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 II or salts thereof effective for inhibiting the enzyme wherein
formula II is
and salts thereof,
where:
Y is —OR 4 , or —NH 2 ;
p is 1, 2 or 3;
R 4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R 5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R 10 is an —NR 6 R 7 group or hydrogen, where:
R 6 and R 7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
where substitution, if present, 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 comprises contacting a microorganism having UGM or contacting the environment of the microorganism with the one or more compounds of formula II, 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 formula II or salts thereof as defined herein, wherein
formula II is
and salts thereof,
where:
Y is —OR 4 , or —NH 2 ;
p is 1, 2 or 3;
R 4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R 5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R 10 is an —NR 6 R 7 group or hydrogen,
where:
R 6 and R 7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
where substitution, if present, 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 bacterium, a fungus, an algae or a nematode.
5. The method of claim 4 , wherein the microorganism is a mycobacterium or a nematode.
6. The method of claim 4 , where, in the compound of formula II, Y is OH, both R 5 are methyl, R 10 is —NR 6 R 7 , R 6 is hydrogen and R 7 is 1-phenylethyl.
7. 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 II or salts thereof, wherein:
formula II is
and salts thereof,
where:
Y is —OR 4 , or —NH 2 ;
p is 1, 2 or 3;
R 4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R 5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R 10 is an —NR 6 R 7 group or hydrogen,
where:
R 6 and R 7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
where substitution, if present, 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 bacterium, a fungus, an algae or a nematode.
8. The method of claim 7 , wherein the infection is tuberculosis.
9. The method of claim 7 , where in the compound of formula II Y is OH, both R 5 are methyl, R 10 is —NR 6 R 7 , R 6 is hydrogen and R 7 is 1-phenylethyl.
10. A pharmaceutically acceptable composition which comprises one or more compounds of formula II or salts thereof and a pharmaceutically acceptable carrier wherein formula II is
and salts thereof,
where:
Y is —OR 4 , or —NH 2 ;
p is 1, 2 or 3;
R 4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R 5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R 10 is an —NR 6 R 7 group or hydrogen,
where:
R 6 and R 7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
where substitution, if present, 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 when R 4 is an alkyl group, the alkyl has 6-12 carbon atoms, and with the exception that the compound is not compound 10 of formula:
or
compound 14 of formula:
11. A compound of formula II or a salt thereof, wherein formula II is
and salts thereof,
where:
Y is —OR 4 , or —NH 2 ;
p is 1, 2 or 3;
R 4 is selected from the group consisting of an alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl group, each of which groups are optionally substituted, and hydrogen;
each R 5 is independently hydrogen or an optionally substituted alkyl group having 1-3 carbon atoms; and
R 10 is an —NR 6 R 7 group or hydrogen,
where:
R 6 and R 7 are independently selected from the group consisting of hydrogen, or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl groups;
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 when R 4 is an alkyl group, the alkyl has 6-12 carbon atoms, and with the exception that the compound is not compound 10 of formula:
or
compound 14 of formula:
12. A compound or salt thereof of claim 11 , where R 10 is —NR 6 R 7 , R 6 is hydrogen or methyl and R 7 is a substituted phenyl, benzyl or phenethyl group.
13. A compound or salt thereof of claim 12 , where the phenyl, benzyl or phenethyl group is substituted with one or more halogen, one or more alkoxy, one or more alkyl, or one or more nitro groups.
14. A compound or salt thereof of claim 12 , where the phenyl, benzyl or phenethyl group is substituted with one or more halogen.
15. The method of claim 4 , where in the compound of formula II, Y is OH and R 10 is —NR 6 R 7 .
16. The composition of claim 10 , where, in the compound of formula II, Y is OH, and R 10 is —NR 6 R 7 .
17. The compound or salt of claim 11 , wherein Y is OH and R 10 is —NR 6 R 7 .
18. A compound of formula II:
and salts thereof,
wherein Y is OH, both R 5 are methyl, R 10 is —NR 6 R 7 , R 6 is hydrogen and R 7 is 1-phenylethyl.
19. A pharmaceutically acceptable composition which comprises a compound of claim 18 or salts thereof and a pharmaceutically acceptable carrier.