WO2002007516A2

WO2002007516A2 - Uses for nad synthetase inhibitors

Info

Publication number: WO2002007516A2
Application number: PCT/US2001/022203
Authority: WO
Inventors: Wayne J. Brouillette; Christie G. Brouillette; Lawrence J. Delucas
Original assignee: The Uab Research Foundation
Priority date: 2000-07-14
Filing date: 2001-07-13
Publication date: 2002-01-31
Also published as: WO2002007516A3; CA2415900A1; EP1301074A2; JP2004510704A; BR0112514A; AU2001280548A1; IL153575A0

Abstract

Disclosed are methods for increasing production of food animals, treating or preventing of infection by a spore-forming bacterium in an animal, killing the vegetative cell of a spore-forming bacterium in an environment, treating a fungal or bacterial disease in a plant, for disinfecting, sterilizing, and decontaminating an object. The methods involve the use of an inhibitor of NAD synthetase of a microbe.

Description

USES FOR NAD SYNTHETASE INHIBITORS

CROSS-REFERENCE TO A RELATED APPLICATION This application claims the benefit of U.S. provisional patent application No.

60/218,405, filed July 14, 2000, the disclosure of which is incorporated by reference.

FIELD OF THE INVENTION

The present invention relates in general to the uses of nicotinamide adenine dinucleotide ("NAD") synthetase inhibitors, and in particular, but not limited, to the use of NAD synthetase inhibitors in treating the environment against microbial contamination, in agriculture, e.g., in raising foodcrops and food animals, and in medicine, e.g., to disinfect, sterilize, or decontaminate equipments, devices, rooms, and people.

BACKGROUND OF THE INVENTION The use of antibiotics in food animal feeds and the extent to which the use contributes to the development of drug resistance have been under recent discussion, see, e.g., C. Marwick, "Animal Feed Antibiotic Use Raises Drug Resistance Fear," Journal of the American Medical Association, 282(2): 120-2, July 14, 1999, and T. R. Shryock,

"Relationship between usage of antibiotics in food-producing animals and the appearance of antibiotic resistant bacteria," International Journal of Antimicrobial Agents, 12(4):275- 8, Aug 1999. The use of antibiotics as well as biocides can lead to antibiotic or drug- resistant organisms, see, e.g., A. D. Russel, "Mechanisms of bacterial resistance to antibiotics and biocides," Progress in Medicinal Chemistry, 35:133-97, 1998. In view of the foregoing, there exists a need for new agents to fight microorganisms.

Spore-forming bacteria can be lethal. For example, Bacillus anthracis causes the deadly disease, anthrax. There exists an uncertainty relating to the efficacy of currently available vaccines against Bacillus anthracis. Further, there is a likelihood that terrorists could employ antibiotic-resistant strains, e.g., engineered strains that are not recognized by B. anthracis antibodies or common bacteria engineered to carry the virulence gene (see, e.g., T. C. Dixon et al., "Anthrax," New England Journal of medicine, 341 (11), 815- 826, Sept. 1999). The foregoing shows that there exists a need for a novel treatment against spore-forming bacteria, particularly B. anthracis or bacteria carrying the virulence gene of B. anthracis.

Further, in view of the risks such as toxicity or carcinogenicity associated with many common pesticides, fungicides, or bactericides, new approaches are needed to control pests in the environment, as well as fungal and bacterial diseases in plants and food crops, see, e.g., D. W. Wong and G. H. Robertson, "Combinatorial chemistry and its applications in agriculture and food," Advances in Experimental Medicine & Biology, 464:91-105, 1999, and S. H. Zahm and M. H. Ward, "Pesticides and childhood cancer," Environmental Health Perspectives, 106, Suppl. 3:893-908, June 1998.

These and other objects and advantages of the present invention will be apparent from the description of the embodiments of the invention set forth below.

SUMMARY OF THE INVENTION The present invention ameliorates some of the disadvantages of the prior art. The present invention provides a method for increasing production of food animals comprising administering to the food animal an effective amount of at least one inhibitor of NAD synthetase of a microbe capable of infecting the food animal. The present invention further provides a method for the treatment or prevention of infection by a spore-forming bacterium in an animal comprising treating an environment of the animal with an effective amount of at least one inhibitor of NAD synthetase of the spore-forming bacterium. The present invention further provides a method for killing the vegetative cell of a spore- forming bacterium in an environment comprising treating the environment with an effective amount of at least one inhibitor of NAD synthetase of the bacterium. The present invention also provides a method for treating a fungal or bacterial disease in a plant comprising treating the plant or the environment of the plant with an effective amount of at least one inhibitor of NAD synthetase of the fungus or bacterium. The present invention further provides a method for disinfecting, sterilizing, or decontaminating an object comprising treating the object with an effective amount of at least one inhibitor of NAD synthetase of a microbe.

While the invention has been described and disclosed below in connection with certain embodiments and procedures, it is not intended to limit the invention to those specific embodiments. Rather it is intended to cover all such alternative embodiments and modifications as fall within the spirit and scope of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 depicts a step in the biosynthesis of NAD.

Fig. 2 depicts the dose response of an inhibitor of a NAD synthetase to inhibit the growth of Bacillus subtilis.

SPECIFIC DESCRIPTION OF THE INVENTION

NAD synthetase ("NADs") is an enzyme which catalyzes the last step in the biosynthesis of NAD. See Figure 1. NAD is an essential cellular cofactor required for numerous oxidation-reduction reactions in all bacteria, in fungi and molds, and in insects. Since all of these organisms require NADs for survival and growth, inhibitors of NAD synthetase have numerous practical applications. The present invention provides, in an embodiment, a method for increasing production of a food animal comprising administering to the food animal an effective amount of at least one inhibitor of NADs of a microbe capable of infecting the food animal.

In another embodiment, the present invention provides a method for the treatment or prevention of infection by a spore-forming bacterium in an animal comprising treating an environment of the animal with an effective amount of at least one inhibitor of NADs of the spore-forming bacterium. In a further embodiment, the present invention provides a method for killing the vegetative cell of a spore-forming bacterium in an environment comprising treating the environment with an effective amount of at least one inhibitor of NADs of the bacterium. An example of a spore-forming bacterium is a biological warfare agent, e.g., Bacillus anthracis.

In still another embodiment, the present invention provides a method for treating a fungal or bacterial disease in a plant comprising treating the plant or an environment of the plant with an effective amount of at least one inhibitor of NADs of the fungus or bacterium. In a further embodiment, the present invention provides a method for a treating plant comprising the treating the plant, or an environment thereof, with a pesticidal effective amount of at least one inhibitor of NADs of a pest. An example of the plant is a food crop.

In yet another embodiment, the present invention provides a method for disinfecting, sterilizing, or decontaminating an object comprising treating the object with an effective amount of at least one inhibitor of NADs of a microbe. The microbe is a microorganism, e.g., bacterium or fungus. An example of a fungus is mold or yeast.

Any suitable object can be disinfected, sterilized, or decontaminated. Examples of suitable objects include an article of clothing, an animal, an organ of an animal, a structure, an equipment, a furniture, an environment, a food crop, a chicken, a chicken skin, and an egg, e.g., egg shell. In accordance with the present invention, the environment being disinfected, sterilized, or decontaminated can be land, air, or water, or a combination thereof.

An example of the environment includes a medical environment. Thus, for example, a medical device, medical equipment, hospital, or surgical room can be disinfected. Medical personnel also can be disinfected or decontaminated. In accordance with the present invention, medical devices such as implantable medical devices, e.g., catheters can be disinfected, sterilized, or decontaminated. Medical equipment such as a surgical equipment may also be disinfected, sterilized, or decontaminated. Further, the organs of animals, including human, can be disinfected or decontaminated. An example of an organ is the digestive tract. In a further embodiment, the present invention provides a method for controlling insect population in an environment comprising treating the environment with an effective amount of at least one inhibitor of NADs of the insect. Any suitable environment can be treated. For example, a household environment or an agricultural environment can be treated. For the treatment of food animals to increase production, the inhibitor or antimicrobial agent may be mixed with animal feed at a typical concentration of 1-500 mg per kg of feed. Alternatively, similar concentrations may be added to the animals' drinking water. Further alternatively, the antimicrobial agent may be administered as an oral pill or may be injected, either intramuscularly or intravenously. The method of the present invention in an embodiment is useful in the prophylaxis or therapy of biological warfare agents, including, but not limited to, the spore-forming bacterium such as Bacillus anthracis or a microorganism carrying the virulent gene of a spore-forming bacteria such as Bacillus anthracis. In Bacillus anthracis and other spore- forming bacteria, NADs is required for outgrowth of the germinated spore. Since inhibitors of NADs also prevent vegetative growth, this represents two different points of attack on the life cycle of these bacteria and should provide extremely effective prophylaxis and/or therapy.

In the treatment of plants, in a typical application, the antimicrobial agent in a suitable vehicle is sprayed onto growing plants to either prevent or treat fungal and/or bacterial diseases. Alternatively, application may be made by deposition of solutions or solid preparations on the soil near growing plants.

In an application of NADs inhibitors as pesticides for controlling pests and insects in the household and/or for agricultural uses, NADs inhibitors with pesticidal or insecticidal activities and in a suitable vehicle, e.g., organic or aqueous vehicle, are sprayed in areas of homes that are commonly treated with existing insecticidal preparations. In a typical agricultural application, the pesticidal or insecticidal agent in a suitable vehicle is sprayed onto growing plants to either prevent or treat infestation by insects. Alternatively, pesticidal or insecticidal application to plants may be made by deposition on the soil near growing plants. In a typical application for disinfection, sterilization or decontamination of structural surfaces, a solution of the microbicidal compound in a suitable vehicle would be painted, sprayed, or soaked (by immersion into a solution) onto the surface of the object. For treatment of the soil or ground, a solution of the microbicidal agent in a suitable vehicle may be sprayed onto or soaked into the ground, or a solid form may be mixed with the soil. The microbicidal agent may also be added to contaminated water supplies in sufficient concentration (1-100 micromolar) to cause sterilization. In processing, handling, and packaging animal foods, such as eggs or chickens, a solution of the microbicidal compound in a suitable vehicle may be painted, sprayed, or soaked (by immersion into a solution) onto the surface of the food. Numerous related beneficial applications are possible, including decontamination of chicken skins, e.g., to reduce Salmonella typhimurium, egg shells (carriers of Salmonella), and disinfection of other foods.

In the field of sterilization, disinfecting and decontamination including, microbicidal concentrations of NADs inhibitors have the potential for use in a variety of situations benefiting from sterilization or decontamination, including the treatment of clothing, surfaces of structures, equipment, furniture, and natural environmental surfaces such as the ground and water supplies.

A typical application for disinfection of implantable devices would involve soaking the device in a solution of the microbicidal compound. Alternatively, the implantable device may be manufactured to contain a releasable or bioactive form of the microbicidal compound, either by mechanical entrapment in the polymeric material composing the surface of the device or by covalent chemical attachment to the polymeric material composing the surface of the device. For treatment of transplantable organs, the organ may be immersed in a solution of the microbicidal agent contained in a suitable vehicle. Whole body washing can be accomplished by thoroughly wiping the body with a solution of the microbicidal agent, or by immersion of the body in a suitable solution. Control of dental caries and/or gum disease may be accomplished by washing of the oral cavity with a suitable solution of the microbicidal agent, or by incorporation into a toothpaste used in brushing the teeth.

Numerous medical applications and devices requiring disinfection or decontamination are possible such as pacemakers, defϊbrillators, artificial hearts or parts thereof, whole body washing of infected patients, treatment of transplantable organs for transplantation, decontamination of surgical rooms and surgical equipment, and control of dental caries or gum disease.

Decontamination associated with spore-forming bacteria such as Bacillus anthracis, inhibitors of germination may cause damage to the spore and should be bactericidal to the vegetative cell. Thus these inhibitors may be used to decontaminate a variety of environments including, but not limited to, environmental surfaces and drinking water. In the treatment, prevention, or control of fungal and bacterial diseases in plants and foodcrops, the inhibitor can be carried in a suitable vehicle and sprayed onto the plants to either prevent or treat fungal and/or bacterial diseases. Alternatively, application may be made by deposition of solutions or solid preparations on the soil near growing plants.

Numerous medical applications requiring disinfection or decontamination are possible. These include digestive tract decontamination in humans related to surgery (see G. Ramsay and R. H. van Saene, "Selective gut decontamination in intensive care and surgical practice: where are we [Review]," World Journal of Surgery, 22(2): 164-70, Feb 1998; and G. Basha et al., "Local and systemic effects of intraoperative whole-colon washout with 5 per cent povidone-iodine," British Journal of Surgery. 86(2):219-26, Feb. 1999), the disinfection of, or impregnation of NADs inhibitors into, materials used in implantable devices such as intravenous catheters (see O. Traore et al., "Comparison of in- vivo antibacterial activity of two skin disinfection procedures for insertion of peripheral catheters: povidone iodine versus chlorhexidine," Journal of Hospital Infection. 44(2): 147-50, Feb 2000; and T.S. Elliott, "Role of antimicrobial central venous catheters for the prevention of associated infections," [Review] Journal of antimicrobial Chemotherapy. 43(4):441-6, Apr. 1999), pacemakers, defibrillators, artificial hearts or parts thereof, whole body washing of infected patients, treatment of transplantable organs for transplantation, decontamination of surgical rooms and surgical equipment, and control of dental caries or gum disease (see B.M. Eley, "Antibacterial agents in the control of supragingival plaque—a review, "British Dental Journal, 186(6):286-96, Mar 27 1999). In the practice of the embodiments of the present invention, any suitable inhibitor of the NADs can be used. Examples of suitable inhibitors of NADs include those compounds disclosed within International Publication Nos. WO 99/36422, WO

00/10996, and WO 01/00197, U.S. Provisional Patent Application No. 60/141,436 filed June 29, 1999, and U.S. Patent Application Nos. 09/606,256 filed June 29, 2000 and 09/617,258, July 14, 2000. Each of the foregoing publications and applications are incorporated by reference in their entirety. For example, the inhibitor of NAD synthetase has the Structure 2:

Structure 2 wherein n is an integer of from 1 to 12, Ri - R₇ each, independently, is H, an unsubstituted or a substituted cyclic or aliphatic group, a branched or an unbranched group; the linker is a cyclic or aliphatic, branched or an unbranched alkyl, alkenyl, or an alkynyl group; and the linker may also contain heteroatoms. In a preferred embodiment, all of R_x - R₇ are not H simultaneously.

A particular example of the inhibitor of NAD synthetase has the Structure 4:

Structure 4 wherein X is a C, N, O or S within a monocyclic or bicyclic moiety, and A and B represent the respective sites of attachment for the linker. In the formula above, in a preferred embodiment, X is a C or N within a monocyclic or bicyclic moiety, R R₇ each, independently, is H, an unsubstituted or substituted cyclic or aliphatic, branched or unbranched hydrocarbon, and the linker is cyclic or aliphatic, branched or unbranched alkyl, alkenyl, or alkynyl.

In a particular embodiment, n in the above formulas is from 5 to 9, and preferably from 6 to 9. In an embodiment, the linker has the formula A-(C, Heteroatom)n-B, wherein n is from 5 to 9. Examples of suitable linkers include A-(CH₂)n-B, A-(CH₂)n-O- C(=O)-B, A-O(CH₂)n-O-C(=O)-B, A-(CH₂)n-O-C(=O)CH₂-B, and A-O(CH₂)n-O- C(=O)CH₂-B.

In a preferred embodiment, the inhibitor of NAD synthetase has the Structure 2':

Structure 2' wherein Aryl 1 is indolyl or phenyl; Aryl 2 is phenyl, pyridinyl, indolyl, or quinolinyl; and the linker is -(CH₂)n-, -(CH₂)n-O-C(=O)-, -O(CH₂)n-O-C(=O)-, -(CH₂)n-O- C(-=O)CH₂-, or -O(CH₂)n-O-C(=O)CH₂-.

For example, in Structures 2, 2', and 4, R₁-R₃ are independently selected from the group consisting of H, aryloxy, hydroxyaryl, aryl C C₆ alkoxy, - alkoxy, -C_O alkoxycarbonyl, C C₆ alkyl, Cι-C₆ alkylcarbonyl, arylcarbonyl, nitro, halo, carboxy, halo C_rC₆ alkyl, perhalo C C₆ alkyl, triphenylmethoxy, phenylcarbonylamino, C C₆ alkoxycarbonyl C₂-C₆ alkenyl, arylcarbonyl C₂-C₆ alkenyl, benzofuranyl carbonyl, C C₆ alkylbenzylfuranyl carbonyl, arylaminocarbonyl, arylcarbonyloxy, aminocarbonyl, Cι-C₆ alkoxycarbonylamino, phthalidimido, morpholino, pyrrolidinyl, phenylhydantoinyl, and acetylpiperazinyl; and R^-R_? are independently selected from the group consisting of H, C C₆ alkylamino, C C₆ dialkylamino, C C₆ trialkylammonium, - N-alkyl, and C C₆ alkoxycarbonyl. In an embodiment, R₃-R are independently H.

In some embodiments, Aryl 1 is indolyl. In some other embodiments, Aryl 1 is phenyl. In certain embodiments, Aryl 2 is phenyl. In certain other embodiments, Aryl 2 is pyridinyl. In further embodiments, Aryl 2 is quinolinyl. In other embodiments, Aryl 2 is indolyl.

In certain embodiments, particularly where Aryl 1 is indolyl or phenyl, more particularly indolyl, Rι-R₃ are independently selected from the group consisting of H, phenoxy, hydroxyphenyl, benzyloxy, methoxy, methoxycarbonyl, isopropyl, butyl, acetyl, phenylcarbonyl, nitro, fluoro, carboxy, trifϊuoromethyl, triphenylmethoxy, phenylcarbonylamino, methoxycarbonyl ethenyl, phenylcarbonyl ethenyl, benzofuranyl carbonyl, butylbenzylfuranyl carbonyl, phenylaminocarbonyl, phenylcarbonyloxy, aminocarbonyl, methoxycarbonylamino, phthalidimido, morpholino, pyrrolidinyl, phenylhydantoinyl, and acetylpiperazinyl.

In other embodiments, particularly where Aryl 1 is phenyl, R₁-R₃ are independently selected from the group consisting of H, phenoxy, hydroxyphenyl, benzyloxy, acetyl, phenylcarbonyl, nitro, phenylcarbonyl ethenyl, benzofuranyl carbonyl, butylbenzylfuranyl carbonyl, phenylaminocarbonyl, phenylcarbonyloxy, aminocarbonyl, and methoxycarbonylamino.

Other examples of inhibitors of NAD synthetase has the Structure 300:

Structure 300 wherein Y is C, N, O, S, ester, amide, or ketone, n is an integer of from 1 to 12, a is an integer from 1-3, and R R₅ each, independently, is H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, or an alkyl, alkenyl, or alkynyl, or an aryl group.

A further example of the inhibitor of NAD synthetase has the Structure 400:

Structure 400 wherein Y is C, N, O, S, ester, amide, or ketone; Z is C, N, O, or S; AA is a natural or unnatural stereoisomer of an a-, β-, γ-, or δ-amino acid in which the carboxyl carbonyl is attached to Z, and the amino grouping may be a primary, secondary, tertiary, or quaternary ammonium compound; n is an integer of from 1 to 12; and R R₅ each, independently, is H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, or an alkyl, alkenyl, alkynyl, aryl, aryl alkyl, or aryl alkoxy group.

In Structures 300 and 400, R R₂ may also be H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group.

Particular examples of inhibitors of NAD synthetase are 5940, 5949, 5951, 5409, 5948, 5270, 5939, 5947, 5953, and 5274:

In this application, the term "alkyl" as used herein refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. The term "cycloalkyl" intends a cyclic alkyl group of from three to eight, preferably five or six carbon atoms.

The term "alkoxy" as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy" group may be defined as -OR where R is alkyl as defined above. A "lower alkoxy" group intends an alkoxy group containing from one to six, more preferably from one to four, carbon atoms.

The term "alkylene" as used herein refers to a difunctional saturated branched or unbranched hydrocarbon chain containing from 1 to 24 carbon atoms, and includes, for example, methylene (-CH₂-), ethylene (-CH₂-CH₂-), propylene (-CH₂-CH₂-CH₂-), 2- methylpropylene [-CH₂-CH(CH₃)-CH₂-], hexylene [-(CH₂)₆-] and the like. The term "cycloalkylene" as used herein refers to a cyclic alkylene group, typically a 5- or 6- membered ring.

The term "alkene" as used herein intends a mono-unsaturated or di-unsaturated hydrocarbon group of 2 to 24 carbon atoms. Asymmetric structures such as (AB)C=C(CD) are intended to include both the E and Z isomers. This may be presumed in structural formulae herein wherein an asymmetric alkene is present.

The term "alkynyl" as used herein refers to a branched or unbranched unsaturated hydrocarbon group of 2 to 24 carbon atoms wherein the group has at least one triple bond. The term "cyclic" as used herein intends a structure that is characterized by one or more closed rings. As further used herein, the cyclic compounds discussed herein may be saturated or unsaturated and may be heterocyclic. By heterocyclic, it is meant a closed- ring structure, preferably of 5 or 6 members, in which one or more atoms in the ring is an element other than carbon, for example, sulfur, nitrogen, etc. The term "bicyclic" as used herein intends a structure with two closed rings. As further used herein, the two rings in a bicyclic structure can be the same or different. Either of the rings in a bicyclic structure may be heterocyclic.

By the term "effective amount" of a compound as provided herein is meant a sufficient amount of the compound to provide the desired treatment or preventive effect. As will be pointed out below, the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound used, its mode of administration, and the like. An appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation. It is preferred that the effective amount be essentially non-toxic to the subject, but it is contemplated that some toxicity will be acceptable in some circumstances where higher dosages are required.

By "pharmaceutically acceptable carrier" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the compounds of the invention without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained.

As used herein, "NAD synthetase enzyme" is defined as the enzyme that catalyzes the final reaction in the biosynthesis of NAD, namely, the transformation of NaAD into NAD. As used herein, the term "catalytic sites" are defined as those portions of the NAD synthetase enzyme that bind to substrates, and cofactors, including nicotinic acid adenine dinucleotide (NaAD), NAD, adenosine triphosphate (ATP), adenosine monophosphate (AMP), pyrophosphate, magnesium and ammonia in yeast. The term "receptor site" or "receptor subsite" relates to those portions of the yeast NAD synthetase enzyme in which the yeast NAD synthetase enzyme inhibitors disclosed herein are believed to bind. For the purposes of this disclosure, the terms "catalytic site," "receptor site" and "receptor subsite" may be used interchangeably.

Some examples of inhibitors of NAD synthetase, particularly for killing an yeast are: 14

1094

10 18

19

10

10

1090

X^" = F^", Cr, Br^", T , acetate, or any pharmaceutically acceptable anion. In one embodiment, the methods of the invention comprise the use of a compound having the general structure of Structure 2 as set forth above, wherein n is an integer of from 1 to 12, R_t - R₇ each, independently, is H, an unsubstituted or a substituted cyclic or aliphatic group, a branched or an unbranched group, and wherein the linker is a cyclic or aliphatic, branched or an unbranched alkyl, alkenyl, or an alkynyl group and wherein the linker may also contain heteroatoms. By heteroatoms, it is meant that one or more atoms is an element other than carbon, e.g., O, N, S, or other atoms.

R R₇ may also be one of the following groups: an H, alkyl, alkenyl, alkynyl, or an aryl. Ri -R₇, may further be a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups. Note that n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. The tethered active molecule, e.g., in this example denoted "aryl," moieties may be the same or different.

In a further embodiment, the invention comprises the use of a compound of Structure 4 set forth above, wherein X is a C, N, O, or S with a monocyclic or bicyclic moiety, A and B represent the respective sites of attachment of the linker, n in an integer of from 1 to 12, Ri-R₇ each, independently, is H, an unsubstituted or a substituted cyclic group, or an aliphatic group, or a branched or an unbranched group, and the linker is a saturated or unsaturated cyclic group or an aliphatic branched or unbranched alkyl, alkenyl or alkynyl group, and wherein the linker may also contain heteroatoms.

Ri-R₇may also be one of the following groups: an H. alkyl, alkenyl, alkynyl, or an aryl group. R R₇ may also be a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups. One of skill in the art would know what moieties are considered to constitute derivatives of these groups, n may be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.

In a further embodiment, the methods of the invention comprise administering a compound of Structure 6:

STRUCTURE 6:

Linker

wherein:

X is C, N, O or S, Y is C, N, O, S, carboxy, ester, amide, or ketone, A and B represent the respective sites of attachment for a linker, n is an integer of from 1 to 12, and Ri-R₇ each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, and the linker is a saturated or unsaturated cyclic or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.

Ri-R₇ may also be one of the following groups: an H, alkyl, alkenyl, alkynyl, or an aryl. R R₇, may further be a hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen or the common derivatives of these groups. Note that n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. The tethered active molecule, e.g., in this example denoted "aryl," moieties may be the same or different.

In a further embodiment, the methods of the invention comprise administering a compound of Structure 7:

STRUCTURE 7

wherein X is C, N, O or S, Y is C, N, O, S, carboxy, ester, amide, or ketone, A and B represent the respective sites of attachment for a linker, n is an integer of from 1 to 12, and Ri-R_<5 each, independently, is H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, and the linker is a saturated or unsaturated cyclic or aliphatic group, branched or unbranched alkyl, alkenyl, or alkynyl group and wherein the linker may also contain heteroatoms.

R R_<5 may also be one of the following groups: an H, alkyl, alkenyl, or alkynyl, or an aryl group. Ri-Rg may also be H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, sulfonate, or halogen and the common derivatives of these groups. One of skill in the art would know what moieties are considered to constitute derivatives of these groups, n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.

In a further embodiment, the methods of the invention comprise administering a compound of Structure 8:

STRUCTURE 8:

wherein n is an integer of from 1 to 12, Ri is H, methoxy, benzyloxy, or nitro and R₂ is 3- pyridyl, N-methyl-3-pyridyl, 3-quinolinyl, N-methyl-3 -quinolinyl, 3- (dimethylanτino)phenyl, 3 -(trimethylammonio)phenyl, 4-(dimethylamino)phenyl, 4(trimethylammonio)phenyl, 4-(dimethylamino)phenylmethyl, or 4- (trimethylammonio)phenylmethyl. n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.

In a further embodiment, the methods of the invention comprise administering a compound of Structure 10:

STRUCTURE 10:

wherein: n is an integer of from 1 to 12, Ri is an H, CO₂H, -OCH₃, or -OCH₂Ph R₂ is H, CO₂H, or CH=CHCO₂H, R₃ is H or CO₂H, and Y is N-linked pyxidine-3-carboxylic acid, N-linked pyridine, N-linked quinoline, or N-linked isoquinoline. n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. h a further embodiment, the methods of the invention comprise the use of a compound of Structure 12:

STRUCTURE 12:

wherein n is an integer of from 1 to 12, Ri is H, F, or NO₂, R₂ is H, CH₃, CF₃, NO₂, phenyl, n-butyl, isopropyl, F, phenyloxy, triphenylmethyl, methoxycarbonyl, methoxy, carboxy, acetyl, or benzoyl, R₃ is H or CF₃ and Y is N-linked pyridine-3-carboxylic acid, N-linked pyridine, N-linked quinoline, or N-linked isoquinoline. n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.

In a further embodiment, the methods of the invention comprise administering a compound of Structure 14 :

STRUCTURE 14:

wherein n is an integer of from 1 to 12, Ri is H, phenyloxy, isopropyl, acetyl, or benzoyl, R₂ is H or CF₃, and Y is 3-(dimethylamino)phenyl, 3-(trimelthylammonio)phenyl, 4- (dimethylamino)phenyl, 4-(trimethylammonio)phenyl, 2-(phenyl)phenyl, diphenylmethyl, 3-pyridyl, 4-pyridyl, or pyridine-3-methyl. n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.

In further embodiments of the invention herein, the invention comprises administering compounds of the structures denoted in Tables 102-128 as Compounds 1- 274 can be synthesized utilizing the methods disclosed previously in WO 99/36422.

For Compounds 1-274, structures denoted as Fragments I-X each represent an active molecule, as defined previously herein, which can be included in the compounds of the present invention as further described in the respective Tables. In Fragments I-X, the point of attachment for the linker compound is at the nitrogen. In the chemical structures that follow, and as intended for the compounds of this invention, the symbol T^" or X^" designates generally the presence of an anion. As contemplated by the present invention, the type of anion in the compounds of this invention is not critical. The compounds of this invention may be comprised of any such moieties known generally to one of skill in the art or that follow from the synthesis methods disclosed in WO 99/36422.

In separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to Structure 100:

Structure 100

wherein R' is as defined below (Illustration 1):

and n is an integer of from 1 to 12. n may also be from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9.

In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 100 and as further defined in Table 100. For those compounds that correspond to Structure 100, n may also be an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9.

STRUCTURE 100:

TABLE 100: SUBSTITUENT GROUPS FOR COMPOUNDS 1-24

Jn the above Table, R' corresponds to a Fragment as previously defined in Illustration 1 and n indicates the number of linker groups separating the two tethered active molecule groups in the compound.

As set out below in relation to Compounds 25 - 274, Fragments A - G are set out. The group denoted R in A-G can be a benzyl group, a methyl group or a hydrogen. The point of attachment of the linker group to Fragments A-G is at the nitrogen group.

In one embodiment, the methods of the invention comprise administering a compound corresponding to compounds of Structure 101. For those compounds that correspond to Structure 101, n is an integer of from 1 to 12, more preferably from 3 to 10, more preferably from 5 to 9 and, still more preferably from 6 to 9. The point of attachment of the linker group for both Ri and R' is at the respective nitrogen groups of each illustrated fragment.

Structure 101

wherein R' is:

wherein RI is:

wherein the R group in Fragments A-G is a benzyl group, a methyl group or a hydrogen. In one embodiment of the invention herein, the compounds may include the Fragments illustrated below (Illustration 2).

FRAGMENTS A-G IN COMPOUNDS 25-274 In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 102. For those compounds that correspond to Structure 102, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 102, as further set out in Table 102.

STRUCTURE 102:

TABLE 102: SUBSTITUENT GROUPS FOR COMPOUNDS 25-48

In the above Table, R' corresponds to a Fragment as previously shown in

Illustration 1, A corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and A in the respective compounds. Groups I, II, VII, and VIII each have a benzyl group and Groups I*, IIP, VII*, and VIII* each have a hydrogen, respectively, in the position designated R in Fragment A of Illustration 2.

In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 104. For those compounds that correspond to Structure 104, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 104, as further set out in Table 104.

STRUCTURE 104:

TABLE 104: SUBSTITUENT GROUPS FOR COMPOUNDS 49-66

In the above Table, R' corresponds to a Fragment as defined in Illustration 1, B corresponds to a Fragment as defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and B in the respective compounds. Groups I, VII, and VIII each have a benzyl group and Groups I*, VII*, and VIII* each have a hydrogen, respectively, in the position designated R in Fragment B of Illustration 2.

In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 106. For those compounds that correspond to Structure 106, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 106, as further set out in Table 106.

STRUCTURE 106:

TABLE 106: SUBSTITUENT GROUPS FOR COMPOUNDS 67-90

In the above Table, R' corresponds to a Fragment as previously defined in Illustration 1, C corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and C in the respective compounds. Groups I, II, VII, and VIII each have a benzyl group and Groups I*, III*, VII*, and VIII* each have a hydrogen, respectively, in the position designated R in Fragment C of Illustration 2.

In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 108. For those compounds that correspond to Structure 108, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 108, as further set out in Table 1 8.

STRUCTURE 108:

TABLE 108: SUBSTITUENT GROUPS FOR COMPOUNDS 91-108

Jn the above Table, R' corresponds to a Fragment as previously defined in Illustration 1, D corresponds to a fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and D in the compound. Groups I, VII, and VIII each have a benzyl group and Groups I*, VII*, and VIII* each have a hydrogen, respectively, in the position designated R in Fragment D of Illustration 2.

In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 110. For those compounds that correspond to Structure 110, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 110, as further set out in Table 110.

STRUCTURE 110:

TABLE 110: SUBSTITUENT GROUPS FOR COMPOUNDS 109-126

In the above Table, R' corresponds to a Fragment as previously defined in Illustration 1, E corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and E in the respective compounds. Groups I, VII, and VIII each have a benzyl group and Groups I*, VII*, and VIII* each have a hydrogen, respectively, in the position designated R in Fragment E of Illustration 2.

In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 112. For those compounds that correspond to Structure 112, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 112, as further set out in Table 112.

STRUCTURE 112:

TABLE 112: SUBSTITUENT GROUPS FOR COMPOUNDS 127-144

In the above Table, R' corresponds to a Fragment as previously defined in

Illustration 1, F corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and F in the respective 1 5 compounds. Groups 1, VII, and VIII each have a benzyl group and Groups I*, VII*, and VIII* each have a hydrogen, respectively, in the position designated R in Fragment F of Illustration 2.

In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 114. For those compounds that correspond to Structure 114, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 114, as further set out in Table 114.

STRUCTURE 114:

TABLE 114: SUBSTITUENT GROUPS FOR COMPOUNDS 145-162

In the above Table, R' corresponds to a Fragment as previously defined in Illustration 1, G corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and G in the respective compounds. Groups I, VII, and VIII each have a benzyl group and Groups I*, VII*, and VIII* each have a hydrogen, respectively, in the position designated R in Fragment G of Illustration 2. In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 116. For those compounds that correspond to Structure 116, n is an integer of from 1 to 12, from 3 to 100, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 116, as further set out in Table 116.

STRUCTURE 116:

TABLE 116: SUBSTITUENT GROUPS FOR COMPOUNDS 163-178

In the above Table, R' corresponds to a Fragment as previously defined in

Illustration 1, A corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and A in the respective compounds. Groups I and II each have a methyl group and Groups I* and III* each have a hydrogen, respectively, in the position designated R in Fragment A of Illustration 2. In further separate embodiments of the invention herein, the method of invention comprise the use of a compound corresponding to the structures set out in Structure 118. For those compounds that correspond to Structure 118, n in an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 118, as further set out in Table 118.

STRUCTURE 118:

TABLE 118: SUBSTITUENT GROUPS FOR COMPOUNDS 179-194

In the above Table, R' corresponds to a Fragment as previously defined in Illustration 1, B corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and B in the respective compounds. Groups I and II each have a methyl group and Groups I* and III* each have a hydrogen, respectively, in the position designated R in Fragment B of Illustration 2. In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 120. For those compounds that correspond to Structure 120, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 120, as further set out in Table 120.

STRUCTURE 120:

TABLE 120: SUBSTITUENT GROUPS FOR COMPOUNDS 195-210

In the above Table, R' corresponds to a Fragment as previously defined in Illustration 1, C corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and C in the respective compounds. Groups I and II each have a methyl group and Groups I*and II * each have a hydrogen, respectively, in the position designated R in Fragment C of Illustration 2.

In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding n Structure 122. For those compounds that correspond to Structure 122, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 122, as further set out in Table 122.

STRUCTURE 122:

TABLE 122: SUBSTITUENT GROUPS FOR COMPOUNDS 211-226

In the above Table, R' corresponds to a Fragment as previously defined in Illustration 1, D corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and D in the respective compounds. Groups I and II each have a methyl group and Groups I and III each have a hydrogen, respectively, in the position designated R in Fragment D of Illustration 2. In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 124. For those compounds that correspond to Structure 124, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 124, as further set out in Table 124.

STRUCTURE 124:

TABLE 124: SUBSTITUENT GROUPS FOR COMPOUNDS 227-242

In the above Table, R' corresponds to a Fragment as previously defined in

Illustration 1 , E corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and E in the respective compounds. Groups I and II each have a methyl group and Groups I* and III* each have a hydrogen, respectively, in the position designated R in Fragment E of Illustration 2. In further separate embodiments of the invention herein, the methods of the invention comprise the use of a compound corresponding to the structures set out in Structure 126. For those compounds that correspond to Structure 126, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 126, as further set out in Table 126.

STRUCTURE 126:

TABLE 126: SUBSTITUENT GROUPS FOR COMPOUNDS 243-258

In the above Table, R' corresponds to a Fragment as previously defined in Illustration 1, F corresponds to a Fragment as previously defined in Illustration 2, and n indicates the number of linker groups separating Groups R' and F in the respective compounds. Groups I and II each have a methyl group and Groups P and IP each have a hydrogen, respectively, in the position designated R in Fragment F of Illustration 2. In further separate embodiments of the invention herein, the methods of the invention comprise administering a compound corresponding to the structures set out in Structure 128. For those compounds that correspond to Structure 128, n is an integer of from 1 to 12, from 3 to 10, more preferably from 5 to 9, and still more preferably from 6 to 9. In further embodiments, the compounds herein correspond to Structure 128, as further set out in Table 128.

STRUCTURE 128:

TABLE 128: SUBSTITUENT GROUPS FOR COMPOUNDS 259-274

In the above Table, R' corresponds to a Fragment as previously defined in Illustration 1, G corresponds to a Fragment as previously defined in Illustration 1, and n indicates the number of linker groups separating Groups R' and G in the respective compounds. Groups I and II each have a methyl group and Groups I* and IIP each have a hydrogen, respectively, in the position designated R in Fragment G of Illustration 2.

As used herein, the following terms are defined as follows: Ph: phenyl; Ipropyl-= isopropyl; OPh ^O-Phenyl; and diNO₂-=dinifro.

In further embodiments, the compounds administered in the methods of the present invention correspond to compounds of the Structure 130 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 130 are set out in Table 130.

STRUCTURE 130:

TABLE 130: COMPOUNDS CORRESPONDING TO STRUCTURE 130

In further embodiments, the compounds used according to the methods of the present invention correspond to compounds of the Structure 132 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further from 6 to 9 and wherein and R is 5-H, 6-CF₃, 5-CH₃, 5,7-diF, 5,7-diNO₂, 5-Butyl, 5-ipropyl, 5-Phenyl, 5-

NO₂, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF₃, 5-COCH₃, 5-OCH₃, 5-

COOCH₃ or 5-COOH. Further embodiments of the compounds corresponding to Structure 132 are set out in Table 132. STRUCTURE 132:

TABLE 132: COMPOUNDS 282-389 CORRESPONDING TO STRUCTURE 132

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 134 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-H, 6-CF₃, 5-CH₃, 5,7-diF, 5,7-diNO₂,5-Butyl, 5-iPropyl, 5- Phenyl, 5-NO₂, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF₃, 5-COCH₃, 5-OCH₃, 5-COOCH₃, or 5-COOH. Further embodiments of the compounds corresponding to Structure 134 are set out in Table 134. STRUCTURE 134:

134: COMPOUNDS 390-497 CORRESPONDING TO STRUCTURE 134

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 136 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-H, 6-CF₃, 5-CH₃, 5,7-diF, 5,7-diNO₂, 5-Butyl, 5-iPropyl, 5- Phenyl, 5-NO₂, 5-Trityl, 5-F, 5-OPh, 5-COPh, 5-CF₃, 5-COCH₃, 5-OCH₃, 5-COOCH₃, or 5-COOH. Further embodiments of the compounds corresponding to Structure 136 are set out in Table 136. STRUCTURE 136:

TABLE 136: COMPOUNDS 498-605 CORRESPONDING TO STRUCTURE 136

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 138 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-CF₃, 5-OPh, 5-iPropyl, 5-COCH₃, or 5-COPh and Y is 3-N,N- dimethylaminophenyl (3-N,N-diCH₃), 4-N,N-dimethylaminophenyl (4-N,N-diCH₃), or 2Ph. Further embodiments of the compounds corresponding to Structure 138 are set out in Table 138. STRUCTURE 138:

Table 138: COMPOUNDS 606-650 CORRESPONDING TO STRUCTURE 138

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 140 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 5-CF₃, 5-OPh, 5-iPropyl, 5-COCH₃ or 5-COPh, and Z is CH(Ph)₂ or 3-Pyridyl. Further embodiments of the compounds corresponding to Structure 140 are set out in Table 140.

STRUCTURE 140:

TABLE 140: COMPOUNDS 651-680 CORRESPONDING TO STRUCTURE 140

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 142 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from

6 to 9 and wherein R is 6-CF₃, 5-OPh, 5-iPropyl, 5-COCH₃, or 5-COPh. Further embodiments of the compounds corresponding to Structure 142 are set out in Table 142.

STRUCTURE 142:

TABLE 142: COMPOUNDS 681-695 CORRESPONDING TO STRUCTURE 142

In further embodiments, the compounds administered according tO the methods of the present invention correspond to compounds of the Structure 144 wherein n is an integer of from 1 to 12, more preferably, from 3 to IO, from 5 to 9 and, still further, 1 0 from 6 to 9 and wherein R is 6-CF₃, 5-OPh, 5-iPropyl, 5-COCH₃, or 5-COPh. Further embodiments of the compounds corresponding to Structure 144 are set out in Table 144.

STRUCTURE 144:

TABLE 144: COMPOUNDS 696-710 CORRESPONDING TO STRUCTURE 144

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 146 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 146 are set out in Table 146. STRUCTURE 146:

TABLE 146: COMPOUNDS 711-714 CORRESPONDING TO STRUCTURE 146

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 148, as further defined in Table 148.

STRUCTURE 148:

TABLE 148: COMPOUND 715 CORRESPONDING TO STRUCTURE 148

715

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 150 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 150 are set out in Table 150.

STRUCTURE 150:

TABLE 150: COMPOUNDS 716-718 CORRESPONDING TO STRUCTURE 150

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 152 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 152 are set out in Table 152.

STRUCTURE 152:

TABLE 152: COMPOUNDS 719-725 CORRESPONDING TO STRUCTURE 152

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 154 wherein n is an integer of from 1 to 12, more preferably, from 3 to 1O, from 5 to 9 and, still further, from 6 to 9 and wherein Z is CH(DiPh), 4-(N,N-dimethylamino)ρhenyl, CH₂CH₂-(3-ρyridyι), or (2-phenyl)-phenyl. Further embodiments of the compounds corresponding to Structure 154 are set out in Table 154. STRUCTURE 154:

TABLE 154: COMPOUNDS 726-729 CORRESPONDING TO STRUCTURE 154

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 156 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ or -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 156 are set out in Table 156.

STRUCTURE 156:

TABLE 156: COMPOUNDS 730-739 CORRESPONDING TO STRUCTURE 156

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 158 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ or -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 158 are set out in Table 158.

STRUCTURE 158:

TABLE 158: COMPOUNDS 740-749 CORRESPONDING TO STRUCTURE 158

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 160 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ or -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 160 are set out in Table 160.

STRUCTURE 160:

TABLE 160: COMPOUNDS 750-759 CORRESPONDING TO STRUCTURE 160

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 162 wherein n is an integer of from lto 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ or -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 162 are set out in Table 162.

STRUCTURE 162:

TABLE 162: COMPOUNDS 760-769 CORRESPONDING TO STRUCTURE 162

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 164 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ or -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 164 are set out in Table 164.

STRUCTURE 164:

TABLE 164: COMPOUNDS 770-779 CORRESPONDING TO STRUCTURE 164

In further embodiments, the compounds employed according to the methods of the present invention correspond to cohipounds of the Structure 166 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ or -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 166 are set out in Table 166.

STRUCTURE 166:

TABLE 166: COMPOUNDS 780-789 CORRESPONDING TO STRUCTURE 166

In further embodiments, the compounds used according to the methods of the present invention correspond to compounds of the Structure 168 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ or -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 168 are set out in Table 168.

STRUCTURE 168:

TABLE 168: COMPOUNDS 790-799 CORRESPONDING TO STRUCTURE 168

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 170 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ or -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 170 are set out in Table 170.

STRUCTURE 170:

TABLE 170: COMPOUNDS 800-809 CORRESPONDING TO STRUCTURE 170

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 172 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ and -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 172 are set out in Table 172.

STRUCTURE 172:

TABLE 172: COMPOUNDS 810-819 CORRESPONDING TO STRUCTURE 172

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 174 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is -OCH₃ and -OCH₂Ph. Further embodiments of the compounds corresponding to Structure 174 are set out in Table 174.

STRUCTURE 174:

TABLE 174: COMPOUNDS 820-829 CORRESPONDING TO STRUCTURE 174

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 176 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein Z is 3-quinoline, 3-(N,N-dimethylamino)phenyl, or 4-(N,N- dimethylamino)phenyl. Further embodiments of the compounds corresponding to Structure 176 are set out in Table 176.

STRUCTURE 176:

TABLE 176: COMPOUNDS 830-847 CORRESPONDING TO STRUCTURE 176

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 178 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 178 are set out in Table 178.

STRUCTURE 178:

TABLE 178: COMPOUNDS 848-853 CORRESPONDING TO STRUCTURE 178

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 180 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 180 are set out in Table 180.

STRUCTURE 180:

TABLE 180: COMPOUNDS 854-860 CORRESPONDING TO STRUCTURE 180

hi further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 182 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9. Further embodiments of the compounds corresponding to Structure 182 are set out in Table 182.

STRUCTURE 182:

TABLE 182: COMPOUNDS 861-867 CORRESPONDING TO STRUCTURE 182

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 184 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 6-CF₃, 5-OPh, 5-CH(CH₃)₂, 5-COCH₃ or 5-COPh. Further embodiments of the compounds corresponding to Structure 184 are set out in Table 184.

STRUCTURE 184:

TABLE 184: COMPOUNDS 868-882 CORRESPONDING TO STRUCTURE 184

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 186 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF₃, 5-OPh, 5-CH(CH₃)₂, 5-COCH₃ or 5-COPh. Further embodiments of the compounds corresponding to Structure 186 are set out in Table 186.

STRUCTURE 186:

TABLE 186: COMPOUNDS 883-897 CORRESPONDING TO STRUCTURE 186

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 188 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 6-CF₃, 5-OPh, 5-CH(CH₃)₂, 5-COCH₃ or 5-COPh. Further embodiments of the compounds corresponding to Structure 188 are set out in Table 188.

STRUCTURE 188:

TABLE 188: COMPOUNDS 898-912 CORRESPONDING TO STRUCTURE 188

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 190 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 6-CF₃, 5-OPh, 5-CH(CH₃)₂, 5-COCH₃ or 5-COPh. Further embodiments of the compounds corresponding to Structure 190 are set out in Table 190.

STRUCTURE 190:

TABLE 190: COMPOUNDS 913-927 CORRESPONDING TO STRUCTURE 190

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 192 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein and R is 6-CF₃, 5-OPh 5-CH(CH₃)₂, 5-COCH₃ or 5-COPh. Further embodiments of the compounds corresponding to Structure 192 are set out in Table 192.

STRUCTURE 192:

TABLE 192: COMPOUNDS 928-942 CORRESPONDING TO STRUCTURE 192

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 194 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and R¹ is an H or -OCH₂Ph and R² is H or COOCH₃. Further embodiments of the compounds corresponding to Structure 194 are set out in Table 194.

STRUCTURE 194:

TABLE 194: COMPOUNDS 943-954 CORRESPONDING TO STRUCTURE 194

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 196 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from

6 to 9 and wherein R¹ is H or a -OCH₂Ph and R² is H or COOCH₃. Further embodiments of the compounds corresponding to Structure 196 are set out in Table 196. STRUCTURE 196:

TABLE 196: COMPOUNDS 955-966 CORRESPONDING TO STRUCTURE 196

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 198 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R¹ is H or a -OCH₂Ph and R₂ is H, or COOCH₃. Further embodiments of the compounds corresponding to Structure 198 are set out in Table 198.

STRUCTURE 198:

TABLE 198: COMPOUNDS 967-978 CORRESPONDING TO STRUCTURE 198

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 200 wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R¹ is H or a -OCH₂Ph and R² is H or COOCH₃. Further embodiments of the compounds corresponding to Structure 200 are set out in Table 200.

STRUCTURE 200:

TABLE 200: COMPOUNDS 979-990 CORRESPONDING TO STRUCTURE 200

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 202 A.

STRUCTURE 202A

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 202 A wherein n is an integer of from 1 to 12, more preferably, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is H; 4-NO₂; 2-CONHPh; 2-NO₂; 4-[l^,(4*-acetylpiperazine)]; 2- COCH₃; 3-OCOCH₃; 3-OCH₃; 4-COCH₃; 3-OCOPh; 2-CONH₂; 4-CH=CHCOCH₃; 4- Oph; 4-(N-phthalimide); 3-(N-morpholine); 2-(N-pyrrolidine); 2-(N-morpholine); or 4- OCH₂Ph. Further embodiments of the compounds corresponding to Structure 202 are set out in Table 202.

TABLE 202: COMPOUNDS 991-1021 CORRESPONDING TO STRUCTURE 202A

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 204 A wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 4-NO₂; 2-CONHPh; 2-NO₂; 4-[l'(4'-acetylpiperazine)]; 2-COCH₃; 3- OCOCH₃; 3-OCH₃; 4-COCH₃; 3-OCOPh; 2-CONH₂; 4-CH=CHCOCH₃; 4-OCOPh; 4- CH-CHCOPh; 4-{CO-3'[2'-butylbenzo(b)furan]); 3-NO₂; 4-[5'-(5'-phenylhydantoin)]; 2- CH=CHCOPh; 2-OCH₃; 4-COPh; 4-CONH₂; 3-COCH₃; 4-OPh; 4-(N-phthalimide); 3-(N- morpholine); 2-(N-pyrrolidine); 2-(N-morpholine); or 4-OCH₂Ph. Further embodiments of the compounds corresponding to Structure 204 are set out in Table 204.

STRUCTURE 204A:

TABLE 204: COMPOUNDS 1022-1048 CORRESPONDING TO STRUCTURE 204A

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 206 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still fiirther, from 6 to 9 and wherein R is H; 4-NO₂; 2-CONHPh; 2-NO₂; 2-COCH₃; 3-OCH₃; 4-COCH3; 3-OCOPh; 2-CONH₂; 4-CH=CHCOCH₃; 4-OCOPh; 4-CH=CHCOPh; 4-{CO- 3'[2'butylbenzo(b)furan]}; 3-NO₂; 2-CH-CHCOPh; 2-OCH₃; 4-COPh; 3-COCH₃; 4-OPh; 4-(N-phthalimide); or 4-OCH₂Ph. Further embodiments of the compounds corresponding to Structure 206 are set out in Table 206.

STRUCTURE 206:

TABLE 206: COMPOUNDS 1049-1068 CORRESPONDING TO STRUCTURE 206

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 208 wherein n is an integer of from 1 to 12, from 3 to 10, from 5 to 9 and, still further, from 6 to 9 and wherein R is 4-NO₂; 2-CONHPh; 2-NO₂; 2-COCH₃; 3-OCH3; 4-COCH₃; 3-OCOPh, 2-

CONH₂; 4-CH=CHCOCH₃; 4-OCOPh; 4-CH=CHCOPh; 4-{CO-

3'[2'butylbenzo(b)furan]); 3-NO₂; 2-CH=CHCOPh; 2-OCH₃; 4-COPh; 3-COCH3; 4-OPh;

4-(N-phthalimide); 3-(N-morpholine); 2-(N-morρholine); or 4-OCH₂Ph. Further embodiments of the compounds corresponding to Structure 208 are set out in Table 208.

STRUCTURE 208:

TABLE 208: COMPOUNDS 1073-1094 CORRESPONDING To STRUCTURE 208

In further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 210 wherein R is NH₂; NMe₂; NMe₃-I; NH₂.HC1; NMe₂.HCl. Further embodiments of the compounds corresponding to Structure 210 are set out in Table 210. STRUCTURE 210:

TABLE 210: COMPOUNDS 1095-1099 CORRESPONDING TO STRUCTURES 210

h further embodiments, the compounds employed according to the methods of the present invention correspond to compounds of the Structure 212 wherein R' is PhCONH or Ph₃C and R" is H or COOCH₃. Further embodiments of the compounds corresponding to Structure 212 are set out in Table 212.

STRUCTURE 212:

TABLE 212: COMPOUNDS 1100-1101 CORRESPONDING TO STRUCTURE 212

h further embodiments, the compounds administered according to the methods of the present invention correspond to compounds of the Structure 214 wherein R is 4- hydroxyphenyl or 3-hydroxy-4-methylphenyl. Further embodiments of the compounds corresponding to Structure 214 are set out in Table 214.

STRUCTURE 214:

Table 214: COMPOUNDS 1102-1103 CORRESPONDING TO STRUCTURE 214

In further embodiments, the compounds administered according to the methods of the present invention correspond to compounds to Structure 216 wherein R' is PhCONH and R" is H or COOCH₃ and n=7 or 8. Further preferred embodiments of the compounds corresponding to Structure 216 are set out in Table 216.

STRUCTURE 216:

TABLE 216: COMPOUNDS 1104-1105 CORRESPONDING TO STRUCTURE 216

Further embodiments of the invention include compounds having Structure 300:

Structure 300

wherein Y is C, N, 0, S, ester, amide, or ketone, n is an integer of from 1 to 12, a is an integer from 1-3, and Rι-R₅ each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, or an alkyl, alkenyl, or alkynyl, an aryl, an arylalkyl, or arylalkoxy group. Ri -R₂ may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group. The (CH₂), linker may be saturated or unsaturated and contain cyclic or aliphatic groups, branched or unbranched alkyl, alkenyl, or alkyl substituents, and wherein the linker may also contain heteroatoms. The aryl group is an aromatic grouping which may contain one or more rings, and the quaternary nitrogen may be part of the ring (as, for example, in pyridines and quinolines) or outside the ring (as, for example, in anilines and aminonaphthalenes). The value for n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. Specific examples include Structure 1300

1300

Yet more examples of suitable compounds include those having Structure 400:

Structure 400

wherein Y is C, N, 0, S, ester, amide, or ketone; Z is C, N, 0, or S; AA is a natural or unnatural stereoisomer of an -, β-, 7-, or δ-amino acid in which the carboxyl carbonyl is attached to Z, and the amino grouping may be a primary, secondary, tertiary, or quaternary ammonium compound; n is an integer of from 1 to 12; and R R₅ each, independently, is an H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, or an alkyl, alkenyl, or alkynyl, or an aryl group. R R₂ may also be an H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group. The (CH₂)_n linker may be saturated or unsaturated and contain cyclic or aliphatic groups, branched or unbranched alkyl, alkenyl, or.alkynyl substituents, and wherein the linker may also contain heteroatoms. The value for n may also be an integer of from 3 to 10, more preferably 5 to 9 and, still more preferably 6 to 9. Specific examples include Structure 1230:

1230

and Structure 1260:

1260

In the method of killing yeast, as well as in the method of decreasing the growth of yeast, the NADs enzyme inhibitor is a compound that selectively binds with catalytic sites or subsites on a yeast NADs enzyme to reduce or eliminate the production of NAD by the yeast. In such methods, it is particularly preferable that there is little or no inhibitory activity on the host cell. For example, when the method is utilized to inhibit yeast activity in a mammal, it is preferred that there is little or no attendant affect on the NAD synthetase activity of the host. In one embodiment, the host is a mammal. In a further embodiment, the host is a plant. Depending on the intended mode of administration, the compounds of the present invention can be in pharmaceutical compositions in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, lotions, creams, gels, or the like, preferably in unit dosage form suitable for single administration of a precise dosage. The compositions will include, as noted above, an effective amount of the selected composition, possibly in combination with a pharmaceutically acceptable carrier and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, diluents, and the like. Parenteral administration of the compounds of the present invention, if used, is generally characterized by injection. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. As used herein, "parenteral administration" includes intradermal, subcutaneous, intramuscular, intraperitoneal, iiuravenous and infrafracheal routes. One approach for parenteral administration involves use of a slow release or sustained release system such that a constant dosage is maintained. These compounds can be present in a pharmaceutically acceptable carrier, which can also include a suitable adjuvant.

Routes of administration for the compounds herein are preferably in a suitable and pharmacologically acceptable formulation. When administered to a human or an animal subject, the yeast NAD synthetase enzyme inhibitor compounds of the invention herein are preferably presented to animals or humans orally, rectally, intramuscularly, intravenously, infravesicularly or topically (including inhalation). The dosage preferably comprises between about 0.1 to about 15g per day and wherein the dosage is administered from about 1 to about 4 times per day. The preferred dosage may also comprise between 0.001 and 1 g per day, still preferably about 0.01, 0.05, 0.1, and 0.25, 0.5, 0.75 and 1.0 g per day. Further preferably, the dosage may be administered in an amount of about 1, 2.5, 5.0, 7.5,10.0, 12.5 and 15.0 g per day. The dosage may be administered at a still preferable rate of about 1, 2, 3, 4 or more times per day. Further, in some circumstances, it may be preferable to administer the compounds invention continuously, as with, for example, intravenous administration. The exact amount of the compound required will vary from subject to subject, depending on the species, age, weight and general condition of the subject, the particular compound used, its mode of administration and the like. Thus, it is not possible to specify an exact amount for every compound. However, an appropriate amount can be determined by one of ordinary skill in the art using only routine experimentation given the teachings herein.

The following effects of NADs inhibitors are observed on Bacillus subtilis, a spore forming bacterium closely related to Bacillus anthracis. The compounds below inhibit both the germination and outgrowth of Bacillus subtilis spores, in addition to the vegetative growth. Similar results are observed with Bacillus anthracis.

Compound | MICio_Q(μM) | MIC₁₀₀(μM)

The microscopic evidence for one selected compound suggested spore disruption. As can be seen from the dose response in Figure 2, the inhibition of outgrowth is apparent at a 0.2 mM concentration.

The inhibitors of NAD synthetase according to the present invention can be employed in a variety of processes for the treatment of humans, animals and plants as well as decontamination, sterilization and/or disinfectant techniques. The present invention further provides a method for preventing germination of spore-forming bacteria and/or the vegetative growth of bacteria, fungi and/or molds comprising administering an effective amount of at least one inhibitor of NAD synthetase, e.g. prophylactically or therapeutically, e.g., to at least one of a human, a mammal, or an animal.

The references cited herein, including patents, patent applications, and publications, are hereby incorporated by reference in their entirety. While this invention has been described with an emphasis upon certain embodiments, it will be obvious to those of ordinary skill in the art that variations of the embodiments may be used and that it is intended that the invention may be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims.

Claims

WHAT IS CLAIMED IS:

1. A method for increasing production of a food animal comprising administering to the food animal an effective amount of at least one inhibitor of nicotinamide adenine dinucleotide (NAD) synthetase of a microbe capable of infecting the food animal.

2. A method for the treatment or prevention of infection by a spore-forming bacterium in an animal comprising treating an environment of the animal with an effective amount of at least one inhibitor of NAD synthetase of the spore-forming bacterium.

3. A method for killing the vegetative cell of a spore-forming bacterium in an environment comprising treating the environment with an effective amount of at least one inhibitor of NAD synthetase of the bacterium.

4. The method of claim 2 or 3, wherein the spore-forming bacterium is a biological warfare agent.

5. The method of claim 4, wherein the biological warfare agent is Bacillus anthracis.

6. A method for freating a fungal or bacterial disease in a plant comprising treating the plant or an environment of the plant with an effective amount of at least one inhibitor of NAD synthetase of the fungus or bacterium.

7. A method for a treating plant comprising the treating the plant, or an environment thereof, with a pesticidal effective amount of at least one inhibitor of NAD synthetase of a pest.

8. The method of claim 6 or 7, wherein the plant is a food crop.

9. A method for disinfecting, sterilizing, or decontaminating an object comprising treating the object with an effective amount of at least one inhibitor of NAD synthetase of a microbe.

10. The method of claim 9, wherein the microbe is a bacterium.

11. The method of claim 9, wherein the microbe is a fungus.

12. The method of claim 11, wherein the fungus is a mold or yeast.

13. The method of any of claims 9-12, wherein the object is an article of clothing, an animal, an organ of an animal, a structure, an equipment, a furniture, an environment, a food crop, a chicken, a chicken skin, or an egg.

14. The method of claim 13, wherein the environment includes land, air, or water.

15. The method of claim 13, wherein the environment includes a medical environment.

16. The method of claim 15, wherein the medical environment includes a medical device, medical equipment, hospital, or surgical room.

17. The method of claim 16, wherein the medical device includes an implantable medical device.

18. The method of claim 17, wherein the implantable device is a catheter.

19. The method of claim 16, wherein the medical equipment is a surgical equipment.

20. The method of claim 13, wherein the organ is the digestive tract of an animal.

21. A method for controlling insect population in an environment comprising treating the environment with an effective amount of at least one inhibitor of NAD synthetase of the insect.

22. The method of claim 21, wherein the environment includes a household environment.

23. The method of claim 21, wherein the environment includes an agricultural environment.

24. The method of any of claims 2, 4, 5, 13, and 20, wherein the animal is a human.

25. The method of any of claims 1-24, wherein the inhibitor of NAD synthetase has the formula:

wherein n is an integer of from 1 to 12, Ri - R₇ each, independently, is H, an unsubstituted or a substituted cyclic or aliphatic group, a branched or an unbranched group; the linker is a cyclic or aliphatic, branched or an unbranched alkyl, alkenyl, or an alkynyl group; and the linker may also contain heteroatoms.

26. The method of any of claims 1-25, wherein the inhibitor of NAD synthetase has the formula:

wherein X is a C, N, O or S within a monocyclic or bicyclic moiety, and A and B represent the respective sites of attachment for the linker.

27. The method of claim 25 or 26, wherein n is from 5 to 9.

28. The method of any of claims 25-27, wherein the linker has the formula A-(C, Heteroatom)n-B, wherein n is from 5 to 9.

29. The method of any of claims 26-28, wherein the linker is selected from the group consisting of A-(CH₂)n-B, A-(CH₂)n-O-C(=O)-B, A-O(CH₂)n-O-C(=O)-B, A-(CH₂)n-O- C(=O)CH₂-B, and A-O(CH₂)n-O-C(=O)CH₂-B.

30. The method of any of claims 26-29, wherein X is a C or N within a monocyclic or bicyclic moiety, R R₇ each, independently, is H, an unsubstituted or substituted cyclic or aliphatic, branched or unbranched hydrocarbon, and the linker is cyclic or aliphatic, branched or unbranched alkyl, alkenyl, or alkynyl.

31. The method of any of claims 1-30, wherein the inhibitor of NAD synthetase has the formula:

wherein Aryl 1 is indolyl or phenyl; Aryl 2 is phenyl, pyridinyl, indolyl, or quinolinyl; and the linker is -(CH₂)n-, -(CH₂)n-O-C(=O)-, -O(CH₂)n-O-C(=O)-, -(CH₂)n-O- C(=O)CH₂-, or -O(CH₂)n-O-C(-=O)CH₂-.

32. The method of any of claims 25-31, wherein R R₃ are independently selected from the group consisting of H, aryloxy, hydroxyaryl, aryl C C₆ alkoxy, - alkoxy, Ci-C₆ alkoxycarbonyl, Ci-C₆ alkyl, C C₆ alkylcarbonyl, arylcarbonyl, nitro, halo, carboxy, halo C C₆ alkyl, perhalo C-*-C₆ alkyl, triphenylmethoxy, phenylcarbonylamino, Cι-C₆ alkoxycarbonyl C₂-C₆ alkenyl, arylcarbonyl C₂-C₆ alkenyl, benzofuranyl carbonyl, C-*-C₆ alkylbenzylfuranyl carbonyl, arylaminocarbonyl, arylcarbonyloxy, aminocarbonyl, Ci-C₆ alkoxycarbonylamino, phthalidimido, morpholino, pyrrolidinyl, phenylhydantoinyl, and acetylpiperazinyl.

33. The method of any of claims 25-32, wherein R^-R? are independently selected from the group consisting of H, - alkylamino, Ci-C₆ dialkylamino, C C₆ trialkylammonium, C N-alkyl, and Cι-C₆ alkoxycarbonyl.

34. The method of any of claims 25-33, wherein R₃- i are independently H.

35. The method of any of claims 31-34, wherein Aryl 1 is indolyl.

36. The method of any of claims 31-34, wherein Aryl 1 is phenyl.

37. The method of any of claims 31-36, wherein Aryl 2 is phenyl.

38. The method of any of claims 31-36, wherein Aryl 2 is pyridinyl.

39. The method of any of claims 31-36, wherein Aryl 2 is quinolinyl.

40. The method of any of claims 31-36, wherein Aryl 2 is indolyl.

41. The method of claim 35, wherein R R₃ are independently selected from the group consisting of H, phenoxy, hydroxyphenyl, benzyloxy, methoxy, methoxycarbonyl, isopropyl, butyl, acetyl, phenylcarbonyl, nitro, fluoro, carboxy, trifluoromethyl, triphenylmethoxy, phenylcarbonylamino, methoxycarbonyl ethenyl, phenylcarbonyl ethenyl, benzofuranyl carbonyl, butylbenzylfuranyl carbonyl, phenylaminocarbonyl, phenylcarbonyloxy, aminocarbonyl, methoxycarbonylamino, phthalidimido, morpholino, pyrrolidinyl, phenylhydantoinyl, and acetylpiperazinyl.

42. The method of claim 36, wherein R R₃ are independently selected from the group , consisting of H, phenoxy, hydroxyphenyl, benzyloxy, acetyl, phenylcarbonyl, nitro, phenylcarbonyl ethenyl, benzofuranyl carbonyl, butylbenzylfuranyl carbonyl, phenylaminocarbonyl, phenylcarbonyloxy, aminocarbonyl, and methoxycarbonylamino.

43. The method of any of claims 1-24, wherein the inhibitor of NAD synthetase has the formula:

wherein Y is C, N, O, S, ester, amide, or ketone, n is an integer of from 1 to 12, a is an integer from 1-3, and R R₅ each, independently, is H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, or an alkyl, alkenyl, or alkynyl, or an aryl group.

44. The method of any of claims 1-24, wherein the inhibitor of NAD synthetase has the formula:

wherein Y is C, N, O, S, ester, amide, or ketone; Z is C, N, O, or S; AA is a natural or unnatural stereoisomer of an a-, β-, y-, or δ-amino acid in which the carboxyl carbonyl is attached to Z, and the amino grouping may be a primary, secondary, tertiary, or quaternary ammonium compound; n is an integer of from 1 to 12; and Ri-R₅ each, independently, is H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, or an alkyl, alkenyl, alkynyl, aryl, aryl alkyl, or aryl alkoxy group.

45. The method of claim 43 or 44, wherein R R₂ may also be H, hydroxyl, ketone, nitro, amino, amidino, guanidino, carboxylate, amide, ester, sulfonate, halogen, alkoxy, or aryloxy group.

46. The method any of claims 1 -45, wherein the inhibitor of NAD synthetase is one of the following compounds, wherein I^" is an anion:

47. The method of any of claims 1-24, wherein the inhibitor of NAD synthetase has the formula:

wherein Y is C, N, O, S, ester, amide, or ketone; Z is C, N, O, or S; AA is a natural or unnatural stereoisomer of an -, β-, 7-, or δ-amino acid in which the carboxyl carbonyl is attached to Z, and the amino grouping may be a primary, secondary, tertiary, or quaternary ammonium compound; n is an integer of from 1 to 12; and Ri-R₅ each, independently, is H, unsubstituted or substituted cyclic group or an aliphatic group, a branched or an unbranched group, or an alkyl, alkenyl, alkynyl, aryl, aryl alkyl, or aryl alkoxy group.