Compounds and methods for treating mammalian gastrointestinal microbial infections
Described herein are compounds, and pharmaceutically acceptable salts and prodrugs thereof, which are useful as inhibitors of IMPDH. In certain embodiments, a compound of the invention selectively inhibits a parasitic IMPDH versus a host IMPDH. Further, the invention provides pharmaceutical compositions comprising one or more compounds of the invention. The invention also relates to methods of treating various parasitic and bacterial infections in mammals. 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 thereof, represented by Formula XIII:
wherein, independently for each occurrence,
X is O;
m is 1;
one occurrence of R 2 is hydrogen, and the other occurrence of R 2 is alkyl;
p is 0, 1, 2, or 3;
q is 0, 1, 2, 3, or 4; and
R 5 is halo, azido, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heterocycloalkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaralkyl, hydroxy, alkoxy, haloalkyloxy, aryloxy, heteroaryloxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, acyl, carboxyl, alkoxycarbonyl, carboxylic acid, acyloxy, alkylthio, sulfonate, sulfonyl, sulfonamido, formyl, cyano, oxime, or isocyano;
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, formyl, cyano, and isocyano.
2. The compound of claim 1 , wherein
3. The compound of claim 1 , wherein
4. The compound of claim 1 , wherein
5. The compound of claim 1 , wherein
6. The compound of claim 1 , wherein
7. The compound of claim 1 , wherein
8. A compound, or a pharmaceutically acceptable salt thereof, selected from the group consisting of
9. The compound of claim 1 , wherein one occurrence of R 2 is hydrogen, and the other occurrence of R 2 is methyl.
10. 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 .
11. The method of claim 10 , wherein said microbe is a protozoon, a bacterium, or a fungus.
12. The method of claim 10 , wherein said microbe is a protozoon or a bacterium selected from the group consisting of the genera Eimeria, Cryptosporidium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania, Trypanosoma, Helicobacter, Borrelia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.
13. The method of claim 11 , wherein said microbe is a protozoon; and said protozoon is selected from the group consisting of the genera Eimeria, Cryptosporidium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania and Trypanosoma.
14. The method of claim 11 , wherein said microbe is a bacterium; and said bacterium is selected from the group consisting of the genera Helicobacter, Borrelia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.
15. A method of treating or preventing a microbial infection in a mammal comprising the step of administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .
16. The method of claim 15 , wherein said microbial infection is caused by a protozoon, a bacterium, or a fungus.
17. The method of claim 15 , wherein said microbial infection is caused by a protozoon or a bacterium selected from the group consisting of the genera Eimeria, Cryptosporidium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Leishmania, Trypanosoma, Helicobacter, Borrelia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.
18. The method of claim 16 , wherein said microbial infection is caused by a protozoon; and said protozoon is selected from the group consisting of the genera Eimeria, Cryptosporidium, Babesia, Theileria, Neospora, Sarcocystis, Giardia, Entamoeba, Trichomonas, Tritrichomonas, Leishmania and Trypanosoma.
19. The method of claim 15 , wherein said microbial infection is caused by a bacterium; and said bacterium is selected from the group consisting of the genera Helicobacter, Borrelia, Streptococcus, Campylobacter, Arcobacter, Bacteroides, Fusobacterium, Burkholderia, Clostridia, Neisseria, Mycobacterium , and Acinetobacter.
20. The method of claim 13 , wherein the protozoon is of the genera Cryptosporidium.
21. The method of claim 18 , wherein the protozoon is of the genera Cryptosporidium.