herein are small molecule naphthoquinone- and phthalimide-based lipocations for use as anti-parasitic agents and methods for treating or preventing parasitic diseases, including malaria, Chagas disease, and African Sleeping Sickness. The methods of preventing or treating parasitic diseases described herein include administering to the subject a small molecule naphthoquinone- and phthalimide-based lipocation. Such small molecule naphthoquinone- and phthalimide-based lipocations are administered in an effective amount to prevent or treat one or more symptoms of parasitic diseases.

I. Compounds

A class of small molecule phthalimide-based lipocations useful in the methods described herein includes compounds represented by Formula I:

or a pharmaceutically acceptable salt or prodrug thereof.

In Formula I, n is an integer from 1 to 15. Optionally, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some examples, n is 3, 5, or 9.

Also in Formula I, Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted

heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Optionally, Y is methyl, benzyl, cyclohexyl, or n-butyl. Optionally, Y is substituted or unsubstituted phenyl. Y can be, for example, meta-substituted phenyl, ortho-substituted phenyl, or para-substituted phenyl. In some examples, the substituted phenyl is 2-methylphenyl, 4- fluorophenyl, or 4-methoxyphenyl.

Examples of Formula I include the following compounds:

Compound 1-4 Compound 1-5 Compound 1-6

Compound 1-7 Compound 1-8 Compound 1-9

Compound 1-10

A class of small molecule naphthoquinone-based lipocations useful in the methods described herein includes compounds represented by Formula II:

or a pharmaceutically acceptable salt or prodrug thereof.

In Formula II, n is an integer from 1 to 15. Optionally, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some examples, n is 2 or 10.

Also in Formula II, Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted

heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Optionally, Y is benzyl or cyclohexyl. Optionally, Y is substituted or unsubstituted phenyl. Y can be, for example, meta-substituted phenyl, ortho-substituted phenyl, or para-substituted phenyl. In some examples, the substituted phenyl is 4-fluorophenyl or 4-methoxyphenyl.

Additionally in Formula II, Z is hydrogen or substituted or unsubstituted alkyl.

Examples of Formula II include the following compounds:

Compound II-l Compound II-2 Compound II-3

Compound II-4 Compound II-5 Compound II-6

A class of small molecule naphthoquinone-based lipocations useful in the methods described herein includes compounds represented by Formula III:

or a pharmaceutically acceptable salt or prodrug thereof.

In Formula III, n is an integer from 1 to 15. Optionally, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some examples, n is 1, 4, 5, 9, or 10.

Also in Formula III, Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted

Additionally in Formula III, Z is hydrogen, hydroxyl, acetoxy, or substituted or unsubstituted alkyl. Optionally, Z is hydrogen, methyl, hydroxyl, or acetoxy.

Examples of Formula III include the following compounds:

Compound 111-16 Compound 111-17 Compound 111-18

Compound 111-19 Compound 111-20 Compound 111-21

A class of small molecule naphthoquinone-based lipocations useful in the methods described herein includes compounds represented by Formula IV:

or a pharmaceutically acceptable salt or prodrug thereof.

In Formula IV, n is an integer from 1 to 15. Optionally, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some examples, n is 1, 2, or 8.

Also in Formula IV, Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted

Additionally in Formula IV, Z is hydrogen, hydroxyl, acetoxy, alkoxy, or substituted or unsubstituted alkyl. Optionally, Z is hydroxyl, acetoxy, or methoxy.

Examples of Formula IV include the following compounds:

Compound IV-5

A class of small molecule naphthoquinone-based lipocations useful in the methods described herein includes compounds represented by Formula V:

or a pharmaceutically acceptable salt or prodrug thereof.

In Formula V, n is an integer from 1 to 15. Optionally, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some examples, n is 2 or 9.

Also in Formula V, Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted

Additionally in Formula V, Z is hydrogen, hydroxyl, acetoxy, or substituted or unsubstituted alkyl. Optionally, Z is hydrogen or methyl.

Examples of Formula V include the following compounds:

Compound V-2

A class of small molecule naphthoquinone-based lipocations useful in the methods described herein includes compounds represented by Formula VI:

or a pharmaceutically acceptable salt or prodrug thereof.

In Formula VI, n is an integer from 1 to 15. Optionally, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some examples, n is 1.

Also in Formula VI, Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted

Additionally in Formula VI, Z is hydrogen, hydroxyl, acetoxy, or substituted or unsubstituted alkyl. Optionally, Z is hydrogen or methyl.

An example of Formula VI includes the following compound:

Compound VI-1

A class of small molecule naphthoquinone-based lipocations useful in the methods described herein includes compounds represented by Formula VII:

or a pharmaceutically acceptable salt or prodrug thereof.

In Formula VII, n is an integer from 1 to 15. Optionally, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15. In some examples, n is 1, 4, or 8.

Also in Formula VII, Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted

Additionally in Formula VII, Z is hydrogen, hydroxyl, acetoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl. Optionally, Z is hydrogen, methyl, cyclohexyl, benzyl, 4-chlorobenzyl, or 4-methoxyphenyl.

Compound VII-4 Compound VII-5 Compound VII-6

Compound VII-10 Compound VII-11

Further examples of small molecule naphthoquinone-based lipocations useful in the methods described herein include the following compounds:

Compound 1 Compound 2

The compounds according to Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Compound 1, and Compound 2 can be present as a salt. Optionally, the compounds are present as a bromide salt.

As used herein, the term alkyl includes straight- and branched-chain monovalent substituents. Examples include methyl, ethyl, isobutyl, and the like. A range of these groups useful with the compounds and methods described herein includes C1-C2₀ alkyl. Additional ranges of these groups useful with the compounds and methods described herein include C1-C12 alkyl, Ci-Ce alkyl, and C₁-C₄ alkyl.

Heteroalkyl is defined similarly as alkyl, but can contain O, S, or N heteroatoms or combinations thereof within the backbone. A range of this group useful with the compounds and methods described herein includes C1-C2₀ heteroalkyl. Additional ranges of this group useful with the compounds and methods described herein include C1-C12 heteroalkyl, Ci-Ce

heteroalkyl, and C1-C4 heteroalkyl.

The term cycloalkyl includes cyclic alkyl groups having a single cyclic ring or multiple condensed rings. Examples include cyclohexyl, cyclopentylethyl, and adamantanyl. Ranges of these groups useful with the compounds and methods described herein include C3-C2₀ cycloalkyl, C5-C12 cycloalkyl, and C5-C6 cycloalkyl. The term heterocycloalkyl is defined similarly as cycloalkyl, but can contain O, S, or N heteroatoms or combinations thereof within the cyclic backbone. Ranges of these groups useful with the compounds and methods described herein include C3-C2₀ heterocycloalkyl, C5-C12 heterocycloalkyl, and C5-C6 heterocycloalkyl.

Aryl molecules include, for example, cyclic hydrocarbons that incorporate one or more planar sets of, typically, six carbon atoms that are connected by delocalized electrons numbering the same as if they consisted of alternating single and double covalent bonds. An example of an aryl molecule is benzene. Heteroaryl molecules include substitutions along their main cyclic chain of atoms such as O, N, or S. When heteroatoms are introduced, a set of five atoms, e.g., four carbon and a heteroatom, can create an aromatic system. Examples of heteroaryl molecules include furan, pyrrole, thiophene, imidazole, oxazole, pyridine, and pyrazine. Aryl and heteroaryl molecules can also include additional fused rings, for example, benzofuran, indole, benzothiophene, naphthalene, anthracene, and quinoline. The aryl and heteroaryl molecules can be attached at any position on the ring, unless otherwise noted.

The alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, or heterocycloalkyl molecules used herein can be substituted or unsubstituted. As used herein, the term substituted includes the addition of an alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, or heterocycloalkyl group to a position attached to the main chain of the alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, or heterocycloalkyl, e.g., the replacement of a hydrogen by one of these molecules. Examples of substitution groups include, but are not limited to, hydroxyl, alkoxy (e.g., methoxy), halogen (e.g., F, Br, CI, or I), alkyl (e.g., methyl) and carboxyl groups. Conversely, as used herein, the term unsubstituted indicates the alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, or

heterocycloalkyl has a full complement of hydrogens, i.e., commensurate with its saturation level, with no substitutions, e.g., linear decane (-(CH₂)9-CH₃).

II. Pharmaceutical Formulations

The compounds described herein or derivatives thereof can be provided in a

pharmaceutical composition. Depending on the intended mode of administration, the pharmaceutical composition can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, or suspensions, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include a therapeutically effective amount of the compound described herein or derivatives thereof in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, or diluents. By

pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, which can be administered to an individual along with the selected compound without causing unacceptable biological effects or interacting in a deleterious manner with the other components of the pharmaceutical composition in which it is contained.

As used herein, the term carrier encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia,

Lippincott, Williams & Wilkins, Philadelphia Pa., 2005. Examples of physiologically acceptable carriers include buffers, such as phosphate buffers, citrate buffer, and buffers with other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins;

hydrophilic polymers, such as polyvinyl pyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrins; chelating agents, such as EDTA; sugar alcohols, such as mannitol or sorbitol; salt-forming counterions, such as sodium; and/or nonionic surfactants, such as TWEEN^® (ICI, Inc.; Bridgewater, New Jersey), polyethylene glycol (PEG), and PLURONICS™ (BASF; Florham Park, NJ). Compositions containing the compound described herein or derivatives thereof suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants, such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be promoted by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. Isotonic agents, for example, sugars, sodium chloride, and the like may also be included. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration of the compounds described herein or derivatives thereof include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the compounds described herein or derivatives thereof is admixed with at least one inert customary excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia, (c) humectants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) solution retarders, as for example, paraffin, (f) absorption accelerators, as for example, quaternary ammonium compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, (h) adsorbents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols, and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others known in the art. They may contain opacifying agents and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration of the compounds described herein or derivatives thereof include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include additional agents, such as wetting, emulsifying, suspending, sweetening, flavoring, or perfuming agents.

Suspensions, in addition to the active compounds, may contain additional agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions of the compounds described herein or derivatives thereof for rectal administrations are optionally suppositories, which can be prepared by mixing the compounds with suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of the compounds described herein or derivatives thereof include ointments, powders, sprays, and inhalants. The compounds described herein or derivatives thereof are admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, ointments, powders, and solutions are also contemplated as being within the scope of the compositions.

The compositions can include one or more of the compounds described herein and a pharmaceutically acceptable carrier. As used herein, the term pharmaceutically acceptable salt refers to those salts of the compound described herein or derivatives thereof that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of subjects without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds described herein. The term salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compounds described herein. These salts can be prepared in situ during the isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactobionate, methane sulphonate, and lauryl sulphonate salts, and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to ammonium,

tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. (See S.M. Barge et al, J. Pharm. Sci. (1977) 66, 1, which is incorporated herein by reference in its entirety, at least, for compositions taught therein.)

Administration of the compounds and compositions described herein or pharmaceutically acceptable salts thereof can be carried out using therapeutically effective amounts of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein for periods of time effective to treat a disorder. The effective amount of the compounds and compositions described herein or pharmaceutically acceptable salts thereof as described herein may be determined by one of ordinary skill in the art and includes exemplary dosage amounts for a mammal of from about 0.5 to about 200mg/kg of body weight of active compound per day, which may be administered in a single dose or in the form of individual divided doses, such as from 1 to 4 times per day. Alternatively, the dosage amount can be from about 0.5 to about 150mg/kg of body weight of active compound per day, about 0.5 to lOOmg/kg of body weight of active compound per day, about 0.5 to about 75mg/kg of body weight of active compound per day, about 0.5 to about 50mg/kg of body weight of active compound per day, about 0.5 to about 25mg/kg of body weight of active compound per day, about 1 to about 20mg/kg of body weight of active compound per day, about 1 to about lOmg/kg of body weight of active compound per day, about 20mg/kg of body weight of active compound per day, about lOmg/kg of body weight of active compound per day, or about 5mg/kg of body weight of active compound per day. Those of skill in the art will understand that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the species, age, body weight, general health, sex and diet of the subject, the mode and time of administration, rate of excretion, drug combination, and severity of the particular condition.

III. Methods of Making the Compounds

The compounds described herein can be prepared in a variety of ways known to one skilled in the art of organic synthesis or variations thereon as appreciated by those skilled in the art. The compounds described herein can be prepared from readily available starting materials. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art.

Variations on Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Compound 1, and Compound 2 include the addition, subtraction, or movement of the various constituents as described for each compound. Similarly, when one or more chiral centers are present in a molecule, the chirality of the molecule can be changed. Additionally, compound synthesis can involve the protection and deprotection of various chemical groups. The use of protection and deprotection, and the selection of appropriate protecting groups can be determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, 2006, which is incorporated herein by reference in its entirety.

Reactions to produce the compounds described herein can be carried out in solvents, which can be selected by one of skill in the art of organic synthesis. Solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products under the conditions at which the reactions are carried out, i.e., temperature and pressure.

Reactions can be carried out in one solvent or a mixture of more than one solvent. Product or intermediate formation can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., ^lH or ¹³C) infrared spectroscopy, spectrophotometry (e.g., UV- visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.

The compounds described by Formula I can be made, for example, using the method shown in Scheme I:

Scheme I:

Method A: PY₃, μ\Λ , 0.5 h; B: P(2-PhMe)₃, 1 10 °C, 16-40 h; C: PMe₃, 'PrOH:PhMe, 90 °C, 48-72 h.

N-Alkylphthalimides can be prepared from dibromoalkanes of various chain lengths and then coupled with a tertiary phosphine under microwave or conventional heating conditions (Method A-C) to afford phosphonium bromides (Scheme 1). In some instances, the bromide anion of the product can be replaced afterwards with a non-nucleophilic mesylate counterion by repeated washings of a dichloromethane (DCM) solution of the lipocation with 5% NaOMs.

The compounds described by Formula II can be made, for example, using the method shown in Scheme II:

Scheme II:

As shown in Scheme II, compounds according to Formula II can be synthesized from quinones using a nucleophilic addition of straight-chain amino alcohols to 1,4-naphthoquinone (Z = H), followed by mesylation of the corresponding alcohol, and generation of the

phosphonium salts under microwave irradiation. The compounds described by Formula III can be made, for example, using the methods shown in Scheme III, IV, or V:

Scheme III:

h

Z = Me

Compounds according to Formula III, where n is 1 and Z is Me, can be synthesized by chloroalkylating a naphthoquinone (Z = Me) with 37% formaldehyde and subsequently converting to the triphenylphosphonium salt (Scheme III).

Scheme IV:

As shown in Scheme IV, compounds according to Formula III can be synthesized from quinones by alkylating naphthoquinone (Z = H, Me) via radical decarboxylation. The resulting bromides can be converted to the lipocations (Method A-C, Scheme I). Residual quinol byproduct can be re-oxidized to the quinone using nitric oxide generated in situ from a 0₂.

Scheme V:

Compounds according to Formula III, where Z is OAc or OH, can be synthesized by installing the terminal bromoalkyl sidechain to which the phosphonium substituent will be subsequently bound (Scheme V). As shown in Scheme V, the hydrocarbon "linker" is attached using the Kochi -Anderson radical decarboxylation procedure with 1,4- naphthoquinone as the base material. The alkylated product next undergoes epoxidation and is treated with sulfuric acid to give the 2-hydroxy naphthoquinone. Numerous attempts were made afterwards to directly convert the naphthoquinone to the phosphonium cation; however, complex mixtures of highly polar products always resulted. This problem was circumvented by acetylating the hydroxy to preclude side reactions from occurring. The phosphonium salts can be generated cleanly from the acylated quinone under conventional heating in 3: 1 isopropanoktoluene for 20- 72 h. Acid-catalyzed hydrolysis of the acetyl group provides the desired 2-hydroxy

naphthoquinone products.

The compounds described by Formula IV can be made, for example, using the method shown in Scheme VI and Scheme VII:

Scheme VI:

As shown in Scheme VI, compounds described by Formula IV, where Z is OAc or OH, are prepared from a phenyliodonium ylide utilizing a BF₃-mediated arylation procedure. The ylide is generated in high yield from lawsone. The diacetoxyiodobenzene is then coupled with 4-(bromoalkoxy)-benzaldehydes under reflux in CHCI₃. Acetylation of the C-2 hydroxyl followed by alkylation of PPI1₃ and O-deprotection gives the aryl-linked 1,4-naphthoquinone cations analogs according to Formula IV.

Scheme VII:

As shown in Scheme VII, compounds described by Formula IV, where Z is OMe, are prepared by methylation of the C-2 hydroxyl followed by alkylation of PPI1₃.

The compounds described by Formula V can be made, for example, using the method shown in Scheme VIII:

Scheme VIII:

n = 2, 4

The compounds described by Formula VI can be made, for example, using the method shown in Scheme IX: Scheme IX:

The compounds described by Formula VII can be made, for example, using the method shown in Scheme X, Scheme XI, or Scheme XII. The compounds described by Formula VII where Z is H or Me can be made by the method shown in Scheme X:

Scheme X:

The compounds described by Formula VII where Z is cyclohexyl, benzyl, or 4- chlorobenzyl can be made, for example, using the method shown in Scheme XI:

Scheme XI:

n = 1 , 4

The compounds described by Formula VII where Z is 4-methoxyphenyl can be made, for example, using the method shown in Scheme XII: Scheme XII:

IV. Methods of Use

Provided herein are methods to treat, prevent, or ameliorate a parasitic disease and symptoms thereof in a subject. The methods include administering to a subject an effective amount of one or more of the compounds or compositions described herein, or a

pharmaceutically acceptable salt or prodrug thereof. The expression "effective amount," when used to describe an amount of compound in a method, refers to the amount of a compound that achieves the desired pharmacological effect or other effect, for example, an amount that results in a reduction in the onset or expansion of a parasitic infection. The compounds and compositions described herein or pharmaceutically acceptable salts thereof are useful for treating parasitic diseases in humans, including, without limitation, pediatric and geriatric populations, and in animals, e.g., veterinary applications. Optionally, the parasitic disease is a Plasmodium related disease, such as, for example, malaria. Optionally, the parasitic disease is a

Trypanosoma related disease, such as, for example, Chagas disease or African Sleeping

Sickness.

The methods of treating or preventing a parasitic disease in a subject can further comprise administering to the subject a second therapeutic agent. Thus, the provided compositions and methods can include one or more additional agents. The one or more additional agents and the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof can be administered in any order, including concomitant, simultaneous, or sequential administration. Sequential administration can be temporally spaced order of up to several days apart. The methods can also include more than a single administration of the one or more additional agents and/or the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof. The administration of the one or more additional agents and the compounds described herein or pharmaceutically acceptable salts or prodrugs thereof can be by the same or different routes and concurrently or sequentially.

Therapeutic agents include, but are not limited to, anti-parasitic agents such as antimalarial agents. Examples of suitable therapeutic agents for use in the methods described herein include proguanil, chloroquine, quinine, quinidine, amodiaquine, mefloquine, sulfadoxine, pyrimethamine, a tetracyline antibiotic, clindamycin, a sulfa antibiotic, doxycyline, dapsone, primaquine, artemisinin, artesunate, artelinate, artemether, arteether, dihydroartemisinin, halo- fantrine, atovaquone, pyronaridine, desferrioxamine, azithromycin, SC-50083, Ro 40-4388, ((benzyloxycarbonyl)phenylalanyl)arginyl fiuoromethyl ketone,

((morpholinocarbonyl)phenylalanyl)homophenylalanyl fiuoromethyl ketone,

(((morpholinocarbonyl)leucyl)homophenylalanyl)vinyl phenyl sulfone, oxalic bis((2-hydroxy-l- naphthylmethylene)hydrazide), l-(2,5-dichlorophenyl)-3-(4-quinolinyl)-2-propen-l-one, and 7- chloro-l,2-dihydro-2-(2,3-dimethoxyphenyl)-5,5-dioxide-4-(lH, 10H)-phenothiazinone. Further examples of suitable anti-parasitic agents include nifurtimox, benznidazole,

(((morpholinocarbonyl)phenylalanyl)-homophenylalanyl)vinyl phenyl sulfone,

(((morpholinocarbonyl)phenyl-alanyl)lysyl)vinyl phenyl sulfone,

(((morpholinocarbonyl)phenylalanyl)-valyl)vinyl phenyl sulfone,

(((morpholinocarbonyl)phenylalanyl)-0-benzylseryl)vinyl phenyl sulfone,

(((morpholinocarbonyl)leucyl)-homophenylalanyl)vinyl phenyl sulfone,

(((morpholinocarbonyl)tyrosyl)-homophenylalanyl)vinyl phenyl sulfone, (((tert- butoxycarbonyl)-2-tetrahydroisoquinolylcarbonyl)homophenylalanyl) phenyl vinyl sulfone, (((morpholinocarbonyl)tyrosyl)homophenylalanyl)vinylphenyl sulfone,

(((morpholinocarbonyl)phenylalanyl)homophenylalanyl fiuromethylketone, and

(((morpholinocarbonyl)phenylalanyl)homophenylalanyl)valine benzylamide.

Any of the aforementioned therapeutic agents can be used in any combination with the compositions described herein. Combinations are administered either concomitantly (e.g., as an admixture), separately but simultaneously (e.g., via separate intravenous lines into the same subject), or sequentially (e.g., one of the compounds or agents is given first followed by the second). Thus, the term combination is used to refer to concomitant, simultaneous, or sequential administration of two or more agents.

The methods and compounds as described herein are useful for both prophylactic and therapeutic treatment. For prophylactic use, a therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein are administered to a subject prior to onset (e.g., before obvious signs of malaria, Chagas disease, or African Sleeping Sickness), during early onset (e.g., upon initial signs and symptoms of malaria, Chagas disease, or African Sleeping Sickness), or after the development of malaria, Chagas disease, or African Sleeping Sickness. Prophylactic administration can occur for several days to years prior to the manifestation of symptoms of malaria, Chagas disease, or African Sleeping Sickness. Therapeutic treatment involves administering to a subject a therapeutically effective amount of the compounds and compositions or pharmaceutically acceptable salts thereof as described herein after malaria, Chagas disease, or African Sleeping Sickness is diagnosed.

The methods and compounds described herein are also useful in inhibiting a parasite, such as, for example, Plasmodium falciparum, Trypanosoma cruzi, or Trypanosoma brucei. The methods include contacting the parasite with an effective amount of one or more compounds as described herein. Optionally, the contacting is performed in vivo. Optionally, the contacting is performed in vitro.

The methods described herein for prophylactic and therapeutic treatment optionally comprise selecting a subject with or at risk of developing malaria, Chagas disease, or African Sleeping Sickness. A skilled artisan can make such a determination using, for example, a variety of prognostic and diagnostic methods.

V. Kits

Also provided herein are kits for treating or preventing parasitic diseases (e.g., malaria, Chagas disease, or African Sleeping Sickness) in a subject. A kit can include any of the compounds or compositions described herein. For example, a kit can include a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Compound 1, Compound 2, or combinations thereof. A kit can further include one or more additional agents, such as anti-malarial agents (e.g., proguanil). A kit can include an oral formulation of any of the compounds or compositions described herein. A kit can additionally include directions for use of the kit (e.g., instructions for treating a subject), a container, a means for administering the compounds or compositions, and/or a carrier.

As used herein the terms treatment, treat, or treating refer to a method of reducing one or more symptoms of a disease or condition. Thus in the disclosed method, treatment can refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of one or more symptoms of the disease or condition. For example, a method for treating a disease is considered to be a treatment if there is a 10% reduction in one or more symptoms or signs (e.g., development or growth of a parasite) of the disease in a subject as compared to a control. As used herein, control refers to the untreated condition (e.g., the subject not treated with the compounds and compositions described herein). Thus the reduction can be a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percent reduction in between 10% and 100% as compared to native or control levels. It is understood that treatment does not necessarily refer to a cure or complete ablation of the disease, condition, or symptoms of the disease or condition.

As used herein, the terms prevent, preventing, and prevention of a disease or disorder refer to an action, for example, administration of a composition or therapeutic agent, that occurs before or at about the same time a subject begins to show one or more symptoms of the disease or disorder, which inhibits or delays onset or severity of one or more symptoms of the disease or disorder.

As used herein, references to decreasing, reducing, or inhibiting include a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater as compared to a control level. Such terms can include, but do not necessarily include, complete elimination.

As used herein, subject means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g., apes and monkeys; cattle; horses; sheep; rats; mice; pigs; and goats. Non-mammals include, for example, fish and birds.

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application.

The examples below are intended to further illustrate certain aspects of the methods and compositions described herein, and are not intended to limit the scope of the claims.

EXAMPLES

Chemicals were acquired from commercial sources and used without further purification. Reaction products were purified by column chromatography on silica gel (60-100 mesh) and visualized under UV on TLC plates (silica gel 60 F254). Melting points were determined with a melting point apparatus and were left uncorrected. Mass spectrometry was performed by electrospray ionization (ESI). ^lH and ¹³C NMR spectra were recorded on a Varian Inova 500 MHz spectrometer. Chemical shifts were expressed in δ (ppm) values with tetramethylsilane or residual solvent (i.e., CHCI₃) as an internal standard. Example 1 : Synthesis of 2-Alkyl Naphthoquinones Phosphonium Salts (Formula III, where Z = H or Me)

Preparation of naphthoquinones (1):

General procedure. Naphthoquinones (3.2 mmol), 1 -bromoalkylcarboxylic acid (3.5 mmol), and AgNC>3 (1.6 mmol) were combined in 30 mL of dry MeCN and heated at 60 °C. Ammonium persulfate (6.1 mmol) dissolved in 30 mL of distilled water was next added dropwise over a 2.5 h period. After overnight stirring, the solution was transferred to a separatory funnel with EtOAc (15 mL) and the aqueous phase was removed. The organic layer was washed with water and brine, dried over Na₂S0₄, and evaporated. The resulting material was purified by flash chromatography, applying a 3-10% EtOAc in hexanes gradient, to provide the naphthoquinone (1).

By this method were prepared the following:

2-(10-bromodecyl)naphthalene-l,4-dione (la): Yield: 58%; yellow solid, m.p.: 43-45 °C; TLC (Si0₂) R 0.36 (7: 1 hexanes: EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.10-8.07 (m, 1H), 8.05-8.03 (m, 1H), 7.74-7.71 (m, 2H), 6.78 (s, 1H), 3.40 (t, 2H, J= 7.0 Hz), 2.56 (t, 2H, J= 7.5 Hz), 1.84 (qnt, 2H, J= 7.0 Hz), 1.58 (qnt, 2H, J= 7.5 Hz), 1.43-1.29 (m, 12H); ¹³C NMR (125 MHz, CDC1₃) δ 185.2, 185.1, 151.9, 134.7, 133.6, 132.3, 132.1, 126.6, 126.0, 34.0, 32.8, 29.6, 29.4, 29.4, 29.3, 28.7, 28.2, 27.1.

2-(5-bromopentyl)naphthalene-l,4-dione (lb): Yield: 13%; yellow solid, m.p.: 56-58 °C; TLC (Si0₂) R 0.50 (7: 1 hexanes: EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.12-8.03 (m, 2H), 7.95-7.70 (m, 2H), 6.79 (s, 1H), 3.45-3.41 (m, 2H), 2.64-2.57 (m, 2H), 1.95-1.89 (m, 2H), 1.70- 1.51 (m, 4H); ¹³C NMR (125 MHz, CDC1₃) δ 185.2, 185.1, 151.4, 134.8, 133.7, 133.6, 132.2, 132.0, 126.6, 126.0, 35.5, 32.3, 29.4, 27.8, 27.2.

2-(l 0-bromodecyl)-3-methylnaphthalene-l ,4-dione (lc): Yield: 67%; yellow solid, m.p.: 44-46 °C; TLC (Si0₂) R 0.45 (7: 1 hexanes :EtO Ac); ^XH NMR (500 MHz, CDC1₃) δ 8.07 (dd, 2H, J= 6.0, 3.5 Hz), 7.69 (dd, 2H, J= 6.0, 3.5 Hz), 3.40 (t, 2H, J= 7.0 Hz), 2.63 (t, 2H, J= 8.0 Hz), 2.19 (s, 3H), 1.85 (qnt, 2H, J= 7.0 Hz) 1.49-1.30 (m, 14H); ¹³C NMR (125 MHz, CDC1₃) δ 185.4, 184.7, 147.5, 143.1, 133.32, 133.29, 132.21, 132.17, 26.3, 126.2, 34.1, 32.8, 30.0, 29.42, 29.41, 29.39, 28.8, 28.2, 27.1, 12.7; MS (m/z): 392.1 (28), 390.1 (28), 227.1 (20), 187.1 (98), 186.0 (100).

2-(5-bromopentyl)-3-methylnaphthalene-l,4-dione (Id): Yield: 17%; yellow solid, m.p.: 32-34 °C; TLC (Si0₂) R_f 0.53 (9: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.03-8.01 (m, 2H), 7.67-7.65 (m, 2H), 3.42 (t, 2H, J= 7.0 Hz), 2.62 (t, 2H, J= 7.5 Hz), 2.17 (s, 3H), 1.91 (qnt, 2H, J= 7.0 Hz), 1.57-1.48 (m, 4H); ¹³C MR (125 MHz, CDC1₃) δ 185.0, 184.5, 146.8, 143.2, 133.3, 132.0, 126.2, 126.1, 33.7, 32.4, 28.4, 27.7, 26.8, 12.7.

2-(4-bromobutyl)-3-methylnaphthalene-l,4-dione (le): Yield: 19%; yellow solid, m.p.: 43-45 °C; TLC (Si0₂) R 0.48 (7: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.07-8.05 (m, 2H), 7.70-7.68 (m, 2H), 3.46 (t, 2H, J= 7.0 Hz), 2.66 (t, 2H, J= 8.0 Hz), 2.20 (s, 3H), 1.97 (qnt, 2H, J= 7.0 Hz), 1.65 (qnt, 2H, J = 8.0 Hz); ¹³C MR (125 MHz, CDC1₃) δ 185.1, 184.5,

146.5, 143.5, 133.4, 132.0, 126.27, 126.22, 33.2, 32.6, 27.1, 26.0, 12.7; MS (m/z): 308.0 (11), 306.0 (12), 228.1 (17), 227.1 (100), 199.1 (14), 185.0 (16), 157.1 (31).

Synthesis of 2-alkyl naphthoquinones phosphonium salts:

General Procedure. A trisubstituted phosphine (0.15 mmol) and naphthoquinone 1 were combined in a 5 mL conical-shaped tube and reacted under conventional heating or microwave irradiation according to procedures describe for Methods A-C. The resulting dark residue was dissolved in DCM (3 mL) and NaN0₂ (0.5 mmol equiv) was added followed by 1 drop of concentrated HCI. Filtered air was bubbled into the solution to re-oxidize any 1,4-naphthodiol byproduct which appears fluorescent blue under UV (254 nm) on TLC. The mixture was then directly loaded onto a silica gel column using 100% acetone to flush out nonpolar impurities followed by 9: 1 DCM:MeOH to obtain the naphthoquinone phosphonium bromide. Subsequent conversion to the mesylate salt was achieved by dissolving the phosphonium bromides in DCM and washing three times with 0.1 M sodium mesylate solution.

( 10-( 1, 4-Dioxo-l, 4-dihydronaphthalen-2yl)decyl)triphenyl-phosphonium

methanesulfonate (Compound III- 3): orange oil; ¾ NMR (500 MHz, CDC1₃) δ 8.02-8.00 (m, 1H), 7.98-7.97 (m, 1H), 7.76-7.65 (m, 17H), 6.70 (s, 1H), 3.51-3.47 (m, 2H), 2.63 (s, 3H), 2.47 (t, 2H, J= 7.5 Hz), 1.50-1.44 (m, 2H), 1.30-1.15 (m, 12H); ¹³C MR (125 MHz, CDC1₃) δ 185.4, 185.2, 152.0, 135.2, 135.1, 134.8, 133.7, 133.6, 132.4, 132.2, 130.7, 130.6, 126.7, 126.1, 118.8, 118.1, 39.6, 30.5, 30.4, 29.8, 29.6, 29.40, 29.36, 29.3, 29.22, 29.17, 28.1, 22.7, 22.5, 22.1.

Tribenzyl(l 0-(3-methyl-l, 4-dioxo-l, 4-dihydronaphtha-len-2-yl)decyl)phosphonium methanesulfonate (Compound III- 8): yellow oil; 'H NMR (500 MHz, CDC1₃) δ 8.08-8.06 (m, 2H), 7.71-7.67 (m, 2H), 7.35-7.25 (m, 15H), 4.01 (d, 6H, J=15.0 Hz), 2.91(s, 3H), 2.63 (t, 2H, J = 7.5 Hz), 2.19 (s, 3H), 1.92-1.86 (m, 2H), 1.56-1.42 (m, 2H), 1.42-1.34 (m, 2H), 1.30-1.11 (m, 12H). ¹³C MR (125 MHz, CDC1₃) δ 185.4, 184.7, 147.4, 143.2, 133.4, 132.2, 130.4, 130.3, 129.6, 128.5, 128.1, 128.0, 126.3, 126.2, 39.8, 30.9, 30.8, 29.9, 29.3, 29.2, 29.1, 28.7, 27.1, 26.7, 26.4, 21.6, 19.0, 18.7, 12.7

Tributyl(l 0-(3-methyl-l , 4-dioxo-l, 4-dihydronaphthalen-2-yl)decyl)phosphonium methanesulfonate (Compound III-9) : brown oil; 'H NMR (500 MHz, CDC1₃) δ 8.08 (m, 2H), 7.70 (m, 2H), 2.74 (s, 3H), 2.63 (t, 2H, J= 8.0 Hz), 2.33 (m, 10H), 2.19 (s, 3H), 1.53-1.26 (m, 28H), 0.98 (m, 9H); ¹³C NMR (125 MHz, CDC1₃) δ 185.4, 184.8, 147.5, 143.2, 133.4, 132.2, 132.1, 126.3, 126.2, 35.5, 35.0, 31.3, 31.2, 30.01, 29.96, 29.7, 29.40, 29.36, 29.3, 29.0, 28.7, 27.2, 27.1, 27.0, 26.9, 26.6, 26.5, 26.3, 26.1, 25.5, 22.8, 15.5, 15.2, 12.7.

( 10-( 3-Methyl-l, 4-dioxo-l, 4-dihydronaphthalen-2yl)decyl)-tri-o-tolylphosphonium methanesulfonate (Compound III- 10): yellow oil; ^XH NMR (500 MHz, CDC1₃) δ 8.09-8.03 (m, 2H), 7.75-7.68 (m, 4H), 7.63-7.49 (m, 10H), 3.50-3.46 (m, 2H), 2.74 (s, 3H), 2.60 (t, 2H, J= 7.5 Hz), 2.26 (s, 9H), 1.68-1.60 (m, 4H), 1.46-1.21 (m, 12H).

Tricyclohexyl(10-(3-methyl-l, 4-dioxo-l, 4-dihydronaph-thalen-2-yl)decyl)phosphonium methanesulfonate: (Compound III- 12): orange oil; ^XH NMR (500 MHz, CDC1₃) δ 8.09-8.07 (m, 2H), 7.72-7.69 (m, 2H), 2.74 (m, 3H), 2.63 (t, 2H, J= 8.0 Hz), 2.58-2.51 (m, 3H) 2.38-2.32 (m, 4H), 2.19 (s, 3H), 2.01-1.81 (m, 16H), 1.56-1.25 (m, 30H); ¹³C NMR (125 MHz, CDC1₃) δ 185.4, 184.8, 147.5, 143.2, 133.4, 132.2, 132.1, 126.24, 126.19, 35.5, 35.0, 31.3, 31.2, 30.01, 29.96, 29.7, 29.40, 29.36, 29.3, 29.0, 28.7, 27.2, 27.1, 27.0, 26.9, 26.6, 26.5, 26.3, 26.1, 25.5, 22.8, 15.5, 15.2, 12.7.

Tris(4-methoxyphenyl)(l 0-(3-methyl-l , 4-dioxo-l ,4-dihydro-naphthalen-2- yl)decyl)phosphonium methanesulfonate (Compound 111-13): yellow oil; ^XH NMR (500 MHz,

CDCI₃) δ 8.09-8.04 (m, 2H), 7.08-7.67 (m, 2H), 7.65 (dd, 6H, J= 12.0, 9.0 Hz), 7.17 (dd, 6H, J = 9.0, 2.5 Hz), 3.32-3.24 (m, 2H), 2.75 (s, 3H), 2.61 (t, 2H, J= 7.5 Hz), 2.18 (s, 3H), 1.57-1.53 (m, 2H), 1.46-1.41 (m, 2H), 1.38-1.33 (m, 2H), 1.30-1.21 (m, 10H); ^ljC NMR (125 MHz, CDC1₃) δ 185.8, 185.6, 164.8, 164.7, 147.7, 143.3, 135.6, 135.5, 133.5, 132.4, 126.4, 126.3, 116.3, 116.2, 109.7, 109.0, 56.1, 56.0, 39.7, 30.7, 30.1, 29.8, 29.5, 29.4, 29.3, 28.9, 27.3, 22.9, 22.7, 12.7.

(4-(3-Methyl-l, 4-dioxo-l, 4-dihydronaphthalen-2-yl)butyl)triphenyl phosphonium bromide (Compound III- 15): orange oil; ^XH NMR (500 MHz, CDC1₃) δ 8.04-8.02 (m, 1H), 7.97- 7.96 (m, 1H), 7.81-7.68 (m, 17H), 3.69-3.63 (m, 2H), 2.68-2.66 (m, 5H), 2.17 (s, 3H), 1.86-1.80 (m, 2H), 1.76-1.69 (m, 2H); ¹³C NMR (125 MHz, CDC1₃) δ 1.85.1, 184.9, 146.0, 144.4, 135.09, 135.06, 133.64, 133.56, 133.5, 133.4, 132.1, 131.9, 130.6, 130.5, 126.3, 126.2, 118.6, 117.9.

Example 2: Synthesis of 2-Amino Naphthoquinones Phosphonium Mesylates (Formula II)

Preparation of 2-aminoaikyi naphthoquinones (3):

General procedure. A suspension of quinone (0.2 mmol) in ethanol (2 mL) and amine (0.2 mmol) was stirred at room temperature for 18 h or until the reaction was complete as determined by TLC. Purification of the reaction mixture by column chromatography using a hexane/EtOAc gradient (3:1 to 1: 1) gave the product as an orange or a red solid.

2-(10-hydroxydecylamino)naphthalene-l,4-dione (3a) Yield: 76%; red solid, m.p.: 117- 118 °C; TLC (Si0₂) R/0.38 (1: 1 Hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.05 (d, 1H, J = 7.5 Hz), 7.98 (d, 1H, J= 7.5 Hz), 7.67 (t, 1H, J= 7.5 Hz), 7.56 (t, 1H, J= 7.5 Hz), 5.92-5.88 (m, 1H), 5.68 (s, 1H), 3.59 (t, 2H, J= 6.5 Hz), 3.13 (q, 2H, J= 6.5 Hz), 1.64 (qnt, 2H, J= 7.0 Hz), 1.52 (qnt, 2H, J= 7.0 Hz), 1.39-1.33 (m, 12H); ¹³C NMR (125 MHz, CDC1₃) δ 183.2 182.0, 148.2, 134.9, 133.8, 132.1, 130.6, 126.4, 126.3, 100.7, 63.1, 42.7, 32.9, 29.6, 29.5, 29.4, 29.3, 28.4, 27.1, 25.8; MS (m/z): 329.3(33), 228.2(41), 214.2(10), 200.2(10), 186.1(100), 174.1(81).

2-(10-hydroxydecylamino)-3-methylnaphthalene-l,4-dione (3b) Yield: 23%; red solid, m.p.: 51-54 °C; TLC (Si0₂) R_f 0.19 (3: 1 Hexanes:EtOAc); 'H NMR (500 MHz, CDC1₃) δ 8.04

(d, 1H, J= 7.5 Hz), 7.95 (d, 1H, J= 7.5 Hz), 7.64 (t, 1H, J= 7.5 Hz), 7.53 (t, 1H, J= 7.5 Hz),

5.70 (s, 1H), 3.60 (t, 2H, J= 6.5 Hz), 3.50 (q, 2H, J= 6.5 Hz), 2.20 (s, 3H), 1.59 (qnt, 2H, J=

7.0 Hz), 1.52 (qnt, 2H, J= 7.0 Hz), 1.36-1.22 (m, 12H); ¹³C NMR (125 MHz, CDC1₃) δ 183.8, 182.7, 146.4, 134.5, 133.7, 131.9, 130.5, 126.4, 126.1, 112.1, 63.2, 45.7, 32.9, 31.1, 29.7, 29.6, 29.5, 29.4, 26.8, 25.9, 1 1.4; MS (m/z): 200.1(73), 186.0(52).

2-(2-hydroxyethylamino)naphthalene-l,4-dione (3c) Yield: 87%; red oil; TLC (S1O₂) Rf 0.40 (1 : 1 Hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.10 (d, 1H, J= 7.5 Hz), 8.05 (d, 1H, J= 7.5 Hz), 7.73 (t, 1H, J= 7.5 Hz), 7.62 (t, 1H, J= 7.5 Hz), 6.22 (bs, 1H), 5.77 (s, 1H), 3.95- 3.91 (m, 2H), 3.39-3.35 (m, 2H); MS (m/z): 216.1(12), 215.1(86), 200.1(100), 160.1(35), 132.1(13).

Preparation of 2-aminoalkyl naphthoquinone mesylates (4):

3a-c 4a-c

General procedure. Naphthoquinone (0.44 mmol), mesyl chloride (39 μί, 0.49 mmol), and Et3N (129 μί, 0.89 mmol) were combined in 10 mL of DCM at 0 °C. The mixture was stirred at room temp for 18 h and then was transferred to a separatory funnel with 10 mL of DCM, washed with distilled water (10 mL) and 5% NaHC0₃ (10 mL), dried over MgS0₄, filtered, and evaporated to provide the product.

10-(1 ,4-dihydro-l ,4-dioxonaphthalen-3-ylamino)decyl methanesulfonate (4a): Yield: 97%; red solid, m.p.: 102-104 °C; TLC (SiO₂) R/0.53 (3 : 1 hexanes:EtOAc); ^ NMR ^OO MHz, CDCI₃) δ 8.01 (d, 1H, J= 7.5 Hz), 7.95 (d, 1H, J= 7.5 Hz), 7.65 (t, 1H, J= 7.5 Hz), 7.53 (t, 1H, J= 7.5 Hz), 7.92-7.89 (m, 1H), 5.65 (s, 1H), 4.15 (t, 2H, J= 7.0 Hz), 3.10 (q, 2H, J= 7.0 Hz), 2.95 (s, 3H), 1.67 (qnt, 2H, J= 7.0 Hz), 1.59 (qnt, 2H, J= 7.0 Hz), 1.35-1.22 (m, 12H); ¹³C NMR (125 MHz, CDC1₃) δ 182.8, 181.9, 148.0, 134.7, 133.7, 131.9, 130.5, 126.3, 126.2, 70.3, 42.6, 37.4, 37.3, 29.5, 29.3, 29.1, 28.9, 28.2, 27.0, 25.4; MS (m/z): 311.3(26), 242.2(12), 228.2(36), 214.1(10), 200.2(11), 186.1(100).

10-(l,4-dihydro-2-methyl-l,4-dioxonaphthalen-3-ylamino)decyl methanesulfonate (4b) Yield: 99%; red solid, m.p.: 57-59 °C; TLC (Si0₂) R 0.26 (3: 1 hexanes:EtOAc); 'H NMR (500 MHz, CDCI3) δ 8.00 (d, 1H, J= 8.0 Hz), 7.90 (d, 1H, J= 8.0 Hz), 7.60 (t, 1H, J= 7.5 Hz), 7.49 (t, 1H, J= 7.5 Hz), 5.67 (bs, 1H), 4.16 (t, 2H, J= 7.0 Hz), 3.51-3.45 (m, 2H), 2.95 (s, 3H), 2.16 (s, 3H), 1.67 (qnt, 2H, J = 7.5 Hz), 1.58 (qnt, 2H, J= 7.0 Hz), 1.33-1.23 (m, 12H); ¹³C NMR (125 MHz, CDCI₃) δ 183.6, 182.6, 146.2, 134.4, 133.6, 131.8, 130.3, 126.2, 126.0, 111.9, 70.3, 45.5, 37.3, 32.8, 30.9, 29.6, 29.4, 29.2, 29.0, 26.7, 25.5, 11.3; MS (m/z): 325.3(22), 200.1(100).

10-(l,3-dioxoisoindolin-2-yl)decyl methanesulfonate (4c): Yield: 91%; colorless oil; TLC (Si0₂) R 0.20 (4: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 7.85-7.83 (m, 2H), 7.73-7.71 (m, 2H), 4.22 (t, 2H, J= 7.0 Hz), 3.67 (t, 1H, J= 7.5 Hz), 3.02 (s, 3H), 1.74 (qnt, 2H, J= 7.0 Hz), 1.69-1.63 (m, 2H), 1.41-1.36 (m, 2H), 1.33-1.24 (m, 10H); ¹³C MR (125 MHz, CDCI₃) δ 168.5, 133.9, 132.2, 123.2, 70.3, 38.1, 37.5, 29.4, 29.2, 29.2, 29.0, 28.6, 26.8, 25.5; MS (m/z): 199.0(51), 186.0(100).

Preparation of -amino naphthoquinones phosphonium mesylates:

4a-c Formula II

General procedure. A trisubstituted phosphine (0.13 mmol) and methanesulfonate (0.13 mmol) were combined in a 5 mL conical-shaped microwave with stir bar. The tube was capped and the mixture was homogenated at 110 °C. The tube was then placed in microwave reactor where it was irradiated on high absorption (100-210 watts) for 0.5 h at 150 °C. The mixture was then directly loaded onto a silica gel column using 100% acetone to flush out nonpolar impurities followed by 5-10% gradient of DCM in MeOH to elute the naphthoquinone phosphonium methanesulfonate.

(2-( 1, 4-dihydro-l, 4-dioxonaphthalen-3-ylamino)ethyl)triphenylphosphonium

methanesulfonate (Compound II-l): Yield: 20%; red oil; TLC (SiO₂) R/0.11 (9: 1 DCM:MeOH); 'H NMR (500 MHz, CDCI₃) δ 8.03 (m, 1H), 7.69 (d, 1H, J = 7.5 Hz), 7.87-7.72 (m, 16H), 7.65 (t, 1H, J= 7.5 Hz), 7.56 (t, 1H, J= 7.5 Hz), 5.17 (s, 1H), 4.15-4.08 (m, 2H), 3.68-3.60 (m, 2H), 2.88 (s, 3H); ¹³C NMR (125 MHz, CDC1₃) δ 183.2, 180.8, 165.8, 135.6, 135.6, 134.5, 133.8, 133.7, 133.3, 132.2, 131.0, 130.9, 130.8, 126.6, 125.9, 118.1, 39.7, 36.3, 29.8.

( 10-( 1, 4-dihydro-l, 4-dioxonaphthalen-3-ylamino)decyl)triphenylphosphonium methanesulfonate (Compound 11-5): Yield: 40%>; red oil; TLC (Si0₂) R 0.24 (9: 1

DCM:MeOH); 'H NMR (500 MHz, CDC1₃) δ 8.03 (dd, 1H, J= 8.0, 1.0 Hz), 7.98 (dd, 1H, J= 8.0, 1.0 Hz), 7.76-7.64 (m, 16H), 7.56 (dt, 1H, J= 7.5 Hz, 1.0 Hz), 5.95 (bs, 1H), 5.66 (s, 1H), 3.52-3.46 (m, 2H), 3.12 (q, 2H, J= 6.5 Hz), 2.66 (s, 3H), 1.64-1.55 (m, 4H), 1.32-1.27 (m, 2H), 1.26-1.20 (m, 10H); ^ljC NMR (125 MHz, CDC1₃) δ 183.1, 182.1, 148.2, 135.2, 135.2, 134.9, 133.9, 133.8, 133.7, 132.1, 130.7, 130.6, 130.5, 126.4, 126.3, 1 18.9, 1 18.3, 42.7, 39.6, 30.6, 30.4, 29.4, 29.2, 29.1, 28.2, 27.0, 22.8, 21.8.

( 10-( 1, 4-dihydro-l, 4-dioxonaphthalen-3-ylamino)decyl)tricyclohexyl-phosphonium methanesulfonate (Compound II-6): Yield: 47%; red oil; TLC (Si0₂ ) R 0.27 (9: 1

DCM:MeOH); 'H NMR (500 MHz, CDC1₃) δ 8.10 (d, 1H, J= 7.5 Hz), 8.04 (d, 1H, J= 7.5 Hz), 7.73 (t, 1H, J= 7.5 Hz), 7.62 (t, 1H, J= 7.5 Hz), 5.96 (bs, 1H), 5.73 (s, 1H), 3.18 (q, 2H, J= 6.5 Hz), 2.75 (s, 3H), 2.56 (q, 3H, J= 12.0 Hz), 2.44-2.39 (m, 2H), 1.83-1.80 (m, 4H), 1.72-1.65 (m, 2H), 1.54-1.31 (m, 40H); ¹³C NMR (125 MHz, CDC1₃) δ 185.7, 185.5, 150.1, 134.9, 132.1, 126.4, 126.3, 42.7, 39.8, 31.4, 30.2, 29.9, 29.5, 29.4, 29.2, 28.3, 27.3, 27.1, 26.7, 26.6, 25.7.

Example 3: Synthesis of iV-alkyl phthalimide phosphonium salts (Formula I):

Method A: PY₃, μ\Λ/, 0.5 h; B: P(PhMe)₃, 1 10 °C, 16-40 h; C: PMe₃, 'PrOH:PhMe, 90 °C, 48-72 h.

General Procedure. Phthalimide (890 mg, 6 mmol) and CS2CO₃ (1.97 g, 6 mmol) were combined in dry MeCN (50 mL) and refluxed for 0.5 h. The dibromoalkane (12 mmol) was then added and the reaction was stirred overnight at 80 °C. The solution was next cooled to rt, filtered, and concentrated. A 1 : 1 mixture of hexanes :EtO Ac was added and the solution was again filtered and concentrated. The 4, 6, and 10-bromoalkyl phthalimide products 5, respectively, were then isolated as white solids by precipitation with hexanes and used without further purification.

Subsequent conversion to the phosphonium salts was performed by 3 methods:

Method A: The appropriate trisubstituted phosphine (1.5 mol equiv) and phthalimide 5 (1 mol equiv) were combined in a 5 mL conical-shaped reaction tube. The mixture was homogenated at

110 °C and the tube was placed in a microwave reactor where it was irradiated on high absorption (100-210 watts) for 0.5 h at 150 °C. Purification by silica gel chromatography using acetone to elute nonpolar impurities followed by 9: 1 DCM:MeOH afforded the phosphonium bromide phthalimide products. Subsequent conversion to the mesylate salts was achieved by dissolving the phosphonium bromides in DCM and washing three times with 0.1 M NaOMs solution. After the organic layer was dried over MgS0₄ and evaporated, successful anion exchange was confirmed by the mesylate signal at δ 2.7 in the ^XH NMR.

Method B: Tri(o-tolyl)phosphine (1.5 mol equiv) and phthalimide 5 (1 mol equiv) in a 5 mL conical-shaped reaction tube. The mixture was then stirred at 110 °C for 40 h under Ar.

Purification by silica gel chromatography using acetone to elute nonpolar impurities followed by 9: 1 DCM:MeOH afforded the phosphonium bromide phthalimide product 2h. Subsequent conversion to the mesylate salts was achieved by dissolving the phosphonium bromides in DCM and washing three times with 0.1 M NaOMs solution.

Method C: Phthalimide 5 (20.9 mg, 57 μιηοΐ) was combined with a 3 : 1 solution of 'PrOH:PhMe (4.9 mL) in a 5 mL conical-shaped reaction tube. The tube was sealed with a crimp cap rubber septum and trimethylphosphine (9 μΐ, 85 μιηοΐ) was added via a microsyringe. The solution was then stirred at 110 °C for 72 h. The solution was concentrated and the product was isolated as a white solid by trituration in EtOAc.

(4-(l,3-Dioxoisoindolin-2-yl)butyl)triphenylphosphonium methanesulfonate (Compound 1-2): colorless oil; 'H NMR (500 MHz, CDC1₃) δ 7.83-7.66 (m, 19H), 3.82-3.75 (m, 4H), 2.71 (s, 3H), 2.13-2.09 (m, 2H), 1.65-1.57 (m, 2H); ¹³C NMR (125 MHz, CDC1₃) δ 168.4, 135.0, 134.2, 133.7, 133.6, 131.7, 130.5, 130.4, 123.2, 1 18.4, 1 17.8, 39.5, 36.3, 28.6, 28.5, 19.5.

(6-(l,3-Dioxoisoindolin-2-yl)hexyl)triphenylphosphonium methanesulfonate (Compound 1-3): Yield: 82%; colorless oil; ^XH NMR (500 MHz, CDC1₃) δ 7.83-7.73 (m, 19H), 3.63-3.56 (m, 4H), 2.68 (s, 3H), 1.69-1.58 (m, 6H), 1.37-1.33 (m, 2H); ¹³C NMR (125 MHz, CDC1₃) δ 168.4, 135.09, 135.07, 134.0, 133.55, 133.47, 131.9, 130.6, 130.5, 123.1, 1 18.9, 117.8, 39.4, 37.6, 29.8, 29.7, 28.1, 26.2, 22.4, 22.3, 21.9.

(10-(1, 3-Dioxoisoindolin-2-yl)decyl)tris( 4-fluorophenyl)-phosphonium methanesulfonate (Compound 1-4): white oil; ^XH NMR (500 MHz, CDC1₃) δ 7.95-7.90 (m, 6H), 7.83-7.81 (m, 2H), 7.74-7.72 (m, 2H), 7.44 (t, 6H, J= 6.0 Hz), 3.65-3.63 (m, 4H), 2.65 (s, 3H), 1.64-1.58 (m, 6H), 1.26-1.20 (m, 10H); ¹³C NMR (125 MHz, CDC1₃) δ 168.5, 166.7 (dd, app J_C-_F = 259.0, 3.4 Hz), 136.6 (dd, app Jc-_F = 11.5, 9.5 Hz), 133.9, 132.1, 123.1, 118.5 (m), 1 14.0 (dd, app J_C-_F = 90.0, 3.4 Hz), 39.5, 37.9, 30.4, 30.2, 29.7, 29.2, 29.04, 29.95, 28.4, 29.7, 22.5, 22.1.

Tribenzyl(l 0-( 1, 3-dioxoisoindolin-2-yl)decyl) triphenylphosphonium methanesulfonate (Compound 1-5): Yield: 63%; colorless oil; TLC (SiO₂) R/0.51 (9: 1 DQVLMeOH); ^XH NMR (500 MHz, CDCI₃) δ 7.84-7.82 (m, 2H), 7.73-7.71 (m, 2H), 7.34-7.26 (m, 15H), 4.02 (d, 6H, J= 15.0 Hz), 3.66 (t, 2H, J= 7.5 Hz), 2.91 (s, 3H), 1.92-1.88 (m, 2H), 1.69-1.63 (m, 2H), 1.35-1.07 (m, 14H); ¹³C MR (125 MHz, CDC1₃) δ 168.5, 134.0, 132.1, 130.6, 130.4, 130.3, 129.6, 128.6, 128.2, 128.1, 127.8, 123.2, 39.9, 38.0, 30.9, 30.8, 29.2, 29.1, 29.0, 28.7, 28.6, 26.9, 26.8, 26.5, 21.7, 18.7.

Tributyl(10-(l,3-dioxoisoindolin-2-yl)decyl) methanesulfonate (Compound 1-6) : colorless oil; ^XH NMR (500 MHz, CDC1₃) δ 7.84 (dd, 2H, J= 5.0, 3.0 Hz), 7.73 (dd, 2H, J= 10.0, 3.0 Hz), 3.67 (t, 2H, J= 7 Hz), 2.73 (s, 3H), 2.40-2.31 (m, 8H), 1.71-1.65 (m, 6H), 1.57-1.41 (m, 14H), 1.32-1.27 (m, 12H), 0.97 (t, 9H, J= 6.5 Hz); ¹³C MR (125 MHz, CDC1₃) δ 168.5, 133.9, 132.1, 123.2, 39.6, 38.0, 30.8, 29.3, 29.1, 29.0, 28.9, 28.5, 27.9, 27.4, 26.7, 24.4, 23.2, 23.9, 23.8, 21.9, 19.2, 19.0, 18.6, 13.7, 13.5.

Tricyclohexyl(10-( 1, 3-dioxoisoindolin-2-yl)decyl) phosphonium methanesulfonate (Compound 1-9): Yield: 82%; colorless oil; TLC (SiO₂) R/0.48 (9: 1 DCM:MeOH); ¾ NMR (500 MHz, CDCI₃) δ 7.85-7.83 (m, 2H), 7.74-7.72 (m, 2H), 3.67 (t, 2H, J= 7.5 Hz), 2.74 (s, 3H), 2.48 (q, 3H, J= 12.5 Hz), 2.29-2.24 (m, 2H), 2.01-1.95 (m, 6H), 1.85-1.81 (m, 4H), 1.70- 1.63 (m, 2H), 1.56-1.29 (m, 34H); ¹³C MR (125 MHz, CDC1₃) δ 168.6, 134.0, 132.1, 123.2, 50.5, 38.0, 31.3, 31.2, 30.0 ,29.7, 29.3, 29.2, 29.1, 29.0, 28.6, 27.2, 27.1, 26.8, 26.6, 26.5, 25.5, 22.8, 15.6, 15.3.

(10-(l ,3-Dioxoisoindolin-2-yl)decyl)triphenylphosphonium methanesulfonate

(Compound 1-7): Yield: 42%; colorless oil; TLC (Si0₂) R 0.36 (9:1 DCM:MeOH); ^XH NMR (500 MHz, CDCI₃) δ 7.83-7.79 (m, 9H), 7.78-7.75 (m, 2H), 7.75-7.69 (m, 8H), 3.64 (t, 2H, J= 7.5 Hz), 3.56-3.48 (m, 2H), 2.70 (s, 3H), 1.65-1.57 (m, 6H), 1.28-1.18 (m, 10H); ¹³C NMR (125 MHz, CDC1₃) 6 168.4, 135.1, 135.0, 133.9, 133.6, 133.5, 132.1, 130.6, 130.5, 123.1, 118.7, 118.1, 37.9, 30.4, 30.2, 29.3, 29.1, 29.0, 28.5, 26.7, 22.6, 21.8.

(10-(l,3-Dioxoisoindolin-2-yl)decyl)tris(4-methoxyphenyl)phosphonium

methanesulfonate (Compound I- 10): Yield: 87%; colorless oil; TLC (SiO₂) R 0.23 (9: 1

DCM:MeOH); 'H NMR (500 MHz, CDC1₃) δ 7.83-7.81 (m, 2H), 7.74-7.72 (m, 2H), 7.63 (dd, 6H, J= 11.5 , 8.5 Hz), 7.19 (dd, 6H, J= 8.5 , 2.5 Hz), ; ¹³C NMR (125 MHz, CDC1₃) δ 168.3, 164.6, 164.5, 135.3, 135.2, 133.9, 131.9, 123.0, 116.2, 116.1, 109.3, 108.6, 55.9, 55.8, 39.3, 37.8, 30.4, 30.3, 29.2, 29.0, 28.9, 28.8, 28.4, 26.6, 23.3, 22.4.

Example 4: Synthesis of 2-Acetoxy and 2-Hydroxy Napthoquinone Phosphonium Salts (Formula III, where Z = OAc or OH, and Formula IV) Preparation of 2-alkylated 1 ,4-naphthoquinones:

General procedure. Naphthoquinone (3.2 mmol), 1-bromoalkylcarboxylic acid (3.5 mmol), and AgNC^ (1.6 mmol) were combined in 30 mL of anhydrous MeCN at room temperature. The reaction mixture was heated 60 °C and 30 mL ammonium persulfate aqueous solution (6.1 mmol) was then slowly added (over a 2.5 hours period). The reaction mixture was heated at 60 °C for 20 hours. After cooling to room temperature, the mixture was redissolved in EtOAc (15 mL) and washed with brine. The organic layer was dried over Na₂S0₄, filtered, and evaporated. The final compound 4 was separated by flash chromatography on silica gel using 9: 1 hexanes:EtOAc in accordance to product R_f values.

By this method were prepared the following:

2-(5-Bromopentyl)naphthalene-l,4-dione 4a. Yield: 11%; yellow solid, mp 56-58 °C; TLC (Si0₂) R_f 0.50 (7: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.12-8.03 (m, 2H), 7.95-7.70 (m, 2H), 6.79 (s, 1H), 3.45-3.41 (m, 2H), 2.64-2.57 (m, 2H), 1.95-1.89 (m, 2H), 1.70- 1.51 (m, 4H); ¹³C NMR (125 MHz, CDC1₃) δ 185.2, 185.1, 151.4, 134.8, 133.7, 133.6, 132.2, 132.0, 126.6, 126.0, 35.5, 32.3, 29.4, 27.8, 27.2.

2-(l 0-Bromodecyl)naphthalene-1 ,4-dione 4b. Yield: 75%; yellow solid, mp 43-45 °C; TLC (Si0₂) R_f 0.36 (7: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.10-8.07 (m, 1H), 8.05-8.03 (m, 1H), 7.74-7.71 (m, 2H), 6.78 (s, 1H), 3.40 (t, 2H, J= 7.0 Hz), 2.56 (t, 2H, J= 7.5 Hz), 1.84 (qnt, 2H, J= 7.0 Hz), 1.58 (qnt, 2H, J= 7.5 Hz), 1.43-1.29 (m, 12H); ¹³C NMR (125 MHz, CDC1₃) δ 185.2, 185.1, 151.9, 134.7, 133.6, 132.3, 132.1, 126.6, 126.0, 34.0, 32.8, 29.6, 29.4, 29.4, 29.3, 28.7, 28.2, 27.1.

Preparation of la-(bromoaikyi)naphtho[2,3-fi]oxirene- -dione 5:

General procedure. A solution of 30% H₂0₂ (1.5 niL), a₂C03 (60 mg, 0.57 mmol) and H₂0 (0.6 mL) was added to a stirring suspension of 1,4-naphthoquinone (4.4 mmol) in 3 mL EtOH at room temperature. The mixture was stirred at that temperature for 1 -3 h until the epoxidation was complete. Water (3 mL) was added and the solution was extracted three times with DCM (6 mL). The combined organic layer was dried over MgS0₄, filtered, and concentrated to provide the product that was used without further purification.

By this method were prepared the following:

l -(10-Bromodecyl)naphtho[2,3-(i]oxirene-2, 7(loH, 7 H)-dione 5b. Yield: 82%; white semi-solid; TLC (Si0₂) R_f0.48 (7: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.03-8.01 (m, 1H), 7.96-7.94 (m, 1H), 7.78 (m, 2H), 3.87 (s, 1H), 3.41 (t, 2H, J= 6.5 Hz), 2.31-2.05 (m, 1H), 1.91-1.82 (m, 3H), 1.52-1.47 (m, 2H), 1.42-1.38 (m, 4H), 1.29 (m, 8H); ¹³C MR (125 MHz, CDC1₃) δ 192.2, 191.9, 134.7, 134.5, 132.6, 132.0, 127.6, 126.9. 64.2, 60.4, 34.3, 32.9, 29.8, 29.6, 29.5, 29.4, 28.9, 28.4, 28.3, 24.7.

Preparation of 2-(bromoalkyl)-3-hydroxynaphthalene-l,4-dione 6:

General procedure. Concentrated H₂S0₄ (1.4 mL) was mixed with epoxide 5 (1.3 mmol) and was stirred at room temperature for 10 minutes. The mixture was then chilled to 0 °C and was added 10 mL of saturated aqueous NaHCC^ solution. The resulting mixture was then extracted twice with DCM (10 mL), dried over MgS0₄, filtered and concentrated. The final product was separated by flash chromatography on silica gel in accordance to product R_f values.

2-(5-Bromopentyl)-3-hydroxynaphthalene- 1 ,4-dione 6a. Yield: 20%; yellow solid mp 109-110 °C; TLC (Si0₂) R_f 0.36 (7: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.12 (d, 1H, J= 7.5 Hz), 8.07 (d, 1H, J= 7.0 Hz), 7.75 (t, 1H, J= 7.5 Hz), 7.67 (t, 1H, J= 7.5 Hz), 7.42 (s, 1H), 3.42 (t, 2H, J= 7.0 Hz), 2.62 (t, 2H, J= 7.0 Hz), 1.92 (qnt, 2H, J= 7.0 Hz), 1.60-1.49 (m, 4H); ¹³C NMR (125 MHz, CDC1₃) δ 184.6, 181.4, 153.1, 134.9, 132.9, 132.8, 129.4, 126.7, 126.1, 124.2, 33.7, 32.5, 28.1, 27.3, 23.0; MS (EI, 70 eV): mlz (%) = 322 (M, 48%), 242 (15), 213 (15), 188 (100), 160 (28).

2-(Bromodecyl)-3-hydroxynaphthalene-l,4-dione 6b. Yield 65%; yellow solid; TLC (Si0₂) R_f 0.43 (7: 1 hexanes:EtOAc); 'H NMR (500 MHz, CDC1₃) δ 8.11 (d, 1H, J= 7.5 Hz), 8.06 (d, 1H, J= 7.5Hz), Ί.Ί6-Ί.Ί2, (m, 1H), 7.69-7.65 (m, 1H), 7.38 (s, 1H), 3.41-3.38 (t, 2H, J= 7.0 Hz), 2.61 (t, 2H, J= 7.5 Hz), 1.84 (qnt, 2H, J= 7.0 Hz), 1.55 (qnt, 2H, J= 7.0 Hz), 1.40-1.25 (m, 12H); ¹³C MR (125 MHz, CDC1₃) δ 184.9, 181.6, 153.2, 134.9, 134.7, 134.5, 133.1, 133.0, 132.6, 129.6, 127.6, 126.93, 129.91, 126.2, 124.9, 34.3, 33.0, 29.9, 29.7, 29.6, 29.5, 28.9, 28.4, 28.3, 23.5.

Preparation of 3-(10-bromoalkyl)-l,4-dioxo-l,4-dihydronaphthalen-2-yl acetate 7:

General procedure. Quinone (0.375 mmol) was added into a chloroform (5 mL) solution of acetyl chloride (54 μΐ, 0.75 mmol) and 2,6-lutidine (70 μΐ,, 0.68 mmol). The reaction was stirred at 0 °C for 5 minutes. 0.5 M HC1 (5 mL) was then added and the aqueous layer was extracted five times with DCM (1 mL). The combined organic layer was washed five times with brine (1 mL), dried over MgS0₄, filtered, and concentrated. The product was isolated as white solid and was used without further purification.

3-(10-Bromodecyl)-l,4-dioxo-l,4-dihydronaphthalen-2-yl acetate 7a. Yield 98%; yellow solid, mp 52-54 °C; TLC (Si0₂) R_f 0.48 (7: 1 hexanes:EtOAc); ¾ NMR (500 MHz, CDC1₃) δ 8.13-8.09 (m, 2H), 7.75-7.73 (m, 2H), 3.04 (t, 2H, J= 6.5 Hz), 2.55 (t, 2H, J= 8.0 Hz), 2.41 (s, 3H), 1.85 (qnt, 2H, J= 7.0 Hz), 1.51 (t, 2H, J= 7.0 Hz), 1.42-1.29 (m, 12H); ¹³C MR (125 MHz, CDCI₃) δ 184.8, 178.3, 168.2, 151.3, 140.0, 134.3, 134.0, 132.3, 131.1, 126.9, 126.8, 34.3, 33.0, 29.9, 29.6, 29.4, 28.9, 28.7, 28.3, 24.5, 20.6.

Preparation of (3-acetoxy-l ,4-dioxo-l ,4-dihydronaphthaien-2-yi)phosphonium bromide (Formula III wher = OAc and Formula IV where Z = OAc):

Formula III (Z = OAc)

Formula IV (Z = OAc)

General procedure. Triphenylphosphine (2 equiv) and naphthoquinone (7, 15) were combined in a 5 mL conical-shaped tube containing 3 : 1 iPrOH:PhMe. The tube was sealed with a crimp-top cap and heated to 100 °C. After 18-72 h, the solution was evaporated and the crude residue was purified by flash chromatography on silica gel using acetone to elute nonpolar impurities followed by 19: 1 to 9: 1 DCM:MeOH.

( 10-( 3-Acetoxy-l, 4-dioxo-l, 4-dihydronaphthalen-2-yl)decyl)triphenyl-phosphonium bromide (Compound III- 16): Yield: 30%; pale yellow oil; TLC (Si0₂) R_f 0.27 (10: 1

CHCl₃:MeOH); ¾ NMR (500 MHz, CDC1₃) δ 8.09-8.06 (m, 2H), 7.85-7.73 (m, 17H), 3.68 (s, 2H), 2.53 (t, 2H, J= 7.5 Hz), 2.40 (s, 3H), 2.17 (s, 2H), 1.62 (s, 4H), 1.48-1.45 (m, 2H), 1.32- 1.21 (m, 8H); ¹³C MR (125 MHz, CDC1₃) δ. 185.7, 184.6, 178.1, 168.1, 151.1, 139.8, 135.1,

134.1, 133.9, 133.7, 133.6, 132.0, 130.8, 130.6, 130.5, 126.7, 126.6, 118.6, 117.5, 30.5, 30.4, 29.6, 29.3, 29.2, 29.1, 28.5, 24.3, 22.9, 22.6, 20.5.

(4-(3-Acetoxy-l, 4-dioxo-l, 4-dihydronaphthalen-2-yl)butyl)triphenyl-phosphonium bromide 8b. Yield: 4%; yellow oil; TLC (Si0₂) R_f 0.40 (9:1 DCM:MeOH); ^XH NMR (500 MHz, CDC1₃) δ 8.08-8.05 (m, 2H), 7.87-7.69 (m, 17H), 3.87-3.82 (m, 2H), 2.52 (t, 2H, J= 7.5 Hz), 2.44 (s, 3H), 1.78-1.77 (m, 2H), 1.67-1.64 (m, 2H), 1.50-1.48 (m, 2H); ¹³C NMR (125 MHz, CDCI₃) δ 184.7, 177.9, 168.4, 151.4, 139.1, 135.0, 134.1, 133.9, 133.7, 131.9, 130.8, 130.6, 130.5, 126.6, 118.7, 117.9, 30.3, 30.2, 27.9, 23.9, 22.4, 20.8; HRMS (ESI): mlz = calcd for C₃5H320₃P⁺ [M]⁺ 547.20327, found 547.20385.

(4-(l 0-(3-acetoxy-l , 4-dioxo-l ,4-dihydronaphthaien-2-yi) phenyl)bromodecyloxy) triphenylphosphonium bromide (Compound IV-1). Yield: 10%; orange red oil; TLC (S1O₂) R_f 0.18 (9: 1 CHCls eOH^H NMR ^OO MHz, CDC1₃) δ 8.17-8.13 (m, 2H), 7.86-7.78 (m, 10H), 7.72-7.70 (m, 7H), 7.31 (d, 2H, J= 8.0 Hz), 7.96 (d, 2H, J= 8.0 Hz), 3.98 (t, 2H, J= 6.0 Hz), 3.79-3.75 (m, 2H), 2.27 (s, 3H), 1.77 (qnt, 2H, J= 6.5 Hz), 1.41 (qnt, 2H, J= 6.5 Hz), 1.29-1.24 (m, 12H); ¹³C NMR (125 MHz, CDC1₃) δ 184.2, 178.6, 168.4, 160.3, 149.6, 137.1, 135.0, 135.0, 134.3, 134.0, 133.8, 133.7, 132.1, 131.6, 130.9, 130.6, 130.5, 127.1, 126.5, 120.9, 118.8, 118.1,

114.2, 68.1, 29.4, 29.3, 29.2, 29.2, 29.1, 26.0, 22.7, 20.5. (4-(3-(3-Acetoxy-l,4-dioxo-l,4-dihydronaphthalen-2-yl)

phenyl)bromopropoxy)triphenylphosphonium bromide 16a. Yield: 13%; brown oil; TLC (S1O₂) R_f 0.56 (9:1 CHCl₃:MeOH); 'H NMR (500 MHz, CDC1₃) δ 8.08 (t, 2H, J= 5.0 Hz), 7.87-7.85 (m, 6H), 7.82-7.74 (m, 3H), 7.73-7.69 (m, 8H), 3.87-3.82 (t, 2H, J= 13.0 Hz), 2.52 (t, 2H, J = 7.0 Hz), 1.78 (qnt, 2H, J= 6.5 Hz), 1.66 (qnt, 2H, J= 6.5 Hz), 1.49 (qnt, 2H, J= 6.5 Hz); ¹³C NMR (125 Hz, CDC1₃) δ 184.5, 177.9, 168.4, 151.4, 139.1, 135.0, 134.1, 133.9, 133.7, 133.6, 131.9, 130.8, 130.6, 130.5, 126.6, 118.6, 117.9, 30.3, 30.2, 27.9, 23.9, 22.4, 20.7; HRMS (ESI): mlz = calcd for C₄oH₃₄0₅P⁺ [M]⁺ 625.21384, found 625.21403

Deprotection of acetyl group:

Formula IV (Z = OAc) Formula IV (Z = OH)

General procedure. 3-Acetoxy phosphonium bromide (Formula III and Formula IV, where Z = OAc) was added into a mixture of 5N of HC1 and z^'-PrOH (1 : 1), the mixture was heated at 65 °C for 12 hours. After that, the solution was cooled down to room temperature and was purified by silica gel chromatography using acetone to elute the nonpolar impurities followed by 10: 1 CHCl₃:MeOH. The final product was obtained in accordance to product Rf value.

(5-(3-Hydroxy-l,4-dioxo-l,4-dihydronaphthalen-2-yl)pentyl)triphenyl-phosphonium bromide 9a. Yield: 22%; red oil; TLC (Si0₂) R_f 0.46 (9: 1 CHCl₃:MeOH); ^XH NMR (500 MHz, CDCI₃) δ 8.02 (m, 2H), 7.85-7.76 (m, 17H), 3.72 (m, 2H), 2.50 (m, 2H), 1.71 (m, 4H), 1.54 (m, 2H); ¹³C MR (125 Hz, CDC1₃) δ 185.4, 184.7, 150.0, 135.04, 135.02, 134.4, 133.7, 133.7, 133.1, 132.6, 130.6, 130.5, 129.9, 126.4, 126.1, 123.5, 118.7, 118.0, 29.6, 27.2, 22.8, 22.2, 21.9; HRMS (ESI): mlz = calcd for C₃3H₃o0₃P⁺ [M]⁺ 505.19271, found 505.19268. ( 10-( 3-Hydroxy-l, 4-dioxo-l, 4-dihydronaphthalen-2-yl)decyl)tributylphosphonium bromide (Compound III- 19). orange red oil; TLC (Si0₂) R_f 0.23 (9: 1 CHCl₃:MeOH); 'H NMR (500 MHz, CDC1₃) δ 8.81 (d, 1H, J= 7.5 Hz), 8.07 (d, 1H, J= 7.5 Hz), 7.75 (t, 1H, J= 7.5 Hz), 7.67 (t, 1H, J= 7.5 Hz), 2.59 (t, 2H, J= 8.0 Hz), 2.44-2.33 (m, 10H), 1.53-1.35 (m, 22H), 1.27- 1.19 (m, 18H), 0.97-0.93 (12H); ¹³C NMR (125 MHz, CDC1₃) δ 184.8, 150.0, 134.8, 133.0,

132.9, 129.6, 126.7, 126.1, 124.7, 32.2?, 32.0?, 30.8, 30.7, 29. 7, 29.29, 29.27, 29.22, 28.9, 28.2, 26.4, 24.1, 24.0, 23.9, 23.8, 23.4, 22.0, 19.6, 19.4, 19.2, 19.0, 14.2, 13.5.

( 10-( 3-Hydroxy-l, 4-dioxo-l, 4-dihydronaphthalen-2-yl)decyl)tribenzyl-phosphonium bromide (Compound III- 20). orange red oil; TLC (Si0₂) R_f 0.22 (9: 1 CHCl₃:MeOH); 'H NMR (500 MHz, CDCI₃) δ 8.10 (d, 2H, J= 7.0 Hz), 8.07 (d, 2H, J= 7.0 Hz), 7.35-7.27 (m, 15H), 4.18 (d, 6H, J= 15.0 Hz), 2.61-2.58 (m, 2H), 1.99-1.95 (m, 2H), 1.55-1.51 (m, 2H), 1.37-1.31 (m, 2H), 1.28-1.21 (m, 10H); ¹³C MR (125 MHz, CDC1₃) δ 185.4, 185.3, 165.5, 161.8, 134.9, 132.9, 130.3, 129.6, 128.6, 128.0, 127.9, 126.7, 126.1, 124.7, 103.3, 30.8, 29.6, 29.2, 29.0, 28.7, 28.2, 26.5, 23.3, 21.6

(10-( 3-Hydroxy-l, 4-dioxo-l, 4-dihydronaphthalen-2-yl)decyl)triphenyl-phosphonium bromide (Compound 111-21). red oil; TLC (Si0₂) R_f 0.14 (10: 1 CHCl₃:MeOH); 'H NMR (500 MHz, CDCI₃) δ 8.08 (d, 1H, J= 7.5 Hz), 8.02 (d, 1H, J= 7.5 Hz), 7.84-7.77 (m, 9H), 7.72-7.67 (m, 7H), 7.62 (t, 1H, J= 7.5 Hz), 3.74-3.70 (m, 2H), 2.55 (t, 2H, J= 7.5 Hz), 1.62-1.58 (m, 4H), 1.50-1.46 (m, 2H), 1.31-1.19 (m, 10H); ¹³C MR (125 MHz, CDC1₃) δ 184.8, 181.4, 153.2, 135.0, 134.8, 133.8, 133.7, 133.0, 132.9, 130.67, 130.5, 129.6, 126.7, 126.1, 124.8 118.8, 118.2, 30.4, 30.3, 29.6, 29.3, 29.2, 29.1, 29.1, 28.2, 23.3, 22.6.

(4-(3-(3-Hydroxy-l, 4-dioxo-l, 4-dihydronaphthalen-2-yl) phenyl)propoxy)-tripheny phosphonium bromide 17a. Orange solid, mp 237-239 °C; TLC (Si0₂) R_f 0.67 (9: 1

CHCl₃:MeOH); ¾ NMR (500 MHz, CDC1₃) δ 8.18 (d, 2H, J= 7.5 Hz), 8.14 (d, 2H, J= 7.5 Hz), 7.88-7.71 (m, 15H), 7.70 (d, 2H, J= 5.5 Hz), 6.93 (d, 2H, J= 5.5 Hz), 4.42 (m, 2H), 4.12 (m, 2H), 2.53-2.27 (m, 4H), 2.01 (m, 4H), 1.68-1.60 (m, 8H).

(4-(l 0-(3-Hydroxy-l, 4-dioxo-l, 4-dihydronaphthalen-2-yl)-phenyl)decyloxy)- triphenylphosphonium bromide (Compound IV-4). Yield: 3%; orange red oil; TLC (Si0₂) R_f 0.12 (9: 1 CHCl₃:MeOH); ^XH NMR (500 MHz, CDC1₃) δ 8.18 (d, 1H, J= 7.5 Hz), 8.13 (d, 1H, J = 7.5 Hz), 7.87-7.73 (m, 16H), 7.48 (d, 2H, J= 8.0 Hz), 6.96 (d, 2H, J= 8.0 Hz), 3.99 (t, 2H, J= 5.5 Hz), 1.79-1.75 (m, 2H), 1.69-1.65 (m, 4H), 1.45-1.40 (m, 2H), 1.31-1.23 (m, 10H); ¹³C NMR (125 MHz, CDCI₃) δ 184.1, 181.8, 159.5, 151.9, 150.0, 135.2, 134.3, 134.2, 133.1, 132.9, 132.3, 130.9, 130.8, 129.4, 127.3, 126.1, 122 .0, 121.9, 1 18.9, 1 18.2, 114.1, 68.0, 32.6, 31.0, 29.5, 29.4, 29.3, 29.2, 26.0, 22.9.

Example 5: Synthesis of Napthoquinone Phosphonium Salts (Formula V, Formula VI, and Formula VII)

O-Alkylation of 2-hydroxy-l ,4-naphthoquinones:

or

41

42

General procedure. In 8 mL of dry THF was combined quinone (10, 23; 35; 41; 1 equiv), alkylating agent (2.2 equiv), K2CO₃ powder (1.1 equiv), and tetrabutylammonium iodide (0.1 equiv). The solution was stirred at 70 °C for 15 minutes, then was added 18-crown-6 (21 μΐ, 0.1 equiv). The solution was stirred at that temperature for 2-40 hours. After cooling to room temperature, the reaction mixture was concentrated, redissolved in EtOAc and washed twice with 5% a₂C0₃. The aqueous layer was extracted once more with EtOAc, and then, the combined organic layer was dried over MgS04, filtered, and evaporated. The product (28a-c, 30, 36a-e, 42) was separated by flash chromatography on silica gel using hexanes to elute nonpolar impurities followed by 10-15% EtOAc in hexanes.

2-(l 0-Bromodec lox )-3-methylnaphthalene-l ,4-dione 28a. Yield: 48%; yellow oil; TLC (Si0₂) R_f 0.62 (7: 1 hexanes: EtOAc); ¾ NMR (500 MHz, CDC1₃) δ 8.06-8.04 (m, 1H), 8.00-7.98 (m, 1H), 7.71-7.65 (m, 2H), 5.10 (s, 2H), 4.35 (t, 2H, J= 6.5 Hz), 3.48 (t, 2H, J= 6.5 Hz), 2.22 (qnt, 2H, J= 6.5 Hz), 2.16 (s, 3H); ¹³C NMR (125 MHz, CDC1₃) δ 185.8, 181.3, 157.6, 133.7,

133.2, 132.0, 131.9, 131.5, 126.1, 73.7, 34.0, 32.8, 30.5, 29.4, 29.3, 28.7, 28.2, 25.8, 9.4; MS (EI, 80 eV): mlz (%) = 406 (M - 16, 4%), 207 (23), 201 (30), 188 (100), 172 (34), 160 (29).

2-(6-Bromohexyloxy)-3-methylnaphthalene-l,4-dione 28b. Yield: 57%; yellow solid, mp 35-36 °C; TLC (Si0₂) R_f 0.43 (5: 1 hexanes :EtOAc); ¾ NMR (500 MHz, CDC1₃) δ 8.03-7.99 (m, 2H), 7.69-7.64 (m, 2H), 4.33 (t, 2H, J= 6.5 Hz), 3.42 (t, 2H, J= 6.0 Hz), 2.08 (s, 3H), 1.88 (qnt, 2H, J= 7.0 Hz), 1.79 (qnt, 2H, J= 7.0 Hz), 1.52-1.47 (m, 4H); ¹³C NMR (125 MHz, CDC1₃) δ 185.7, 181.3, 157.4, 133.7, 133.2, 132.0, 131.9, 131.5, 126.1, 73.4, 33.8, 32.7, 30.4, 27.9, 25.1, 9.5; MS (EI, 80 eV): mlz (%) = 352 (M - 14, 4%), 201 (44), 188 (100), 172 (43), 160 (45), 132 (28).

2-(3-Bromopropoxy)-3-methylnaphthalene-l,4-dione 28c. Yield: 67%; yellow oil; TLC

(Si0₂) R_f 0.71 (7: 1 hexanes: EtOAc); ¾ NMR (500 MHz, CDC1₃) δ 8.06-8.02 (m, 2H), 7.71- 7.68 (m, 2H), 4.47 (dt, 2H, J= 7.0, 1.5 Hz), 3.65 (dt, 2H, J= 7.0, 1.5 Hz), 2.34 (qnt, 2H, J= 6.5 Hz); ¹³C NMR (125 MHz, CDC1₃) δ 185.7, 181.3, 157.1, 133.9, 133.4, 132.3, 132.1, 131.5,

126.3, 126.3, 70.9, 33.5, 29.8, 9.5; MS (EI, 70 eV): mlz (%) = 310 (M +1, 4%), 229 (18), 201 (91), 188 (27), 172 (100), 160 (41), 132 (40).

2-(3-Bromopropoxy)naphthalene-l,4-dione 28d. Yield: 12%; yellow solid, mp 102-104 °C; TLC (Si0₂) R_f 0.22 (5: 1 hexanes: EtOAc); ¾ NMR (500 MHz, CDC1₃) δ 8.12 (d, 1H, J= 7.0 Hz), 8.08 (d, 1H, J= 7.0 Hz), 7.77-7.72 (m, 2H), 4.17 (t, 2H, J= 5.0 Hz), 3.63 (t, J= 5.5 Hz), 2.49-2.43 (m, 2H); ¹³C NMR (125 MHz, CDC1₃) δ 185.0, 180.6, 159.6, 134.5, 133.5, 132.1, 131.3, 126.8, 126.4, 110.7, 1 10.6, 66.9, 31.4, 29.5; MS (EI, 80 eV): mlz (%) = 294 (M + 1, 5%), 215 (30), 197 (21), 187 (61), 158 (100), 146 (31), 130 (30).

2-(6-Bromohexyloxy)naphthalene-l,4-dione 28e. Yield: 20%; yellow oil; TLC (S1O₂) R_f 0.60 (5: 1 hexanes:EtOAc); 'H NMR (500 MHz, CDC1₃) δ 8.12 (d, 1H, J= 7.0 Hz), 8.07 (d, 1H, J= 7.0 Hz), 7.74-7.71 (m, 2H), 4.01 (t, 2H, J= 6.5 Hz), 3.44-3.42 (m, 2H), 1.92-1.91 (m, 4H), 1.53 (s, 4H); ¹³C MR (125 MHz, CDC1₃) δ 185.2, 180.3, 159.9, 134.4, 133.5, 132.2, 131.3, 126.8, 126.3, 110.4, 69.6, 33.8, 32.7, 28.3, 27.9, 25.3; MS (EI, 80 eV): mlz (%) = 336 (M + 1, 9%), 281 (26), 207 (78), 187 (52), 175 (100), 158 (74), 146 (79), 130 (30), 123 (25).

tert-Butyl 2-((3-methyl-l ,4-dioxo-l ,4-dihydronaphthalen-2-yl)oxy)acetate 30. Yield: 62%; yellow solid, mp 62-64 °C; TLC (Si0₂) R_f 0.34 (9: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.07 (d, 1H, J= 7.0 Hz), 8.00 (d, 1H, J= 7.0 Hz), 7.68 (qnt, 2H, J= 7.0 Hz), 5.02 (s, 2H), 2.16 (s, 3H), 1.47 (s, 9H); ¹³C NMR (125 MHz, CDC1₃) δ 185.5, 181.7, 168.4, 155.7, 134.0, 133.3, 132.1, 131.5, 130.7, 126.3, 126.2, 82.6, 69.2, 28.2, 9.6; MS (EI, 70 eV): mlz (%) = 302 (M, 1%), 246 (18), 201 (100), 187 (22), 172 (19).

3-bromopropyI 2-((3-methyl-l ,4-dioxo-l ,4-dihydronaphthalen-2-yl)oxy)acetate 31.

Yield: 26%; yellow solid, mp 54-55 °C; TLC (S1O2) R_f 0.21 (5: 1 hexanes:EtOAc); ¾ NMR (500 MHz, CDCI₃) δ 8.06-8.02 (m, 2H), 7.71-7.67 (m, 2H), 4.34 (t, 2H, J= 6.5 Hz), 3.40 (t, 2H, J= 6.5 Hz), 2.10 (s, 3H), 1.87-1.76 (m, 4H), 1.45-1.29 (m, 12H); ¹³C NMR (125 MHz, CDC1₃) δ

185.2, 181.3, 155.1, 133.9, 133.2, 131.8, 131.1, 126.2, 68.5, 62.3, 31.6, 29.2, 9.5; MS (EI, 80 eV): mlz (%): 245 (M - 122, 12%), 230 (40), 207 (57), 201 (100), 188 (22), 172 (22), 160 (17), 144 (14), 131 (20).

2-(4-Chlorobenzyl)-3-hydroxynaphthalene-l,4-dione 35a. Yield: 65%; yellow solid, mp 159-160 °C; TLC (Si0₂) R_f 0.42 (7: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDCI3) δ 8.09 (d, 1H, J= 7.5 Hz), 8.05 (d, 1H, J= 8.0 Hz), 7.74 (t, 1H, J= 8.0 Hz), 7.67 (t, 1H, J= 7.5 Hz), 7.31 (d, 2H, J= 7.5 Hz), 7.20 (d, 2H, J= 7.0 Hz), 3.89 (s, 2H); ¹³C NMR (125 MHz, CDC1₃) δ 184.3, 181.6, 153.1, 137.4, 135.1, 133.1, 132.7, 132.1, 132.1, 130.6, 129.4, 128.6, 126.2, 122.6, 28.5; MS (EI, 80 eV): mlz (%) = 298 (M, 100%), 281 (26), 263 (83), 235 (69), 217 (32), 207 (59), 189 (26), 178 (31), 131 (27), 125 (24).

2-Benzyl-3-hydroxynaphthalene-l,4-dione 35b. Yield: 47%; brown solid, mp 118-120 °C; TLC (Si0₂) R_f 0.38 (7: 1 hexanes:EtOAc); 'H NMR (500 MHz, CDC1₃) δ 8.11 (d, 1H, J= 8.0 Hz), 8.05 (d, 1H, J= 8.0 Hz), 7.73 (t, 1H, J= 7.0 Hz), 7.66 (t, 1H, J= 7.0 Hz), 7.39 (d, 2H, J= 8.0 Hz), 7.26 (t, 2H, J= 6.5 Hz), 7.14 (t, 1H, J= 7.5 Hz), 3.95 (s, 2H); ¹³C NMR (125 MHz, CDCI₃) δ 184.6, 181.9, 153.2, 139.1, 135.2, 133.2, 132.9, 129.6, 129.4, 128.6, 127.1, 126.5,

126.3, 123.3, 29.3; MS (EI, 80 eV): mlz (%) = 264 (M, 100%), 247 (21), 218 (16), 207 (14), 189 (16), 178 (14), 165 (11), 130 (13). 2-Cyclohexyl-3-hydroxynaphthalene-l,4-dione 35c. Yield: 35%; yellow solid; TLC (Si0₂) R_f 0.40 ( 7: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.12 (d, 1H, J= 8.0 Hz), 8.05 (d, 1H, J= 8.0 Hz), 7.75 (t, 1H, J= 7.0 Hz), 7.66 (t, 2H, J= 7.0 Hz), 3.08 (t, 1H, J= 12.5 Hz), 1.98 (q, 2H, J= 12.5 Hz), 1.82 (d, 2H, J= 12.5 Hz), 1.72 (d, 1H, J= 10.0 Hz), 1.61 (d, 2H, J= 12.0 Hz), 1.41-1.26 (m, 3H); ¹³C NMR (125 MHz, CDC1₃) δ 184.6, 181.9, 152.9, 134.9, 133.2, 132.7, 129.2, 127.9, 126.9, 125.9, 35.2, 29.2, 26.8, 25.9.

2-(4-Chlorobenzyl)-3-(6-bromohexyloxy)naphthalene-l,4-dione 36a. Yield: 29%; yellow oil; TLC (Si0₂) R_f 0.25 (7: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.04 (d, 1H, J= 6.5 Hz), 8.01 (d, 1H, J= 6.5 Hz), 7.70-7.65 (m, 2H), 7.25-7.20 (m, 4H), 4.41 (t, 2H, J= 6.0 Hz), 3.90 (s, 2H), 3.41 (t, 2H, J= 6.0 Hz), 1.88-1.84 (m, 2H), 1.78-1.75 (m, 2H), 1.49-1.46 (m, 4H); ¹³C NMR (125 MHz, CDC1₃) δ 185.13, 181.92, 157.53, 137.8, 134.1, 133.5, 132.9, 132.1, 131.9, 131.6, 130.5, 128.6, 126.4, 126.3, 73.8, 33.9, 32.7, 30.5, 28.9, 27.9, 25.2.

2-Benzyl-3-((6-bromohexyl)oxy)naphthalene-l,4-dione 36b. Yield: 46 mg, 57%; yellow oil; TLC (Si0₂) R_f 0.47 (9: 1 hexanes:EtOAc); IR (neat) (v_max, cm^"1): 1669, 1597, 1217; ^XH NMR (500 MHz, CDC1₃) δ 8.06 (d, 1H, J= 6.5 Hz), 8.02 (d, 1H, J= 6.5 Hz), 7.68-7.67 (m, 2H), 7.32- 7.31 (m, 2H), 7.26-7.24 (m, 2H), 7.18-7.16 (m, 1H), 4.38 (t, 2H, J= 6.5 Hz), 3.95 (s, 2H), 3.41 (t, 2H, J= 6.5 Hz), 1.87 (t, 2H, J= 6.5 Hz), 1.77 (t, 2H, J= 6.5 Hz), 1.48 (m, 4H); ¹³C NMR (125 MHz, CDC1₃) δ 185.3, 182.0, 157.6, 139.4, 134.0, 133.8, 133.4, 132.1, 131.7, 129.2, 128.6, 126.5, 126.3, 73.8, 33.9, 32.8, 30.5, 29.6, 28.0, 25.2; MS (m/z): 428 (M + 2, 4), 426 (M, 4), 263 (40), 247 (10).

2-((6-Bromohexyl)oxy)-3-cyclohexylnaphthalene-l,4-dione 36c. Yield: 72%; yellow oil; TLC (Si0₂) R_f 0.34 (19: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.05 (d, 1H, J= 7.0 Hz), 8.00 (d, 1H, J= 6.5 Hz), 7.69-7.66 (m, 2H), 4.28-4.27 (m, 2H), 3.45-3.43 (m, 2H), 3.12 (t, 1H, J= 12.5 Hz), 2.00-1.55 (m, 14H), 1.37-1.26 (m, 4H); ¹³C NMR (125 MHz, CDC1₃) δ 185.7, 182.2, 158.0, 139.7, 133.9, 133.2, 132.6, 131.6, 126.5, 126.0, 73.8, 36.2, 34.0, 32.9, 30.3, 30.2, 28.1, 27.1, 26.3, 25.3; MS (m/z): 420 (M + 2, 13%), 418 (M, 13), 256 (100)

2-Benzyl-3-((3-bromopropyl)oxy)naphthalene-l,4-dione 36d. Yield: 36%; yellow oil; TLC (Si0₂) R_f 0.29 (9: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.08 (d, 1H, J= 5.5 Hz), 8.04 (d, 1H, J= 5.5 Hz), 7.69 (m, 2H), 7.30-7.17 (m, 5H), 4.51 (t, 2H, J= 5.5 Hz), 3.96 (s, 2H), 3.55 (t, 2H, J= 6.5 Hz), 2.29 (qnt, 2H, J= 6.5 Hz); ¹³C NMR (125 MHz, CDC1₃) δ 185.3, 185.1, 156.9, 149.9, 138.9, 133.9, 133.8, 133.3, 131.8, 128.9, 128.5, 126.4, 126.2, 71.1, 33.4, 29.4; MS (EI, 80 eV): m/z (%) = 386 (M + 1, 19%), 263 (100), 247 (73), 235 (40), 189 (33), 178 (30).

2-(3-Bromopropoxy)-3-cyclohexylnaphthalene- 1 ,4-dione 36e. Yield: 114 mg, 82%; bright yellow oil; TLC (Si0₂) R_f 0.50 (9: 1 hexanes:EtOAc); IR (neat) (v_max, cm^"1): 1668, 1596, 1329, 1292, 1239, 1192; ¾ NMR (500 MHz, CDC1₃) δ = 8.06 (d, 1H, J= 7.0 Hz), 8.02 (d, 1H, J = 7.5 Hz), 7.72-7.66 (m, 2H), 4.39 (t, 2H, J= 5.0 Hz), 3.68 (t, 2H, J= 5.5 Hz), 3.11 (t, 1H, J= 12.0 Hz), 2.39 (t, 2H, J= 5.5 Hz), 1.98-1.91 (m, 2H), 1.84-1.82 (m, 2H), 1.73-1.74 (m, 1H), 1.62-1.60 (m, 2H), 1.41-1.25 (m, 5H); ¹³C MR (125 MHz, CDC1₃) δ = 185.7, 181.9, 157.5, 140.3, 133.9, 133.3, 132.5, 131.5, 126.6, 126.1, 71.2, 36.3, 33.5, 30.3, 29.9, 27.1, 26.2; MS (m/z): 376 (M, 46), 378 (45), 255 (100), 187 (43).

2-(3-Bromopropoxy)-3-(4-methoxyphenyl)naphthalene-l,4-dione 42. Yield: 48%; red oil; TLC (Si0₂) R_f 0.48 (7: 1 hexanes:EtOAc); ^XH NMR (500 MHz, CDC1₃) δ 8.12-8.09 (m, 2H), 7.76-7.72 (m, 2H), 7.34 (d, 2H, J= 7.5 Hz), 6.98 (d, 2H, J= 7.5 Hz), 4.24 (t, 2H, J= 5.0 Hz), 3.86 (s, 3H), 3.03 (t, 2H, J= 6.5 Hz), 2.08 (qnt, 2H, J= 6.0 Hz); ¹³C NMR (125 MHz, CDCI3) δ 184.9, 181.9, 159.9, 156.1, 134.1, 133.5, 132.9, 132.0, 131.4, 126.7, 126.1, 122.5, 113.4, 71.3, 55.3, 33.1, 29.9.

Preparation of naphthoquinone phosphonium bromides (Formula V, Formula VI, Formula VII (where Z = H or Me), and Formula VII (where Z = Ce 11, Bn, or p-ClBn):

26 Formula V

31 Formula VI

or

42 Formula VII (Z = OMe)

General procedure. Triphenylphosphine (2 equiv) and naphthoquinone (26, 28, 31, 36, 42) were combined in a 5 mL conical-shaped tube containing 3 : 1 iPrOH:PhMe. The tube was sealed with a crimp-top cap and heated to 100 °C. After 18-72 h, the solution was evaporated and the crude residue was purified by flash chromatography on silica gel using acetone to elute nonpolar impurities followed by 9: 1 DCM:MeOH. The purest fractions were isolated, evaporated, and reported yield.

4-( 1, 4-Dihydro-2-methyl-l, 4-dioxonaphthalen-3-yl) butanoate triphenyl-phosphonium bromide (Compound V-l). Yield: 1 1%; red oil; TLC (Si0₂) R_f 0.65 (9: 1 DCM: MeOH); ¾ NMR (500 MHz, CDC1₃) δ 8.10 (d, 2H, J= 7.0 Hz), 8.02 (d, 1H, J= 7.0 Hz), 8.01-7.89 (m, 6H), 7.86-7.80 (m, 3H), 7.80-7.70 (m, 8H), 4.15-4.09 (m, 2H), 3.33 (s, 2H), 2.14-2.11 (m, 5H); ¹³C NMR (125 MHz, CDC1₃) δ 184.7, 178.1, 170.5, 151.0, 136.7, 135.24, 135.22, 134.3, 133.9, 133.8, 132.1, 130.8, 130.7, 130.6, 126.9, 126.6, 1 18.5, 117.8, 33.4, 21.9, 18.5, 10.3; HRMS (ESI): mlz = calcd for C₃3H₂₈0₄P⁺ [M]⁺ 519.17197, found 519.17192.

11-(1 ,4-Dihydro-2-methyl-l ,4-dioxonaphthalen-3-yl)undecanoate triphenylphosphonium bromide (Compound V-2). Yield: 9%; red oil; TLC (Si0₂) R_f 0.60 (9: 1 DCM:MeOH); ¾ NMR (500 MHz, CDC1₃) δ 8.11-8.10 (m, 1H), 8.08-8.07 (m, 1H), 7.86-7.79 (m, 9H), 7.75-7.70 (m, 8H), 3.75 (s, 2H), 2.65 (t, 2H, J= 7.5 Hz), 2.09 (s, 3H), 1.76 (qnt, 2H, J= 7.5 Hz), 1.64 (s, 4H), 1.41 (qnt, 2H, J= 7.0 Hz), 1.26-1.21 (m, 8H); ¹³C NMR (125 MHz, CDC1₃) δ 184.5, 178.2, 170.8, 151.3, 136.1, 135.2, 135.1, 134.1, 133.9, 133.8, 133.7, 132.1, 130.9, 130.7, 130.6, 126.8, 126.7, 118.8, 118.1, 33.9, 30.6, 30.4, 29.8, 29.3, 29.27, 29.21, 29.0, 24.9, 22.8, 10.0; HRMS (ESI): mlz = calcd for C₄oH420₄P⁺ [M]⁺ 617.28152, found 617.28165.

3-(Propyi 2-( 1, 4-dihydro-2-methyl-l , 4-dioxonaphthalen-3-yloxy)acetate)- triphenylphosphonium bromide (Compound VI-1). Yield: 7%; red oil; TLC (S1O₂) R_f 0.40 (9: 1 DCM:MeOH); ^XH NMR (500 MHz, CDC1₃) δ 8.05 (d, 1H, J= 7.0 Hz), 7.89-7.85 (m, 6H), 7.81- 7.78 (m, 4H), 7.72-7.69 (m, 7H), 7.61 (t, 1H, J= 7.5 Hz), 5.05 (s, 2H), 4.55 (t, 2H, J= 6.0 Hz), 4.06-4.03 (m, 2H), 2.17-1.11 (m, 5H; ¹³C NMR (125 MHz, CDC1₃) δ 185.2, 181.4, 168.9, 155.2, 135.2, 134.0, 133.8, 133.7, 133.2, 131.9, 131.3, 131.1, 130.6, 130.5, 126.3, 126.0, 118.4, 117.7, 68.8, 64.2, 29.7, 22.3, 9.6; HRMS (ESI): mlz = calcd for C₃₄H₃o0₅P⁺ [M]⁺ 549.18254, found 549.18264.

10-(2-Oxy-3-methylnaphthalene-l, 4-dione)decyl triphenylphosphonium bromide

(Compound VII-1). Yield: 3%; orange oil; TLC (Si0₂) R_f 0.30 (9: 1 DCM:MeOH); ^XH NMR (500 MHz, CDCI₃) δ 8.06-8.04 (m, 2H), 7.86-7.71 (m, 17H), 4.33-4.31 (m, 2H), 3.74 (m, 2H), 2.09 (s, 3H), 1.82-1.22 (m, 16H); ¹³C NMR (125 MHz, CDC1₃) δ 185.7, 185.5, 181.6, 157.7, 150.6, 135.2, 133.9, 133.8, 133.4, 132.1, 131.7, 130.7, 130.6, 126.3, 118.9, 118.3, 81.5, 73.9, 48.7, 34.3, 30.6, 29.6, 29.4, 29.3, 28.8, 28.2, 25.9, 22.8, 9.6.

3-(2-Oxynaphthaiene-l,4-dione)propyi triphenylphosphonium bromide (Compound VII- 4). Yield: 3%; yellow solid; TLC (Si0₂) R_f 0.61 (9: 1 DCM:MeOH); ^XH NMR (500 MHz, CDCI₃) δ 8.08-8.06 (m, 2H), 7.95-7.91 (m, 5H), 7.81-7.79 (m, 3H), 7.75-7.73 (m, 9H), 6.24 (s, 1H), 4.44 (m, 2H), 4.23 (m, 2H), 2.34 (m, 2H); ¹³C NMR (125 MHz, CDC1₃) δ 184.6, 180.3,

159.1, 150.1, 135.3, 134.6, 134.2, 134.1, 133.4, 132.3, 131.2, 130.9, 130.8, 126.5, 118.7, 117.9, 48.7, 30.1, 22.9.

6-(2-Oxynaphthalene-l,4-dione)hexyl triphenylphosphonium bromide (Compound VII-5). Yield: 3 mg, 5%; orange oil; TLC (Si0₂) R_f 0.26 (19: 1 DCM:MeOH); ¾ NMR (500 MHz, CDCI₃) δ 8.06 (m, 2H), 7.87-7.80 (m, 10H), 7.72-7.71 (m, 7H), 6.14 (s, 1H), 3.39 (m, 2H), 3.79 (m, 2H), 1.86 (m, 2H), 1.78 (m, 2H), 1.69 (m, 2H), 1.54 (m, 2H); ¹³C NMR (125 MHz, CDC1₃) δ 185.1, 180.4, 159.9, 150.1, 135.2, 134.4, 133.9, 133.8, 133.4, 132.2, 131.2, 130.7, 130.6, 126.7, 126.3, 118.8, 118.1, 110.5, 110.4, 69.6, 31.1, 30.0, 29.8, 27.9, 25.6, 22.6.

3-(2-Oxy-3-(4-chlorobenzyl)naphthalene-l,4-dione)propyl triphenyl-phosphonium bromide (Compound VII-6). Yield: 5.5 mg, 10%; green oil; TLC (Si02) R_f 0.32 (9: 1

DCM:MeOH); 'H NMR (500 MHz, CDC1₃) δ 8.04-8.02 (m, 1H), 7.97-7.96 (m, 1H), 7.80-7.70 (m, 17H), 7.18 (d, 2H, J= 5.5 Hz), 7.06 (d, 2H, J= 5.5 Hz), 4.01-3.62 (m, 7H), 2.20-1.93 (m, 2H); ¹³C NMR (125 MHz, CDC1₃) δ 184.9, 181.5, 157.0, 137.5, 135.2, 135.1, 134.1, 133.8, 133.7, 133.68, 133.65, 133.2, 131.9, 131.7, 131.4, 130.7, 130.6, 130.5, 130.2, 128.5, 126.4, 126.3, 118.6, 118.3, 117.9, 117.7, 71.9, 53.7, 53.6, 28.9, 23.9, 23.2, 22.8, 22.2.

6-(2-Oxy-3-benzylnaphthalene-l, 4-dione)hexyl triphenylphosphonium bromide

(Compound VII-7). Yield: 44 mg, 62%; orange oil; TLC (Si0₂) R_f 0.31 (9: 1 DCM:MeOH); ^XH NMR (500 MHz, CDC1₃) δ 8.03-8.02 (m, 1H), 7.98-7.97 (m, 1H), 7.85-7.79 (m, 9H), 7.70 (m, 8H), 7.26 (m, 2H), 7.18 (m, 2H), 7.08 (m, 1H), 4.30(m, 2H), 3.89 (s, 2H), 3.77 (m, 2H), 1.72- 1.65 (m, 6H), 1.45 (m, 2H); ¹³C MR (125 MHz, CDCI₃) δ 185.2, 181.8, 157.4, 139.2, 135.1, 133.9, 133.7, 133.7, 133.4, 131.8, 131.5, 130.6, 130.5, 129.0 ,128.4, 126.3, 126.2, 118.6, 117.9, 77.4, 73.6, 30.1, 30.0, 29.7, 29.4, 25.5, 22.7.

6-(2-Oxy-3-cyciohexyinaphthaiene-l, 4-dione)hexyl triphenylphosphonium bromide (Compound VII-8). Yield: 3%; red oil; TLC (Si0₂) R_f 0.42 (9: 1 DCM:MeOH); ¾ NMR (500 MHz, CDCI₃) δ 8.03 (d, 1H, J= 7.0 Hz), 7.97 (d, 1H, J= 7.0 Hz), 7.88-7.78 (m, 9H), 7.72-7.64 (m, 8H), 4.18 (t, 2H, J= 6.0 Hz), 3.89-3.83 (m, 2H), 3.05 (t, 1H, J= 12.5 Hz), 1.94-1.86 (m, 4H), 1.79-1.74 (m, 6H), 1.71-1.68 (m, 4H), 1.55-1.52 (m, 4H), 1.33-1.26 (m, 2H); ¹³C NMR

(125 MHz, CDCI₃) δ 185.7, 185.5, 185.4, 182.1, 166.0, 157.9, 150.1, 139.8, 135.2, 133.9, 133.8, 133.2, 132.5, 131.6, 130.7, 130.6, 126.5, 125.9, 118.9, 118.2, 110.1, 73.8, 36.2, 30.2, 30.0, 27.0, 26.2, 25.7, 22.9.

3-(2-Oxy-3-benzylnaphthalene-l, 4-dione)propyl triphenylphosphonium bromide (Compound VII-9). Yield: 7.4 mg, 78%; yellow oil; TLC (Si0₂) R_f 0.32 (9: 1 DCM:MeOH); ^XH NMR (500 MHz, CDC1₃) δ 8.05 (d, 1H, J= 7.0 Hz), 7.96 (d, 1H, J= 7.0 Hz), 7.87-7.81 (m, 3H), 7.79-7.75 (m, 7H), 7.71-7.66 (m, 7H), 7.21 (d, 2H, J= 7.0 Hz), 7.09 (t, 2H, J= 7.0 Hz), 6.99 (t, 1H, J= 7.0 Hz), 4.69 (m, 2H), 4.08-4.05 (m, 2H), 3.93 (s, 2H), 1.19-1.18 (m, 2H); ¹³C NMR (125 MHz, CDCI₃) δ 185.1, 181.7, 157.1, 146.7, 139.0, 135.2, 134.2, 133.9, 133.8, 133.7, 133.5, 131.9, 131.6, 130.7, 130.6, 128.8, 128.6, 126.6, 126.4, 118.6, 117.9, 72.5 , 48.7, 29.6, 24.1, 23.4, 23.1.

3-(2-Oxy-3-cyclohexylnaphthalene-l, 4-dione)propyl triphenylphosphonium bromide (Compound VII-10). Yield: 32 mg, 68%; yellow oil; TLC (Si0₂) R_f 0.33 (9: 1 DCM:MeOH); ^XH NMR (500 MHz, CDC1₃) δ 8.02 (d, 1H, J= 7.0 Hz), 7.75 (d, 1H, J= 7.0 Hz), 7.92-7.87 (m, 5H), 7.82-7.80 (m, 4H), 7.74- 7.68 (m, 8H), 4.44 (m, 2H), 4.16-4.10 (m, 2H), 3.00 (t, 1H, J= 11.0 Hz), 1.85 (q, 2H, J= 12.5 Hz), 1.75 (d, 2H, J= 12.5 Hz), 1.67 (d, 1H, J= 12.0 Hz), 1.56 (d, 2H, J= 12.0 Hz), 1.30-1.22 (m, 3H), 1.19-1.18 (m, 2H); ¹³C MR (125 MHz, CDC1₃) δ 185.6, 181.2, 157.3, 140.6, 135.3, 134.1, 134.0, 133.9, 133.8, 133.4, 132.5, 131.3, 130.8, 130.7, 126.5, 126.1, 118.7, 117.9, 72.9, 72.8, 36.5, 30.4, 26.9, 26.0, 24.0, 23.3, 22.9.

3-(2-Oxy-3-(4-methoxyphenyl)naphthalene-l,4-dione)propyl triphenylphosphonium bromide (Compound VII-11). Yield: 3%; red oil; TLC (Si0₂) R_f 0.31 (9: 1 DCM:MeOH); ^XH NMR (500 MHz, CDC1₃) δ 8.09-8.05 (m, 2H), 7.79-7.68 (m, 17H), 7.32 (d, 2H, J= 6.5 Hz), 6.81 (d, 2H, J= 6.5 Hz), 4.48 (s, 2H), 3.74 (s, 2H), 3.67 (s, 3H), 1.98 (s, 2H); ¹³C NMR (125 MHz, CDC1₃) 5 184.9, 182.0, 159.8, 156.2, 135.2, 134.4, 134.2, 133.9, 133.8, 133.7, 133.6, 132.6, 132.3, 132.0, 131.5, 130.6, 130.5, 126.8, 126.3, 122.9, 118.5, 118.4, 117.9, 113.7, 72.9, 72.8, 55.4, 23.9.

Example 6: Antiplasmodial Activity of Compounds of Formulas I, II, and III

Naphthoquinone- and phthalimide-based lipocations as described herein and controls were evaluated for their antiplasmodial activity against the P. falciparum W2 strain. Minimum inhibitory concentrations (IC₅₀) were determined for the phthalimide-based lipocations

(Compounds I-l, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, and 1-10) against the chloroquine-resistant P. falciparum (W2 strain) according to the methods as described in Coteron et al, J. Med.

Chem., 53: 61 -52 (2010) (see Table 1).

Formula I Control 1 Control 2: (n = 8) 141.6 ± 3.5 nM

(Table ! ) >10.0 μΜ Control 3: (n = 2) 3.5 ± 0.5 μΜ

Table 1

Compd n Y IC₅₀ (nM) Log If MW'

I-l 9 Me > 10,000 -0.08 362.5

1-2 3 Ph >3,000 0.01 464.5

1-3 5 Ph 1021 ± 93.2 1.14 492.6

1-4 9 4-PhF 345.6 ± 15.3 2.13 602.6

1-5 9 Bn 288.5 ± 35.2 1.37 590.8 n-Bu 194.2 ± 3.8 ³·^{68 488}·⁷

Ph 172.7 ± 4.0 ^{L67 548}·⁷

2-PhMe 143.4 ± 7.0 ^"°·^{75 590}·⁸

C₆H_U 140.6 ± 0.7 ⁴·⁵° ⁵⁶⁶·⁸

4-PhOMe 134.0 ± 1.7 3.19 638.7

CQ^C 66.93 ± 2.3 319.9 ameasured by 1-octanol-water partition at pH 7.4

b molecular weights of lipocations 1-1 through 1-10 minus the counterion

c chloroquine (CQ)

The IC5₀ values ranged from 134 nM to >3 μΜ (Table 1), compared to 66.9 nM for known anti-malarial chloroquine (CQ). Analysis of the structure-activity relationships revealed that antiplasmodial effects were conferred by the phosphonium moiety, and the presence or absence of the phthalimide group had minimal influence on activity. This conclusion was established by inclusion of phthalimide (Control 1) and alkyltriphenylphosphonium cations (Controls 2 and 3) in the study. Conversely, substituents (Y) on the phosphonium moiety and the lipid chain length (n) had a moderate impact on activity. The P-substituent could be either alkyl (e.g., Y = cyclohexyl, Compound 1-9) or aromatic (e.g. Y = Ph, Compound 1-7), with only a moderate effect on the IC5₀ values. The trimethyl derivative (Compound 1-1) was an exception, with less activity compared to analogs of equal chain length (i.e., Compound 1-4, Compound 1-5, Compound 1-6, Compound 1-7, Compound 1-8, and Compound 1-9). A similar effect was observed for lipocations possessing shorter chain lengths, with the 4- and 6- carbon chain analogs, Compound 1-2 and Compound 1-3 respectively, demonstrating 4-15 fold reduced activity compared to the 10-carbon chain lipocation (Compound 1-7).

Susceptibility testing of the naphthoquinone-based lipocations against W2-strain P. falciparum revealed an SAR profile similar to that of the phthalimide series (Table 2).

Formula II Formula III Control 4:(X=NH) >10 μΜ

(Table 2) (Table 2) Control 5: (X=CH₂) >10 μΜ Table 2

Compd n Y Z ICso (nM) Log D^a MW^b

II-l 2 Ph H 519.9 ± 61.2 -1.08 462.5

II-2 10 4-PhF H 292 ± 53.2 1.67 628.7

II-3 10 Bn H 214.6 ± 0.5 2.80 616.8

II-4 10 4-PhOMe H 134.2 ± 10.5 4.37 664.8

II-5 10 Ph H 113.9 ± 7.6 3.60 574.7

II-6 10 ^C6^H11 H 94.4 ± 35.2 3.41 592.9

III-l 10 Bn H 1303.5 ± 13.4 5.32 601.8

III-2 10 4-PhF H 846.3 ± 0.7 1.66 613.7

III-3 10 Ph H 259.2 ± 18.7 4.08 559.7

III-4 5 Ph H 156.6 ± 6.5 1.00 489.6

III-5 5 Me Me 955.6 ± 2.5 0.21 317.4

III-6 1 Ph Me 543.4 ± 79.2 1.89 447.5

III-7 10 Me Me 404.2 ± 16.7 1.95 373.5

III-8 10 Bn Me 212 ± 27.2 6.64 615.8

III-9 10 n-Bu Me 155.8 ± 9.0 5.10 513.8

III-10 10 2-PhMe Me 143.4 ± 7.0 3.58 615.8

III-ll 10 Ph Me 143.4 ± 6.3 3.97 573.7

111-12 10 ^C6^H11 Me 134.3 ± 1.8 3.64 591.9

111-13 10 4-PhOMe Me 130.9 ± 6.6 3.52 663.8

111-14 5 Ph Me 48.3 ± 1.5 2.15 503.6

111-15 4 Ph Me 18.7 ± 0.3 1.91 489.6

ART^C - - - 7.31 ± 0.14 - 262.3

ATV^C - - - 0.28 ± 0.19 - 366.3 a measured by 1-octanol-water partition at pH 7.4

b molecular weights of lipocations II-l through II-6 and III-l through 111-15 minus the counterion

c artemisinin (ART), atovaquone (ATV)

Antiplasmodial activity was conferred by installing a phosphonium-containing hydrocarbon chain, and a variety of Y substituents were utilized without significant alterations in the IC5₀ values (e.g., Compound III-9, Compound III-10, Compound III-ll, Compound III- 12, and Compound 111-13). The activities for many of the 10-carbon chain analogs were comparable to lipocation Control 2. The major exceptions were lipocations Compound 11-14 and Compound 111-15, which displayed 3-7 fold greater efficacy than Control 2. The 5- and 4- carbon chain analogs were more active than their 10-carbon chain counterpart Compound III- ll, a reversal in the SAR profile observed for the phthalimide series. In addition, a comparison of analog Compound 111-15 to its 4-carbon chain Control 3 (Table 1) established that the naphthoquinone component was useful for achieving sub-50 nM activities.

The phosphonium lipocations also displayed anti-parasitic activity against Trypanosoma cruzi and Trypanosoma brucei, the causative agents of Chagas disease and African Sleeping Sickness, respectively. Compound III-8 demonstrated an IC₅₀ value of 3 ± 1.32 μΜ for Trypanosoma cruzi; Compound II-5 demonstrated an IC₅₀ value of 1.60 ± 0.54 μΜ for

Trypanosoma cruzi; and Compound III-ll demonstrated an IC₅₀ value of 1.60 ± 1.32 μΜ for Trypanosoma cruzi. Compound III-3 demonstrated an IC₅₀ value of 20 nM for Trypanosoma brucei.

Example 7: Antitrypanosomal Activity of Compounds of Formula II and III

The naphthoquinone-derived lipocations were additionally evaluated as growth inhibitors against Trypanosoma cruzi, the etiological agent of Chagas disease. Like P. falciparum, T. cruzi has a complex life cycle which includes infective, non-replicating bloodstream trypomastigote forms and intracellular amastigotes that infect cardiac and other cells, leading to disease. The compounds were assessed for efficacy against Vero cell-infected T. cruzi amastigotes. The IC5₀S for inhibition of parasite development ranged from 1.6 to 5.4 μΜ and variable degrees of Vero cell toxicity was observed (Table 3). For comparison, benznidazole was used as a positive control (IC₅₀ 2.1 μΜ) and was non-toxic at the concentrations indicated.

Table 3

T. cruzi IC₅₀ Vero Cell Toxicity^d (μΜ)

Compd n Y

(μ ) 25 12.5 6.25

Control 4 17.3 ± 7.1 - - -

Control 5 9.3 ± 1.3 - - -

111-14 5 Ph 5.4 ± 0.1 + - -

III-9 10 n-Bu 4.0 ± 3.6 + + -

III-8 10 Bn 3.7 ± 1.8 + + -

III-l 10 Bn 3.0 ± 1.3 - - -

111-15 4 Ph 2.7 ± 1.0 - - -

111-12 10 CeHn 2.4 ± 0.7 + + -

II-5 10 Ph 1.6 ± 0.5 + + +

III-ll 10 Ph 1.6 ± 0.5 + + +

Benznidazole 2.1 ± 0.4 - - -

+, cytotoxicity observed; -, cytotoxicity not evident

As with P. falciparum, the lipocation analogs were more effective antitrypanosomal agents than their uncharged naphthoquinone counterparts Control 4 and Control 5. Chain length and P-substituent type appeared to have little effect on the activity, but were influential on Vero cell cytotoxicity and may have resulted in the increased efficacy observed for lipocations Compounds II-5 and III-2 (IC₅₀S 1.6 μΜ). The most potent compound not displaying toxicity at 25 μΜ was the 4-carbon chain analog Compound 111-15 (IC50 2.7 μΜ) which also possessed the highest antiplasmodial activity at 18.7 nm. Additional testing of lipocation Compound III- 15 further revealed therapeutic index values {TI = [ICso(Vero)]/ [ICsoCparasite)]} of 19.5 and 2818 for T. cruzi and P. falciparum, respectively.

Example 8: Antiplasmodial Activity of Compounds of Formula III and Formula IV

Comparisons of antiplasmodial activities were performed by minimum inhibitory concentrations (IC₅₀) against the chloroquine-resistant P. falciparum (W2 strain) according to methods described in Example 6. Each of the 2-hydroxy 1,4-naphthoquinone cations possessed weak activity in the medium-low μΜ range (Table 4). The O-acetyl analogs displayed low antiparasitic activity. The activity data for the uncharged controls (Control 6 and Control 7) confirmed that the phosphonium moiety had an adverse effect on the IC5₀S. The methoxy analog displayed higher antiparasitic activity.

Table 4

Formula III Formula IV Control 6 (Z = OAc) IC₅₀ 392 nM

(Table 4) (Table 4) Control 7 (Z = OH) \C_m 339 n M

Compd n Y z ICso (nM)

IV-1 8 - OAc 7,123

IV-3 1 - OH 6,731

IV-4 8 - OH 6,642

IV-2 2 - OAc 5,440

IV-5 1 - OMe 53.8 ± 14.3

111-18 4 Ph OH 4,075

111-19 8 n-Bu OH 3,865

111-16 8 Ph OAc 3,592

111-20 8 Bn OH 3,282

111-21 8 Ph OH 2,175

111-17 4 Ph OAc 1,896

Chloroquione 142.7 ± 0.8

Artemisinin 18.1 ± 2.2 Example 9: Antiplasmodial Activity of Compounds of Formula V, Formula VI, and Formula VII

Comparisons of antiplasmodial activities were performed by minimum inhibitory concentrations (IC5₀) against the chloroquine-resistant P. falciparum (W2 strain) according to methods described in Example 6. The results are shown in Table 5.

Table 5

Compd n Z ICso (nM)

V-l 2 Me 4,604

V-2 9 Me 1,377

VI I - - 1,230

VII-1 8 Me 119.3 ± 11.3

VII-2 4 Me 42.7 ± 1.4

VII-3 1 Me 41.9 ± 4.0

VII-4 1 H 40.0 ± 0.8

VII-5 4 H 28.5 ± 3.0

VII-6 4 ^-ClBn 49.5 ± 7.8

VII-7 4 Bn 49.1 ± 6.3

VII-8 4 CeHn 47.9 ± 6.3

VII-9 1 Bn 46.7 ± 4.4

VII-10 1 CeHn 42.3 ± 0.0

VII-11 1 />-OMeBn 17.4 ± 4.1

VII-10 1 CeHn 42.3 ± 0.0

Atovaquone 0.50 ± 0.2

Example 10: Antiplasmodial Activity of Pyridinium- and Imidazolium-Containing Naphthoquinone Compounds

Naphthoquinone compounds containing non-phosphonium cations were also explored. Compound 1, a pyridinium-containing compound, and Compound 2, an imidazolium containing compound, were prepared and the antiplamodial activities were determined against the chloroquine-resistant P. falciparum (W2 strain) according to methods described in Example 4. The structures and the IC5₀ values are shown below:

167.0 ± 0.2 nM 164.7 ± 23.5 nM Example 11: Therapeutic Efficacy in Malarial Mouse Model

In vivo efficacy studies for the compounds described herein are performed using P. berghei models. Swiss-Webster mice are infected by the ip inoculation of P. berghei-m^' fected murine erythrocytes from available frozen stocks. For efficacy experiments, control and treated mice are administered 106 infected erythrocytes obtained from a previously-infected mouse. Animals are then treated following standard protocols for the in vivo assessment of lipocation efficacy. Variations of the 4-day "Peters test" are performed. Initial experiments include parenteral (ip or sc) dosing, and effective compounds are then evaluated with oral dosing.

Treatment schedules are based on the pharmacokinetics data. After treatment, parasitemias is followed daily by assessment of Giemsa stained blood smears obtained from tail nicks. Infection with 106 parasites leads to the development of high parasitemias necessitating euthanasia after 6- 8 days. Effective treatment leads to delays or complete blocks in the progression of infection. The animals are monitored for 42 days after the initiation of treatment, and those which are parasite free at 42 days are considered cured.

The compounds and methods of the appended claims are not limited in scope by the specific compounds and methods described herein, which are intended as illustrations of a few aspects of the claims and any compounds and methods that are functionally equivalent are within the scope of this disclosure. Various modifications of the compounds and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compounds, methods, and aspects of these compounds and methods are specifically described, other compounds and methods and combinations of various features of the compounds and methods are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, all other

combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

Claims

WHAT IS CLAIMED IS:

1. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

n is an integer from 1 to 15; and

Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

2. The compound of claim 1, wherein n is 3, 5, or 9.

3. The compound of claim 1 or 2, wherein Y is methyl, substituted or unsubstituted phenyl, benzyl, cyclohexyl, or n-butyl.

4. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

n is an integer from 1 to 15;

Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

Z is hydrogen or substituted or unsubstituted alkyl.

5. The compound of claim 4, wherein n is 2 or 10.

6. The compound of claim 4 or 5, wherein Y is substituted or unsubstituted phenyl, benzyl, or cyclohexyl.

7. The compound of any of claims 4-6, wherein Z is hydrogen.

8. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

n is an integer from 1 to 15;

Z is hydrogen or substituted or unsubstituted alkyl.

9. The compound of claim 8, wherein n is 1, 4, 5, 9, or 10.

10. The compound of claim 8 or 9, wherein Y is methyl, substituted or unsubstituted phenyl, benzyl, cyclohexyl, or n-butyl.

1 1. The compound of any of claims 8-10, wherein Z is hydrogen, methyl, hydroxyl, or acetoxy.

12. The compound of any of claims 8-11, wherein Z is methyl.

13. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

n is an integer from 1 to 15;

Y is substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and Z is hydrogen, hydroxyl, acetoxy, alkoxy, or substituted or unsubstituted alkyl.

14. The compound of claim 13, wherein n is 1, 2, or 8.

15. The compound of claim 13 or 14, wherein Y is substituted or unsubstituted phenyl.

16. The compound of any of claims 13-15, wherein Z is acetoxy, hydroxyl, or methoxy.

17. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

n is an integer from 1 to 15;

Y is substituted or unsubstituted alkyl, substituted or unsubstituted

heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

Z is hydrogen, hydroxyl, acetoxy, or substituted or unsubstituted alkyl.

18. The compound of claim 17, wherein n is 2 or 9.

19. The compound of claim 17 or 18, wherein Y is substituted or unsubstituted phenyl.

20. The compound of any of claims 17-19, wherein Z is methyl.

21. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein: n is an integer from 1 to 15;

Z is hydrogen, hydroxyl, acetoxy, or substituted or unsubstituted alkyl.

22. The compound of claim 21, wherein n is 1.

23. The compound of claim 21 or 22, wherein Y is substituted or unsubstituted phenyl.

24. The compound of any of claims 21-23, wherein Z is methyl.

25. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

n is an integer from 1 to 15;

Z is hydrogen, hydroxyl, acetoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl.

26. The compound of claim 25, wherein n is 1, 4, or 8.

27. The compound of claim 25 or 26, wherein Y is substituted or unsubstituted phenyl.

28. The compound of any of claims 25-27, wherein Z is hydrogen, methyl, cyclohexyl, benzyl, 4-chlorobenzyl, or 4-methoxyphenyl.

A compound of the following structure:

pharmaceutically acceptable salt or prodrug thereof.

A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof.

31. A composition comprising one or more of the compounds of claims 1-30 and a pharmaceutically acceptable carrier.

32. A method of treating or preventing a parasitic disease in a subject, comprising administering to the subject an effective amount of one or more compounds or compositions of claims 1-31.

33. The method of claim 32, wherein the parasitic disease is a Plasmodium related disease.

34. The method of claim 33, wherein the Plasmodium related disease is malaria.

35. The method of claim 32, wherein the parasitic disease is a Trypanosoma related disease.

36. The method of claim 35, wherein the Trypanosoma related disease is Chagas disease.

37. The method of claim 35, wherein the Trypanosoma related disease is African Sleeping Sickness.

38. The method of any of claims 32-37, further comprising administering a second therapeutic agent to the subject.

39. The method of claim 38, wherein the second therapeutic agent is an antimalarial agent.

40. A method of inhibiting a parasite, comprising contacting the parasite with an effective amount of one or more compounds or compositions of claims 1-31.

41. The method of claim 40, wherein the parasite is selected from the group consisting of Plasmodium falciparum, Trypanosoma cruzi, and Trypanosoma brucei.

42. The method of claim 40 or 41, wherein the contacting is performed in vivo.

43. The method of any of claims 40-42, wherein the contacting is performed in vitro.