Novel chemotypes for treating parasitic diseases and methods of use

Abstract

The present disclosure provides novel chemotypes, pharmaceutical compositions thereof, and method of use thereof for treating parasitic infection, including infection caused by parasitic flatworms.

Description

NOVEL CHEMOTYPES FOR TREATING PARASITIC DISEASES AND METHODS OF USE CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Patent Application No. 63 / 698,467, filed September 24, 2024, the content of which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION

[0002] The disclosed technology is generally directed to antiparasitic agents. More particularly the technology is directed to flatworm TRPMPZQ (transient receptor potential melastatin- praziquantel) channel inhibitors. BACKGROUND

[0003] Infectious diseases caused by parasitic flatworms (e.g., trematodes, cestodes, and monogeneans) cause significant clinical (human) and veterinary (animal) disease worldwide. There are limited drug options for treating these infections which have significant healthcare and economic impact. Given the worldwide burden of neglected tropical diseases, there is ongoing need to develop novel agents to strengthen the pipeline of drugs to combat these burdensome infections. Many diseases caused by parasitic flatworms are treated using the anthelmintic drug praziquantel (PZQ), employed for decades as the key clinical agent to treat schistosomiasis. PZQ activates a flatworm transient receptor potential (TRP) channel within the melastatin family (TRPMPZQ) to mediate sustained Ca2+influx and worm paralysis. In addition, a known compound that retains efficacy against juvenile worms is the benzodiazepine meclonazepam (MCLZ). MCLZ potently activates a transient receptor potential ion channel ofthe melastatin subfamily, namedthrough engagement of a binding pocket within the voltage-sensor-like domain of the ion channel.

[0004] There remains a need to develop novel agents, such as alternatives to PZQ and MCLZ, to help battle parasitic infections. SUMMARY OF THE INVENTION

[0005] The present disclosure describes novel chemotypes that are broad-spectrum flatwormtransient receptor potential melastatin channel (e.g., TRPMPZQand TRPMMCLZ) ligands orinhibitors andmethods of use thereof for treatment of parasitic infections, particularly parasiticflatworm infections.

[0006] In one aspect, the present disclosure provides new chemotypes that engage a parasiteion channel that could potentially be developed as new anti-infective agents for diseases caused by parasitic flatworms. The effectiveness of the new chemotypes can be demonstrated, for example, by results derived from a target-based screen using a Ca2+reporter assay.

[0007] In another aspect, the present disclosure provides a composition comprising the compound as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] In another aspect, the present disclosure provides a method of treating a parasitic infection in a subject in need thereof, the method comprises administering to the subject an effective amount of the compound as described herein, or derivative or a pharmaceutically acceptable salt thereof. In some embodiments, the parasitic infection is a parasitic flatworm infection. For example, the parasitic flatworm can be trematode, cestode, monogenean, schistosome, tapeworm, or a combination thereof.

[0009] In another aspect, the present disclosure provides a method of treating schistosomiasis in a subject in need thereof, the method comprises administering to the subject an effective amount of the compound as described herein, or derivative or a pharmaceutically acceptable salt thereof.

[0010] In another aspect, the present disclosure provides a method of activating a transientreceptor potential channel of a parasitic flatworm, the method comprising introducing to the parasitic flatworm an effective amount of the compound as described herein, or derivative or a salt thereof. For example, the transient receptor potential channel may comprise TRPMPZQor TRPMMCLZ.

[0011] In another aspect, the present disclosure provides a method of causing paralysis or inhibiting growth, reproduction or egg laying of a parasitic flatworm, the method comprising introducing to the parasitic flatworm an effective amount of the compound as described herein, or derivative or a salt thereof, or the composition as described herein.

[0012] In some embodiments, the parasitic flatworm is in an infected subject. In some embodiments, the subject is a human. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG. 1A Overview of high throughput screening (HTS) assay. Example of HTS data looking for inhibitors (arrowed region) of control responses relative to signals caused by the canonical agonist PZQ at EC50(half maximal concentration) and maximal concentration.

[0014] FIG.1B Higher magnification view of typical high throughput screening (HTS) data. Each point represents a fluorescence signal measured for compound inhibition of a PZQresponse, relative to standard high control, low control and reference controls on each plate. Signals were measured using a high affinity Ca2+reporter dye.

[0015] FIG. 1C Successful miniaturization of fluorescence reporter assay to 1536 well format. Top left, control trace shows no response to vehicle (DMSO) or PZQ. Fluorescence reported vertically and time horizontally, as per scale bar. Bottom right, in cells expressing TRPMPZQ, PZQ shows a clear, robust reproducible fluorescence signal which was used to evaluate the effect if antagonists. Right, example of 1536 well plate used for screening assays.

[0016] FIG. 2 illustrates structures of representative compounds identified by high throughput screening.

[0017] FIG. 3A Effect of various analogs on blockade of PZQ-evoked Ca2+signals through Sm.TRPMPZQ. Magnitude of Ca2+signal evoked by PZQ (black circle) is reduced in the presence of various Sm.TRPMPZQantagonists (ANT101 to ANT 133, final concentration 10μM). Examples of antagonists of the same chemotype are shown as orange squares. Data from a fluorescence Ca2+reporter assay using a high affinity Ca2+indicator.

[0018] FIG.3B Evidence for a structure activity relationship of novel antagonist series (ANT118-126) at Sm.TRPMPZQ. Top, Antagonists within a similar chemotype show variable ability to block TRPMPZQ. Compounds run left to right. Action in a Ca2+reporter assay with PZQ alone (top, in duplicate above red line), and with 10μM of different antagonist (below red line). Bottom, IC50for TRPMPZQblockade for each compound at Sm.TRPMPZQ (y-axis) is plotted against IC50for same compounds at inhibiting PZQ-evoked worm contraction (x-axis). Strong correlation is observed between potency of blockade of target with potency of block of worm contraction.

[0019] FIG. 4A Selectivity of ANT-126 chemotype for TRPMPZQ. Top, three different replicates of a Ca2+reporter assay (each shown in duplicates) showing the inhibition of PZQ action (500nM) at TRPMPZQby ANT-114 (10μM final concentration). Bottom, under similar conditions ANT-114 (10μM final concentration) shows no inhibition of MCLZ action (1μM) at TRPMMCLZ. These data confirm ANT-114 is a selective blocker of TRPMPZQ. Right, structure of ANT-114.

[0020] FIG. 4B ANT-126 shows a concentration dependent block of TRPMPZQactivity at both Schistosoma mansoni TRPMPZQand Fasciola hepatica TRPMPZQevidencing broad spectrum activity at parasitic flatworm TRPMPZQ.

[0021] FIG. 5A Selectivity of ANT-114 for TRPMPZQ. Top, three different replicates of a Ca2+reporter assay (each shown in duplicates) showing the inhibition of PZQ action (500nM) at TRPMPZQby ANT-114 (10μM final concentration). Bottom, under similar conditions ANT-114 (10μM final concentration) shows no inhibition of MCLZ action (1μM) at TRPMMCLZ. These data confirm ANT-114 is a selective blocker of TRPMPZQ. Right, structure of ANT-114.

[0022] FIG. 5B ANT-114 blocks different TRPMPZQ orthologs. ANT-114 shows a concentration dependent block of TRPMPZQactivity at both Schistosoma mansoni TRPMPZQand Fasciola hepatica TRPMPZQevidencing broad spectrum activity at parasitic flatworm TRPMPZQ.

[0023] FIG.6A Effects of TRPMPZQ anatagonists on schistosome eggs. Bar chart collating effect of different treatments on number of eggs laid in a standardized egg laying assay. Total number of eggs (y-axis) as well as embryo developmental phenotypes (normal, green; deleterious effect, red) are scored using light microscopy.

[0024] FIG. 6B Effects of TRPMPZQanatagonists on egg morphology and miracidia development. Left, quantification of egg area and developmental phenotype categorized as fully developed embryo (gree), developing embryo (yellow) and no embryo (red) in untreated as well as vehicle (DMSO) and ANT114 and ANT126 (both at 5μM) treated samples. Data shows a significant effect of both antagonist chemotypes on miracidial development.

[0025] FIG. 6C Top, examples of the different phenotypes highlighted by relevant colors. Bottom, normal development of egg into miracidia.

[0026] The drawings illustrate only example embodiments and are therefore not to be considered limiting of the scope of the embodiments described herein, as other embodiments are within the scope of the disclosure DETAILED DESCRIPTION OF THE INVENTION

[0027] Before the present materials and methods are described, it is understood that this invention is not limited to the particular methodology, protocols, materials, and reagents described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention which will be limited only by the appended claims.

[0028] As used in this specification and the claims, the singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise. For example, the term “a compound” should be interpreted to mean “one or more compounds” unless the context clearly dictates otherwise. As used herein, the term “plurality” means “two or more.”

[0029] As used herein, the terms “about”, “approximately,” “substantially,” and “significantly” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of the term which are not clear topersons of ordinary skill in the art given the context in which it is used, “about” and “approximately” will mean up to plus or minus 10% of the particular term and “substantially” and “significantly” will mean more than plus or minus 10% of the particular term.

[0030] As used herein, the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.” The terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms “consist” and “consisting of” should be interpreted as being “closed” transitional terms that do not permit the inclusion of additional components other than the components recited in the claims. The term “consisting essentially of” should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter.

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All publications and patents specifically mentioned herein are incorporated by reference for all purposes, including those describing and disclosing the chemicals, cell lines, vectors, animals, instruments, statistical analysis and methodologies which might be useful in connection with the present disclosure. In the case of conflict, the present specification, including definitions, will control.

[0032] Definitions

[0033] Chemical entities and the use thereof may be disclosed herein and may be described using terms known in the art and defined herein. Derivatives of the compounds as described herein include structural variants that can be obtained by modifications of the synthesis of such compounds, as generally understood in the art of organic synthesis. As an example, esters and amides of a compound having a reactive group (e.g., COOH, OH, or NH2) can be viewed as derivatives of the original compounds.

[0034] As used herein, "salt" refers to acid addition salts and basic addition salts. It may also refer to those salts that may be prepared in situ during the final isolation and purification of the present compounds.

[0035] The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereo isomers of these compounds and mixturesthereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated "(±)" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise.

[0036] Pharmaceutically acceptable salts of the present compounds are contemplated and may be utilized in the methods disclosed herein. The term “pharmaceutically acceptable salt” as used herein, refers to salts of the compounds, which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds as disclosed herein with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts. It will be appreciated by the skilled reader that most or all of the compounds as disclosed herein are capable of forming salts and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free acids or bases.

[0037] Acids commonly employed to form acid addition salts may include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of suitable pharmaceutically acceptable salts may include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleat-, butyne-, 1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, α-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like.

[0038] Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Bases useful in preparing such salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

[0039] The particular counter-ion forming a part of any salt of a compound disclosed herein may not be critical to the activity of the compound, so long as the salt as a whole is pharmacologically acceptable and as long as the counter-ion does not contribute undesired qualities to the salt as a whole. Undesired qualities may include undesirably solubility or toxicity.

[0040] Pharmaceutically acceptable esters and amides of the compounds can also be employed in the compositions and methods disclosed herein. Examples of suitable esters include alkyl, aryl, and aralkyl esters, such as methyl esters, ethyl esters, propyl esters, dodecyl esters, benzyl esters, and the like. Examples of suitable amides include unsubstituted amides, monosubstituted amides, and disubstituted amides, such as methyl amide, dimethyl amide, methyl ethyl amide, and the like.

[0041] Compounds

[0042] In one aspect, the present disclosure provides a compound, which is(ANT-112, or 6-(4-fluorophenyl)-5-phenyl-7-(3-(trifluoromethyl)phenyl)-2,3,6,7-tetrahydropyrrolo[3,4- e][1,4]diazepin-8(1H)-one),(ANT-134, or methyl 4-(2-(1-(2,3-dimethylphenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin- 5-yl)acetamido)benzoate),(ANT-139, or 7-(4-isopropylphenyl)-N-(2-methoxyphenyl)-5-methyl-4,5,6,7-tetrahydro- [1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide),(ANT-124, or 2-(4-((5-chloro-2-methoxyphenyl)sulfonyl)piperazin-1-yl)-N-(4- fluorophenyl)acetamide),(ANT-126, or methyl 4-(2-(4-((5-chloro-2-methoxyphenyl)sulfonyl)piperazin-1- yl)acetamido)benzoate,(ANT-129, or methyl 2-amino-1-(2-chlorophenyl)-1H-pyrrolo[2,3-b]quinoxaline-3- carboxylate),(ANT-106, 3-((4-chlorophenyl)amino)-3-(4-(methylthio)phenyl)-1-(p-tolyl)propan-1-one),(ANT-119, or N-(3,4-difluorophenyl)-2-(4-((4-fluorophenyl)sulfonyl)piperazin-1- yl)acetamide),(ANT-135, or N-(4-methoxyphenyl)-2-((5-(2-methoxyphenyl)-4-(1H-pyrrol-1-yl)-4H-1,2,4- triazol-3-yl)thio)acetamide),(ANT-105, or N-(2-methoxyphenyl)-2-methyl-4-oxo-3,4,5,6-tetrahydro-2H-2,6- methanobenzo[g][1,3]oxazocine-5-carboxamide),(ANT-120, or 2-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-N-(4-phenoxyphenyl)acetamide),(ANT-107, (E)-N-(3-((4-methoxyphenethyl)amino)-3-oxo-1-(thiophen-3-yl)prop-1-en-2-yl)- 3,4-dimethylbenzamide),(ANT-109, or (Z)-N'-(4-((1-methyl-1H-imidazol-2-yl)thio)-3-nitrobenzylidene)-3- nitrobenzohydrazide), ((ANT-104, or N-(2,4-bis(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-N-methylthiophene-2-carboxamide),(ANT-118, or 5-((4-benzylpiperidin-1-yl)sulfonyl)-N-(2,3-dimethylphenyl)-2- fluorobenzamide),(ANT-137, or (4-benzhydrylpiperazin-1-yl)(4-(thiophen-2-yl)tetrahydro-2H-pyran-4- yl)methanone),(ANT-128, or 5-(((2R,3S)-2-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4- fluorophenyl)morpholino)methyl)-1,2-dihydro-3H-1,2,4-triazol-3-one),(ANT-110, or 2-((5-((4-cyclohexylphenoxy)methyl)-4-phenyl-4H-1,2,4-triazol-3-yl)thio)-N- (furan-2-ylmethyl)acetamide),(ANT-115, or (E)-3-((4-chlorobenzyl)thio)-2-cyano-3-((4-ethoxyphenyl)amino)-N-(furan-2- ylmethyl)acrylamide),(ANT-127, or (E)-2-cyano-3-((2,4-dimethylbenzyl)thio)-3-((4-ethylphenyl)amino)-N-(furan-2- ylmethyl)acrylamide),(ANT-102, or N-(4-bromobenzyl)-N-(4-iodophenyl)-2-methylbenzamide),(ANT-132, or (E)-3-(5-bromofuran-2-yl)-N-(4-morpholinophenyl)acrylamide),(ANT-136, or methyl 4-(2-((5-(2-chlorophenyl)-4-(1H-pyrrol-1-yl)-4H-1,2,4-triazol-3- yl)thio)acetamido)benzoate),(ANT-101, or N-((2-(2-chloroacetyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)methyl)cyclohexanecarboxamide),(ANT-133, or N-(benzo[d]thiazol-2-yl)-2-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-isoindol-2- yl)-N-(3-methoxyphenyl)acetamide),(ANT-138, or 2-methyl-4-(4-nitrophenyl)-N-(m-tolyl)thiazole-5-carboxamide), or a derivative or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the compound isderivative or a pharmaceutically acceptable salt thereof.

[0044] In some embodiments, the compound isor a derivative or a pharmaceutically acceptable salt thereof.

[0046] Pharmaceutical Compositions

[0047] The compounds employed in the compositions and methods disclosed herein may be administered as pharmaceutical compositions. Such compositions may take any physical form which is pharmaceutically acceptable; illustratively, they can be orally administered pharmaceutical compositions. Such pharmaceutical compositions contain an effective amount of a disclosed compound, which effective amount is related to the dose of the compound to be administered.

[0048] In one aspect, the present disclosure provides a composition comprising the compounds as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0049] The compositions may contain from about 0.5% to about 50% of the compound in total, depending on the desired doses and the type of composition to be used. The amount of the compound may be defined as the “effective amount”, which is the amount of the compound that provides the desired dose to the patient in need of such treatment. The activity of the compounds employed in the compositions and methods disclosed herein are not believed to depend greatly on the nature of the composition, and, therefore, the compositions can be chosen and formulated primarily or solely for convenience and economy. In some embodiments, the pharmaceutical composition includes a compound as described herein in a range from about 0.1 to about 2000 mg, such as from about 0.5 to 500 mg or from about 1 to about 100 mg. The pharmaceutical composition may be administered to provide the compound at a daily dose of about 0.01 mg / kg to about 1000 mg / kg body weight, such as about 0.01 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 1000 mg / kg, about 0.1 to about 500 mg / kg, about 0.1 to about 100 mg / kg, or about 50 to about 100 mg / kg body weight.

[0050] In some embodiments, after the pharmaceutical composition is administered to a subject (e.g., after about 1, 2, 3, 4, 5, or 6 hours post-administration), the concentration of the compound at the site of action may be within a concentration range bounded by end-points selected from μM, 0.005 μM, 0.01 μM, 0.5 μM, 0.1 μM, 1.0 μM, 10 μM, and 100 μM (e.g., 0.1 μM - 1.0 μM).

[0051] The term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Suitable pharmaceutically acceptable carriers include, but are not limited to, for example, suitable diluents, vehicles, excipients, preservatives, solubilizers, emulsifiers, liposomes, ornanoparticles, among others. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of nonaqueous solutions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include isotonic solutions, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.

[0052] The formulation should be selected according to the mode of administration. The compositions may include a pharmaceutical carrier, excipient, or diluent, which are nontoxic to the subject being exposed thereto at the dosages and concentrations employed. Examples of pharmaceutical carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; 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 brand surfactant, polyethylene glycol (PEG), and PLURONICSTMsurfactant.

[0053] Oral administration is an illustrative route of administering the compounds employed in the compositions and methods disclosed herein. Other illustrative routes of administration include transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, intrathecal, intracerebral, or intrarectal routes. The route of administration may be varied in any way, limited by the physical properties of the compounds being employed and the convenience of the subject and the caregiver.

[0054] Suitable formulations include those that are suitable for more than one route of administration. For example, the formulation can be one that is suitable for both oral and intravenous administration. Alternatively, suitable formulations include those that are suitable for only one route of administration as well as those that are suitable for one or more routes of administration, but not suitable for one or more other routes of administration. For example, the formulation can be one that is suitable for oral, topical, transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, and / or intrathecal administration but not suitablefor intracerebral administration.

[0055] The inert ingredients and manner of formulation of the pharmaceutical compositions may be selected from conventional technologies. The usual methods of formulation used in pharmaceutical science may be used here. Suitable types of compositions include, but are not limited to, tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches, and suspensions.

[0056] Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules. The usual diluents include inert powdered substances (such as starches), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol and sucrose), grain flours, and similar edible powders, but any suitable capsule formulation can be used.

[0057] Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants, and disintegrators (in addition to the compounds). Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives can also be used. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, and the like). Natural and synthetic gums can also be used, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders.

[0058] Tablets can be coated with sugar, e.g., as a flavor enhancer and sealant. The compounds also may be formulated as chewable tablets, by using large amounts of pleasant-tasting substances, such as mannitol, in the formulation. Instantly dissolving tablet-like formulations can also be employed, for example, to assure that the patient consumes the dosage form and to avoid the difficulty that some patients experience in swallowing solid objects.

[0059] A lubricant can be used in the tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils.

[0060] Tablets can also contain disintegrators. Disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins, and gums. As further illustration, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp, sodium lauryl sulfate, and carboxymethylcellulose can be used.

[0061] The composition can be formulated as enteric formulations, for example, to protect theactive ingredient from the strongly acid contents of the stomach. Such formulations can be created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments and soluble in basic environments. Illustrative films include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate.

[0062] Transdermal patches can also be used to deliver the compounds. Transdermal patches can include a resinous composition in which the compound will dissolve or partially dissolve; and a film which protects the composition, and which holds the resinous composition in contact with the skin. Other, more complicated patch compositions can also be used, such as those having a membrane pierced with a plurality of pores through which the compound is pumped by osmotic action.

[0063] Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis.

[0064] Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, impregnated dressings, sprays, aerosols or oils and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

[0065] For applications to the eye or other external tissues, for example the mouth and skin, the pharmaceutical compositions are in some embodiments applied as a topical ointment or cream. When formulated in an ointment, the compound may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the compound may be formulated in a cream with an oil-in-water cream base or a water-in-oil base. Pharmaceutical compositions adapted for topical administration to the eye include eye drops where the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.

[0066] The composition can be prepared with materials (e.g., actives excipients, carriers (such as cyclodextrins), diluents, etc.) having properties (e.g., purity) that render the formulation suitable for administration to humans or non-human subjects. In some embodiments, the composition is suitable for use in humans. In some embodiments, the composition is prepared with materials having purity and / or other properties that render it suitable for administration to non-human subjects, but not suitable for administration to humans.

[0067] Each dosage unit may contain the dose of a given compound, for example, a daily dose, or each dosage unit may contain a fraction of the daily dose, such as one-half or one-third of thedose. The amount of each compound to be contained in each dosage unit can depend, in part, on the identity of the particular compound chosen for the therapy and other factors, such as the indication for which it is given. The pharmaceutical compositions disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing well known procedures.

[0068] The composition may include a single compound or a combination of compounds as described herein for administration. For example, a two or more of the compounds described herein may be administered for an anti-parasitic effect. In addition, the composition may include solvate forms of the compounds or salts, esters, and / or amides, thereof. Solvate forms may include ethanol solvates, hydrates, and the like.

[0069] The disclosed compounds or pharmaceutical compositions comprising the disclosed compounds may be administered with additional therapeutic agents. The additional therapeutic agent may include, for example, one or more known agent for treating parasitic infection. In some embodiments of the disclosed methods, one or more additional therapeutic agents are administered with the disclosed compounds or with pharmaceutical compositions comprising the disclosed compounds, where the additional therapeutic agent is administered prior to, concurrently with, or after administering the disclosed compounds or the pharmaceutical compositions comprising the disclosed compounds. In some embodiments, the disclosed pharmaceutical compositions are formulated to comprise the disclosed compounds and further to comprise the one or more additional therapeutic agents.

[0070] Methods of Use

[0071] The compounds as described herein may effectively inhibit the growth and propagation of parasites in vivo, in particular the growth and propagation of flatworms within a subject. The compounds as described herein may effectively inhibit the reproduction or egg laying of parasites.

[0072] In one aspect, the present disclosure provides a method of treating a parasitic infection in a subject in need thereof, the method comprises administering to the subject an effective amount of the compounds as described herein, or a derivative or a pharmaceutically acceptable salt thereof, or the composition as described herein.

[0073] In another aspect, the present disclosure provides a method of treating schistosomiasis in a subject in need thereof, the method comprises administering to the subject an effective amount of the compounds as described herein, or a derivative or a pharmaceutically acceptable salt thereof, or the composition as described herein.

[0074] In some embodiments, the methods of treatment disclosed herein may comprise administering to the subject an additional agent, such as an agent selected from PZQ and MCLZ. The additional agent can be administered in a combination with an effective amount of the compounds as described herein, or a derivative or a pharmaceutically acceptable salt thereof, or the composition as described herein. The combination can be a simultaneous or sequential combination.

[0075] In use, the compounds as described herein may be cytotoxic to the parasite but not to the subject being treated. Also provided is a compound, or a derivative or a pharmaceutically acceptable salt thereof, as described herein for use in therapy. In particular, the present disclosure provides a compound, or a derivative or a pharmaceutically acceptable salt thereof as described herein, for use in the treatment of parasitic infection in a subject in need thereof. Also provided is a compound, or a derivative or a pharmaceutically acceptable salt thereof as described herein, for use in the manufacture of a medicament for the treatment of parasitic infection in a subject in need thereof.

[0076] Suitable subjects include mammals and non-mammals. Mammals include any member of the class Mammalia. Examples of mammals include, but are not limited to, humans, non- human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds, fish, crustaceans, among others. A subject can be any suitable age or sex. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human subject, such as a fish, a bird, a dog, a cat, or a livestock.

[0077] As used herein, “treating” or “treatment” describes the management and care of a subject for combating the disease, condition, or disorder. Treating includes the administration of the compound or composition described herein to reduce, prevent, ameliorate and / or improve the onset of the symptoms or complications, alleviating the symptoms or complications, or reducing or eliminating the disease, condition, or disorder associated with a parasitic infection, such as a flatworm parasitic infection. The term treating as described herein includes the inhibiting or reducing growth and / or propagation / reproduction / egg-laying of parasites within a subject (i.e., in vivo).

[0078] Symptoms of parasitic infections include, but are not limited to, for example, stomach cramps and pain, nausea or vomiting, dehydration, weight loss, swollen lymph nodes, digestive problems including unexplained constipation, diarrhea or persistent gas, skin issuessuch as rashes, eczema, hives, and itching, continuous muscle and joint pain, fatigue, depression or feeling of apathetic, constant hunger, iron deficiency / anaemia, grinding teeth during sleep, unexplained feelings of anxiety, recurrent yeast infections, itching of the anus or vagina, itching, redness, irritation, and an unusual discharge from the genital area, trouble falling asleep or waking up multiple times during the night.

[0079] As used herein the term “effective amount” or "therapeutically effective amount" refers to the amount or dose of the present compound or composition, which, upon single or multiple dose administration to the subject, provides the desired effect in the subject under diagnosis or treatment. The disclosed methods may include administering an effective amount of the disclosed compounds (e.g., as present in a pharmaceutical composition) for treating a disease or disorder, e.g., a parasitic infection.

[0080] An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors can be considered by the attending diagnostician, such as: the species of the subject; its size, age, and general health; the degree of involvement or the severity of the disease or disorder involved; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances.

[0081] The term “administering” or “administration” refers to introducing the present compounds or compositions into the body of the subject, such as by oral delivery. Suitable routes of administration include, but are not limited to, oral, topical, transdermal, buccal, sublingual, pulmonary, transdermal, transmucosal, rectal, as well as subcutaneous, intraperitoneal, intravenous, and intramuscular injection.

[0082] The methods of treating a parasitic infection include treating a parasitic flatworm infection. In some embodiments, the parasitic infection is a parasitic flatworm infection. Suitable flatworm infections contemplated to be treated using the compound and compositions described herein include, but are not limited to, trematode (i.e. flukes, such as schistosoma species (blood fluke), Fasciola species (liver fluke), Paragonimus westermani (lung fluke), clonorchis sinensis (liver fluke), Opisthorchis viverrini (liver fluke)), cestode (i.e. tapeworms, such as pork tapeworm (taenia solium), beef tapeworm (taenia saginata), Echinococcus species, Dipylidium caninum (heartworm), Diphyllobothrium species, Gyrodactcylus species, and dwarf tapeworm (hymenolepis nana)), turbellaria (planarians), monogenean (i.e.monopisthocotyleans and the polyopisthocotyleans), and turbellaria (such as temnocephala lamothei, dugesia aenigma, dugesia bifida, planaria simplex, girardia dorotocephala, girardia tigrina). In particular embodiments, the present method can be used to treat a parasitic flatworm infection, in which the parasitic flatworm is trematode, cestode, monogenean, schistosome, tapeworm, or a combination thereof.

[0083] The compounds as disclosed herein may provide treatment for a disease caused by parasitic worms in multiple species (such as humans), including fasciolosis, schistosomiasis, and other diseases. Schistosomiasis is a disease caused by parasitic flatworms, namely, schistosomes. In another aspect, the present disclosure provides a method of treating schistosomiasis in a subject in need thereof, the method comprises administering to the subject an effective amount of the compounds as described herein, or a derivative or a pharmaceutically acceptable salt thereof, or the composition as described herein. As nonlimiting examples, the present compounds can be used in medications (e.g., drugs) for treatment of clinical and veterinary diseases caused by parasitic flatworms. The present disclosure also provides a compound, or a derivative or a pharmaceutically acceptable salt thereof as described herein, for use in the treatment of schistosomiasis in a subject in need thereof. Also provided is a compound, or a derivative or a pharmaceutically acceptable salt thereof as described herein, for use in the manufacture of a medicament for the treatment of schistosomiasis in a subject in need thereof

[0084] The present compounds may block a flatworm transient receptor potential (TRP) channel, which may in turn mediate worm paralysis. Thus, the disclosed compounds may act as ion channel blockers to treat parasitic flatform infections. In another aspect, the present disclosure provides a method of blocking a transient receptor potential channel of a parasitic flatworm, the method comprising introducing to the parasitic flatworm an effective amount of the compounds as described herein, or a derivative or a salt thereof, or the composition as described herein. In some embodiments, the transient receptor potential channel is a member of the melastatin family (TRPM), such as TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, and TRPM8.

[0085] In some embodiments, the transient receptor potential channel comprises TRPMPZQ.

[0086] In some embodiments, the transient receptor potential channel comprisesTRPMMCLZ.

[0087] The present compound may be used to effectively control infection or growth of a parasitic flatworm. In another aspect, the present disclosure provides a method of causing paralysis or inhibiting growth, reproduction, or egg laying of a parasitic flatworm, the methodcomprising introducing to the parasitic flatworm an effective amount of the compounds as described herein, or a derivative or a salt thereof, or the composition as described herein.

[0088] For the present methods, the compounds as described herein, or a salt thereof, or the composition as described herein may be introduced to a parasitic flatworm that is in an infected subject (e.g., to inhibit the growth of, or treat an infection caused by, the parasitic flatworm in the subject). In some embodiments, the subject is a human. Alternatively, the compound or composition may be introduced to a parasitic flatworm that is in an environment (outside the body of a subject), such as a river, a lake, a water reservoir, a grassland, or a forest. In these cases, the effective amount of the compound or composition refers to an amount that provides desired effect of activating a TRP channel and / or causing paralysis or inhibiting growth of the parasitic flatworm in such environment.

[0089] The compounds utilized in the methods disclosed herein may be administered in conventional dosage forms prepared by combining the active ingredient with standard pharmaceutical carriers or diluents according to known procedures, including for example mixing, granulating, compressing, and / or dissolving various ingredients as appropriate to the desired preparation.

[0090] In some embodiments, the subject may be administered a dose of the disclosed compound as low as 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 100 mg, 200 mg, 500 mg, 1000 mg, or 2000 mg once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times per week in order to treat the disease or disorder in the subject. In some embodiments, the subject may be administered a dose of the disclosed compound as high as 1.25 mg, 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 42.5 mg, 45 mg, 47.5 mg, 50 mg, 52.5 mg, 55 mg, 57.5 mg, 60 mg, 62.5 mg, 65 mg, 67.5 mg, 70 mg, 72.5 mg, 75 mg, 77.5 mg, 80 mg, 82.5 mg, 85 mg, 87.5 mg, 90 mg, 100 mg, 200 mg, 500 mg, 1000 mg, or 2000 mg, once daily, twice daily, three times daily, four times daily, once weekly, twice weekly, or three times per week in order to treat the disease or disorder in the subject. Minimal and / or maximal doses of the compounds may include doses falling within dose ranges having as endpoints any of these disclosed doses (e.g., 2.5 mg – 200 mg).

[0091] Kits

[0092] In another aspect, the present disclosure provides a kit comprising a pharmaceuticalcomposition comprising the compounds as disclosed herein and instructional material.

[0093] The term "instructional material" refers to a publication, a recording, a diagram, or any other medium of expression which is used to communicate the usefulness of the present pharmaceutical composition for one of the purposes set forth herein in a human. The instructional material can also, for example, describe an appropriate dose of the present pharmaceutical composition. The instructional material of the present kit can, for example, be affixed to a container which contains a pharmaceutical composition as disclosed herein or be shipped together with a container which contains the pharmaceutical composition. Alternatively, the instructional material can be shipped separately from the container with the intention that the instructional material and the pharmaceutical composition be used cooperatively by the recipient.

[0094] It should be apparent to those skilled in the art that many additional modifications beside those already described are possible without departing from the inventive concepts. Other features and advantages of the invention will be apparent from the present description and claims. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. EXAMPLES

[0095] The following examples are, of course, offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description and the following examples and fall within the scope of the appended claims.

[0096] Example 1: Novel chemotypes identified

[0097] Various compounds were identified in screening studies, such as target-basedTRPMPZQ antagonist assays. Exemplary compounds identified include:

[0098] Example 2. HTS experimental methods (Figures 1A-1C)

[0099] HTS screening workflow. HEK cells were transfected with cDNA (400μg / ml DNA)encoding Sm.TRPMPZQ using a Maxcyte STX electroporation system and incubated overnight at 37°C. Briefly, the HEK cells were resuspended at 1e8 / ml in Maxcyte electroporation buffer. Plasmid DNA is added to the cells in buffer to achieve a concentration of 400μg / ml from a stock of 5mg / ml (in TE buffer). This mixture is loaded into the appropriate cassette, inserted into the machine, and cells electroporated. Cells were then frozen to provide a single supply of transfected cells for all subsequent assays. On the day of the assays, cells were thawed in a 37 °C waterbath, and resuspended in DMEM + 10% FBS and counted. The cells are pelleted by centrifugation at 1000RPM for 5 minutes. The media is aspirated, and the remaining pellet is resuspended in 1X HBSS with 20mM HEPES and 1% DMSO to achieve 1.33e6cells / ml. This cell suspension is then dispensed at 3μl / well to the 1536 well plates (Greiner Bio One part 789072) at a density of 4,000 cells / well. Measurements of fluorescence intensity (λex=470 nm, λem=535nm) were made using a FLIPR (Molecular Devices FLIPR Tetra). A read of basal fluorescence values was made (5s) prior to addition of compounds or controls (30nl). In both ‘agonist’ and ‘antagonist mode’, the total assay volume was 6μl (1% DMSO). For the primary screen, each compound was tested at a single concentration in triplicate, and responses compared on a per plate basis by evaluating the percentage response of each compound versus the ‘high control’ (response to EC100 PZQ (10μM) for the agonistscreen, DMSO for the antagonist screen)) corrected for ‘low control’ (response to DMSO for the agonist screen, response to EC80 PZQ (500nM) in the presence of DMSO or compounds (nominally 5μM) for the antagonist screen). Ligand performance was categorized using an algorithm based on the activity of the entire dataset to define a ‘hit-cutoff’ parameter for both agonist-mode and antagonist-mode screening. Any compound with greater percent activation than this cutoff was assigned as ‘active’ prior to titration and counter-screening. Titration assays were executed using the same reagents, protocols and detection systems, done as 10- point concentration-response curves, performed in triplicate. Counter-screening was performed using untransfected HEK293 cells for comparison with results testing the same compounds effect on cells expressing Sm.TRPMPZQ, with ATP used as the positive control. For each compound, activity was plotted against compound concentration and data were fitted with a sigmoidal function. In order to be considered a hit at this stage a compound must ahieve a EC50<5μM for agonists and IC50 <5μM for antagonists. All compounds selected for titration were subjected to LC-MS analysis to confirm mass and sample purity. ChemAxon (https: / / www.chemaxon.com) academic licensing was provided for the use of Instant JChem (ver.15.10.12.0) to perform compound mining of the libraries utilized in this effort.

[0100] Example 3 Fluorescence assay and worm contraction experimental methods. (FIGs 3A-3B)

[0101] Ca2+reporter assays. Assays were performed using a Fluorescence Imaging Plate Reader (FLIPRTETRA, Molecular Devices). In brief, HEK293 cells were seeded (20,000 cells / well) in a black-walled clear-bottomed poly-d-lysine coated 384-well plate (Greiner Bio- One, Germany) in DMEM growth media (supplemented with 10% dialyzed FBS). After 24hrs, the growth medium was removed, and cells were loaded with a fluorescent Ca2+indicator (Fluo-4 NW, Invitrogen) by incubation (5μL per well, 1hr at 37°C) in Hank’s balanced salt solution (HBSS, 1.26mM CaCl2, 0.49mM MgCl2, 0.41mM MgSO4, 5.33mM KCl, 0.44mM KH2PO4, 4.17mM NaHCO3, 137.9mM NaCl, 0.34mM Na2HPO4, 5.55mM D-glucose) supplemented with probenecid (2.5mM) and HEPES (20mM). Drug dilutions were prepared in assay buffer, without probenecid and dye, in F-form 384-well plates (Greiner Bio-one, Germany). After loading, the Ca2+assay was performed at room temperature. Basal fluorescence was monitored for 20s, then 25μl of each drug added, and the signal (raw fluorescence units) was monitored over an additional 250s. For quantitative analyses, peak fluorescence increases in each well was normalized to maximum-fold increase over baseline. Except where indicated, all data are presented as mean±SEM.

[0102] Worm contraction assays. Adult schistosome worms (S. mansoni) were washed in DMEM high glucose medium supplemented with HEPES (25mM), pyruvate and 5% heat inactivated FBS (Gibco) and penicillin-streptomycin (100 units / mL) and incubated overnight (37°C / 5% CO2) in vented petri dishes (100x25mm). For movement analyses, assays were performed using 3 male worms per well in a six well dish. Video recordings were captured using a Zeiss Discovery v20 stereomicroscope with a QiCAM 12-bit cooled color CCD camera controlled by Image-Pro imaging software (v.11). Recordings (60 seconds) of worm motility (1 image every 4 secs), before and after addition of various drugs were analyzed by scoring motion in a maximal intensity overlay.

[0103] Similar Ca2+reporter assays were performed for ANT-126. (FIG 4A and 4B) and ANT-114. (FIG 5A and 5B),

[0104] In addition, ANT-114 and ANT-126 TRPMPZQ blockers elicit defects in embryonic development and viability, as demonstrated by manual counting of egg number and scoring development using light microscopy (FIGs 6A-6C).

[0105] Activities of representative compounds as described herein are shown in Table 1.Table 1. Activities of representative compounds

[0106] For reasons of completeness, various aspects and embodiments of the presentdisclosure are set out in the following numbered clauses:

[0107] Clause 1. A compound, which is, , or a derivative or pharmaceutically acceptable salt thereof.

[00108] Clause 2. The compound of clause 1, wherein the compound is, or a derivative or pharmaceutically acceptable salt thereof.

[00109] Clause 3. A composition comprising the compound of any one of clauses1-2, or a derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[00110] Clause 4. A method of treating a parasitic infection in a subject in needthereof, the method comprises administering to the subject an effective amount of the compound of any one of clauses 1-2, or a derivative or a pharmaceutically acceptable salt thereof.

[00111] Clause 5. The method of clause 4, wherein the parasitic infection is aparasitic flatworm infection.

[0112] Clause 6. The method of clause 5, wherein the parasitic flatworm is trematode, cestode, monogenean, schistosome, tapeworm, or a combination thereof.

[0113] Clause 7. A method of treating schistosomiasis in a subject in need thereof, the method comprises administering to the subject an effective amount of the compound of any one of clauses 1-2, or a derivative or a pharmaceutically acceptable salt thereof.

[0114] Clause 8. The method of any one of clauses 4-7, wherein the method comprises administering to the subject an agent selected from PZQ and MCLZ, and an effective amount of the compound of any one of clauses 1-2, or a derivative or a pharmaceutically acceptable salt thereof.

[0115] Clause 9. A method of activating a transient receptor potential channel of a parasitic flatworm, the method comprising introducing to the parasitic flatworm an effective amount of the compound of any one of clauses 1-2, or a derivative or a salt thereof.

[0116] Clause 10. The method of clause 9, wherein the transient receptor potentialchannel comprisesTRPMPZQ.

[0117] Clause 11. The method of clause 9, wherein the transient receptor potentialchannel comprisesTRPMMCLZ.

[0118] Clause 12. A method of causing paralysis or inhibiting growth, reproduction, or egg laying of a parasitic flatworm, the method comprising introducing to the parasitic flatworm an effective amount of the compound of any one of clauses 1-2, or a derivative or a salt thereof.

[0119] Clause 13. The method of any one of clauses 9-12, wherein the parasitic flatworm is in an infected subject.

[0120] Clause 14. The method of any one of clauses 4-8 and 13, wherein the subject is a human.

Claims

CLAIMS What is claimed is:, , or a derivative or pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound isor a derivative or pharmaceutically acceptable salt thereof.

3. A composition comprising the compound of any one of claims 1-2, or a derivativeor a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. A method of treating a parasitic infection in a subject in need thereof, the methodcomprises administering to the subject an effective amount of the compound of any one of claims 1-2, or a derivative or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein the parasitic infection is a parasitic flatworminfection.

6. The method of claim 5, wherein the parasitic flatworm is trematode, cestode, monogenean, schistosome, tapeworm, or a combination thereof.

7. A method of treating schistosomiasis in a subject in need thereof, the method comprises administering to the subject an effective amount of the compound of any one of claims 1-2, or a derivative or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 4-7, wherein the method further comprises administering to the subject an agent selected from PZQ and MCLZ.

9. A method of activating a transient receptor potential channel of a parasitic flatworm, the method comprising introducing to the parasitic flatworm an effective amount of the compound of any one of claims 1-2, or a derivative or a salt thereof.10.The method of claim 9, wherein the transient receptor potential channel comprisesTRPMPZQ.

11. The method of claim 9, wherein the transient receptor potential channel comprisesTRPMMCLZ.

12. A method of causing paralysis or inhibiting growth, reproduction, or egg laying of a parasitic flatworm, the method comprising introducing to the parasitic flatworm an effective amount of the compound of any one of claims 1-2, or a derivative or a salt thereof.

13. The method of any one of claims 9-12, wherein the parasitic flatworm is in an infected subject.

14. The method of any one of claims 4-8 and 13, wherein the subject is a human.

Images