WO2011088474A2 - Sulindac and sulindac derivatives and their uses related to infection - Google Patents

Abstract

The present compositions and methods relate to the use of ((R-S(=0)_0-2- R'_0.1-arylene)-methenyl-indene-3-yl) acetyl compounds for decreasing infection by a pathogen.

Description

SULINDAC AND SULINDAC DERIVATIVES AND THEIR USES RELATED TO INFECTION

This application claims the benefit of U.S. Application No. 61/336,069, filed on January 15, 2010; U.S. Application No. 61/343,594, filed on April 30, 2010, and U.S. Application No. 61/369,808, filed on August 13, 2010, all of which are hereby incorporated in their entirety by this reference.

FIELD OF THE INVENTION

The present compositions and methods relate to the use of compounds for decreasing infection by a pathogen. More particularly, the compositions and methods relate to the use of sulindac, sulindac sulfide, sulindac sulfone and their derivatives, for decreasing infection in a subject by a virus.

BACKGROUND

Infectious diseases affect the health of people and animals around the world, causing serious illness and death. Black Plague devastated the human population in Europe during the middle ages. Pandemic flu killed millions of people in the 20^th century and is a threat to reemerge.

While vaccines have been effective to prevent certain viral infections, relatively few vaccines are available or wholly effective, moreover vaccines have inherent risks and tend to be specific for particular conditions. Vaccines are of limited value against rapidly mutating viruses and cannot anticipate emerging viruses or new bioterrorist designed viruses. Currently there is no good answer to these threats.

Traditional treatments for viral infection include pharmaceuticals aimed at specific virus derived proteins. However, the vast majority of viruses lack an effective drug. Those drugs that exist have several limitations and drawbacks that including limited effectiveness, toxicity, and high rates of viral mutations that render antiviral pharmaceuticals ineffective. Thus, an urgent need exists for alternative treatments for viruses and other infectious diseases.

DESCRIPTION OF THE DRAWINGS

Figure 1 shows an antiviral dose response curve for sulindac.

Figure 2 shows an antiviral dose response curve for sulindac. Figure 3 shows relative cell densities of MRC-5 cells infected with HRV1 A (4 days post-infection, inoculum not washed away).

Figure 4 shows relative cell densities of MRC-5 cells infected with HRV1 A (4 days post-infection, inoculum not washed away).

Figure 5 shows relative CPE inhibition in the presence of drugs / antagonists

(HRV1 A MOI=0.32, 4 days infection, inoculum not washed away).

Figure 6 shows relative CPE inhibition in the presence of drugs / antagonists (HRV1A MOI=0.32, 4 days infection, inoculum not washed away).

Figure 7 shows relative CPE inhibition in MRC-5 cells infected with HRV1 A (MOI=0.1 , 4 days, inoculum not washed away) in the presence of candidate HRV 1 A inhibitors.

Figure 8 discloses sulindac and sulindac-related compounds. There are 136 compounds disclosed in this figure. Any of the 1 6 compounds disclosed herein can be used with any of the methods disclosed herein. Each of the 136 compounds is listed with its formula and IUPAC name.

DETAILED DECRIPTION OF THE INVENTION

The present compositions and methods may be understood more readily by reference to the following detailed description of preferred embodiments and the Examples included therein.

Before the present compounds, compositions and/or methods are disclosed and described, it is to be understood that they are not limited to particular compounds or to particular methods, as such may, of course, 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 be limiting.

As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. The term "or" refers to a single element of stated alternative elements or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B," means "including A, B, or A and B," without excluding additional elements.

Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase "optionally obtained prior to treatment" means obtained before treatment, after treatment, or not at all.

As used throughout, by "subject" is meant an individual. Preferably, the subject is a mammal such as a primate, and, more preferably, a human. Non-human primates include marmosets, monkeys, chimpanzees, gorillas, orangutans, and gibbons, to name a few. The term "subject" includes domesticated animals, such as cats, dogs, etc., livestock (for example, cattle, horses, pigs, sheep, goats, etc.), laboratory animals (for example, ferret, chinchilla, mouse, rabbit, rat, gerbil, guinea pig, etc.) and avian species (for example, chickens, turkeys, ducks, pheasants, pigeons, doves, parrots, cockatoos, geese, etc.). The subjects can also include, but are not limited to fish (for example, zebrafish, koi, goldfish, tilapia, salmon and trout), amphibians and reptiles.

As the term is used herein, a "moiety" is part of a molecule (or compound, or analog, etc.). A "functional group" is a specific group of atoms in a molecule. A moiety can be a functional group or can include one or functional groups.

The term "aryl" as used herein is a ring radical containing 6 to 18 carbons, or preferably 6 to 12 carbons, comprising at least one aromatic residue therein.

Examples of such aryl radicals include phenyl, naphthyl, and isochroman radicals. Moreover, the term "aryl" as used throughout the specification and claims is intended to include both "unsubstituted aryls" and "substituted aryls", the later denotes an aryl ring radical as defined above that is substituted with one or more, preferably 1, 2, or 3 organic or inorganic substituent groups, which include but are not limited to a halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substituted amino, unsubstituted or substituted amido, carbonyl, halogen, sulfhydryl, sulfonyl, sulfonate, sulfamoyl, sulfonamide, azido acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy or haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic ring, ring wherein the terms are defined herein. The organic substituent groups can comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. It will be understood by those skilled in the art that the moieties substituted on the "aryl" can themselves be substituted, as described above, if appropriate.

The term "heteroaryl" as used herein refers to an aryl ring radical as defined above, wherein at least one of the aryl ring carbons has been replaced with a heteroatom, which include but are not limited to nitrogen, oxygen, and sulfur atoms. Examples of heteroaryl residues include pyridyl, bipyridyl, furanyl, and thiofuranyl residues. Substituted "heteroaryl" residues can have one or more organic or inorganic substituent groups, as referred to hereabove for aryl groups, bound to the carbon atoms of the heteroaromatic rings. The organic substituent groups can comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms.

The term "hydrogen" as used herein with a respect to a substituent on an organic moiety has it usual and ordinary meaning.

The term "alkyl" as used herein is a branched or unbranched saturated hydrocarbon moiety. "Unbranched" or "Branched" alkyls comprise a non-cyclic, saturated, straight or branched chain hydrocarbon moiety having from 1 to 24 carbons, 1 to 12 carbons, 1 to 6 carbons, or 1 to 4 carbon atoms. Examples of such alkyl radicals include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, n-propyl, wo-propyl, butyl, n-butyl, sec-butyl, t-butyl, amyl, t-amyl, n-pentyl and the like.

Moreover, the term "alkyl" as used throughout the specification and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter denotes an alkyl radical analogous to the above definition that is further substituted with one, two, or more additional organic or inorganic substituent groups. Suitable substituent groups include but are not limited to H, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, heterocyclyl, amino, mono-substituted amino, di-substituted amino, unsubstituted or substituted amido, carbonyl, halogen, sulfhydryl, sulfonyl, sulfonate, sulfamoyl, sulfonamide, azido, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkoxy, heteroaryl, substituted heteroaryl, aryl or substituted aryl. It will be understood by those skilled in the art that an "alkoxy" can be a substitutent of a carbonyl substituted "alkyl" forming an ester. When more than one substituent group is present then they can be the same or different. The organic substituent moieties can comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms. It will be understood by those skilled in the art that the moieties substituted on the "alkyl" chain can themselves be substituted, as described above, if appropriate.

The term lower "lower alkyl" as used herein refers to a C_1-4 alkyl group, and includes both substituted and substituted lower alkyls.

The term "cycloalkyl" as used herein refers to a hydrocarbon structure wherein the structure is closed to form at least one ring. Cycloalkyls typically comprise a cyclic radical containing 3 to 8 ring carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopenyl, cyclohexyl, cycloheptyl and the like. Cycloalkyl radicals can be multicyclic and can contain a total of 3 to 18 carbons, or preferably 4 to 12 carbons, or 5 to 8 carbons. Examples of multicyclic cycloalkyls include decahydronapthyl, adamantyl, and like radicals.

Moreover, the term "cycloalkyl" as used throughout the specification and claims is intended to include both "unsubstituted cycloalkyls" and "substituted cycloalkyls", the later denotes an cycloalkyl radical analogous to the above definition that is further substituted with one, two, or more additional organic or inorganic substituent groups that can include but are not limited to hydroxyl, cycloalkyl, amino, mono-substituted amino, di-substituted amino, unsubstituted or substituted amido, carbonyl, halogen, sulfhydryl, sulfonyl, sulfonate, sulfamoyl, sulfonamide, azido, acyloxy, nitro, cyano, carboxy, carboalkoxy, alkylcarboxamido, substituted alkylcarboxamido, dialkylcarboxamido, substituted dialkylcarboxamido, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkoxy, heteroaryl, substituted heteroaryl, aryl or substituted aryl. When the cycloalkyl is substituted with more than one substituent group, they can be the same or different. The organic substituent groups can comprise from 1 to 12 carbon atoms, or from 1 to 6 carbon atoms, or from 1 to 4 carbon atoms.

The term "cycloalkenyl" as used herein refers to a cycloalkyl radical as defined above that comprises at least one carbon-carbon double bond. Examples include but are not limited to cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 2- cyclopeiitenyl, 3-cyclopentenyl, 1-cyclohexyl, 2-cyclohexyl, 3-cyclohexyl and the like.

The term "alkenyl" as used herein refers to an alkyl residue as defined above that also comprises at least one carbon-carbon double bond. Examples include but are not limited to vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2- hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5- heptenyl, 6-heptenyl and the like. The term "alkenyl" includes dienes and trienes of straight and branch chains.

The term "alkynyl" as used herein refers to an alkyl residue as defined above that further comprises at least one carbon-carbon triple bond. Examples include but are not limited ethynyl, 1-propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1 - pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl and the like. The term "alkynyl" includes di- and tri-ynes.

The term "alkoxy" as used herein refers to an alkyl residue, as defined above, bonded directly to an oxygen atom, which is then bonded to another moiety. Examples include methoxy, ethoxy, n-propoxy, wo-propoxy, n-butoxy, -butoxy, «ο-butoxy and the like.

The term "substituted" as used herein with respect to lower alkoxy groups refers to an -OR group, in which R is an alkyl group that bears at least one substituent.

The term "cycloalkoxy" as used herein refers to an alkoxy group in which the alkyl portion is cycloalkyl.

The term "haloalkoxy" as used herein refers to a haloalkyl residue as defined above that is directly attached to an oxygen to form trifluoromethoxy,

pentafluoroethoxy, 2-chloroethoxy, or the like.

As used herein, the terms "halo-," "halogen," "halogenated" and similar terms refer to a fluoro, chloro, bromo or iodo group.

The term "haloalkyl" as used herein refers to an alkyl residue as defined above, that is substituted with one or more halogens, such as a trifluoromethyl, pentafluoroethyl, chloromethyl and the like.

The term "acyl" as used herein refers to a R-C(O)- residue having an organic R group containing 1 to 8 carbons. Examples include but are not limited to formyl, acetyl, propionyl, butanoyl, iso-butanoyl, pentanoyl, hexanoyl, heptanoyl, benzoyl and the like, and natural or un-natural amino acids. The term "acyloxy" as used herein refers to an acyl radical as defined above, directly attached to an oxygen to form an organic R-C(O)0- residue. Examples include but are not limited to acetyloxy, propionyloxy, butanoyloxy, iso-butanoyloxy, benzoyloxy and the like.

The term "nitro" as used herein refers to a -N⁺(=O)-O- group.

As used herein, the term "azide", "azido" and their variants refer to any moiety or compound comprising the monovalent group -N3 or the monovalent ion Ν3^"·.

The term "hydroxy" and "hydroxyl" as used herein refer to an -OH group.

The term "hydroxyalkyl" as used herein refers to an alkyl substituent that is substituted with a hydroxyl group.

The term "cyano" as used herein refers to a -C≡N group.

The term "amino" as used herein without modification refers to a -NH₂ group.

The terms "alkylamine" and "alkylamino" as used herein refer to a moiety comprising an NH radical substituted with one organic substituent group, which includes but is not limited to alkyls, substituted alkyls, cycloalkyls, aryls, or arylalkyls. Examples of alkylamino groups include methylamino (-NH-CH₃);

ethylamino (-NHCH₂CH₃), hydroxyethylamino (-NH-CH₂CH₂OH), and the like.

The term "aminoalkylamino" as used herein refers to an alkylamino group in which the alkyl portion is substituted with an additional amino group.

The term "hydroxyalkylamino" as used herein refers to an alkylamino group in which the alkyl portion is further substituted with a hydroxyl group.

The term "polyhydroxyalkylamino" as used herein refers to an alkylamino group in which the alkyl portion is further substituted with two or more hydroxyl groups.

The terms "dialkylamine" and "dialkylamino" as used herein refer to a moiety comprising a nitrogen atom substituted with two organic radicals that can be the same or different, which can be selected from but are not limited to aryl, substituted aryl, alkyl, substituted alkyl or arylalkyl, wherein the terms have the same definitions found throughout. Some examples include dimethylamino, methylethylamino, diethylamino and the like.

The term "dialkylaminoalkyl" as used herein refers to a dialkylamino group in which the amino portion is substituted upon an additional alkyl group. The term "dialkylaminoalkylamino" as used herein refers to a dialkylamino group in which the amine portion is substituted upon an additional alkyl group, and that additional alkyl group is further substituted upon a second amino group.

The term "acylamino" as used herein refers to a moiety having the structure R-C(=O)N(R')R², wherein R, R¹ and R² represent hydrogen or an alkyl group.

The term "N-morpholino" as used herein refers to a substituent in which the nitrogen atom of morpholine [6-member ring -N-(CH₂)-(CH₂)-0-(CH₂)-(CH₂)-] is bonded to an organic moiety.

The term "sulfamyl" as used herein refers to a group represented by the structure -S(=O)₂NH₂, and includes both unsubstituted sulfamyl groups and those substituted with an alkyl group at the N atom.

The term "alkylthio" as used herein refers to a -S-R substituent in which R is an alkyl group.

The term "alkylsulfide" as used herein refers to a -R-S-R' substituent in which R and R' are independently alkyl groups.

The term "mercapto" as used herein refers to a -S-H substituent.

The term "alkylsulfinyl" as used herein refers to a -S(=O)-R group, wherein R is an alkyl group.

The term "alkylsulfonyl" as used herein refers to a -S(=O)2-R group, wherein R is an alkyl group.

The term "carbalkoxy" as used herein refers to a -C(=O)-0-R group, wherein R is an alkyl group.

The term "carbamido" as used herein refers to (Nl^CO in which at least one of the hydrogen atoms is replaced by a bond to an organic moiety.

The term "cation" as used herein refers to a species bearing a positive charge of 1 + or higher. Such cations include but are not limited to the alkali metal cations, alkaline earth metal cations, transition metal cations, ammonium salts, sulfonium salts, phosphonium salts, cycloheptatrienyl cations, hydroazulenium, and other positively charged species.

The term "ester" as used herein is represented by the formula— C(O)OR, where R can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. The term "carbonate group" as used herein is represented by the formula -OC(O)O , where R can be hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.

The term "keto group" as used herein is represented by the formula -C(O)R, where R is an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.

The term "aldehyde" as used herein is represented by the formula -C(O)H or -R- C(O)H, wherein R can be alkyl, alkenyl, alkoxy, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.

The terms "carboxyl" and "carboxylic acid" as used herein refer to a moiety having the formula -C(O)OH.

The term "carbonyl group" as used herein is represented by the formula C=O.

The term "ether" as used herein is represented by the formula AOA¹, where A and A¹ can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.

The term "urethane" as used herein is represented by the formula -OC(O)NRR\ where R and R' can be, independently, hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.

The term "silyl group" as used herein is represented by the formula -SiRR'R", where R, R', and R" can be, independently, hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, alkoxy, or heterocycloalkyl group described above.

The term "sulfo-oxo group" as used herein is represented by the formulas -S(O)₂R, -OS(O)₂R, or , -OS(O)₂0R, where R can be hydrogen, an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described above.

Methods of Decreasing Infection

Disclosed are methods of decreasing infection in a cell or a subject by a pathogen, said method comprising administering to the cell or subject an effective amount of a compound having the structure of a formula set forth in U.S. Patent Nos.

3,654,349. U.S. Patent No. 3,654,349 which are hereby incorporated in their entirety by this reference, at least for material relating to chemicals, chemical structures, and their production. An example is set forth in formula I. Compounds of formula I can be made as described in U.S. Patent No. 3,654,349, which is herein incorporated by reference at least for material related to formula I and its production.

Disclosed are methods of decreasing infection, in a subject by a pathogen comprising administering to the subject an effective amount of a compound having the structure of formula I

wherein Ar may be aryl or heteroaryl; Ri may be hydrogen, lower alkyl or halogenated lower alkyl; R₂ may be hydrogen or alkyl; R₃, R₄, R₅ and R₆ each may be hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamine, dialkylamino, dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, halogenoalkyl, cycloalkyl or cycloalkoxy; R7 may be alkylsulfinyl, alkylsulfide, alkylthio, or alkylsulfonyl, for example methylsulfinyl, methylsulfide, methylthio, methylsulfonyl, ethylsulfinyl, ethylsulfide, ethylthio, ethylsulfonyl, propylsulfinyl, propylsulfide, propylthio, propylsulfonyl, butylsulfinyl, butylsulfide, butylthio, butylsulfonyl, etc.; Re may be hydrogen, halogen, hydroxy, alkoxy, or haloalkyl; and M may be hydroxy, lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N- morpholino, hydroxyalkylamino, polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino, and the group OM', wherein M' is a cation, wherein the compound decreases infection in the subject.

The indene nucleus may be substituted in the 1 -position by an aryl ring system such as benzene, naphthalene or biphenyl or a heteroaryl ring system such as a pyrrole, furan, thiophene, pyridine, imidazole, pyrazine, thiazole, etc. which contains an alkylsulfinyl or alkylsulfonyl substituent and may be further substituted with a halogen (chloro, fluoro or bromo), hydroxy, alkoxy (methoxy, ethoxy, propoxy, etc.) or halo alkyl (fluoromethyl, ehloromethyl, trifluoromethyl, etc.) group.

In preferred compounds, R₃, R₄, R₅ and R₆ each may be halogen (fluoro, chloro or bromo), lower alkoxy (methoxy, ethoxy .i-propoxy, etc.), lower alklower alkyl (methyl, ethyl, propyl, isopropyl, etc.), nitro, amino or substituted amino such as dialkylamino, acylamino, alkylamine, etc. R₃, R₄, R₅ and R₆ are not however limited to this class and may, if desired, represent substituents such as hydrogen, aryl, aryloxy, hydroxy, mercapto, haloalkyl, sulfamyl, carboxy, carboalkoxy, carbamide and many other groups.

Representative compounds are as follows:

5-hydroxy-2-methyl-1-p-methylsulfinylbenzylidene-3-indene acetic acid; 5-methoxy- 2-methyl-1-p-methylsulfinylbenzylidene-3-indene acetic acid; 5-fluoro-2-methyl-l-p- methylsulfinylbenzylidene-3-indene acetic acid; 5-fluoro-2-methyl-1-p- methylthiobenzylidene-3-indene acetic acid; 5-fluoro-2-methyl-l-p- methylsulfonylbenzylidene-3-indene acetic acid; a- 5-fluoro-2-methyl-1-p- methylsulfinylbenzylidene-3-indene) propionic acid; 5,6-difluoro-2-methyl-1-p- methylsulfinylbenzylidene-3-indene acetic acid; 5-chloro-2-methyl-l-p- methylsulfinylbenzylidene-3-indene acetic acid; 5-trifluoromethyl-2-methyl-1-p- methylsulfinyl benzylidene-3-indene acetic acid; 5-methyl-2-methyl-1-p- methylsulfinylbenzylidene-3-indene acetic acid; 5,7-difiuoro-2-methyl-1-p- methylsulfinylbenzylidene-3-indene acetic acid; a-(5,7-difiuoro-2-methyl-1-p- methylsulfinylbenzylidene-3-indene) propionic acid; 5-dimethylamino-6-fluoro-2- methyl-l-p-methylsulfinylbenzylidene-3-indene acetic acid; 5-methoxy-6-fluoro-2- methyl-1-p-methylsulfinylbenzylidene-3-indene acetic acid; a-(5-methoxy-6-fluoro- 2-methyl-1-p-methylsulfinylbenzylidene-3-indene) propionic acid; a-(5,6-difluoro-2- methyl-1-p-methylsulfinyl benzylidene-3-indene) propionic acid; 5-methoxy-2- methyl-1-p-methylsulfonylbenzylidene-3-indene acetic acid; 5,6-difiuoro-2-methyl-1- p-methylsulfonylbenzylidene-3-indene acetic acid; 5,7-difluoro-2-methyl-1-p- methylsulfonylbenzylidene-3-indene acetic acid; 5-dimethylamino-6-fluoro-2-methyl- l-p-methylsulfonylbenzylidene-3-indene acetic acid; 5-methoxy-6-fluoro-2-methyl-l- p-methylsulfonylbenzylidene-3-indene acetic acid; a-(2-methyl-5,6-difiuoro-1-p- methylsulfonylbenzylidene-3-indene) propionic acid; and the corresponding amides, esters and salts.

It should be noted that the compounds disclosed herein may be isomerized into their cis and trans isomers by procedures well known in the art. It should be further noted that the cis isomer of the compounds is substantially more active than the trans isomer. Accordingly, it is to be understood that reference throughout the specification and appended claims to these compounds is intended to encompass not merely the compounds per se but includes their geometric isomers (cis, trans).

It should be further noted by one skilled in the art that the alkylsulfinyl, alkylsulfide, alkylthio, or alkylsulfonyl derivatives can be racemic mixtures of optically active enantiomorphs which may be resolved into their (+) and (-) forms by techniques well known in the art. Furthermore, when Rl is lower alkyl an additional asymmetric atom results which gives rise to two additional enantiomorphs, which are also considered to be within the scope.

One skilled in the art should further note that some of the compounds disclosed herein are polymorphic and have different crystalline structures, melting points and solubility characteristics.

Also provided herein is a method of decreasing infection in a subject by a pathogen comprising administering to the subject an effective amount of sulindac wherein the pathogen is not LdMNPV or influenza. Further provided are methods of decreasing infection in a subject by a respiratory virus said method comprising administering to the subject an effective amount of a compound having the structure of formula I

wherein Ar may be aryl or heteroaryl; Ri may be hydrogen, lower alkyl or halogenated lower alkyl; R₂ may be hydrogen or alkyl; R₃, R₄, Rs and R₆ each may be hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamine, dialkylamino, dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, halogenoalkyl, cycloalkyl or cycloalkoxy; R7 may be alkylsulfinyl, alkylsulfide, alkylthio, or alkylsulfonyl, for example methylsulfinyl, methylsulfide, methylthio, methylsulfonyl, ethylsulfinyl, ethylsulfide, ethylthio, ethylsulfonyl, propylsulfinyl, propylsulfide, propylthio, propylsulfonyl, butylsulfinyl, butylsulfide, butylthio, butylsulfonyl, etc.; Rg may be hydrogen, halogen, hydroxy, alkoxy, or haloalkyl; and M may be hydroxy, lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N- morpholino, hydroxyalkylamino, polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino, and the group OM', wherein M' is a cation, wherein the compound decreases infection in the subject.

Further provided are methods of decreasing infection in a subject by a respiratory virus said method comprising administering to the subject an effective amount of a compound having the structure of formula I

wherein Ar may be aryl or heteroaryl; R₁ may be hydrogen, lower alkyl or halogenated lower alkyl; R₂ may be hydrogen or alkyl; R₃, R₄, R₅ and R₆ each may be hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamine, dialkylamino, dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, halogenoalkyl, cycloalkyl or cycloalkoxy; R7 may be alkylsulfinyl, alkylsulfide, alkylthio, or alkylsulfonyl, for example methylsulfinyl, methylsulfide, methylthio, methylsulfonyl, ethylsulfinyl, ethylsulfide, ethylthio, ethylsulfonyl, propylsulfinyl, propylsulfide, propylthio, propylsulfonyl, butylsulfinyl, butylsulfide, butylthio, butylsulfonyl, etc.; Rg may be hydrogen, halogen, hydroxy, alkoxy, or haloalkyl; and M may be hydroxy, lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N- morpholino, hydroxyalkylamino, polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino, and the group OM', wherein M' is a cation; and wherein the respiratory virus is a rhinovirus and the compound decreases infection in the subject. In a particular embodiment Ar is a phenyl ring, and R7 is bonded at the ring's para- position. Further provided are methods of decreasing infection in a subject by a pathogen by said method, comprising administering to the subject an effective amount of sulindac having the structure of formula II

wherein the compound decreases infection in the subject.

Further provided are methods of decreasing in a subject infection by a respiratory virus said method comprising administering to the subject an effective amount of sulindac having the structure of formula II wherein the compound decreases infection in the subject.

Disclosed herein is a method of decreasing infection in a subject by a respiratory virus said method comprising administering to the subject an effective amount of sulindac having the structure of formula II wherein the respiratory virus is a rhinovirus, and wherein the compound decreases infection in the subject.

Further provided are methods of decreasing infection in a subject by a pathogen said method comprising administering to the subject an effective amount of sulindac sulfide having the structure of formula III

wherein the compound decreases infection in the subject.

Further provided are methods of decreasing in a subject infection by a respiratory virus said method comprising administering to the subject an effective amount of sulindac sulfide having the structure of formula I I I wherein the compound decreases infection in the subject.

Further provided are methods of decreasing infection in a subject by a respiratory virus said method comprising administering to the subject an effective amount of sulindac sulfide having the structure of formula I II wherein the respiratory virus is a rhinovims, and wherein the compound decreases infection in the subject.

Further provided are methods of decreasing infection in a subject by a pathogen said method comprising administering to the subject an effective amount of sulindac sulfone having the structure of formula IV

wherein the compound decreases infection in the subject.

Further provided are methods of decreasing infection in a subject by a respiratory virus said method comprising administering to the subject an effective amount of sulindac sulfone having the structure of formula IV wherein the compound decreases infection in the subject.

Further provided is a method of decreasing infection in a subject by a respiratory virus said method comprising administering to the subject an effective amount of sulindac sulfone having the structure of formula IV wherein the respiratory virus is a rhinovirus, and wherein the compound decreases infection in the subject.

The subject can be found to be in need of a decrease in infection. For example, the subject can be diagnosed with an infection, such as a viral infection. The viral infection can be a respiratory virus, such as rhinovirus. Methods of detecting a viral infection are known to those of skill in the art. For example, viral infections can be diagnosed via growth of the virus in a cell culture from a specimen taken from the subject, or by detection of virus-specific antibodies in the blood, or by detection of virus antigens, or by detection of virus nucleic acids, or by observation of virus particles by electron microscopy, or by hemagglutination assay. Examples of detecting viruses ca be found, for example, in U.S. Patent Applications

2005/0227223, and 2006/01 15875, hereby incorporated by reference for their teachings concerning detecting viral infection.

Also disclosed herein is a method of decreasing infection in a subject by a pathogen comprising: a) determining that a subject has an infection; and b) administering to the subject an effective amount of a compound having the structure of formula I

wherein Ar may be aryl or heteroaryl; l may be hydrogen, lower alkyl or halogenated lower alkyl; R2 may be hydrogen or alkyl; R₃ , R₄ , R₅ and R₆ each may be hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamine, dialkylatnino, dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, halogenoalkyl, cycloalkyl or cycloalkoxy; R7 may be alkylsulfinyl, alkylsulflde, alkylthio, or alkylsulfonyl; R8 may be hydrogen, halogen, hydroxy, alkoxy, or haloalkyl; and M may be hydroxy, lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino,

polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino, and the group ΟΜ', wherein M' is a cation, wherein the compound decreases infection in the subject. In one example, the subject is diagnosed with an infection prior to treatment. The infection can be a viral infection, and can be diagnosed by the methods previously disclosed.

Further disclosed is a method of preventing infection by a pathogen in a subject comprising administering to the subject an effective amount of a compound to prevent infection having the structure of any one of formulas I-I V. In one example, the subject can be found to be in need of prevention of infection. Examples include, but are not limited to, a COPD or asthma patient and/or an immune suppressed patient.

Also disclosed is a method of inhibiting or reducing virus replication comprising administering to the subject an effective amount of a compound to inhibit or reduce the virus replication having the structure of any one of formulas I-IV.

Inhibiting or reducing viral replication includes the spread to additional host cells or tissues. The

Any of the compounds disclosed herein can be administered in combination with an additional therapeutic agent, including more than one additional therapeutic agents. As disclosed herein, the therapeutic agent can be an antiviral compound, antibacterial agent, antifungal agent, antiparasitic agent, anti-inflammatory agent, or anti-cancer agent. The therapeutic agent can be used to treat rhinovirus or influenza, for example. The additional therapeutic agent can be in the same or in a different formulation as the compound having the structure of any one of formulas I-IV.

Also disclosed is a method of treating or preventing asthma or associated conditions, including exacerbations, comprising administering to the subject a compound having the structure of any one of formulas I-IV, thereby treating or preventing asthma or associated conditions in the subject. The subject can be diagnosed with asthma prior to treatment. The asthma or associated conditions can be treated or prevented by treating or preventing rhinovirus.

By "exacerbations" is meant a worsening of the disease or symptoms compared to what it would have been if the subject were not infected with a virus, such as rhinovirus. For example, the subject can be 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or 2, 3, 4, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times worse compared to the subject's symptoms without rhinovirus present.

Also disclosed is a method of treating or preventing chronic obstructive pulmonary disease (COPD) or associated conditions, including exacerbations, comprising administering to the subject a compound having the structure of any one of formulas I-IV, thereby treating or preventing COPD or associated conditions. The COPD or associated conditions can be treated or prevented by treating or preventing rhinovirus.

The compounds disclosed herein can be administered intranasally, orally, or intramuscularly. The compound can also be administered via inhalation.

Also disclosed is a compound having the structure of formula I (sulindac) and an additional therapeutic agent. The therapeutic agent can be an anti-infective agent, such as an antiviral agent. Such antiviral agents are disclosed herein.

Disclosed herein is a composition comprising sulindac formulated for antiviral administration in a dose that decreases at least one adverse clinical side effect of the clinically approved sulindac (150mg or 200mg twice daily dose). The dosage can be, for example, 50, 60, 70, 80, 90, 100, 1 10, 120, 130, 140, 160, 170, 180, 190 mg, or any amount below, or in between that decreases at least one adverse clinical side effect. The dosage is typically administered twice daily for a total daily dose. Thus, the methods provided herein could utilize a total daily dose of less than 400mg or 300mg per day, for example 100, 1 10, 120, 130, 140, 150, 160, 170, 180, 1 0, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 310, 320, 330, 340, 350, 360, 370, 380, 390 mg per day, or any amount below or in between that decreases at least one adverse clinical side effect compared to the currently approved 300mg and 400mg daily sulindac dose.

Also disclosed is a composition comprising sulindac in packaging having a label with a decreased adverse clinical side effect profile compared to sulindac approved in the United States for arthritis (Osteoarthritis, Rheumatoid arthritis), Ankylosing spondylitis, Acute painful shoulder (Acute subacromial

bursitis/supraspinatus tendonitis) and Acute gouty arthritis.

The composition can be modified for example by changing the dose, or formulation. A label having decreased adverse clinical side effect profile can be obtained by changing the dosage, formulation, administration frequency, or administration course of sulindac. As to the frequency and duration of the administration, given the effectiveness of sulindac on acute viral infections, sulindac could be administered for shorter duration than it is currently utilized, for example for a single dose, or for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 day administration course. Thus, given a shorter duration of administration, the dose of sulindac could be greater than the currently approved 150 and 200mg twice a day dose (for example 250, 300mg etc.). Likewise, it could be administered other than twice a day (for example once a day, three times a day, four times a day etc.).

Sulindac potential side effects include ulcer with gastrointestinal bleeding and stomach perforation, and severe hypersensitivity with liver failure. The current sulindac label can be found in Example 4.

By "decreasing adverse clinical side effects" is meant a reduction in any of the known or unknown clinical side effects of sulindac. Examples include, but are not limited to, constipation, diarrhea, dizziness, gas, headache, heartburn, nausea, stomach upset, severe allergic reactions (rash; hives; itching; trouble breathing; tightness in the chest, swelling of the mouth, face, lips, or tongue), bloody or black, tarry stools; change in the amount of urine produced; chest pain; confusion; dark urine; depression; fainting; fast or irregular heartbeat; fever, chills, or persistent sore throat; flushing; lower back or side pain; mental or mood changes; muscle or unusual joint aches or pain; numbness of an arm or leg; one-sided weakness; red, swollen, blistered, or peeling skin; ringing in the ears; seizures; severe headache or dizziness; severe or persistent stomach pain, nausea, or vomiting; shortness of breath; sudden or unexplained weight gain; swelling of hands, legs, or feet; unusual bruising or bleeding; unusual joint or muscle pain; unusual tiredness or weakness; vision or speech changes; vomit that looks like coffee grounds; yellowing of the skin or eyes. Others are gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI perforation and intestinal strictures (diaphragms) have been reported rarely. Liver function abnormalities; jaundice, sometimes with fever;

cholestasis; hepatitis; hepatic failure. There have been rare reports of Sulindac metabolites in common bile duct "sludge" and in biliary calculi in patients with symptoms of cholecystitis who underwent a cholecystectomy. Other examples are pancreatitis, ageusia; glossitis, stomatitis, sore or dry mucous membranes, alopecia, photosensitivity. Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis have been reported. Congestive heart failure, especially in patients with marginal cardiac function; palpitation; hypertension, thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia; bone marrow depression, including aplastic anemia; hemolytic anemia; increased prothrombin time in patients on oral anticoagulants. Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome. Renal calculi containing Sulindac metabolites have been observed rarely. Vertigo; insomnia; somnolence; paresthesia; convulsions; syncope; aseptic meningitis (especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease. Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste. Anaphylaxis; angioneurotic edema; bronchial spasm; dyspnea. Hypersensitivity vasculitis.

A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic reactions— see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain, tachycardia). A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with nonsteroidal anti-inflammatory agents, sometimes with fatal outcome.

Pharmaceutically acceptable salts of all of the compounds set forth herein are also provided. "Pharmaceutically acceptable salts" are those salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Nonlimiting examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Salts derived from appropriate bases include alkali metal (e.g. sodium), alkaline earth metal (e.g. magnesium) and ammonium salts. Preferred salts include hydrochlorides, hydrobromides, sulfates, mesylates, maleates, and fumarates. Throughout this application, references to a compound include the compounds as well as its pharmaceutically acceptable salts.

An infection can be a viral infection, bacterial infection, fungal infection or a parasitic infection, to name a few. All strains and types of pathogenic infection are contemplated herein. A decrease or inhibition of infection can occur in a cell, in vitro, ex vivo or in vivo. As utilized throughout, the term "infection" encompasses all phases of pathogenic life cycles including, but not limited to, attachment to cellular receptors, entry, internalization, disassembly, replication, genomic integration of pathogenic sequences, transcription of viral RNA, translation of viral RNA, transcription of host cell mRNA, translation of host cell mRNA, proteolytic cleavage of pathogenic proteins or cellular proteins, assembly of particles, endocytosis, cell lysis, budding, and egress of the pathogen from the cells, alone or combination. Therefore, a decrease in infection can be a decrease in attachment to cellular receptors, a decrease in entry, a decrease in internalization, a decrease in disassembly, a decrease in replication, a decrease in genomic integration of pathogenic sequences, a decrease in translation of mRNA, a decrease in proteolytic cleavage of pathogenic proteins or cellular proteins, a decrease in assembly of particles, a pathogen from the cells. This decrease does not have to be complete as this can range from decrease in endocytosis, a decrease in cell lysis, a decrease in budding, or a decrease in egress of the a slight decrease to complete ablation of the infection. A decrease in infection can be at least about 10%, 20%, 30%, 40%, 50%, 60, 70%, 80%, 90%, 95%, 100% or any other percentage decrease in between these percentages as compared to the level of infection in a cell that has not been contacted with a compound set forth herein.

Throughout this application, by "treat," "treating," or "treatment" is meant a method of reducing the effects of an existing infection. Treatment can also refer to a method of reducing the disease or condition itself rather than just the symptoms. The treatment can be any reduction from native levels and can be, but is not limited to, the complete ablation of the disease or the symptoms of the disease. Treatment can range from a positive change in a symptom or symptoms of viral infection to complete amelioration of the viral infection as detected by art-known techniques. For example, a disclosed method is considered to be a treatment if there is about a 10% reduction in one or more symptoms of the disease in a subject with the disease when compared to native levels in the same subject or control subjects.

The methods disclosed herein can also result in a decrease in the amount of time that it normally takes to see improvement in a subject. For example, a decrease in infection can be a decrease of hours, a day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, thirteen days, fourteen days, fifteen days or any time in between that it takes to see improvement in the symptoms, viral load or any other parameter utilized to measure improvement in a subject. For example, if it normally takes 7 days to see improvement in a subject not taking the composition, and after administration of the composition, improvement is seen at 6 days, the composition is effective in decreasing infection. This example is not meant to be limiting as one of skill in the art would know that the time for improvement can vary depending on the infection.

As utilized herein, by "prevent," "preventing," or "prevention" is meant a method of precluding, delaying, averting, obviating, forestalling, stopping, or hindering the onset, incidence, severity, or recurrence of infection. For example, the disclosed method is considered to be a prevention if there is about a 10% reduction in onset, incidence, severity, or recurrence of infection, or symptoms of infection (e.g., inflammation, fever, lesions, weight loss, etc.) in a subject exposed to an infection when compared to control subjects exposed to an infection that did not receive a composition for decreasing infection. Thus, the reduction in onset, incidence, severity, or recurrence of infection can be about a 10, 20, 30, 40, 50, 60, 70, 80, 90, 100%, or any amount of reduction in between as compared to control subjects. For example, and not to be limiting, if about 10% of the subjects in a population do not become infected as compared to subjects that did not receive preventive treatment, this is considered prevention.

Examples of viral infections include but are not limited to, infections caused by RNA viruses (including negative stranded RNA viruses, positive stranded RNA viruses, double stranded RNA viruses and retroviruses) and DNA viruses. All strains, types, subtypes of DNA and RNA viruses are contemplated herein.

Examples of RNA viruses include, but are not limited to picornaviruses, which include aphthoviruses (for example, foot and mouth disease virus O, A, C, Asia 1, SAT1, SAT2 and SAT3), cardioviruses (for example, encephalomycarditis virus and Theiller's murine encephalomyelitis virus), enteroviruses (for example polioviruses 1 , 2 and 3, human enteroviruses A-D, bovine enteroviruses 1 and 2, human coxsackieviruses A1-A22 and A24, human coxsackieviruses B1-B5, human echoviruses 1-7, 9, 1 1-12, 24, 27, 29-33, human enteroviruses 68-71, porcine enteroviruses 8-10 and simian enteroviruses 1-18), erboviruses (for example, equine rhinitis virus), hepatovirus (for example human hepatitis A virus and simian hepatitis A virus), kobuviruses (for example, bovine kobuvirus and Aichi virus),

parechoviruses (for example, human parechovirus 1 and human parechovirus 2), rhinovirus (for example, rhinovirus A, rhinovirus B, rhinovirus C, HRV16, HRVit (VR-1 1757), HRV14 (VR-284), or HRV_1A (VR-1559), human rhinovirus 1-100 and bovine rhinoviruses 1-3) and teschoviruses (for example, porcine teschovirus).

Additional examples of RNA viruses include caliciviruses, which include noroviruses (for example, Norwalk virus), sapoviruses (for example, Sapporo virus), lagoviruses (for example, rabbit hemorrhagic disease virus and European brown hare syndrome) and vesiviruses (for example vesicular exanthema of swine virus and feline calicivirus).

Other RNA viruses include astroviruses, which include mamastorviruses and avastroviruses. Togaviruses are also RNA viruses. Togaviruses include alphaviruses (for example, Chikungunya virus, Sindbis virus, Semliki Forest virus, Western equine encephalitis, Getah virus, Everglades virus, Venezuelan equine encephalitis virus and Aura virus) and rubella viruses. Additional examples of RNA viruses include the the flaviviruses (for example, tick-borne encephalitis virus, Tyuleniy virus, Aroa virus, Dengue virus (types 1 to 4), Kedougou virus, Japanese encephalitis virus (JEV), West Nile virus (WNV), Kokobera virus, Ntaya virus, Spondweni virus, Yellow fever virus, Entebbe bat virus, Modoc virus, Rio Bravo virus, Cell fusing agent virus, pestivirus, GB virus A, GBV-A like viruses, GB virus C, Hepatitis G virus, hepacivirus (hepatitis C virus (HCV)) all six genotypes), bovine viral diarrhea virus (BVDV) types 1 and 2, and GB virus B).

Other examples of RNA viruses are the coronaviruses, which include, human respiratory coronaviruses such as SARS-CoV, HCoV-229E, HCoV-NL63 and HCoV- OC43. Coronaviruses also include bat SARS-like CoV, turkey coronavirus, chicken coronavirus, feline coronavirus and canine coronavirus. Additional RNA viruses include arteriviruses (for example, equine arterivirus, porcine reproductive and respiratory syndrome virus, lactate dehyrogenase elevating virus of mice and simian hemorraghic fever virus). Other RNA viruses include the rhabdoviruses, which include Iyssaviruses (for example, rabies, Lagos bat virus, Mokola virus, Duvenhage virus and European bat lyssavirus), vesiculoviruses (for example, VSV-Indiana, VSV- New Jersey, VSV-Alagoas, Piry virus, Cocal virus, Maraba virus, Isfahan virus and Chandipura virus), and ephemeroviruses (for example, bovine ephemeral fever virus, Adelaide River virus and Berrimah virus). Additional examples of RNA viruses include the filoviruses. These include the Marburg and Ebola viruses (for example, EBOV-Z, EBOV-S, EBOV-IC and EBOV-R.

The paramyxoviruses are also RNA viruses. Examples of these viruses are the rubulaviruses (for example, mumps, parainfluenza virus 5, human parainfluenza virus type 2, Mapuera virus and porcine rubulavirus), avulaviruses (for example, Newcastle disease virus), respoviruses (for example, Sendai virus, human parainfluenza virus type 1 and type 3, bovine parainfluenza virus type 3), henipaviruses (for example, Hendra virus and Nipah virus), morbilloviruses (for example, measles, Cetacean morvilliirus, Canine distemper virus, Peste-des-petits-ruminants virus, Phocine distemper virus and Rinderpest virus), pneumoviruses (for example, human respiratory syncytial virus A2, Bl and S2, bovine respiratory syncytial virus and pneumonia virus of mice), metapneumoviruses (for example, human

metapneumovirus and avian metapneumovirus). Additional paramyxoviruses include Fer-de-Lance virus, Tupaia paramyxovirus, Menangle virus, Tioman virus, Beilong virus, J virus, Mossman virus, Salem virus and Nariva virus. Additional RNA viruses include the orthomyxoviruses.

These viruses include influenza viruses and strains (e.g., influenza A, influenza A strain A/Victoria/3/75, influenza A strain A/Puerto Rico/8/34, influenza A H1N1 (including but not limited to A/WS/33, A/NWS/33 and A California/04/2009 strains) influenza B, influenza B strain Lee, and influenza C viruses) H₂N2, H3N2, H5N1, H7N7, H 1N2, H9N2, H7N2, H7N3 and H 10N7), as well as avian influenza (for example, strains H5N1, H5N1 Duck/MN/1525/81 , H5N2, H7N1, H7N7 and H9N2) thogotoviruses and isaviruses. Orthobunyaviruses (for example, Akabane virus, California encephalitis, Cache Valley virus, Snowshoe hare virus,) nairoviruses (for example, Nairobi sheep virus, Crimean-Congo hemorrhagic fever virus Group and Hughes virus), phlebo viruses (for example, Candiru, Punta Toro, Rift Valley Fever, Sandfly Fever, Naples, Toscana, Sicilian and Chagres), and hantaviruses (for example, Hantaan, Dobrava, Seoul, Puumala, Sin Nombre, Bayou, Black Creek Canal, Andes and Thottapalayam) are also RNA viruses. Arenaviruses such as lymphocytic choriomeningitis virus, Lujo virus, Lassa fever virus, Argentine hemorrhagic fever virus, Bolivian hemorrhagic fever virus, Venezuelan hemorrhagic fever virus, SABV and WWAV are also RNA viruses. Borna disease virus is also an RNA virus. Hepatitis D (Delta) virus and hepatitis E are also RNA viruses.

Additional RNA viruses include reoviruses, rotaviruses, birnaviruses, chrysoviruses, cystoviruses, hypoviruses partitiviruses and totoviruses. Orbiviruses such as African horse sickness virus, Blue tongue virus, Changuinola virus, Chenuda virus, Chobar Gorge Corriparta virus, epizootic hemorraghic disease virus, equine encephalosis virus, Eubenangee virus, Ieri virus, Great Island virus, Lebombo virus, Orungo virus, Palyam virus, Peruvian Horse Sickness virus, St. Croix River virus, Umatilla virus, Wad Medani virus, Wallal virus, Warrego virus and Wongorr virus are also RNA viruses.

Retroviruses include alpharetroviruses (for example, Rous sarcoma virus and avian leukemia virus), betaretroviruses (for example, mouse mammary tumor virus, Mason-Pfizer monkey virus and Jaagsiekte sheep retrovirus), gammaretroviruses (for example, murine leukemia virus and feline leukemia virus, deltraretroviruses (for example, human T cell leukemia viruses (HTLV-1, HTLV-2), bovine leukemia virus, STLV-1 and STLV-2), epsilonretriviruses (for example, Walleye dermal sarcoma virus and Walleye epidermal hyperplasia virus 1), reticuloendotheliosis virus (for example, chicken syncytial virus, lentiviruses (for example, human immunodeficiency virus (HIV) type 1 , human immunodeficiency virus (HIV) type 2, human immunodeficiency virus (HIV) type 3, simian immunodeficiency virus, equine infectious anemia virus, feline immunodeficiency virus, caprine arthritis encephalitis virus and Visna maedi virus) and spumaviruses (for example, human foamy virus and feline syncytia-forming virus).

Examples of DNA viruses include polyomaviruses (for example, simian virus 40, simian agent 12, B virus, JC virus, Merkel Cell polyoma virus, bovine polyoma virus and lymphotrophic papovavirus), papillomaviruses (for example, human papillomavirus, bovine papillomavirus, adenoviruses (for example, adenoviruses A-F, canine adenovirus type I, canined adeovirus type 2), circoviruses (for example, porcine circovirus and beak and feather disease virus (BFDV)), parvoviruses (for example, canine parvovirus), erythroviruses (for example, adeno-associated virus types 1-8), betaparvoviruses, amdoviruses, densoviruses, iteraviruses, brevidensoviruses, pefudensoviruses, herpes viruses 1 ,2, 3, 4, 5, 6, 7 and 8 (for example, herpes simplex virus 1, herpes simplex virus 2, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus, Kaposi's sarcoma associated herpes virus, human herpes virus-6 variant A, human herpes virus-6 variant B and cercophithecine herpes virus 1 (B virus)), poxviruses (for example, smallpox (variola), cowpox, monkeypox, vaccinia, Uasin Gishu, camelpox, psuedocowpox, pigeonpox, horsepox, fowlpox, turkeypox and swinepox), and hepadnaviruses (for example, hepatitis B and hepatitis B-like viruses). Chimeric viruses comprising portions of more than one viral genome are also contemplated herein.

For animals, in addition to the animal viruses listed above, viruses include, but are not limited to, the animal counterpart to any above listed human virus. The provided compounds can also decrease infection by newly discovered or emerging viruses. Such viruses are continuously updated on http://en.wikipedia.org/wiki/Virus and www.virology.net.

Examples of bacterial infections include, but are not limited to infections caused by the following bacteria: Listeria (sp.), Franscicella tularensis,

Mycobacterium tuberculosis, Rickettsia (all types), Ehrlichia, Chlamydia. Further examples of bacteria that can be targeted by the present methods include M.

tuberculosis, M. bovis, M. bovis strain BCG, BCG substrains, M. avium, M.

intracellulare, M. africanum, M. lcansasii, M. marinum, M. ulcerans, M. avium subspecies paratuberculosis, Nocardia asteroides, other Nocardia species, Legionella pneumophila, other Legionella species, Salmonella typhi, other Salmonella species, Shigella species, Yersinia pestis, Pasteurella haemolytica, Pasteurella multocida, other Pasteurella species, Actinobacillus pleuropneumoniae, Listeria monocytogenes, Listeria ivanovii, Brucella abortus, other Brucella species, Cowdria ruminantium, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydia psittaci, Coxiella burnetii, other Rickettsial species, Ehrlichia species, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus agalactiae. Bacillus anthracis, Escherichia coli, Vibrio cholerae, Kingella kingae,

Campylobacter species, Neiserria meningitidis, Neiserria gonorrhea, Pseudomonas aeruginosa, other Pseudomonas species, Haemophilus influenzae, Haemophilus ducreyi, other Hemophilus species, Clostridium tetani, other Clostridium species, Yersinia enterolitica, and other Yersinia species. Examples of parasitic infections include, but are not limited to infections caused by the following parasites: Cryptosporidium, Plasmodium (all species), American trypanosomes (Γ. cruzi), African trypanosomes, Acanthamoeba, Entaoeba histolytica, Angiostrongylus, Anisakis, Ascaris, Babesia, Balantidium, Baylisascaris, lice, ticks, mites, fleas, Capillaria, Clonorchis, Chilomastix mesnili, Cyc!spora, Diphyllobothrium, Dipylidium caninum, Fasciola, Giardia, Gnathosioma,

Hetetophyes, Hymenolepsis, Isospora, Loa loa, Microsporidia, Naegleria, Toxocara, Onchocerca, Opisthorchis, Parago imus, Baylisascaris, Strongyloides, Taenia, Trichomonas and Trichuris.

Furthermore, examples of protozoan and fungal species contemplated within the present methods include, but are not limited to, Plasmodium falciparum, other Plasmodium species, Toxoplasma gondii, Pneumocystis carinii, Trypanosoma cruzi, other trypanosomal species, Leishmania donova i, other Leishmania species, Theileria annulata, other Theileria species, Eimeria tenella, other Eimeria species, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, Coccidioides immitis, Paracoccidioides brasiliensis, Penicillium marneffei, and Candida species. The provided compounds can also decrease infection by newly discovered or emerging bacteria, parasites or fungi, including multidrug resistant strains of same.

The compositions disclosed herein can also be used to treat multiple infections in the same individual simultaneously. The compositions can also be used to treat various individuals with different pathogenic infections. For example, the compositions disclosed herein can be used to treat an individual with both influenza virus as well as rhinovirus infection. In another example, the compositions disclosed herein can be used to treat one individual with influenza virus, and another individual with rhinovirus infection.

A compound can be single compound or a mixture, cocktail or combination of two or more compounds, for example, two or more compounds having a structure selected from the group consisting of formula I, II, III and IV, as defined above. It is understood that any compound set forth herein and derivatives of same can be utilized in the methods set forth herein.

The compounds set forth herein can be used alone or in combination with other therapeutic agents such as antiviral compounds, antibacterial agents, antifungal agents, antiparasitic agents, anti-inflammatory agents, anti-cancer agents, etc. The compounds set forth herein can be used in combination with antiviral agents that directly target the virus or the host, including for example viral entry inhibitors, un- coating inhibitors, reverse transcription inhibitors, integrase inhibitors,

translation/transcription inhibitors, nucleotides/nucleoside analogs, protease inhibitors, and assembly and release phase inhibitors. All of the compounds described herein can be contacted with a cell in vitro, ex vivo or in vivo.

Examples of antiviral compounds include, but are not limited to, amantadine, rimantadine, ribavirin, zanamivir (Relenza®) and oseltamivir (Tamiflu®) for the treatment of flu and its associated symptoms. Antiviral compounds useful in the treatment of rhinovirus infection include pleconaril and BTA-798. Antiviral compounds useful in the treatment of HIV include, but are not limited to, Combivir® (lamivudine-zidovudine), maraviroc, Crixivan® (indinavir), Emtriva®

(emtricitabine), Epivir® (lamivudine), Fortovase® (saquinavir-sg), Hivid®

(zalcitabine), Invirase® (saquinavir-hg), aletra® (lopinavir-ritonavir), LexivaTM (fosamprenavir), Norvir® (ritonavir), Retrovir® (zidovudine), Sustiva® (efavirenz), Videx EC® (didanosine), Videx® (didanosine), Viracept® (nelfinavir), Viramune® (nevirapine), Zerit® (stavudine), Ziagen® (abacavir), Fuzeon® (enfuvirtide), Rescriptor® (delavirdine), Reyataz® (atazanavir), Trizivir® (abacavir-lamivudine- zidovudine), Viread® (tenofovir disoproxil fumarate), Truvada® (tenofovir- emtricitabine), Atripla® (tenofovir-emtricitabine-efavirenz), Epzicom® (abacavir- lamivudine) and Agenerase® (amprenavir). Other antiviral compounds useful in the treatment of Ebola and other filoviruses include ribavirin and cyanovirin-N (CV-N). For the treatment of herpes viruses, Zovirax®(acyclovir), Valtrex® (valacyclovir), Cytovene® (ganciclovir) and Valcyte® (valganciclovir) are is available.

Antibacterial agents include, but are not limited to, antibiotics (for example, penicillin and ampicillin), sulfa Drugs and folic acid Analogs, Beta-Lactams, aminoglycosides, tetracyclines, macrolides, lincosamides, streptogramins, fluoroquinolones, rifampin, mupirocin, cycloserine, aminocyclitol and oxazolidinones.

Antifungal agents include, but are not limited to, amphotericin, nystatin, terbinafine, itraconazole, fluconazole, ketoconazole, and griselfulvin.

Antiparasitic agents include, but are not limited to, anthelmintics, antinematodal agents, antiplatyhelmintic agents, antiprotozoal agents, amebicides, antimalarials, antitrichomonal agents, aoccidiostats and trypanocidal agents. The compositions disclosed herein can also be used to treat or prevent asthma and/or chronic obstructive pulmonary disease (COPD) or associated conditions. The compositions can be administered to the patient with or without symptoms of viral infection that exacerbates or causes asthma and/or COPD. Typically, administration occurs as soon as symptoms of infection occur but can be administered at any point after or before infection that treats or prevents the condition. It is known that viral infections (such as respiratory infections including rhinovirus, for example) trigger the great majority of asthma exacerbations, and rhinoviruses account for two-thirds of these (Johnston SL, Pattemore P , Sanderson G, Smith S, Lampe F, Josephs L, Symington P, O'Toole S, Myint SH, Tyrrell DA, et al. Community study of role of viral infections in exacerbations of asthma in 9-1 1 year old children. BMJ

1995;310: 1225-1229). A recent study detected rhinoviruses in 82% of children admitted to an emergency room for acute asthma ( ling S, Donninger H, Williams Z, Vermeulen J, Weinberg E, Latiff K, Ghildyal R, Bardin P. Persistence of rhinovirus RNA after asthma exacerbation in children. Clin Exp Allergy 2005;35:672-678). Rhinovirus infection has also been associated with nearly half of all COPD exacerbations, including secondary infections resulting from the viral infection (Seemungal T, Harper-Owen R, Bhowmik A, Moric I, Sanderson G, Message S, Maccallum P, Meade TW, Jeffries DJ, Johnston SL, et al. Respiratory viruses, symptoms, and inflammatory markers in acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001 ; 164: 1618-1623). In addition, evidence has emerged that rhinoviruses are the most common cause of wheezing illness in the first year of life, and rhinovirus-induced wheezing illness in the first year of life is the strongest predictor of subsequent third-year wheezing (Lemanske RF, Jackson DJ, Gangnon RE, Evans MD, Li Z, Shult PA, Kirk CJ, Reisdorf E, Roberg KA, Anderson EL, et al. Rhinovirus illnesses during infancy predict subsequent childhood wheezing. J Allergy Clin Immunol 2005; 116:571-577). Therefore, the symptoms and effects of asthma and COPD can be reduced or ameliorated by treatment with the disclosed compositions, such as Sulindac.

Regarding Epstein-Barr Virus (EBV), it has become a recognized cause of central nervous system infection and lymphoproliferative disorders (PTLD), and AIDS-related lymphomas. PTLD consists of a heterogenous group of B-cell neoplasias that arise in a setting of immunosuppression and are associated with EBV infection especially in patients lacking antibodies to this virus. The incidence of PTLD ranges from 1% for renal transplant recipients, but can be as high as 9% for heart/lung and 12% for pancreas transplant patients. Furthermore, recent studies indicate that EBV may be related to the development of COPD (McManus et al. High levels of Epstein-Barr virus in COPD. Eur Respir J. 2008 Jun;31(6): 1221-6).

Therefore, the compositions disclosed herein, such as Sulindac, can also be used to treat diseases and disorders associated with EBV, for example COPD.

Delivery systems

Methods of introduction include, but are not limited to, mucosal, topical, intradermal, intrathecal, intratracheal, intranasal, via nebulizer, via inhalation, intramuscular, otic delivery (ear), eye delivery (for example, eye drops), buccal (cheek), intraperitoneal, vaginal, rectal, intravenous, subcutaneous, intranasal, and oral routes. The compounds can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (for example, nasal mucosa, oral mucosa, rectal, vaginal and intestinal mucosa, etc.) and can be administered together with other biologically active agents. Administration can be systemic or local. Pharmaceutical compositions can be delivered locally to the area in need of treatment, for example by topical application or local injection.

In one example, the compositions disclosed herein can be given via nasal inhaler. The nose can be an important route for the delivery of various substances aimed at treating various ailments. For example, the nose, including its various nasal membranes, cavities and passageways, traditionally has been used as a route for the delivery of substances aimed at treating upper respiratory ailments, such as sinusitis, allergic conditions, reactive airway diseases, and rhinitis.

Most of the substances delivered to a user through their nose, and in particular to the user's nasal membranes, are delivered in aerosol or aqueous form through nasal delivery devices, including pressurized metered dose nasal inhalers, nasal spray containers, and dry powder inhalers. In order to ensure a positive therapeutic effect, substances delivered to the nose to treat the above noted ailments can be, for example, delivered to the area of the nose having a rich blood vessel plexus. This area of the nose typically is found on the lateral sidewall to the interior of the nose, and encompasses the squamous epithelisum prior to the transitional region to the nasal turbinates. It should be understood that the substance could take many forms, depending upon the type of nasal delivery device being used and/or upon the type of ailment being treated. For example, the nasal delivery device can take the form of a spray- pump container or bottle. Alternatively, it can take the form of a pressurized metered dose nasal inhaler, or it can take the form of a simple squeeze-type bottle. The substance can exit the container in the form of a dry powder or as a spray, in aerosol or aqueous form. The term "aerosol" means a suspension of fine solid or liquid particles in a gas, including air. In addition to the compositions disclosed herein, the inhalant can also comprise anti-cholinergic agents, adrenegically acting

decongestants, topical buffering compounds and corticosteriod anti-inflammatory agents. The substance can also include various pain medications. Of course, it should be understood that the nasal inhaler can be used with any substance which is capable of being introduced into a chamber and thereafter dispensed through an air exit passageway in response to the inhalation of a patient, the compression of the chamber, the actuation of the container, and/or some combination of those activities.

The amount of substance in each dosage can be metered, such that the amount remains relatively constant upon each actuation, or it can vary depending on the actuation force applied by the user. It should be understood that, just as the nasal inhaler can be used without the user affirmatively inhaling, the inhaler also can be used without an actuation of the container. For example, the user can entrain the substance, e.g., a dry powder, into the chamber by generating an air flow through inhalation or compression of the chamber.

The compositions disclosed herein can also be given in an inhaler to be administered to the lungs. There are several different types of inhalers. The most common is the pressurized metered-dose inhaler (MDI). In MDIs, medication is most commonly stored in solution in a pressurized canister that contains a propellant, although it may also be a suspension. [Pharmaceutical Inhalation Aerosol

Technology, ed. A. J. Hickey, 2nd edition, Marcel Dekker, NY, 2004.] Besides the MDI, other types of inhalers include dry powder inhalers (DPIs), which release a dose of medicine as a powder aerosol that is inhaled by the patient, and nebulizers, which instead supply the aerosol as a mist created from an aqueous formulation.

The pharmaceutically acceptable carriers useful herein are conventional. Remington 's Pharmaceutical Sciences, by Martin, Mack Publishing Co., Easton, PA, 15th Edition (1975), describes compositions and formulations suitable for pharmaceutical delivery of the therapeutic agents herein disclosed. In general, the nature of the carrier will depend on the mode of administration being employed. For instance, parenteral formulations usually include injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, sesame oil, glycerol, ethanol, combinations thereof, or the like, as a vehicle. The carrier and composition can be sterile, and the formulation suits the mode of administration. In addition to biologically-neutral carriers, pharmaceutical compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.

The composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. For solid compositions (for example powder, pill, tablet, or capsule forms), conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, sodium saccharine, cellulose, magnesium carbonate, or magnesium stearate. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

Embodiments of the disclosure including medicaments can be prepared with conventional pharmaceutically acceptable carriers, adjuvants and counterions as would be known to those of skill in the art.

The amount of therapeutic agent effective in decreasing or inhibiting infection can depend on the nature of the pathogen and its associated disorder or condition, and can be determined by standard clinical techniques. Therefore, these amounts will vary depending on the type of virus, bacteria, fungus, parasite or other pathogen. For example, the dosage can be anywhere from 0.01 mg/kg to 100 mg/kg. This includes 0.01, 0.02, 0.03, 0.04. 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.30, 0.31, 0.32, 0.33, 0.34, 0.35, 0.36, 0.37, 0.38, 0.39, 0.40, 0.41, 0.42, 0.43, 0.44, 0.45, 0.46, 0.47, 0.48, 0.49, 0.50, 0.51 , 0.52, 0.53, 0.54, 0.55, 0.56, 0.57, 0.58, 0.59, 0.60, 0.61, 0.62, 0.63, 0.64, 0.65, 0.66, 0.67, 0.68, 0.69, 0.70, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.80, 0.81 , 0.82, 0.83, 0.84, 0.85, 0.86, 0.87, 0.88, 0.89, 0.90, 0.91, 0.92, 0.93, 0.94, 0.95, 0.96, 0.97, 0.98, 0.99, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1 , 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 1 1.0, 1 1.1, 1 1.2, 1 1.3, 1 1.4, 1 1.5, 11.6, 11.7, 1 1.8, 1 1.9, 12.0, 12.1, 12.2, 12.3, 12.4 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1, 15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, 16.0, 16.1, 16.2, 16.3, 16.4, 16.5, 16.6, 16.7, 16.8, 16.9, 17.0, 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 18.0, 18.1, 18.2, 18.3, 18.4. 18.5, 18.6, 18.7, 18.8, 18.9, 19.0, 19.1, 19.2, 19.3, 19.4, 19.5, 19.6, 19.7, 19.8, 19.9, 20.0, 20.1 , 20.2, 20.3, 20.4, 20.5, 20.6, 20.7, 20.8, 20.9, 21.0, 21.1 , 21.2, 21.3, 21.4, 21.5, 21.6, 21.7, 21.8, 21.9, 22.0, 22.1, 22.2, 22.3, 22.4, 22.5, 22.6, 22.7, 22.8, 22.9, 23.0, 23.1, 23.2, 23.3, 23.4, 23.5, 23.6, 23.7, 23.8, 23.9, 24.0, 24.1, 24.2, 24.3, 24.4, 24.5, 24.6, 24.7, 24.8, 24.9, 25.0, 25.1, 25.2, 25.3, 25.4, 25.5, 25.6, 25.7, 25.8, 25.9, 26.0, 26.1 , 26.2, 26.3, 26.4, 26.5, 26.6, 26.7, 26.8, 26.9, 27.0, 27.1 , 27.2, 27.3, 27.4, 27.5, 27.6, 27.7, 27.8, 27.9, 28.0, 28.1, 28.2, 28.3, 28.4, 28.5, 28.6, 28.7, 28.8, 28.9, 29.0, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 29.8, 29.9, 30.0, 30.1, 30.2, 30.3, 30.4, 30.5, 30.6, 30.7, 30.8, 30.9, 31.0, 31.1 , 31.2, 31.3, 31.4, 31.5, 31.6, 31.7, 31.8, 31.9, 32.0, 32.1, 32.2, 32.3, 32.4, 32.5, 32.6, 32.7, 32.8, 32.9, 33.0, 33.1, 33.2, 33.3, 33.4, 33.5, 33.6, 33.7, 33.8, 33.9, 34.0, 34.1, 34.2, 34.3, 34.4, 34.5, 34.6, 34.7, 34.8, 34.9, 35.0, 35.1, 35.2, 35.3, 35.4, 35.5, 35.6, 35.7, 35.8, 35.9, 36.0, 36.1, 36.2, 36.3, 36.4, 36.5, 36.6, 36.7, 36.8, 36.9, 37.0, 37.1, 37.2, 37.3, 37.4, 37.5, 37.6, 37.7, 37.8, 37.9, 38.0, 38.1, 38.2, 38.3, 38.4, 38.5, 38.6, 38.7, 38.8, 38.9, 39.0, 39.1, 39.2, 39.3, 39.4, 39.5, 39.6, 39.7, 39.8, 39.9, 40.0, 40.1, 40.2, 40.3, 40.4, 40.5, 40.6, 40.7, 40.8, 40.9, 41.0, 41.1 , 41.2, 41.3, 41.4, 41.5, 41.6, 41.7, 41.8, 41.9, 42.0, 42.1 , 42.2, 42.3, 42.4, 42.5, 42.6, 42.7, 42.8, 42.9, 43.0, 43.1, 43.2, 43.3, 43.4, 43.5, 43.6, 43.7, 43.8, 43.9, 44.0, 44.1, 44.2, 42.3, 44.4, 44.5, 44.6, 44.7, 44.8, 44.9, 45.0, 45.1, 45.2, 45.3, 45.4, 45.5, 45.6, 45.7, 45.8, 45.9, 46.0, 46.1, 46.2, 46.3, 46.4, 46.5, 46.6, 46.7, 46.8, 46.9, 47.0, 47.1, 47.2, 47.3 47.4, 47.5, 47.6, 47.7, 47.8, 47.9, 48.0, 48.1 , 48.2, 48.3, 48.4, 48.5, 48.6, 48.7, 48.8, 48.9, 49.0, 49.1, 49.2, 49.3, 49.4, 49.5, 49.6, 49.7, 49.8, 49.9, 50.0, 50.1 , 50.2, 50.3, 50.4, 50.5, 50.6, 50.7, 50.8, 50.9, 51.0, 51.1 , 51.2, 51.3, 51.4, 51.5, 51.6, 51.7, 51.8, 51.9, 52.0, 52.1 , 52.2, 52.3, 52.4, 52.5, 52.6, 52.7, 52.8, 52.9, 53.0, 53.1, 53.2, 53.3, 53.4, 53.5, 53.6, 53.7, 53.8, 53.9, 54.0, 54.1, 54.2, 54.3, 54.4, 54.5, 54.6, 54.7, 54.8, 54.9, 55.0, 55.1, 55.2, 55.3, 55.4, 55.5, 55.6, 55.7, 55.8, 55.9, 56.0, 56.1, 56.2, 56.3, 56.4, 56.5, 56.6, 56.7, 56.8, 56.9, 57.0, 57.1, 57.2, 57.3, 57.4, 57.5, 57.6, 57.7, 57.8, 57.9, 58.0, 58.1, 58.2, 58.3, 58.4, 58.5, 58.6, 58.7, 58.8, 58.9, 59.0, 59.1, 59.2, 59.3, 59.4, 59.5, 59.6, 59.7, 59.8, 59.9, 60.0, 60.1, 60.2, 60.3, 60.4, 60.5, 60.6, 60.7, 60.8, 60.9, 61.0, 61.1, 61.2, 61.3, 61.4, 61.5, 61.6, 61.7, 61.8, 61.9, 62.0, 62.1, 2.2, 62.3, 62.4, 62.5, 62.6, 2.7, 62.8, 62.9, 63.0, 63.1, 63.2, 63.3, 63.4, 63.5, 63.6, 63.7, 63.8, 63.9, 64.0. 64.1, 64.2, 64.3, 64.4, 64.5, 64.6, 64.7, 64.8, 64.9, 65.0, 65.1, 65.2, 65.3, 65.4, 65.5, 65.6, 5.7, 65.8, 65.9, 66.0, 66.1, 66.2, 66.3, 66.4, 66.5, 66.6, 66.7, 66.8, 66.9, 67.0, 67.1, 67.2, 67.3, 67.4, 67.5, 67.6, 67.7, 67.8, 67.9, 68.0, 68.1, 68.2, 68.3, 68.4, 68.5, 68.6, 68.7, 68.8, 68.9, 69.0, 69.1, 69.2, 69.3, 69.4, 69.5, 69.6, 69.7, 69.8, 69.9, 70.0, 70.1, 70.2, 70.3, 70.4, 70.5, 70.6, 70.7, 70.8, 70.9, 71.0, 71.1 , 71.2, 71.3, 71.4, 71.5, 71.6, 71.7, 71.8, 71.9, 72.0, 72.1 , 72.2, 72.3, 72.4, 72.5, 72.6, 72.7, 72.8, 72.9, 73.0, 73.1, 73.2, 73.3, 73.4, 73.5, 73.6, 73.7, 73.8, 73.9, 74.0, 74.1, 74.2, 74.3, 74.4, 74.5, 74.6, 74.7, 74.8, 74.9, 75.0, 75.1, 75.2, 75.3, 75.4, 75.5, 75.6, 75.7, 75.8, 75.9, 76.0, 76.1, 76.2, 76.3, 76.4, 76.5, 76.6, 76.7, 76.8, 76.9, 77.0, 77.1 , 77.2, 77.3, 77.4, 77.5, 77.6, 77.7, 77.8, 77.9, 78.0, 78.1 , 78.2, 78.3, 78.4, 78.5, 78.6, 78.7, 78.8, 78.9, 79.0, 79.1, 79.2, 79.3, 79.4, 79.5, 79.6, 79.7, 79.8, 79.9, 80.0. 80.1, 80.2, 80.3, 80.4, 80.5, 80.6, 80.7, 80.8, 80.9, 81.0, 81.1, 81.2, 81.3, 81.4, 81.5, 81.6, 81.7, 81.8, 81.9, 82.0, 82.1, 82.2, 82.3, 82.4, 82.5, 82.6, 82.7, 82.8, 82.9, 83.0, 83.1, 83.2, 83.3, 83.4, 83.5, 83.6, 83.7, 83.8, 83.9, 84.0, 84.1, 84.2, 84.3, 84.4, 84.5, 84.6, 84.7, 84.8, 84.9, 85.0, 85.1, 85.2, 85.3, 85.4, 85.5, 85.6, 85.7, 85.8, 85.9, 86.0, 86.1, 86.2, 86.3, 86.4, 86.5, 86.6, 86.7, 86.8, 86.9, 87.0, 87.1, 87.2, 87.3, 87.4, 87.5, 87.6, 87.7, 87.8, 87.9, 88.0, 88.1, 88.2, 88.3, 88.4, 88.5, 88.6, 88.7, 88.8, 88.9, 89.0, 89.1, 89.2, 89.3, 89.4, 89.5, 89.6, 89.7, 89.8, 89.9, 90.0, 90.1, 90.2, 90.3, 90.4, 90.5, 90.6, 90.7, 90.8, 90.9, 91.0, 91.1 , 91.2, 91.3, 91.4, 91.5, 91.6, 91.7, 91.8, 91.9, 92.0, 92.1, 92.2, 92.3, 92.4, 92.5, 92.6, 92.7, 92.8, 92.9, 93.0, 93.1, 93.2, 93.3, 93.4, 93.5, 93.6, 93.7, 93.8, 93.9, 94.0, 94.1, 94.2, 94.3, 94.4, 94.5, 94.6, 94.7, 94.8, 94.9, 95.0, 95.1, 95.2, 95.3, 95.4, 95.5, 95.6, 95.7, 95.8, 95.9, 96.0, 96.1, 96.2, 96.3, 96.4, 96.5, 96.6. 96.7, 96.8, 96.9, 97.0, 97.1, 97.2, 97.3, 97.4, 97.5, 97.6, 97.7, 97.8, 97.9, 98.0, 98.1, 98.2, 98.3, 98.4, 98.5, 98.6, 98.7, 98.8, 98.9, 99.0, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99.9, 100.0, 100.1, 100.2, 100.3, 100.4, 100.5, 100.6, 100.7, 100.8, 100.9, 101.0, 101.1, 101.2, 101.3, 101.4, 101.5, 101.6, 101.7, 101.8, 101.9, 102.0, 102.1 , 102.2, 102.3, 102.4, 102.5, 102.6, 102.7, 102.8, 102.9, 103.0, 103.1 , 103.2, 103.3, 103.4, 103.5, 103.6, 103.7, 103.8, 103.9, 104.0, 104.1, 104.2, 104.3, 104.4, 104.5, 104.6, 104.7. 104.8, 104.9, 105.0, 105.1, 105.2, 105.3, 105.4, 105.5, 105.6, 105.7, 105.8, 105.9, 106.0, 106.1, 106.2, 106.3, 106.4, 106.5, 106.6, 106.7,

106.8, 106.9, 107.0, 107.1, 107.2, 107.3, 107.4, 107.5, 107.6, 107.7, 107.8, 107.9,

108.0, 108.1, 108.2, 108.3, 108.4, 108.5. 108.6, 108.7, 108.8, 108.9, 109.0, 109.1,

109.2, 109.3, 109.4, 109.5, 109.6, 109.7, 109.8, 109.9, 110.0, 110.1, 110.2, 110.3,

110.4, 110.5, 110.6, 110.7, 110.8, 110.9, 111.0, 111.1, 111.2, 111.3, 111.4, 111.5,

111.6, 111.7, 111.8, 111.9, 112.0, 112.1, 112.2, 112.3, 112.4 112.5, 112.6, 112.7,

112.8, 112.9, 113.0, 113.1, 113.2, 113.3, 113.4, 113.5, 113.6, 113.7, 113.8, 113.9,

114.0, 114.1, 114.2, 114.3, 114.4, 114.5, 114.6, 114.7, 114.8, 114.9, 115.0, 115.1,

115.2, 115.3, 115.4, 115.5, 115.6, 115.7, 115.8, 115.9, 116.0, 116.1, 116.2, 116.3,

116.4, 116.5, 116.6, 116.7, 116.8, 116.9, 117.0, 117.1, 117.2, 117.3, 117.4, 117.5,

117.6, 117.7, 117.8, 117.9, 118.0, 118.1, 118.2, 118.3, 118.4. 118.5, 118.6, 118.7,

118.8, 118.9, 119.0, 119.1, 119.2, 119.3, 119.4, 119.5, 119.6, 119.7, 119.8, 119.9,

120.0, 120.1, 120.2, 120.3, 120.4, 120.5, 120.6, 120.7, 120.8, 120.9, 121.0, 121.1,

121.2, 121.3, 121.4, 121.5, 121.6, 121.7, 121.8, 121.9, 122.0, 122.1, 122.2, 122.3,

122.4, 122.5, 122.6, 122.7, 122.8, 122.9, 123.0, 123.1, 123.2, 123.3, 123.4, 123.5,

123.6, 123.7, 123.8, 123.9, 124.0, 124.1, 124.2, 124.3, 124.4, 124.5, 124.6, 124.7,

124.8, 124.9, 125.0, 125.1, 125.2, 125.3, 125.4, 125.5, 125.6, 125.7, 125.8, 125.9,

126.0, 126.1, 126.2, 126.3, 126.4, 126.5, 126.6, 126.7, 126.8, 126.9, 127.0, 127.1,

127.2, 127.3, 127.4, 127.5, 127.6, 127.7, 127.8, 127.9, 128.0, 128.1, 128.2, 128.3,

128.4, 128.5, 128.6, 128.7, 128.8, 128.9, 129.0, 129.1, 129.2, 129.3, 129.4, 129.5,

129.6, 129.7, 129.8, 129.9, 130.0, 130.1, 130.2, 130.3, 130.4, 130.5, 130.6, 130.7,

130.8, 130.9, 131.0, 131.1, 131.2, 131.3, 131.4, 131.5, 131.6, 131.7, 131.8, 131.9,

132.0, 132.1, 132.2, 132.3, 132.4, 132.5, 132.6, 132.7, 132.8, 132.9, 133.0, 133.1,

133.2, 133.3, 133.4, 133.5, 133.6, 133.7, 133.8, 133.9, 134.0, 134.1, 134.2, 134.3,

134.4, 134.5, 134.6, 134.7, 134.8, 134.9, 135.0, 135.1, 135.2, 135.3, 135.4, 135.5,

135.6, 135.7, 135.8, 135.9, 136.0, 136.1, 136.2, 136.3, 136.4, 136.5, 136.6, 136.7,

136.8, 136.9, 137.0, 137.1, 137.2, 137.3, 137.4, 137.5, 137.6, 137.7, 137.8, 137.9,

138.0, 138.1, 138.2, 138.3, 138.4, 138.5, 138.6, 138.7, 138.8, 138.9, 139.0, 139.1,

139.2, 139.3, 139.4, 139.5, 139.6, 139.7, 139.8, 139.9, 140.0, 140.1, 140.2, 140.3,

140.4, 140.5, 140.6, 140.7, 140.8, 140.9, 141.0, 141.1, 141.2, 141.3, 141.4, 141.5,

141.6, 141.7, 141.8, 141.9, 142.0, 142.1, 142.2, 142.3, 142.4, 142.5, 142.6, 142.7,

142.8, 142.9, 143.0, 143.1, 143.2, 143.3, 143.4, 143.5, 143.6, 143.7, 143.8, 143.9,

144.0, 144.1, 144.2, 142.3, 144.4, 144.5, 144.6, 144.7, 144.8, 144.9, 145.0, 145.1,

145.2, 145.3, 145.4, 145.5, 145.6, 145.7, 145.8, 145.9, 146.0, 146.1, 146.2, 146.3, 146.4, 146.5, 146.6, 146.7, 146.8, 146.9, 147.0, 147.1, 147.2, 147.3, 147.4, 147.5,

147.6, 147.7, 147.8, 147.9, 148.0, 148.1, 148.2, 148.3, 148.4, 148.5, 148.6, 148.7,

148.8, 148.9, 149.0, 149.1, 149.2, 149.3, 149.4, 149.5, 149.6, 149.7, 149.8, 149.9,

150.0, 150.1 , 150.2, 150.3, 150.4, 150.5, 150.6, 150.7, 150.8, 150.9, 151.0, 151.1,

151.2, 151.3, 151.4, 151.5, 151.6, 151.7, 151.8, 151.9, 152.0, 152.1, 152.2, 152.3,

152.4, 152.5, 152.6, 152.7, 152.8, 152.9, 153.0, 153.1, 153.2, 153.3, 153.4, 153.5,

153.6, 153.7, 153.8, 153.9, 154.0, 154.1 , 154.2, 154.3 , 154.4, 154.5 , 154.6, 154.7,

154.8, 154.9, 155.0, 155.1, 155.2, 155.3, 155.4, 155.5, 155.6, 155.7, 155.8, 155.9,

156.0, 156.1 , 156.2, 156.3, 156.4, 156.5, 156.6, 156.7, 156.8, 156.9, 157.0, 157.1 ,

157.2, 1157.3, 57.4, 157.5, 157.6, 157.7, 157.8, 157.9, 158.0, 158.1 , 158.2, 158.3,

158.4, 158.5, 158.6, 158.7, 158.8, 158.9, 159.0, 159.1, 159.2, 159.3, 159.4, 159.5,

159.6, 159.7, 159.8, 159.9, 160.0, 160.1 , 160.2, 160.3, 160.4, 160.5, 160.6, 160.7,

160.8, 160.9, 161.0, 161.1, 161.2, 161.3, 161.4, 161.5, 161.6, 161.7, 161.8, 161.9,

162.0, 162.1 , 162.2, 162.3, 162.4, 162.5, 162.6, 162.7, 162.8, 162.9, 163.0, 163.1,

163.2, 163.3, 163.4, 163.5, 163.6, 163.7, 163.8, 163.9, 164.0, 164.1, 164.2, 164.3,

164.4, 164.5, 164.6, 164.7, 164.8, 164.9, 165.0, 165.1, 165.2, 165.3, 165.4, 165.5,

165.6, 165.7, 165.8, 165.9, 166.0, 166.1, 166.2, 166.3, 166.4, 166.5, 166.6, 166.7,

166.8, 166.9, 167.0, 167.1, 167.2, 167.3, 167.4, 167.5, 167.6, 167.7, 167.8, 167.9,

168.0, 168.1, 168.2, 168.3, 168.4, 168.5, 168.6, 168.7, 168.8, 168.9, 169.0, 169.1,

169.2, 169.3, 169.4, 169.5, 169.6, 169.7, 169.8, 169.9, 170.0, 170.1, 170.2, 170.3,

170.4, 170.5, 170.6, 170.7, 170.8, 170.9, 171.0, 171.1, 171.2, 171.3, 171.4, 171.5,

171.6, 171.7, 171.8, 171.9, 172.0, 172.1, 172.2, 172.3, 172.4, 172.5, 172.6, 172.7,

172.8, 172.9, 173.0, 173.1, 173.2, 173.3, 173.4, 173.5, 173.6, 173.7, 173.8, 173.9,

174.0, 174.1 , 174.2, 174.3, 174.4, 174.5, 174.6, 174.7, 174.8, 174.9, 175.0, 175.1 ,

175.2, 175.3, 175.4, 175.5, 175.6, 175.7, 175.8, 175.9, 176.0, 176.1, 176.2, 176.3,

176.4, 176.5, 176.6, 176.7, 176.8, 176.9, 177.0, 177.1, 177.2, 177.3, 177.4, 177.5,

177.6, 177.7, 177.8, 177.9, 178.0, 178.1, 178.2, 178.3, 178.4, 178.5, 178.6, 178.7,

178.8, 178.9, 179.0, 179.1, 179.2, 179.3, 179.4, 179.5, 179.6, 179.7, 179.8, 179.9,

180.0. 180.1 , 180.2, 180.3, 180.4, 180.5, 180.6, 180.7, 180.8, 180.9, 181.0, 181.1 ,

181.2, 181.3, 181.4, 181.5, 181.6, 181.7, 181.8, 181.9, 182.0, 182.1, 182.2, 182.3,

182.4, 182.5, 182.6, 182.7, 182.8, 182.9, 183.0, 183.1, 183.2, 183.3, 183.4, 183.5,

183.6, 183.7, 183.8, 183.9, 184.0, 184.1 , 184.2, 184.3, 184.4, 184.5, 184.6, 184.7,

184.8, 184.9, 185.0, 185.1, 185.2, 185.3, 185.4, 185.5, 185.6, 185.7, 185.8, 185.9,

186.0, 186.1 , 186.2, 186.3, 186.4, 186.5, 186.6, 186.7, 186.8, 186.9, 187.0, 187.1 , 187.2, 187.3, 187.4, 187.5, 187.6, 187.7, 187.8, 187.9, 188.0, 188.1, 188.2, 188.3, 188.4, 188.5, 188.6, 188.7, 188.8, 188.9, 189.0, 189.1, 189.2, 189.3, 189.4, 189.5, 189.6, 189.7, 189.8, 189.9, 190.0, 190.1, 190.2, 190.3, 190.4, 190.5, 190.6, 190.7, 190.8, 190.9, 191.0, 191.1, 191.2, 191.3, 191.4, 191.5, 191.6, 191.7, 191.8, 191.9, 192.0, 192.1 , 192.2, 192.3, 192.4, 192.5, 192.6, 192.7, 192.8, 192.9, 193.0, 193.1, 193.2, 193.3, 193.4, 193.5, 193.6, 193.7, 193.8, 193.9, 194.0, 194.1, 194.2, 194.3, 194.4, 194.5, 194.6, 194.7, 194.8, 194.9, 195.0, 195.1, 195.2, 195.3, 195.4, 195.5, 195.6, 195.7, 195.8, 195.9, 196.0, 196.1, 196.2, 196.3, 196.4, 196.5, 196.6. 196.7, 196.8, 196.9, 197.0, 197.1, 197.2, 197.3, 197.4, 197.5, 197.6, 197.7, 197.8, 197.9, 198.0, 198.1, 198.2, 198.3, 198.4, 198.5, 198.6, 198.7, 198.8, 198.9, 199.0, 199.1, 199.2, 199.3, 199.4, 199.5, 199.6, 199.7, 199.8, 199.9, or 200.0 mg/kg. Also contemplated are 210, 220, 230, 240, 240, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg kg. Further contemplated herein are any dosages above, below, or between those amounts specified.

Thus, disclosed herein are dosages and formulations of Sulindac, and the compounds provided herein, that vary from the 150mg and 200mg doses currently used clinically for Sulindac. For example, provided is Sulindac in doses less than 150mg (e.g. 145, 140, 135, 130, 125, 120, 1 15, 110, 105, 100, 95, 90, 85, 80, 75, 70, 65, 0, 55, 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5mg) formulated under GMP for administration to human subjects. In addition because of the acute nature of most infectious diseases, including respiratory viruses, the duration of the administration of sulindac can be reduced. As a result of dose, route of administration and/or duration of administration, the safety of the drug is improved and can result in an improved clinical label. Thus, the compounds disclosed herein, including for example sulindac, are provided in combination with a safety label with decreased adverse clinical side effect profile compared to Sulindac for inflammation, e.g. at the 150mg or 200mg oral doses for time periods extending beyond the period of acute infections. Multiple dosages can also be administered depending on the type of pathogen, and the subject's condition. In addition, in vitro assays can be employed to identify optimal dosage ranges. The precise dose to be employed in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each subject's circumstances. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions. Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration and in particular for viral infection such as a pox virus, BVDV, a herpes virus, HIV, an RSV virus, an influenza virus, a hepatitis C virus, a hepatitis B virus, Epstein Barr Virus, Human Papilloma Virus, CMV, West Nile virus, a rhinovirus, an adenovirus, measles virus, Marburg virus, Ebola virus, Rift Valley Fever Virus, LCM, Junin virus, Machupo virus, Guanarito virus, Lassa Fever virus, Hantavirus, SARS virus, Nipah virus,

Caliciviruses, Hepatitis A, LaCrosse, California encephalitis, VEE, EEE.WEE, Japanese Encephalitis Virus, yasanur Forest Virus, Yellow Fever, Rabies,

Chikungunya virus or a Dengue fever virus. Instructions for use of the composition, in particular instructions for administration to treat viral infection in a subject can also be included. EXAMPLES EXAMPLE 1

Duplicate experiments were performed as follows. Prior to compound exposure cells were seeded into 12-well tissue culture plates and allowed to adhere to the vessel surface. Sulindac was serially diluted and lOOul was added to the growth medium in triplicate wells to obtain the indicated final concentration of compound or solvent. Cells were incubated in the presence of the test compound for 24 hours at 37'C under 5% C0₂.

Following the pre-treatment period, cells were examined under a phase- contrast microscope to determine any cytotoxic effects at the treatment dosages. The pre-treatment medium was then aspirated off the cells, and the specified virus, diluted in serum- and compound-free growth medium, was added to the cells. Virus was allowed to adsorb to the cells at 37°C with the exception of Rhinovirus, which was adsorbed at 33°C, under 5% C0₂. Following adsorption, the viral inoculum was aspirated off the cells and replaced with growth medium supplemented with 2% FBS, 1% L-glutamine, 1% penicillin/streptomycin and the respective concentration of test compound. Cells were incubated under the same conditions for an additional 72 hours. 200ul samples were harvested from each well and viral RNA or DNA was extracted using the PureLink 96 Viral RNA/DNA extraction kit (Invitrogen) as directed by the manufacturer. Viral nucleic acid was subjected to reverse transcription to generate cDNA, which was subsequently used as the template for quantitative real-time TaqMan PCR to titrate viral replication using a Mastercycler ep realplex² (Eppendorf).

Toxicity of the compounds set forth herein was assessed using the CytoTox-

Glo assay (see Niles, A. et al. (2007) Anal. Biochem. 366, 1 7-206 or the Cell-Titer- Glo assay from Promega); however the toxicity of the compounds set forth herein can be assessed via any of the toxicity measurement methods known to one of skill in the art.

Sulindac inhibited infection by rhinovirus 16 (EC50 = 0.13 μΜ). Sulindac sulfide inhibited infection by rhinovirus 16 (EC₅₀ = 5.7 μΜ). Sulindac sulfone inhibited infection by rhinovirus 16 (EC5₀ = 4.3 μΜ). Sulindac inhibited infection by rhinovirus 2 (EC₅₀ = 2.6 μΜ). Sulindac sulfide inhibited infection by rhinovirus 2 (EC5₀ = 7.1 μΜ). Sulindac sulfone inhibited infection by rhinovirus 2 (EC5₀ = 2.6 μΜ). Sulindac inhibited infection by RSV (EC50 = 7.6 μΜ). Sulindac sulfide inhibited infection by RSV (EC50 = 5.0 μΜ). Sulindac sulfone inhibited infection by RSV (EC50 = 2.6 μΜ). Sulindac inhibited infection by influenza (EC50 = 3.2 μΜ). Sulindac sulfide inhibited infection by influenza (EC50 = 2.6 μ ). Sulindac sulfone inhibited infection by influenza (EC50 = 2.6 μΜ). As utilized herein, EC50 is a quantitative measure that indicates the concentration of a test compound needed to inhibit viral infection by 50%.

EXAMPLE 2

The test material was evaluated in MRC-5 cells against the 1 A and 14 strains of human rhinovirus (HRV) in parallel with ribavirin as a control compound.

MATERIALS AND METHODS

Compounds: Test material provided by Zirus, Inc. (ZIR03056.1) was received as a dry powder and was solubilized in DMSO at 40mM. The test solution was stored at -20°C and protected from light. ZIR03056.1 was evaluated using a high test concentration of 100 μΜ and serially diluted in half-log increments for the in vitro antiviral assays. Ribavirin was purchased from Sigma (St. Louis, MO) and used as a protective control compound in the cytoprotection assay.

Anti-HRV Cytoprotection Assay: Cell preparation: MRC-5 cells (human male diploid embryonal lung fibroblast, ATCC) were passaged in T-75 flasks in DMEM medium supplemented with 10% fetal bovine serum, 2 mM L-glutamine, 0.1 mM NEAA, 1 mM sodium pyruvate, 100 μg/ml penicillin. On the day preceding the assay, the cells were split 1 :2 to assure they were in an exponential growth phase at the time of infection. Total cell and viability quantification was performed using a hemocytometer and Trypan Blue dye exclusion. Cell viability was greater than 95% for the cells to be utilized in the assay. The cells were resuspended at lxl 0⁴ cells per well in tissue culture medium and added to the microtiter plates in a volume of 100 μL·. The plates were incubated at 37°C overnight to allow for cell adherence.

Compound Addition: Medium was removed from the cell monolayer and diluted compound was added to the appropriate well in a volume of 100 μL·

Virus Preparation: the viruses used for assays were strains HRV14 (VR- 284) and HRV1A (VR-1559). The viruses were obtained from ATCC and stock virus pools were produced in MRC-5 cells. A pretitered aliquot of virus was removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biological safety cabinet. Virus was resuspended and diluted into assay medium (DMEM supplemented with 2% FBS, 2 mM L-glutamine, 1 mM sodium pyruvate, 0.1 mM NEAA, 100 U/mL penicillin, and 100 μg/mL) such that the amount of virus added to each well in a volume of 100 LL was the amount determined to yield 80 to 90% cell killing at 6 days post-infection.

Plate Format: Each plate contains cell control wells (cells only), virus control wells (cells plus virus), drug toxicity wells (cell plus drug only), drug colorimetric control wells (drug only) as well as experimental wells (drug plus cells plus virus).

Efficacy and Toxicity XTT: Following incubation at 37°C, the test plates were stained with the tetrazolium dye XTT (2,3-bis(2-methoxy-4-nitro-5- sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide). XTT- tetrazolium is metabolized by the mitochondrial enzymes of metabolically active cells to a soluble formazan product, allowing rapid quantitative analysis of the inhibition of HRV induced cell killing. XTT/PMS stock was prepared immediately before use by adding 40 μί of PMS per ml of XTT solution. Fifty microliters of XTT/PMS was added to each well of the plate and the plate was reincubated for 2.5 hours at 37°C. Plates were sealed with adhesive plate sealers and shaken gently or inverted several times to mix the soluble formazan product and the plate was read spectrophotometrically at 450/650 nm with a Molecular Devices Vmax plate reader.

Data Analysis: Raw data was collected from the Softmax Pro 4.6 software and imported into a Microsoft Excel XL fit4 spreadsheet for analysis by four parameter curve fit calculations. Both antiviral activity and toxicity with a graphic representation of the data are provided in a Plate Analysis Report (PAR) summarizing the individual compound activity. The PAR for each compound consists of the following: the plate design demonstrating the microtiter plate assay format, the raw optical density data values imported from Softmax, the cell type and virus strain that was used in the assay, the technician responsible for the performance of the antiviral assay, the project number identification, the dates of assay initiation and completion, the mean values for the reagent, virus and cell controls and differential of virus to cell control, summary table of mean optical density values at each compound concentration in the efficacy, toxicity and colorimetric wells along with calculated percentage of reduction values for viral cytopathic effect (CPE) and cell viability; graphical presentation of the percentage of cell viability and percentage of reduced viral CPE at each test concentration.

RESULTS

Anti-HRV Evaluation: Test compound ZIR03056.1 was evaluated against the 14 and 1A strains of human rhinovirus in MRC-5 cells using a 6 concentration dose response curve. The results of these assays are summarized in Table 1. The graphical representation of these data compares the antiviral efficacy and cellular toxicity expressed as a percentage of the control. Figures 1-2.

The ribavirin control compound was evaluated in parallel with the submitted test materials and yielded an EC50 value of 16.1 μg mL versus HRV14 and 7.6 μg/mL versus HRVi_A. ZIR03056.1 demonstrated similar antiviral activity against the two strains of HRV yielding EC50 values of 2.3 and 5.4 μΜ versus HRV14 and HRVIA, respectively.

EXAMPLE 3

MRC-5 cells are seeded overnight in 96-well plates (2,000 cells per well). On the following day, the medium is aspirated and replaced with 80 μΐ- of fresh medium. Subsequently, candidate inhibitors are added to triplicate wells (10 μΐ. / well). Then, cells are infected by addition of 10 μΐ, of virus / well (MOI = 0.1) to give a total volume per well of 100 μί, and final candidate inhibitor

concentrations of 100 μΜ, 10 μΜ, or 1 μΜ. The inoculum is not removed by washing it away. The cells are incubated for 4 days at 33°C in MEM medium containing 10% FBS, 1% penicillin/streptomycin, 1% L-glutamine, and 40 mM MgCI2. At 4 days post-infection, CPE reduction with candidate inhibitors or interferon C alpha (positive control) is analyzed using the CytoToxGlo kit (Promega). Values from uninfected cells are used for 100% CPE reduction. Values from solvent control treated, infected cells are used for 0% CPE reduction. (Figures 3-7).

EXAMPLE 4: Sulindac Label

Cardiovascular Risk

There may be an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

Gastrointestinal Risk There may be an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events.

CARDIOVASCULAR EFFECTS

Cardiovascular Thrombotic Events

Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk.

Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur.

There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an SAID does increase the risk of serious GI events (see GI WARNINGS).

Two large, controlled, clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke (see

CONTRAINDICATIONS).

Hypertension

NSAIDs, including sulindac, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including sulindac, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy.

Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Sulindac should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation

NSAIDs, including sulindac, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy.

However, even short-term therapy is not without risk.

NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.

To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.

Hepatic Effects In addition to hypersensitivity reactions involving the liver, in some patients the findings are consistent with those of cholestatic hepatitis (see WARNINGS, Hypersensitivity). As with other non-steroidal anti-inflammatory drugs, borderline elevations of one or more liver tests without any other signs and symptoms may occur in up to 15% of patients taking NSAIDs including sulindac. These laboratory abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. The SGPT (ALT) test is probably the most sensitive indicator of liver dysfunction. Meaningful (3 times the upper limit of normal) elevations of SGPT or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. Notable elevations of ALT or AST

(approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with sulindac. Although such reactions as described above are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), sulindac should be discontinued.

In clinical trials with sulindac, the use of doses of 600 mg/day has been associated with an increased incidence of mild liver test abnormalities (see DOSAGE AND ADMINISTRATION for maximum dosage recommendation).

Renal Effects

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal

decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, patients who are volume-depleted, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

Advanced Renal Disease

No information is available from controlled clinical studies regarding the use of sulindac in patients with advanced renal disease. Therefore, treatment with sulindac is not recommended in these patients with advanced renal disease. If sulindac therapy must be initiated, close monitoring of the patient's renal function is advisable.

Anaphylactic/Anaphylactoid Reactions

As with other NSAIDs, anaphylactic/anaphylactoid reactions may occur in patients without known prior exposure to sulindac. Sulindac should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS - Preexisting Asthma). Emergency help should be sought in cases where an

anaphylactic/anaphylactoid reaction occurs.

Skin Reactions

NSAIDs, including sulindac, can cause serious skin adverse events such as exfoliative dermatitis, Stevens- Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity.

Hypersensitivity

Rarely, fever and other evidence of hypersensitivity (see ADVERSE REACTIONS) including abnormalities in one or more liver function tests and severe skin reactions have occurred during therapy with sulindac. Fatalities have occurred in these patients. Hepatitis, jaundice, or both, with or without fever, may occur usually within the first one to three months of therapy. Determinations of liver function should be considered whenever a patient on therapy with sulindac develops unexplained fever, rash or other dermatologic reactions or constitutional symptoms. If unexplained fever or other evidence of hypersensitivity occurs, therapy with sulindac should be discontinued. The elevated temperature and abnormalities in liver function caused by sulindac characteristically have reverted to normal after discontinuation of therapy. Administration of sulindac should not be reinstituted in such patients.

Pregnancy

In late pregnancy, as with other NSAIDs, sulindac should be avoided because it may cause premature closure of the ductus arteriosus.

PRECAUTIONS

General

Sulindac cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of sulindac in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Hematological Effects

Anemia is sometimes seen in patients receiving NSAIDs, including sulindac. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including sulindac, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible.

Patients receiving sulindac who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Preexisting Asthma

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirinsensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other nonsteroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, sulindac should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Renal Calculi

Sulindac metabolites have been reported rarely as the major or a minor component in renal stones in association with other calculus components.

Sulindac should be used with caution in patients with a history of renal lithiasis, and they should be kept well hydrated while receiving sulindac.

Pancreatitis

Pancreatitis has been reported in patients receiving sulindac (see

ADVERSE REACTIONS). Should pancreatitis be suspected, the drug should be discontinued and not restarted, supportive medical therapy instituted, and the patient monitored closely with appropriate laboratory studies (e.g., serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, lipase, etc.). A search for other causes of pancreatitis as well as those conditions which mimic pancreatitis should be conducted.

Ocular Effects

Because of reports of adverse eye findings with non-steroidal antiinflammatory agents, it is recommended that patients who develop eye complaints during treatment with sulindac have ophthalmologic studies.

Hepatic Insufficiency

In patients with poor liver function, delayed, elevated and prolonged circulating levels of the sulfide and sulfone metabolites may occur. Such patients should be monitored closely; a reduction of daily dosage may be required.

SLE and Mixed Connective Tissue Disease

In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, there may be an increased risk of aseptic meningitis (see ADVERSE REACTIONS).

ADVERSE REACTIONS

The following adverse reactions were reported in clinical trials or have been reported since the drug was marketed. The probability exists of a causal relationship between sulindac and these adverse reactions. The adverse reactions which have been observed in clinical trials encompass observations in 1 ,865 patients, including 232 observed for at least 48 weeks. Incidence Greater Than 1% Gastrointestinal The most frequent types of adverse reactions occurring with sulindac are gastrointestinal; these include gastrointestinal pain (10%), dyspepsia**, nausea** with or without vomiting, diarrhea**, constipation**, flatulence, anorexia and gastrointestinal cramps.

Dermatologic Rash**, pruritus.

Central Nervous System Dizziness**, headache**, nervousness.

Special Senses Tinnitus.

Miscellaneous Edema (see WARNINGS).

Incidence Less Than 1 in 100 Gastrointestinal Gastritis, gastroenteritis or colitis. Peptic ulcer and gastrointestinal bleeding have been reported. GI perforation and intestinal strictures (diaphragms) have been reported rarely.

Liver function abnormalities; jaundice, sometimes with fever; cholestasis; hepatitis; hepatic failure.

There have been rare reports of sulindac metabolites in common bile duct "sludge" and in biliary calculi in patients with symptoms of cholecystitis who underwent a cholecystectomy.

Pancreatitis (see PRECAUTIONS).

Ageusia; glossitis.

Dermatologic Stomatitis, sore or dry mucous membranes, alopecia, photosensitivity.

Erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and exfoliative dermatitis have been reported.

Cardiovascular Congestive heart failure, especially in patients with marginal cardiac function; palpitation; hypertension.

Hematologic Thrombocytopenia; ecchymosis; purpura; leukopenia; agranulocytosis; neutropenia; bone marrow depression, including aplastic anemia; hemolytic anemia; increased prothrombin time in patients on oral anticoagulants (see PRECAUTIONS).

Genitourinary Urine discoloration; dysuria; vaginal bleeding; hematuria; proteinuria; crystalluria; renal impairment, including renal failure; interstitial nephritis; nephrotic syndrome.

Renal calculi containing sulindac metabolites have been observed rarely.

Metabolic Hyperkalemia.

Musculoskeletal Muscle weakness. Psychiatric Depression; psychic disturbances including acute psychosis.

Nervous System Vertigo; insomnia; somnolence; paresthesia;

convulsions; syncope; aseptic meningitis (especially in patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease, see

PRECAUTIONS).

Special Senses Blurred vision; visual disturbances; decreased hearing; metallic or bitter taste.

Respiratory Epistaxis.

Hypersensitivity Reactions Anaphylaxis; angioneurotic edema; urticaria; bronchial spasm; dyspnea. Hypersensitivity vasculitis.

A potentially fatal apparent hypersensitivity syndrome has been reported. This syndrome may include constitutional symptoms (fever, chills, diaphoresis, flushing), cutaneous findings (rash or other dermatologic reactions— see above), conjunctivitis, involvement of major organs (changes in liver function including hepatic failure, jaundice, pancreatitis, pneumonitis with or without pleural effusion, leukopenia, leukocytosis, eosinophilia, disseminated intravascular coagulation, anemia, renal impairment, including renal failure), and other less specific findings (adenitis, arthralgia, arthritis, myalgia, fatigue, malaise, hypotension, chest pain, tachycardia).

Causal Relationship Unknown A rare occurrence of fulminant necrotizing fasciitis, particularly in association with Group A β-hemolytic streptococcus, has been described in persons treated with non-steroidal anti-inflammatory agents, sometimes with fatal outcome (see also PRECAUTIONS, General).

Other reactions have been reported in clinical trials or since the drug was marketed, but occurred under circumstances where a causal relationship could not be established. However, in these rarely reported events, that possibility cannot be excluded. Therefore, these observations are listed to serve as alerting information to physicians.

Cardiovascular Arrhythmia.

Metabolic Hyperglycemia.

Nervous System Neuritis.

Special Senses Disturbances of the retina and its vasculature.

Miscellaneous Gynecomastia.

Claims

What is claimed is:

1. A method of decreasing infection in a subject by a pathogen comprising administering to the subject an effective amount of a compound having the structure of formula I

wherein Ar may be aryl or heteroaryl; Ri may be hydrogen, lower alkyl or halogenated lower alkyl; R₂ may be hydrogen or alkyl; R₃, R₄, R₅ and R₆ each may be hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamine, dialkylamino, dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, halogenoalkyl, cycloalkyl or cycloalkoxy; R₇ may be alkylsulfinyl, alkylsulfide, alkylthio, or alkylsulfonyl; Rg may be hydrogen, halogen, hydroxy, alkoxy, or haloalkyl; and M may be hydroxy, lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N- morpholino, hydroxyalkylamino, polyhydroxyalkylamino,

dialkylaminoalkylamino, aminoalkylamino, and the group OM', wherein M' is a cation, wherein the compound decreases infection in the subject.

2. The method of claim 1 , wherein the pathogen is a respiratory virus.

3. The method of claim 2, wherein the respiratory virus is a rhinovirus.

4. The method of claim 1 , wherein the subject has been found to be in need of a decrease in infection.

5. The method of claim 4, wherein the subject has been diagnosed with an infection.

6. The method of claim 5, wherein the subject has been diagnosed with a viral infection.

7. The method of claim 6, wherein the virus is a respiratory virus.

8. The method of claim 7, wherein the virus is a rhinovirus.

9. A method of decreasing infection in a subject by a pathogen comprising: a. determining that a subject has an infection; and

b. administering to the subject an effective amount of a compound having the structure of formula I

wherein Ar may be aryl or heteroaryl; R₁ may be hydrogen, lower alkyl or halogenated lower alkyl; R₂ may be hydrogen or alkyl; R₃, R₄, R₅ and R₆ each may be hydrogen, alkyl, acyloxy, alkoxy, nitro, amino, acylamino, alkylamine, dialkylamino, dialkylaminoalkyl, sulfamyl, alkythio, mercapto, hydroxy, hydroxyalkyl, alkylsulfonyl, halogen, cyano, carboxyl, carbalkoxy, carbamido, halogenoalkyl, cycloalkyl or cycloalkoxy; R₇ may be alkylsulfinyl, alkylsulfide, alkylthio, or alkylsulfonyl; R₈ may be hydrogen, halogen, hydroxy, alkoxy, or haloalkyl; and M may be hydroxy, lower alkoxy, substituted lower alkoxy, amino, alkylamino, dialkylamino, N-morpholino, hydroxyalkylamino,

polyhydroxyalkylamino, dialkylaminoalkylamino, aminoalkylamino, and the group OM', wherein M' is a cation, wherein the compound decreases infection in the subject.

10. The method of claim 9, wherein the subject is diagnosed with an infection prior to treatment.

1 1. The method of claim 9, wherein the subject is diagnosed with a viral infection.

12. The method of claim 11 , wherein the subject is diagnosed with a viral infection by a viral assay.

13. A method of decreasing infection in a subject by a pathogen comprising administering to the subject an effective amount of sulindac having the structure of formula II

wherein the sulindac decreases infection in the subject.

14. The method of claim 13, wherein the pathogen is a respiratory virus.

15. The method of claim 14, wherein the respiratory virus is a rhinovirus.

16. The method of claim 13, wherein the subject has been found to be in need of a decrease in infection.

17. The method of claim 16, wherein the subject has been diagnosed with infection.

18. The method of claim 17, wherein the subject has been diagnosed with a virus.

19. The method of claim 18, wherein the virus is a respiratory virus.

The method of claim 19, wherein the virus is a rhinovirus.

21. The method of claim 13, wherein the total dose of sulindac is less than 400mg administered daily.

22. The method of claim 13, where the total dose of sulindac is less than 300mg administered daily.

23. The method of claim 13, wherein the total dose of sulindac is less than 200mg administered daily.

24. The method of claim 13, wherein the total dose of sulindac is less than lOOmg administered daily.

25. The method of claims 21-24, wherein the total daily dose of sulindac is administered in a two separate doses of approximately equal amount.

26. The method of claim 13, wherein the sulindac is in a formulation that does not include one or more of magnesium stearate, microcrystalline cellulose, starch (corn), and/or stearic acid.

27. A method of decreasing infection in a subject by a pathogen comprising administering to the subject an effective amount of sulindac sulfide having the structure of formula III

wherein the sulindac sulfide decreases infection in the subject.

28. The method of claim 27, wherein the subject has been found to be in need of a decrease in infection.

29. The method of claim 28, wherein the subject has been diagnosed with an infection.

30. The method of claim 28, wherein the subject has been diagnosed with a virus.

31. The method of claim 30, wherein the virus is a respiratory virus.

32. The method of claim 31 , wherein the virus is a rhinovirus.

33. The method of claim 27, wherein the pathogen is a respiratory virus.

34. The method of claim 27, wherein the respiratory virus is a rhinovirus.

35. A method of decreasing infection in a subject by a pathogen comprising administering to the subject an effective amount of sulindac sulfone having the structure of formula IV

wherein the sulindac sulfone decreases infection in the subject.

36. The method of claim 35, wherein the subject has been found to be in need of a decrease in infection.

37. The method of claim 36, wherein the subject has been diagnosed with infection.

38. The method of claim 37, wherein the subject is diagnosed with a viral infection.

39. The method of claim 38, wherein the virus is a respiratory virus.

40. The method of claim 39, wherein the virus is a rhinovirus.

41. The method of claim 35, wherein the pathogen is a respiratory virus.

42. The method of claim 41, wherein the respiratory virus is a rhinovirus.

43. A method of preventing infection by a pathogen in a subject comprising administering to the subject an effective amount of a compound to prevent infection having the structure of any one of formulas I-IV.

44. The method of claim 43, wherein the subject has been found to be in need of prevention of infection.

45. A method of inhibiting or reducing virus replication comprising

administering to the subject an effective amount of a compound to inhibit or reduce the virus replication having the structure of any one of formulas I-IV.

46. The method of claim 45, wherein inhibiting or reducing viral replication includes the spread to additional host cells or tissues.

47. The method of any one of claims 1-46, wherein the compound is

administered in combination with an additional therapeutic agent.

48. The method of claim 47, wherein the compound is administered with more than one additional therapeutic agent.

49. The method of claim 47, wherein the additional therapeutic agent is an antiviral compound, antibacterial agent, antifungal agent, antiparasitic agent, anti-inflammatory agent, or anti-cancer agent.

50. The method of claim 47, wherein the additional therapeutic agent is an antiviral agent.

51. The method of claim 50, wherein the antiviral agent is used to treat rhinovirus.

52. The method of claim 50, wherein the antiviral agent is used to treat influenza.

53. The method of claim 47, wherein the additional therapeutic agent is in the same formulation as the compound having the structure of any one of formulas I-IV.

54. The method of claim 47, wherein the additional therapeutic agent is in a different formulation as the compound having the structure of any one of formulas I-IV.

55. A method of treating or preventing asthma or associated conditions comprising administering to the subject a compound having the structure of any one of formulas I-IV, thereby treating or preventing asthma or associated conditions in the subject.

56. The method of claim 55, wherein the subject is diagnosed with asthma prior to treatment.

57. The method of claim 55, wherein the asthma is treated or prevented by treating or preventing rhinovirus.

58. A method of treating or preventing chronic obstructive pulmonary

disease (COPD) or associated conditions comprising administering to the subject a compound having the structure of any one of formulas I-IV, thereby treating or preventing COPD or associated conditions.

59. The method of claim 58, wherein the COPD is treated or prevented by treating or preventing rhinovirus.

60. The method of any one of claims 1-59, wherein the compound is

administered intranasally, orally, or intramuscularly.

61. The method of any one of claims 1-59, wherein the compound is

administered via inhalation.

62. A compound having the structure of formula I and an additional

therapeutic agent.

63. The compound of claim 62, wherein the additional therapeutic agent is an anti-infective agent.

64. The compound of claim 63, wherein the anti-infective agent is an

antiviral agent.

65. The compound of claim 62, wherein the compound having the structure of formula I is sulindac.

66. A composition comprising sulindac formulated for antiviral

administration in a dose and formulation that decreases the adverse clinical side effects of the sulindac for arthritis.

67. The composition of claim 66, wherein the sulindac is in a dose of less than 150mg.

68. The composition of claim 66, wherein sulindac dose is in a tablet.

69. The method of claim 60, wherein the sulindac dose is less than 150mg per administration.

70. The method of claim 60, wherein the sulindac dose is less than 200mg per administration.

71. A composition comprising sulindac in packaging having a label with a decreased adverse clinical side effect profile compared to sulindac for inflammation.