Inhibitors of UDP-galactopyranose mutase
Compounds and salts thereof which inhibit microbial growth or attenuate the virulence of pathogenic microorganisms and which inhibit UDP-galactopyranose mutase (UGM). Compounds of the invention include triazolothiadiazines, particularly 3,6,7-substituted-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, and 4-(1H-pyrrol-3-yl) thiazoles, particularly 4-(1,2,5-substituted-1H-pyrrol-3-yl)-2-substituted thiazoles, and salts thereof. Methods for inhibiting growth or attenuating virulence of microbial pathogens including mycobacterium, for example, M. tuberculosis and M. smegmatis and Klebsiella , for example, Klebsiella pneumoniae . Methods for inhibiting eukaryotic human and animal pathogens, and fungi and nematodes in particular. Methods for treatment of infections by prokaryotic and eukaryotic pathogens employing compounds of the invention.
1. A method for inhibiting uridine 5′-diphosphate-galactopyranose mutase (UGM) which comprises contacting UGM with an amount of one or more compounds of formula I or salts thereof effective for inhibiting UGM wherein formula I is
where:
Y is —OR 3 , or —NH 2 ,
R 3 is selected from the group consisting of hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, each of which groups is optionally substituted; and
R 1 and R 2 are independently optionally substituted aryl or heteroaryl groups having one or two rings, where two such rings are linked by a single bond or are fused, or are alkyl groups substituted with an optionally substituted aryl, aryloxy, heteroaryl or heteroaryloxy group, wherein the aryl, aryloxy, heteroaryl or heteroaryloxy groups have one or two rings, where two such rings are linked by a single bond or are fused;
where optional substitution is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, isocyano, thiocyano, isothiocyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, sulfonamide (—SO 2 —N(R F ) 2 ), azide, sulfonyl (—SO 2 —R F ), —COOR F , —COR F , —CON(R F ) 2 , —N(R F ) 2 , and C 1 -C 6 haloalkyl groups, where R F is hydrogen or a C 1 -C 6 alkyl group.
2. The method of claim 1 wherein the UGM is that of a mycobacterium or a nematode.
3. The method of claim 1 wherein contacting UGM comprises contacting a microorganism having UGM or contacting the environment of the microorganism having UGM with the one or more compounds of formula I or salts thereof.
4. A method for inhibiting the growth of a microorganism which comprises contacting the microorganism or an environment containing the microorganism with an effective amount of one or more compounds of formula I or salts thereof,
wherein formula I is
where:
Y is —OR 3 , or —NH 2 ,
R 3 is selected from the group consisting of hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, each of which groups is optionally substituted; and
R 1 and R 2 are independently optionally substituted aryl or heteroaryl groups having one or two rings, where two such rings are linked by a single bond or are fused, or are alkyl groups substituted with an optionally substituted aryl, aryloxy, heteroaryl or heteroaryloxy group, wherein the aryl, aryloxy, heteroaryl or heteroaryloxy groups have one or two rings, where two such rings are linked by a single bond or fused;
where optional substitution is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, isocyano, thiocyano, isothiocyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, sulfonamide (—SO 2 —N(R F ) 2 ), azide, sulfonyl (—SO 2 —R F ), —COOR F , —COR F , —CON(R F ) 2 , —N(R F ) 2 , and C 1 -C 6 haloalkyl groups, where R F is hydrogen or a C 1 -C 6 alkyl group, wherein the microorganism is a fungus, algae, bacterium or nematode.
5. The method of claim 4 wherein the microorganism is a mycobacterium or a nematode.
6. A method of treating an infection by a microorganism having UGM in an individual in need of such treatment by administering to the individual an effective amount of one or more compounds of formula I or salts thereof, wherein formula I is:
where:
Y is —OR 3 , or —NH 2 ,
R 3 is selected from the group consisting of hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, each of which groups is optionally substituted; and
R 1 and R 2 are independently optionally substituted aryl or heteroaryl groups having one or two rings, where two such rings are linked by a single bond or are fused, or are alkyl groups substituted with an optionally substituted aryl, aryloxy, heteroaryl or heteroaryloxy group, wherein the aryl, aryloxy, heteroaryl or heteroaryloxy groups have one or two rings, where two such rings are linked by a single bond or fused;
where optional substitution is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, isocyano, thiocyano, isothiocyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, sulfonamide (—SO 2 —N(R F ) 2 ), azide, sulfonyl (—SO 2 —R F ), —COOR F , —COR F , —CON(R F ) 2 , —N(R F ) 2 , and C 1 -C 6 haloalkyl groups, where R F is hydrogen or a C 1 -C 6 alkyl group;
and wherein the infection is an infection by a fungus, algae, bacterium or nematode.
7. The method of claim 6 wherein the infection is tuberculosis.
8. The method of claim 7 wherein R 1 is p-bromo-benzyl and R 2 is p-chloro-phenyl.
9. The method of claim 1 wherein R 1 is p-bromo-benzyl and R 2 is p-chloro-phenyl.
10. The method of claim 1 wherein
Y is —OR 3 ;
R 3 is hydrogen, or a C 1 -C 6 alkyl group; and
R 1 and R 2 are independently optionally substituted aryl groups or are C 1 -C 3 alkyl groups substituted with an optionally substituted aryl group;
where optional substitution is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C 1 -C 6 haloalkyl groups.
11. The method of claim 10 wherein R 1 and R 2 are independently selected from p-halo-substituted phenyl groups, p-halo-substituted benzyl groups, and thien-2-yl groups.
12. The method of claim 10 wherein Y is —OH, R 1 is p-bromo-benzyl and R 2 is p-chloro-phenyl.
13. A compound of formula:
or a salt thereof,
where:
Y is —OR 3 ;
R 3 is selected from the group consisting of hydrogen, an alkyl group, a cycloalkyl group, an alkenyl group, a cycloalkenyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, each of which groups is optionally substituted; and
R 1 and R 2 are independently-p-halo-substituted phenyl groups, p-halo-substituted benzyl groups, or thien-2-yl groups.
14. A pharmaceutically acceptable composition which comprises one or more compounds or salts thereof of claim 13 and a pharmaceutically acceptable carrier
15. The compound of claim 13 or a salt thereof, wherein R 1 or R 2 is p-I-phenyl or p-I-benzyl.
16. The compound of claim 13 or a salt thereof, wherein R 1 is -p-Br-benzyl and R 2 is a group other than p-Cl-phenyl.
17. A compound of formula:
wherein Y is —NH 2 , and
R 1 and R 2 are independently optionally substituted aryl or heteroaryl groups having one or two rings, where two such rings are linked by a single bond or are fused, or are alkyl groups substituted with an optionally substituted aryl, aryloxy, heteroaryl or heteroaryloxy group, wherein the aryl, aryloxy, heteroaryl or heteroaryloxy groups have one or two rings, where two such rings are linked by a single bond or are fused;
where optional substitution is substitution with one or more substituents selected from the group consisting of halogen, nitro, cyano, isocyano, thiocyano, isothiocyano, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, sulfonamide (—SO 2 —N(R F ) 2 ), azide, sulfonyl (—SO 2 —R F ), —COOR F , —COR F , —CON(R F ) 2 , —N(R F ) 2 , and C 1 -C 6 haloalkyl groups, where R F is hydrogen or a C 1 -C 6 alkyl group.
18. The compound of claim 17 wherein R 1 and R 2 are independently selected from p-halo-substituted phenyl groups, a p-halo-substituted benzyl groups and thien-2-yl groups.
19. A pharmaceutically acceptable composition which comprises one or more compounds or salts thereof of claim 17 and a pharmaceutically acceptable carrier.