Compounds and methods for treating mammalian gastrointestinal microbial infections
Disclosed are compounds and pharmaceutically acceptable salts thereof, which are useful as inhibitors of IMPDH. In certain embodiments, a compound selectively inhibits a parasitic IMPDH versus a host IMPDH. Also disclosed are pharmaceutical compositions comprising one or more compounds of the invention. Related methods of treating various parasitic and bacterial infections in mammals are disclosed. Moreover, the compounds may be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, anti-inflammatory agents, antimicrobials and immunosuppressants.
1. A compound, or a pharmaceutically acceptable salt or ester thereof, selected from the group consisting of
2. A compound, or a pharmaceutically acceptable salt or ester thereof, represented by Formula X or Formula XIII:
wherein, independently for each occurrence,
X 3 X is C(R′) 2 , S, or NR′;
wherein R′ is hydrogen, halide, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, aracyl, or heteroaracyl;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
R 14 X is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, aracyl, heteroaracyl sulfonate, sulfonyl, sulfonamido, formyl, carboxyl, alkoxycarbonyl, or acyloxy, or two R 14 X groups taken together form a non-aromatic 3-8 membered ring, or two R 14 X groups taken together form the side chain of a natural or non-natural D or L amino acid;
Z X is hydrogen, halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, or isocyano;
is hydrogen, halogen, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, halogen, amino, amido, acyl, aracyl, heteroaracyl, alkoxy, hydroxyl, carboxyl, alkoxylcarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, isocyano, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl; and
is monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
wherein, independently for each occurrence,
X 3 XIII is absent, O, C(R′) 2 , S, or NR′;
R 14 XIII is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, acyl, aracyl, heteroaracyl sulfonate, sulfonyl, sulfonamido, formyl, carboxyl, alkoxycarbonyl, or acyloxy, or two R 14 XIII groups taken together form a non-aromatic 3-8 membered ring, or two R 14 XIII groups taken together form the side chain of a natural or non-natural D or L amino acid;
Z XIII is halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, or isocyano;
is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, halogen, amino, amido, acyl, aracyl, heteroaracyl, alkoxy, hydroxyl, carboxyl, alkoxylcarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, isocyano, monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl;
is monocyclic or bicyclic cycloalkyl, monocyclic or bicyclic heterocyclyl, or monocyclic or bicyclic heteroaryl;
p is 1, 2, or 3; and
wherein R′ and m are as defined for Formula X;
wherein, any of the aforementioned alkyl, aryl, or heteroaryl may be substituted with one or more groups independently selected from the group consisting of halo, azido, alkyl, haloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, acyloxy, silyl, alkylthio, sulfonate, sulfonyl, sulfonamido, sulfhydryl, formyl, cyano, and isocyano.
3. A compound or a pharmaceutically acceptable salt or ester thereof, selected from the group consisting of
4. A method of killing or inhibiting the growth of a microbe, comprising the step of contacting said microbe with an effective amount of a compound of claim 1 .
5. The method of claim 4 , wherein said microbe is a protozoan or a bacterium.
6. The method of claim 4 , wherein said microbe is a protozoan or a bacterium selected from the group consisting of the genera Toxoplasma, Eimeria, Cryptosporidium, Plasmodium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Tritrichomonas, Leishmania, Trypanosoma, Helicobacter, Borrelia, Salmonella, Shigella, Yersinia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.
7. The method of claim 5 , wherein said microbe is a protozoan; and said protozoan is selected from the group consisting of the genera Cryptosporidium, Entamoeba, Leishmania and Trypanosoma.
8. The method of claim 7 , wherein said protozoan is selected from the genus Cryptosporidium.
9. The method of claim 5 , wherein said microbe is a bacterium; and said bacterium is selected from the group consisting of the genera Acinetobacter, Arcobacter, Bacillus, Bacteroides, Borrelia, Brachyspira, Brucella, Burkholderia, Campylobacter, Clostridia, Coxiella, Enterococcus, Erysipelothrix, Francisella, Fusobacterium, Helicobacter, Lactobacillus, Listeria, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus and Streptococcus.
10. A method of treating or preventing a microbial infection in a mammal or bird comprising the step of administering to a mammal or bird in need thereof a therapeutically effective amount of a compound of claim 1 .
11. The method of claim 10 , wherein said microbial infection is caused by a protozoan or bacterium.
12. The method of claim 10 , wherein said microbial infection is caused by a protozoan or a bacterium selected from the group consisting of the genera Cryptosporidium, Entamoeba, Leishmania, Trypanosoma, Acinetobacter, Arcobacter, Bacillus, Bacteroides, Borrelia, Brachyspira, Brucella, Burkholderia, Campylobacter, Clostridia, Coxiella, Enterococcus, Erysipelothrix, Francisella, Fusobacterium, Helicobacter, Lactobacillus, Listeria, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus and Streptococcus.
13. The method of claim 11 , wherein said microbial infection is caused by a protozoan; and said protozoan is selected from the group consisting of the genera Cryptosporidium, Entamoeba, Leishmania and Trypanosoma.
14. The method of claim 13 , wherein said protozoan is selected from the genus Cryptosporidium.
15. The method of claim 11 , wherein said microbial infection is caused by a bacterium; and said bacterium is selected from the group consisting of the genera Acinetobacter, Arcobacter, Bacillus, Bacteroides, Borrelia, Brachyspira, Brucella, Burkholderia, Campylobacter, Clostridia, Coxiella, Enterococcus, Erysipelothrix, Francisella, Fusobacterium, Helicobacter, Lactobacillus, Listeria, Mycobacterium, Neisseria, Pseudomonas, Staphylococcus and Streptococcus.
16. The method of claim 10 , further comprising the step of co-administering to a mammal or bird in need thereof a therapeutically effective amount of an antimicrobial agent.
17. The method of claim 16 , wherein said antimicrobial agent is an antibiotic.
18. The method of claim 16 , wherein said antimicrobial agent is an antiparasitic.
19. The method of claim 10 , wherein said infection is in a mammal; and the mammal is a primate, a bovine, an ovine, an equine, a porcine, a rodent, a feline, a mustelid, or a canine.
20. The method of claim 10 , wherein said infection is in a mammal; and the mammal is a human.