Abstract:
Compositions and methods for repelling arthropods. The compositions include a carrier and an arthropod repelling compound, which can be a compound discovered by a novel and complex cheminformatic process to demonstrate repellency behavior across a broad spectrum of arthropods. The compound can be a thiane compound, a pyrrolidone compound, a cyclohexadiene compound, a cyclohexenone compound, a cyclohexene compound, a furanone compound, a pyran compound, a tetrahydropyran compound, a thiazolidine compound, a thiazoline compound, a dihydrothiophene compound, a dithiolane compound, a dithiane compound, an epoxide compound, an oxathiane compound, a cyclopentene compound, a cyclohexane compound, a quinoline compound, an oxazoline compound, a tetrahydropyridine compound, and an imidazolidinone compound, or a combination thereof.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of application Ser. No. 15/073,698, filed on Mar. 18, 2016, which claims the benefit of Provisional Patent Application No. 62/134,882, filed on Mar. 18, 2015, all of which are incorporated by reference herein. 
     
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0002]    This invention was made with Government support under Grant No. 1R01DC014092-01A1 from the National Institutes of Health. The Government has certain rights in this invention. 
     
    
     BACKGROUND 
     Field of the Invention 
       [0003]    The invention relates to chemicals and methods for repelling arthropods. 
       Related Art 
       [0004]    Mosquitoes and other blood-feeding insects transmit deadly diseases such as malaria, dengue, lymphatic filariasis, West Nile fever, Yellow fever, sleeping sickness and Leishmaniasis to hundreds of millions of people, causing untold suffering and more than a million deaths every year. In addition, these diseases cause significant morbidity throughout the globe and the daily adjusted life in years (DALY) caused by malaria alone is &gt;25M, implying that new control approaches may have substantial impact in preventing sicknesses transmitted by mosquito bites. Current methods such as insecticide treated bednets provide the main line of protection, however effective insect behavior control methods could provide an additional line of defense for more individuals in an abode, perhaps even protecting outdoors, and diminish concerns associated with heavy insecticide use such as health and emergence of resistance. 
         [0005]    N,N-Diethyl-m-toluamide (DEET) has remained the primary insect repellent used for more than 60 years in the developed world but has very little use in disease control in Africa and Asia due to a high relative cost and the inconvenience of requiring continuous application to skin at high concentrations (30-100%). DEET has been shown to inhibit mammalian cation channels and human acetylcholinesterase, which is also a target of carbamate insecticides [1] that are commonly used in disease-endemic areas, increasing concerns about prolonged use. Several instances of increased resistance to DEET have also been reported in flies [2],  Anopheles albimanus [ 3], and  Aedes aegypti [ 4]. Moreover, DEET is a solvent and melts several forms of plastics, synthetic fabrics, painted and varnished surfaces [5]. 
       SUMMARY 
       [0006]    In one aspect, a composition for repelling an arthropod is provided. The arthropod-repelling composition comprises a carrier, and one or any combination of arthropod repellant compounds that are structurally unrelated and discovered by novel cheminformatic algorithms that were created to understand the biochemical, spacial charge density and many other biochemical and physical factors aside from straight chemical structure for imparting the activity to known repellents such as DEET, picaridin, para-menthane-diol, geraniol, citronella, butyl anthranilate, ethyl anthranilate, and ethyl pyruvate, and then using that novel information to identify whole classes of structurally novel molecules that can be shown to demonstrate repellant activity surprisingly across a unexpectedly broad range of arthropods and not just a few species of mosquitos. 
         [0007]    In some embodiments, the arthropod-repelling composition comprises a carrier, and one or any combination of arthropod repellant compounds selected from the group consisting of a thiane compound, a pyrrolidone compound, a cyclohexadiene compound, a cyclohexenone compound, a cyclohexene compound, a furanone compound, a pyran compound, a tetrahydropyran compound, a thiazolidine compound, a thiazoline compound, a dihydrothiophene compound, a dithiolane compound, a dithiane compound, an epoxide compound, an oxathiane compound, a cyclopentene compound, a cyclohexane compound, a quinoline compound, an oxazoline compound, a tetrahydropyridine compound, and an imidazolidinone compound. 
         [0008]    In some embodiments, the arthropod repellant compounds are selected from the group of compounds listed in  FIG. 1 , or a combination thereof. Thus, the composition can comprise one or any combination of arthropod repellant compounds selected from: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    or a pharmaceutically acceptable or environmentally acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each independently selected from the group consisting of H, O, alkyl, alkenyl, aryl, arylalkyl, alkoxy, an aldehyde group, benzoyl, formyl, cycloalkyl, an ester group, halo, hydroxyl, alkoxycycloalkylalkyl, cycloalkenyl, and cycloakenylalky. In certain embodiments, the alkyl is a C 1 -C 12  alkyl, the alkenyl is a C 2 -C 12  alkenyl, the alkoxy is a C 1 -C 12  alkoxy, the aldehyde group is a C 1 -C 12  aldehyde group, the ester group a C 1 -C 12  ester group, or any combination thereof. 
         [0009]    In some embodiments, the arthropod-repelling composition comprises particular embodiments of the compounds listed in  FIG. 1 . Thus, arthropod repellant compounds can be selected from the group consisting of 4-methylcyclohexene, ethyl cyclopentenolone, 3,4-Dihydro-2H-pyran, and lemon hexadiene. 
         [0010]    In some embodiments, the arthropod-repelling composition comprises particular embodiments of the compounds listed in  FIG. 1 . Thus, the arthropod repellant compound can be selected from the following compounds, or a pharmaceutically acceptable or environmentally acceptable salt thereof: 
         [0011]    a) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 3 , R 4 , and R 5  are each H; R 1  is H, alkyl or alkenyl; and R 2  is H or O. In some embodiments, the alkyl is a C 1 - C 6  alkyl, and the alkenyl is a C 1 -C 6  alkenyl. 
         [0012]    b) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1 , R 2  and R 3  are each independently H, alkyl, alkenyl, or alkoxy. In some embodiments, the alkyl is a C 1 -C 6  alkyl, the alkenyl is a C 1 -C 6  alkenyl, and the alkoxy is a C 1 -C 6  alcohol. 
         [0013]    c) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  is H, alkyl, or hydroxyl; R 2  is H or hydroxyl; R 3 , R 5 , and R 6  are each H; and R 4  is H, alkyl, or alkoxy. In some embodiments, R 1  is a C 1 -C 6  alkyl, R 4  is a C 1 -C 6  alkyl or a C 1 -C 6  alkoxy, or any combination thereof. 
         [0014]    d) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1 , R 4 , R 5  and R 6  are each H; and R 2  and R 3  are each independently H or alkyl. In some embodiments, the alkyl is a C 1 -C 6  alkyl. 
         [0015]    e) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1 , R 3 , R 4 , R 5  and R 6  are each H; and R 2  is H or alkyl. In some embodiments, the alkyl is a C 1 -C 6  alkyl. 
         [0016]    f) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1 , R 2 , and R 4  are each independently H, hydroxyl, or alkyl; and R 3  is H or O. In some embodiments, the alkyl is a C 1 -C 3  alkyl. 
         [0017]    g) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 2  and R 3  are each H; and R 1  and R 4  are each independently H, O or alkyl. In some embodiments, the alkyl is a C 1 -C 6  alkyl. 
         [0018]    h) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 3  and R 4  are each H; R 1  is SH, hydroxyl, alkyl, alkoxy or an ester group; and R 2  is H, O or OH. In some embodiments, the alkyl is a C 1 -C 6  alkyl, the alkoxy is a C 1 -C 4  alkyl, and the ester group is a C 1 -C 6  ester group. 
         [0019]    i) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 3  is H; R 1 , R 4  and R 5  are each independently H or CH 3 ; and R 2  is H or alkyl. 
         [0020]    j) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1 , R 3  and R 5  are H; and R 2  and R 4  are each independently a branched or unbranched alkyl. In some embodiments, the branched or unbranched alkyls is C 2 -C 6  branched or unbranched alkyl. 
         [0021]    k) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 2  and R 3  are each H; and R 1  and R 4  are each independently alkyl or an aldehyde group. In some embodiments, the aldehyde group is a C 2 -C 6  aldehyde group. 
         [0022]    l) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1  and R 2  are each independently H, alkyl, or an aldehyde group. In some embodiments, the aldehyde group is a C 2 -C 6  aldehyde group. 
         [0023]    m) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 3  and R 4  are each H; and R 1  and R 2  are each independently H, alkyl, or an aldehyde group. In some embodiments, the aldehyde group is a C 2 -C 6  aldehyde group. 
         [0024]    n) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are each independently H, O, alkyl, alkenyl, aryl, arylalkyl, alkoxy, an aldehyde group, benzoyl, formyl, cycloalkyl, an ester group, halo, hydroxyl, alkoxycycloalkylalkyl, cycloalkenyl, or cycloakenylalky; or 
         [0025]    o) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 3  is H, alkyl, or an aldehyde group, and R 1  and R 2  are each H. In some embodiments, R 3  is a C 2 -C 6  aldehyde group. 
         [0026]    In more particular embodiments of the arthropod-repelling composition, the arthropod repellant compounds can be any compound listed in Table 1 of  FIG. 3 . 
         [0027]    In some embodiments, the arthropod-repelling composition comprises one arthropod repellant compound, two arthropod repellant compounds, or more than two arthropod repellant compounds. Thus, in some embodiments, the composition can comprise one, two, or more than two, arthropod repellant compounds. 
         [0028]    In some embodiments, the arthropod repellant compounds can be selected from the group consisting of 1,2-epoxyhexane, 1-methyl-1,4-cyclohexadiene, 1-ethyl-2-pyrrolidone, 2-isobutyl-4-methyl-1,3-di oxolane, 2-methyl tetrahydrofuran, 3,4-Dihydro-2H-pyran, 4-hydroxy-2,5-dimethyl-3(2H)-furanone, 4-methyl cyclohexene, dihydropyran, ethyl cyclopentenolone, isopropyl quinoline, methyl 2-(4-tert-butylphenyl)acetate, and nerol oxide, or a pharmaceutically acceptable or environmentally acceptable salt thereof. 
         [0029]    In some embodiments, the arthropod-repellant compounds can be selected from the group consisting of 2-butyl-4,6-dimethyl-5,6-dihydro-2H-pyran, 2-methyl-4-methylidene-6-phenyloxane, 1-methylpyrrolidin-2-one, 10-undecen-1-al, 3-ethyl-2-hydroxycyclopent-2-en-1-one, 1-methyl-1,3-cyclohexadiene, alpha cedrene epoxies, floral methanol, 4,5-epoxy-(E)-2-decenal, oxyquinoline, isobutyl quinolone, 6-methoxyquinoline, 6-methyl quinolone, quinmerac, 4-amino-5-(3-(isopropyl amino)-2,2-dimethyl-3-oxopropoxy)-2-methyl quinoline-3-carboxylic acid, 1-methyl cyclohexene, 3-methyl cyclohexene, mixed cyclohexene, furanone acetate, and 2-methylquinoline, or a pharmaceutically acceptable or environmentally acceptable salt thereof. 
         [0030]    In embodiments of any of the arthropod-repelling compositions: a) the arthropod can be from a broad range of members of arthropods such as insect, tick, mite, spider, centipede or scorpion; b) the arthropod can be a blood-feeding arthropod, which can be a mosquito, gadfly, louse, bedbug, sandfly, blackfly, tsetse fly, midge, mite, or flea; c) the arthropod can be a household or agricultural pest; or d) any combination of a)-c). 
         [0031]    In another aspect, a method of repelling an arthropod is provided. The method includes exposing an arthropod to any of the above described arthropod-repelling compositions in an amount effective to repel the arthropod. In some embodiments, when the compositions and arthropod repellant compounds are applied to living material (such as skin, fruit, plants, and the like), the arthropod repellant compound or compounds can range in concentration between about 0.5% to about 50% vol/vol of the formulation, or about 0.5% to about 50% wt/vol of the formulation, depending on whether the formulation is liquid-based or lotion-based. In certain embodiments, the concentration can be about 0.5% to about 15% vol/vol of the formulation or about 0.5% to about 15% wt/vol of the formulation. When applied on non-living material (such as fabric, net, surfaces, and the like), the concentration of the repellant compound can range from about 1% to about 100% vol/vol of the formulation, or about 1% to about 100% wt/vol of the formulation, depending on the formulation. In certain embodiments, the concentration can be about 0.5% to 15% vol/vol of the formulation or about 0.5% to 15% wt/vol of the formulation. 
         [0032]    In some embodiments of the method: a) the arthropod is exposed to the arthropod-repelling composition by applying the composition to a subject, to an article worn by the subject, to an article associated with the subject, to an agricultural product, to a storage container, shipping container or transport container for an agricultural product, to a structure or part of a structure from which the arthropod is to be repelled, or to an area from which the arthropod is to be repelled; b) the subject can be an animal or a plant; c) the subject can be a human; d) the arthropod can be an insect, tick, mite, spider, centipede or scorpion; e) the arthropod can be a blood-feeding arthropod, which can be a mosquito, gadfly, louse, bedbug, sandfly, blackfly, tsetse fly, midge, mite, or flea; f) the arthropod can be a household or agricultural pest, or any combination thereof; or g) any combination of a)-f). 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0033]    For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which: 
           [0034]      FIGS. 1A-1C  are respective parts of a panel of chemical compounds for repelling an arthropod, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  are each independently selected from the group consisting of H, O, alkyl, alkenyl, aryl, arylalkyl, alkoxy, an aldehyde group, benzoyl, formyl, cycloalkyl, an ester group, halo, hydroxyl, alkoxycycloalkylalkyl, cycloalkenyl, and cycloakenylalky. 
           [0035]      FIG. 2  is a panel of representative photographs of modified arm-in-cage assay testing of 4-MP (4%) with  Aedes aegypti  females. (2a) Control and 4-MP treated gloves; (2b) Mean numbers of landings within minutes 2-5 of the assay. N=4 trials, ˜40 mosquitoes/trial. 
           [0036]      FIGS. 3A-3D  are respective parts of a Table 1 of predicted novel repellents grouped according to similar chemical functional groups. 
       
    
    
     DETAILED DESCRIPTION 
       [0037]    In one aspect, compositions for repelling arthropods are provided that comprise one or more arthropod repellant compounds. In some embodiments, the composition also comprises one or more carriers, which can be dermatologically acceptable or environmentally acceptable carriers, or a combination thereof. 
         [0038]    The term “alkyl” refers to a branched or unbranched saturated hydrocarbon group such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, and decyl. The term “cycloalkyl” refers to a saturated cyclic hydrocarbon group such as, but not limited to, cyclopentyl and cyclohexyl. In some embodiments, an alkyl group can be a C 1-12  alkyl group. 
         [0039]    The term “alkenyl” refers to a branched or unbranched hydrocarbon group containing at least one double bond, such as, but not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, and decenyl. The term “cycloalkenyl” refers to a cyclic hydrocarbon group containing at least one double bond such as, but not limited to, cyclopententyl and cyclohexenyl. In some embodiments, an alkenyl group can be a C 1-12  alkenyl group. 
         [0040]    The term “aryl” refers to an aromatic hydrocarbon group containing a single aromatic ring or multiple aromatic rings that are fused together, linked covalently, or linked to a common group such as a methylene or ethylene moiety. In some embodiments, aryl groups contain one aromatic ring or two fused or linked aromatic rings such as, but not limited to, phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, and benzophenone. In particular embodiments, an aryl group including any substituents can have from 4 to 50 carbon atoms, 4 to 40 carbon atoms, 4 to 30 carbon atoms, 4 to 20 carbon atoms, or 4 to 10 carbon atoms, or more particularly, can have from 6 to 50 carbon atoms, 6 to 40 carbon atoms, 6 to 30 carbon atoms, 6 to 20 carbon atoms or 6 to 10 carbon atoms. 
         [0041]    The term “arylalkyl” refers to an alkyl group with an aryl substituent. 
         [0042]    The terms “halo” and “halogen” are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent. The terms “haloalkyl,” “haloalkenyl” or “haloalkynyl” (or “halogenated alkyl,” “halogenated alkenyl,” or “halogenated alkynyl”) refers to an alkyl, alkenyl or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom. 
         [0043]    The term “functional group” refers to any reactive substituent. Examples of functional groups include, but are not limited to, hydroxy, cyano, halo, nitro, ester, ether, amino and carboxy groups. 
         [0044]    The term “alkoxy” refers to an alkyl group bound through a single, terminal ether linkage; that is, an “alkoxy” group may be represented as —O-alkyl where alkyl is as described above. 
         [0045]    The term “alkoxycycloalkylalkyl” refers to a cycloalkylalkyl group where at least one of the hydrogen atoms of the cycloalkyl group is replaced by an alkoxy group. Examples of alkoxycycloalkylalkyl groups include, but not limited to, cyclopropylmethoxymethyl and 4-methoxycyclohexylmethyl. 
         [0046]    The term “cycloalkenylalkyl” means an alkyl as described above which is substituted by a cycloalkenyl as described above. Examples of cycloalkenylalkyl groups include, but are not limited to, 2-cyclohexen-1-ylmethyl, 1-cyclopenten-1-ylmethyl, 2-(1-cyclohexen-1-yl)ethyl, 3-(1-cyclopenten-1-yl)propyl, 1-(1-cyclohexen-1-ylmethyl)pentyl, and 1-(1-cyclopenten-1-yl)hexyl. 
         [0047]    In some embodiments, the arthropod-repelling composition is used against harmful insects, including those that are directly or indirectly detrimental to humans, for example blood-feeding insects, parasitic insects, pathogenic insects, stinging insects, poisonous insects and generally disagreeable insects. Blood-feeding insects include mosquitoes, gadfly, lice, bedbugs and so on. Parasitic insects include fleas and lice, and pathogenic insects include flies, mosquitoes, croton bugs and lice. Stinging insects include bees, reduviidae species, and poisonous insects include ghungbannalkye, cerambycidae species and Spanish fly. Disagreeable insects include Chironominae, gagiworm and stinkbug. 
         [0048]    In some embodiments, the arthropod-repelling compositions can be used against arthropods such as ticks, spiders, centipedes and scorpions. 
         [0049]    The arthropod can be an arthropod plant pest, an arthropod crop pest, or an arthropod household pest. Examples of plant and crop pests include, but are not limited to, Spotted wing Drosophila, Asian citrus psyllid, Asian longhorned beetle, European grapevine moth, European gypsy moth, light brown apple moth, Mediterranean fruit fly, Mexican fruit fly, oriental fruit fly, khapra beetle, boll weevil, and white fly, soft scales; examples of household pests include, but are not limited to, ants, cockroaches, and termites. 
         [0050]    Thus, the arthropod-repelling compositions can be used against arthropods that carry diseases responsible for health or economic loss in humans, pets, crops or livestock. 
         [0051]    In some embodiments, the arthropod-repelling composition can contain two or more arthropod repellent compounds. In some embodiments, a repellent composition can be used against two or more different arthropods. 
         [0052]    In some embodiments, a subject to be treated with a repellant compound can be a human or animal subject (e.g., dogs, cats, horses, cattle). Animal subjects include pets, livestock, and poultry. Subjects can be directly or indirectly treated, such as by applying the active compound to the skin of the subject, or by applying the active compound to an article worn by or otherwise protecting the subject. 
         [0053]    In other embodiments, the subject is a plant, which can include ornamentals and agricultural crop plants. The plants can be treated in the field, in greenhouses, in storage, and in transit. Repellant compounds can be applied to the plant, or to edible or to inedible plant products. 
         [0054]    Formulations for application to a human or animal subject can be prepared with the use of customary auxiliary skin-compatible and pharmacologically unobjectionable substances and additives. Such additives may be, for example, emulgators, solvents, thickeners, fillers, stabilizers, preservation agents or antioxidants. Moreover, surfactants such as polyoxy ethylene sorbitan acid and esters or salts of bile acid may also be used to improve bio-availability. Dispersion agents such as polyacrylate, lignin, tannates or derivatives thereof may be added to enable insoluble substances to be incorporated. Hydrogels can be produced with the aid of hydrophilic organic solvents such as glycerine, glycol or aliphatic alcohols, for example. Furthermore, active agents can be used in the form of active substance-containing microsomes or liposomes or as liposomally or microsomally capsuled active agents, which can be in parallel with other auxiliary substances and further active agents. 
         [0055]    Formulations and compositions may be processed to obtain practically all forms of preparations suited for application to the human or animal skin, such as tinctures, hydrogels, oil-in-water emulsions, water-in-oil emulsions, suspensions, solutions, lotions, pastes, creams, gels, ointments, powders, sprays, and the like. Delivery devices such as patches, clothing, bracelets, hats, and other articles in contact with a subjects skin and containing one or more arthropod repellant compounds are also contemplated. 
         [0056]    Exemplary cosmetically acceptable and/or dermatologically acceptable carriers that can be included in a formulation or composition include such substances as aqueous or non-aqueous solutions, suspensions, and emulsions. In the case of pastes, creams or gels, examples of the carriers include, but are not limited to, animal oil, vegetable oil, wax, paraffin, starch, tragacanth, cellulose derivative, polyethylene glycol, silicon, bentonite, silica, talc, and zinc oxide. In the case of powders or sprays, examples of the carriers include, but are not limited to, lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide power. For sprays, a propellant such as chlorofluorohydrocarbon, propane/butane or dimethylether can also be included. In the case of solutions or emulsions, examples of the carriers include, but are not limited to, solvents, solubilizers and emulsifiers such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylglycol oil, glycerol fatty acid ester, polyethylene glycol and sorbitan fatty acid ester. In the case of suspensions, examples of the carriers include, but are not limited to, liquid diluents such as water, ethanol and propylene glycol, suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystalline cellulose, aluminum methahydroxide, bentonite, agar, and tragacanth. 
         [0057]    In some embodiments, the arthropod-repelling composition or compound can be applied to an article such as luggage, a bed frame, or the like. In other embodiments, the repellant composition or compound can be applied to a structure or part of a structure, such as a house, window frame, closet, tent, greenhouse, storage shed, or the like. In some embodiments, the repellant composition or compound can be applied to an area, such as a field, garden, yard, outdoor area, or the like. In some embodiments, the repellant composition or compound can be applied to a container such as a storage container, shipping container or transport container, or the like. In some embodiments, the repellant composition or compound can be applied to agricultural and food products such as fruits, vegetables, stored products, stored feed products, prepared foods and food products, prepared feed products, and the like. 
         [0058]    For application to articles, structures, areas, agricultural produces, and the like, that are environmentally acceptable formulations and repellant composition can be prepared in any known manner, for instance by extending the compositions with conventional pesticide dispersible liquid diluent carrier and/or dispersible solid carriers, optionally with the use of carrier vehicle assistants, e.g. conventional pesticide surface-active agents, including emulsifying agents and/or dispersing agents, whereby, for example, in the case where water is used as diluent, organic solvents may be added as auxiliary solvents. Suitable liquid diluents or carriers include, but are not limited to, water, petroleum distillates, or other liquid carrier with or without surface active agents. The choice of dispersing and emulsifying agents and the amount employed is dictated by the nature of the composition and the ability of the agent to facilitate the dispersion of the compositions. Non-ionic, anionic, amphoteric, or cationic dispersing and emulsifying agents may be employed, for example, but not limited to, the condensation products of alkylene oxides with phenol and organic acids, alkyl aryl sulfonates, complex ether alcohols, quaternary ammonium compounds, and the like. 
         [0059]    Examples of carriers include, but are not limited to, an inert or fluid material, which may be inorganic or organic and of synthetic or natural origin, with which an active compound is mixed or formulated to facilitate its application to the skin or hair or other object to be treated, or its storage, transport and/or handling. In general, any of the materials customarily employed in formulating pesticides, herbicides, or fuigicides, are suitable. Embodiments of the compositions and repellant compounds may be employed alone or in the form of mixtures with such solid and/or liquid dispersible carrier vehicles and/or other known compatible active agents such as other pesticides, or pediculicides, acaricides, nematicides, fungicides, bactericides, rodenticides, herbicides, fertilizers, growth-regulating agents, etc., if desired, or in the form of particular dosage preparations for specific application made therefrom, such as solutions, emulsions, suspensions, powders, pastes, and granules which are thus ready for use. Depending on the expected use, embodiments of the compositions can be formulated as gases, solutions, emulsions, suspensions, emulsifiable concentrates, spray powders, pastes, soluble powders, dusting agents, granules, foams, pastes, tablets, aerosols, natural and synthetic materials impregnated with active compounds, microcapsules. Also, formulation used with burning equipment, such as fumigating cartridges, fumigating cans and fumigating coils, as well as ULV cold mist and warn mist formulations, are contemplated. 
         [0060]    In some embodiments, formulations and arthropod-repelling compositions can be applied to a subject&#39;s skin, or can be applied to garments, belts, collars, or other articles worn by the subject from whom insects or other arthropods are to be repelled. In some embodiments, a formulation or repellant composition can be applied to netting or screening that protects a subject, particularly a sleeping subject. In some embodiments, a formulation o repellant composition can be applied to non-human/non-animal subjects from which arthropods are to be repelled, such as plants. Application to a subject can be carried out by spraying, dusting, sprinkling, pouring, dipping, and the like. In some embodiments, a repellant composition or formulation can be applied to an area of pest infestation or an area susceptible to infestation, such as, but not limited to, a body of water, a container, a barn, a carpet, or pet bedding. 
         [0061]    The utility of this novel cheminformatic approach is that the resulting algorithms can be used to identify novel and effective repellents otherwise not known or anticipated to those skilled in the art which chemicals have a variety of different physicochemical properties and safety-to-humans/pets/plants potentially leading to the development of close-to-contact repellents for topical application as well as farther-from-source ones for short range repellency. The vapor pressures of such compounds are predicted to have a large range, opening the possibility for use in different formulations such as body lotions, skin creams, washing detergents, perfumes, on clothes, bednets, house entryways, backyards, etc. 
         [0062]    Since the processes that appear to be impacted by these novel repellants appear to be conserved across fly and mosquito species, this new generation of repellents may also be used tackle disease transmission by other disease vectors and plant pests that cause severe morbidity, mortality, and economical losses. Additionally, since these new repellents are structurally different from DEET and other current commercial repellants they may be effective against DEET-resistant strains. 
         [0063]    The present invention may be better understood by referring to the accompanying examples, which are intended for illustration purposes only and should not in any sense be construed as limiting the scope of the invention. 
       EXAMPLE 1 
       [0064]    The first major limitation to finding effective DEET substitutes was that the molecular targets through which it causes repellence in adult mosquitoes were unknown. Past studies had put forward competing models about mechanisms of DEET action, but demonstration of a causal relationship to repellency was lacking [4, 6-11]. The second major limitation in developing improved repellents is the cost of the screening and development process to find new repellants based on classical screening of existing compounds in trials with mosquito&#39;s and proxies for their targets. This is expensive. It has been suggested that &gt;$30M and several years may be required for identification and subsequent human-safety analyses of new repellent chemistries [15]. In a novel breakthrough the inventors developed a powerful cheminformatics descriptor-based prediction algorithm that allowed for digitally screening &gt;400,000 compounds (including 3000 natural compounds) based on the previously described cheminformatics platform, and have identified &gt;100 natural compounds as candidate repellents that are previously unknown to have insect repellant activity. These chemicals do not dissolve plastic, are affordable, have pleasant odors, and several are already shown as safe for human use. They simply were never anticipated to be broadly active arthropod repellants. 
         [0065]    The identification of these compounds started with understanding the biochemical, spacial charge density and other biochemical and physical factors aside from straight chemical structure for imparting the activity with existing DEET-like chemical structure and are therefore studying just DEET-like properties there were limits in finding completely novel classes of repellents that are not structurally related to DEET. Additional properties were then added. Another class of repellent identified previously has been 4methyl piperidine, and because it is more volatile than DEET, proof-of-principle experiments were performed to test whether it can act as a non-contact repellent that does not require being in close proximity to be effective, such as DEET. Olfactory avoidance to DEET is active over a short range (˜1 cm) and mosquitoes are not repelled beyond the immediate vicinity. Therefore, a modified arm-in-cage assay was developed where a low concentration of 4-MP can be applied to filter paper pieces adjoining the netted landing window of the glove ( FIG. 2 a   ). It was found that 3% 4-methyl piperidine can effectively repel mosquitoes from the skin-exposed net window ( FIG. 2 b   ). These experiments indicate that identification of additional compounds from the inventors&#39; novel algorithms that have biochemical, metabolic and other properties that allow them to interact with the arthropod receptors controlling repellency behavior in a broad range of arthropods is possible but that the inventors could also ‘instruct’ their novel algorithms to include a search for novel compounds that also have practical physical parameters such as varying levels of volatility that will provide valuable product performance characteristics as there is a great need to find novel repellants that could protect from a distance. 
       EXAMPLE 2 
       [0066]    A list of compounds for inclusion in embodiments of the invention are shown in Table 1 of  FIG. 3 . These compounds are predicted by novel algorithms of the inventors using the aforementioned parameters and are expected to have arthropod repellent activity. The compounds were identified by a cheminformatics prediction method, as follows: 
         [0067]    In order to identify novel chemicals with repellent properties a chemical informatics method was utilized for identification of select physicochemical descriptors that are correlated with chemical structure showing a specific activity. Using Sequential Forward Selection and a set of Dragon physicochemical descriptors was identified that correlated with repellency values of one set of known repellents. Next, these descriptors were utilized to rank computational distance from 4-methylpiperidine. It was anticipated that this unusual approach would give several classes of chemicals that would be distinct in chemical functional groups and structure with repellent properties. 
         [0068]    A set of training compounds were utilized, including a non-repellent set of odors that were assigned protection efficacy to zero, and the repellents DEET, Picaridin, butyl anthranilate and ethyl anthranilate, were assigned the highest value since the assumption was made that these would have various properties important for repellence. A compound-by-compound repellency distance matrix was generated from the known repellency data of the training set. A separate compound-by-compound descriptor distance matrix was calculated using the 3,224 descriptor values calculated by the Dragon software package. A Sequential Forward Selection (SFS) approach was then used, where each of the 3224 descriptor were individually tested and selected if they were able to increase the correlation between descriptor values of compounds in training set and their repellency values. This process is continued until no further improvements in correlation occur. This resulted in a unique and novel descriptor set that is optimized for anticipating repellency in compounds heretofore unanticipated to impact repellent behaviour by people skilled in the art. This repellency-optimized descriptor set was utilized to rank computational distance from 4-methylpiperidine amongst compounds from a natural compound library of ˜12000 volatiles identified from the scientific literature as being present in food, cosmetic, fragrances, plant, animal or insect origin. A selection of compounds falling within the computed distance of 0-2.3 from 4-methyl piperidine (&lt;1% of all compounds) were identified and manually inspected for chemical functional groups that are distinct from known repellents like 4-methylpiperidine, DEET, Picaridin, butyl anthranilate and ethyl anthranilate and listed as predicted repellents as listed in Table 1. 
         [0069]    The distance from 4-methypiperidine is computed using the descriptors and represents the Euclidian distance. 
       EXAMPLE 3 
       [0070]    In order to test the repellency prediction rate of the computational approach to find structurally new functional groups of chemicals, ˜15 of these various classes of compounds in Table 1 were randomly selected. These chemicals were tested in behavioral assays to determine percentage success rate of the computational predictions. The three behavior assays and their results are described below and they measured repellency involved 2 species of insects:  Drosophila melanogaster  and  Aedes aegypti.  Overall the rate of success for significant repellency to either one of these species is indicated by a negative value for Preference Index (P.I.) 
         [0071]    T-maze assay was used to test selected compounds. 4-7 day old starved wild-type flies of  Drosophila melanogaster  (20 males plus 20 females/trial) were tested. Under a chemical hood, 10 ul of solvent and 10 ul of test chemical were applied onto filter paper placed in control tubes and test tubes. The flies were loaded into the elevator of a T-maze apparatus and lowered into position where they could make a choice between the solvent tube and the test chemical tube. After allowing flies to make choice for 1 minute in dark, the elevator was closed and number of flies in each tube was counted. Preference Index (P.I.)=(# flies in test arm−#flies in control arm)/(# flies in test arm+#flies in control arm). The results presented in Table 2 report the average Preference Index from 3 independent trials. It was demonstrated that 5 of the 6 compounds tested were repellent as shown in Table 2. 
         [0000]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                   Drosophila melanogaster  T-maze assay 
               
               
                 with compounds at 5% concentration 
               
             
          
           
               
                   
                 Compound 
                 P.I. 
                 S.E.M. 
               
               
                   
                   
               
             
          
           
               
                   
                 3.4-Dihydro-2H-pyran 
                 −0.88 
                 0.07 
               
               
                   
                 1-methyl-1,4-cyclohexadiene 
                 −0.76 
                 0.14 
               
               
                   
                 2-Isobutyl-4-methyl-1,3-dioxolane 
                 −0.3 
                 0.17 
               
               
                   
                 1,2-Epoxyhexane 
                 −0.2 
                 0.13 
               
               
                   
                 Isopropyl quinolone 
                 −0.17 
                 0.13 
               
               
                   
                 Propylene glycol acetone ketal 
                 −0.09 
                 0.14 
               
               
                   
                   
               
               
                   
                 Mean preference index (P.I) of  Drosophila melanogaster  to the tested compounds in the T-maze assay. 
               
               
                   
                 Negative preference index indicates repellency. 
               
               
                   
                 S.e.m. = standard error of mean. 
               
             
          
         
       
     
       EXAMPLE 4 
       [0072]    In a second type of assay, a  Drosophila melanogaster  2-choice trap assay as described previously 4,6  was used with minor modifications. Traps were made with two 1.5 ml microcentrifuge tubes (USA Scientific) and 200 microliter pipette tips (USA Scientific), each cap contained standard cornmeal medium. T-shape piece of filter paper (Whatman #1) was impregnated with 5 ul of acetone (control) or 5 microliters of 5% test odor, diluted in acetone. Traps were placed within a petri dish (100×15 mm, Fisher) containing 10 ml of 1% agarose to provide moisture. Ten wild-type  Drosophila melanogaster  flies 4-7 days old were used per trial, which lasted 48 hours by which time point nearly all flies in the assays had made a choice and were counted. Preference Index (P.I.)=(number of flies in treated trap-number in control trap)/(number of flies in treated+control traps). We demonstrate that 4 of 4 compounds tested were repellent as shown in Table 3. 
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                   Drosophila melanogaster  2-choice Trap 
               
               
                 assay with compounds at 5% concentration 
               
             
          
           
               
                   
                 Compound 
                 P.I. 
                 S.E.M. 
               
               
                   
                   
               
               
                   
                 1,2,3,4-Tetrahydroquinoline 
                 −0.74 
                 0.13 
               
               
                   
                 4-Hydroxy-2,5-Dimethyl-3(2H)-Furanone 
                 −0.24 
                 0.45 
               
               
                   
                 methyl 2-(4-tert-butylphenyl)acetate 
                 −0.14 
                 0.43 
               
               
                   
                 1-Ethyl-2-pyrrolidone 
                 −0.12 
                 0.44 
               
               
                   
                   
               
               
                   
                 Mean preference index (P.I) of  Drosophila melanogaster  to the tested compounds in the 2-choice trap assay. 
               
               
                   
                 Negative preference index indicates repellency. 
               
               
                   
                 S.e.m. = standard error of mean. 
               
             
          
         
       
     
       EXAMPLE 5 
       [0073]    In order to test the compounds in mosquitoes, a Two-choice heat assay in  Aedes aegypti  was performed. A pair of heat sources were prepared using 2 hand warmers fitted into a 100×15 mm petri dish base and covered with 15×15 cm polyester netting secured round the petri dish by a pair or 8 inch plastic cable ties (Gardner Bender, Milwaukee, Wis.) coupling. Excess netting material was trimmed off round the edges of the petri dish. The treatment chemical 500 μl was added at 3% concentration directly onto the netting and the two assembled dishes were placed inside a cage of 20 female  A. aegypti  mosquitoes. Total numbers of mosquito landings on the net covering of each dish were counted during the assay from video recordings of the 5 minute trial. The solvent and DEET positions were alternated between runs. The results are presented in Table 4. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                   Aedes aegypti  2-choice landing assay 
               
               
                 with compounds at 3% concentration 
               
             
          
           
               
                 Compound 
                 P.I. 
                 S.E.M. 
               
               
                   
               
             
          
           
               
                 
                   1,2,3,4-tetrahydroquinoline 
                 
                 −0.996494303 
                 0.002479 
               
               
                 4-methyl cyclohexene 
                 −0.82646711 
                 0.04096 
               
               
                 Ethyl cyclopentenolone 
                 −0.742280162 
                 0.056252 
               
               
                 Dihydropyran 
                 −0.281907175 
                 0.009002 
               
               
                 2-isobutyl-4-methyl-1,3-dioxalane 
                 −0.218927924 
                 0.002592 
               
               
                 2-methyl tetrahydrofuran 
                 −0.181488683 
                 0.062167 
               
               
                 1-Methyl-1,4-cyclohexadiene 
                 −0.158403379 
                 0.036229 
               
               
                 Nerol Oxide 
                 −0.035619389 
                 0.014402 
               
               
                   
               
               
                 Mean preference index (P.I) of female  Aedes aegypti  to the tested compounds in the 2-choice trap assay. 
               
               
                 Two heat sources at 37 C. are used as attractants. 
               
               
                 Negative preference index indicates repellency. 
               
               
                 S.e.m. = standard error of mean. 
               
             
          
         
       
     
       EXAMPLE 6 
       [0074]    In order to test the compounds in mosquitoes, a Two-choice heat assay in  Aedes aegypti  was performed. A pair of heat sources were prepared using 2 hand warmers fitted into a 100×15 mm petri dish base and covered with 15×15 cm polyester netting secured round the petri dish by a pair or 8 inch plastic cable ties (Gardner Bender, Milwaukee, Wis.) coupling. Excess netting material was trimmed off round the edges of the petri dish. The treatment chemical 500 μl was added at 3% concentration directly onto the netting and the two assembled dishes were placed inside a cage of 20 female  A. aegypti  mosquitoes. Total numbers of mosquito landings on the net covering of each dish were counted during the assay from video recordings of the 5 minute trial. The solvent and DEET positions were alternated between runs. The results are presented in Table 5. 
         [0000]    
       
         
               
             
               
               
               
             
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                   Aedes aegypti  1-choice landing assay 
               
               
                 with compounds at 3% concentration 
               
             
          
           
               
                   
                 Average % 
                   
               
               
                 Chemical 
                 Repellency 
                 S.E.M. 
               
               
                   
               
             
          
           
               
                 1,2,3,4-tetrahydroquinoline 
                 99.8240985 
                 0.175901 
               
               
                 Isopropyl Quinoline 
                 96.36376901 
                 1.700953 
               
               
                 4-methyl cyclohexene 
                 90.38873654 
                 3.476294 
               
               
                 Ethyl cyclopentenolone 
                 77.43655406 
                 15.41482 
               
               
                 2-isobutyl-4-methyl-1,3-dioxalane 
                 35.91990601 
                 0.493366 
               
               
                 2-methyl tetrahydrofuran 
                 29.77948258 
                 12.66656 
               
               
                 1-Methyl-1,4-cyclohexadiene 
                 27.01016447 
                 7.65119 
               
               
                 Nerol Oxide 
                 6.804131568 
                 3.799559 
               
               
                   
               
               
                 Average percentage repellency of female  Aedes aegypti  to the tested compounds in a 1-choice trap assay. 
               
               
                 One heat source at 37 C. is used as attractant. 
               
             
          
         
       
     
       REFERENCES 
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         [0079]    Ditzen, M., Pellegrino, M., and Vosshall, L. B. (2008). Insect odorant receptors are molecular targets of the insect repellent DEET. Science 319, 1838-1842. 
         [0080]    Gupta, R. K. a. B., A. K. (2007). Discovery and Design of New Arthropod/Insect Repellents by Computer-Aided Molecular Modeling. In Insect Repellents: principles, methods, and uses, M. Debboun, Frances, S. P., Strickman, D., ed. (Boca Raton: Taylor &amp; Francis Group), pp. 195-228. 
         [0081]    Kain, P., Boyle, S. M., Tharadra, S. K., Guda, T., Pham, C., Dahanukar, A., and Ray, A. (2013). Odour receptors and neurons for DEET and new insect repellents. Nature 502, 507-512. 
         [0082]    Klun, J. A., Strickman, D., Rowton, E., Williams, J., Kramer, M., Roberts, D., and Debboun, M. (2004). Comparative resistance of  Anopheles albimanus  and  Aedes aegypti  to N,N-diethyl-3-methylbenzamide (Deet) and 2-methylpiperidinyl-3-cyclohexen-1-carboxamide (AI3 -37220) in laboratory human-volunteer repellent assays. J Med Entomol 41, 418-422. 
         [0083]    Krajick, K. (2006). Medical entomology—Keeping the bugs at bay. Science 313, 36-38. 
         [0084]    Liu, C., Pitts, R. J., Bohbot, J. D., Jones, P. L., Wang, G., and Zwiebel, L. J. (2010). Distinct olfactory signaling mechanisms in the malaria vector mosquito  Anopheles gambiae.  PLoS Biol 8. 
         [0085]    Pellegrino, M., Steinbach, N., Stensmyr, M. C., Hansson, B. S., and Vosshall, L. B. (2011). A natural polymorphism alters odour and DEET sensitivity in an insect odorant receptor. Nature. 
         [0086]    Reeder, N. L., Ganz, P. J., Carlson, J. R., and Saunders, C. W. (2001). Isolation of a DEET-insensitive mutant of  Drosophila melanogaster  (Diptera: Drosophilidae). J Econ Entomol 94, 1584-1588. 
         [0087]    Stanczyk, N. M., Brookfield, J. F., Ignell, R., Logan, J. G., and Field, L. M. (2010). Behavioral insensitivity to DEET in  Aedes aegypti  is a genetically determined trait residing in changes in sensillum function. Proc Natl Acad Sci U S A 107, 8575-8580. 
         [0088]    Syed, Z., and Leal, W. S. (2008). Mosquitoes smell and avoid the insect repellent DEET. P Natl Acad Sci USA 105, 13598-13603. 
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         [0091]    Xia, Y., Wang, G., Buscariollo, D., Pitts, R. J., Wenger, H., and Zwiebel, L. J. (2008). The molecular and cellular basis of olfactory-driven behavior in  Anopheles gambiae  larvae. Proc Natl Acad Sci U S A 105, 6433-6438. 
         [0092]    Although the present invention has been described in connection with the preferred embodiments, it is to be understood that modifications and variations may be utilized without departing from the principles and scope of the invention, as those skilled in the art will readily understand. Accordingly, such modifications may be practiced within the scope of the invention and the following claims.