Inhibitors of udp-galactopyranose mutase thwart mycobacterial growth

Abstract

Compounds which inhibit microbial growth or attenuate the virulence of pathogen microorganisms. Compounds of the invention inhibit UDP-galactopyranose mutase (UGM) and have activity as inhibitors of microbial growth of microorganisms which contain this enzyme and particularly those microorganisms in which this enzyme is responsible for the incorporation of galactofuranose residues, particularly for uridine 5′-diphosphate (UDP) galactopyranose mutase. Compounds of the invention inhibit UDP-galactopyranose mutase (UGM) and have activity to attenuate virulence of pathogenic microorganisms, including mycobacteria.

1 . A compound of formula: 
       
         
           
           
               
               
           
         
         and salts thereof, 
         where: n is 0 or 1 to indicate the presence or absence of L 1 ; 
         L 1 , if present, is an alkylene, alkenylene or alkyleneoxy linker having 1-6 carbon atoms; 
         Y is CH 2  or NR Y , where R Y  is hydrogen or a C1-C6 alkyl; 
         W is —COOR W , —CON(R W ) 2 , —SO 2 —OR W , —SO 2 —N(R W ) 2 , —OPO 3 R W , —OP(OR W ) 2 R W , or a tetrazolyl group, where each R W , independent of other R W , is hydrogen, C1-C6 alkyl or an aryl or heteroaryl group having one or two 5-member or 6-member rings; 
         m is 1 or 2; 
         the D ring is a 1,3- or 1,2-substituted 5-member or 6-member ring, which is a carbocyclic or heterocyclic ring; 
         R 1  represents no substitution on the D ring or substitution on the D ring with one or more C1-C3 alky, one or more C1-C3 haloalkyl, one or more halogens or combinations thereof; 
         the B and C rings are independently selected from an aryl or heteroaryl group having one or two rings; 
         R B  and R C  represent no substitution on the indicated ring or substitution on the indicated ring by one to five non-hydrogen substituents selected from the group consisting of halogen, nitro, cyano, hydroxyl, C1-C6 alkyl, C1-C6 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 C1-C6 haloalkyl groups, including trifluoromethyl, trichloromethyl and tribromomethyl groups, where R F  is hydrogen or a C1-C6 alkyl group; 
         or wherein R B  and R C  substituents on two adjacent carbons of a B or C ring together form a carbocyclic or heterocyclic ring having 5 to 8 ring atoms; or 
         R B  is -M-L 2 -Q-AR, where: 
         AR is an aryl or heteroaryl group having at least two rings; 
         L 2  is a linker group which is an alkylene, cycloalkylene group, alkenylene group, or an alkyleneoxy group, which contains 5-12 carbon atoms, or 
         L 2  is a linker group which is a 5- or 6-member heterocyclene group containing one or two O, N or S atoms or combinations thereof, a 6-member ring arylene, or a 6-member ring heteroarylene group containing one or two O, N or S atoms or combinations thereof; 
         M and Q are chemical moieties independently be selected from, —O—, —S—, —CO—, —NR M —, carboxyl, amide, sulfonamide, thiourea, urea, carbonate, guanidinium, carbamate, thiocarbamate, alkylene moieties or combinations thereof, where R M  is hydrogen or C1-C6 alkyl. 
       
     
     
         2 . A compound of  claim 1  having formula: 
       
         
           
           
               
               
           
         
         or salts thereof, 
         where n is 0 or 1; 
         m is 1 or 2; 
         Y is CH 2  or NR Y  where R Y  is hydrogen or a C1-C6 alkyl; 
         W is —COOR W , —CON(R W ) 2 , —SO 2 —OR W , —SO 2 —N(R W ) 2 , —OPO 3 R W , —OP(OR W ) 2 R W , or tetrazolyl, where each R W , independent of other R W , is hydrogen, a C1-C6 alkyl, an aryl or heteroaryl group. 
       
     
     
         3 . A compound of  claim 1  having formula: 
       
         
           
           
               
               
           
         
         or salts thereof. 
       
     
     
         4 . A compound of  claim 3  wherein D is S. 
     
     
         5 . A compound of  claim 3  wherein R W  is H, R Y  is H and R 1  is H. 
     
     
         6 . A compound of  claim 3 , where: n is 0 or 1 to indicate the presence or absence of L 1 ; L 1 , if present, is an alkylene, alkenylene or alkyleneoxy linker having 1-6 carbon atoms; Ry is hydrogen or a C1-C6 alkyl; R W  is hydrogen, a C1-C6 alkyl or an aryl or heteroaryl group having one or two 5-member or 6-member rings; D is S or O; R 1  represents hydrogen, a 01-03 alkyl, a 01-03 haloalkyl, or a halogen; R B  represents substitution on the indicated ring by one to five non-hydrogen substituents selected from the group consisting of halogen, nitro, cyano, azide, —COOR F , —COR F , —CON(R F ) 2 , —N(R F ) 2 , and C1-C6 haloalkyl groups, where R F  is hydrogen or a C1-C6 alkyl group; and
 R C  represents substitution on the indicated ring by a halogen at ring position 3, and zero to four non-hydrogen substituents at positions 1, 2, 4, and 5 selected from the group consisting of halogen, hydroxyl, nitro, cyano, 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 C1-C6 haloalkyl groups, where R F  is hydrogen or a C1-C6 alkyl group. 
 
     
     
         7 . A compound of  claim 6  wherein L 1  is an alkylene having 1 to 6 carbon atoms. 
     
     
         8 . A compound of  claim 6  wherein R W  is H, and Ry is hydrogen. 
     
     
         9 . A compound of  claim 6  wherein R B  represents at least one non-hydrogen substituent selected from the group consisting of halogen, nitro, cyano, azide, and C1-C6 haloalkyl groups. 
     
     
         10 . A compound of  claim 1  wherein R B  represents at least one non-hydrogen substituent selected from the group consisting of halogen, nitro, cyano, azide, and C1-C6 haloalkyl groups. 
     
     
         11 . A compound of  claim 1  wherein R C  represents substitution by a halogen at ring position 3 and R B  represents substitution by a halogen at ring position 3, substitution by two halogens at ring positions 2 and 4, substitution by two halogens at ring positions 1 and 3, substitution by a nitro group at ring position 2 or substitution by a hydroxyl group at ring position 3. 
     
     
         12 . A compound of  claim 1  wherein R C  represents substitution by a chlorine, iodine or bromine at ring position 3; and R B  represents substitution by chlorine, iodine or bromine at ring position 3, substitution by two chlorines or fluorines at ring positions 2 and 4, substitution by two chlorines or fluorines at ring positions 1 and 3, substitution by a nitro group at ring position 2, or substitution by a hydroxyl group at ring position 3. 
     
     
         13 . A compound of  claim 12  wherein R C  represents substitution by an iodine at ring position 3. 
     
     
         14 . A compound of  claim 1  wherein L 1  is —CH 2 —. 
     
     
         15 . A compound of  claim 1  wherein R B  and R C  represent substitution on the indicated ring by one to five non-hydrogen substituents selected from the group consisting of halogen, nitro, cyano, azide, and C1-C6 haloalkyl groups. 
     
     
         16 . A compound of  claim 1  wherein R B  represents substitution on the indicated ring by one to five halogen atoms. 
     
     
         17 . A compound of  claim 1  where W is —COOH; n is 1;
 L 1  is an alkylene linker having 1-6 carbon atoms; R B  represents substitution on the indicated ring by one to five non-hydrogen substituents selected from the group consisting of halogen, nitro, cyano, azide, and C1-C6 haloalkyl groups, where R F  is hydrogen or a C1-C6 alkyl group; and 
 R C  represents substitution on the indicated ring by a halogen at ring position 3, and zero to four non-hydrogen substituents, at ring positions 1, 2, 4, and 5, selected from the group consisting of halogen, nitro, cyano, azide, —N(R F ) 2 , and C1-C6 haloalkyl groups, where R F  is hydrogen or a C1-C6 alkyl group. 
 
     
     
         18 . A method for inhibiting UGM which comprises the step of contacting UGM with an amount of one or more compounds of  claim 1  effective for inhibiting the enzyme. 
     
     
         19 . A method for inhibiting the growth of a bacterium or a mycobacterium which comprises contacting the organism or an environment containing the organism with an effective amount of one or more compounds of  claim 1 . 
     
     
         20 . A method for treatment of an infection which comprises the step of administering to a human or a non-human animal an effective amount of one or more compounds of  claim 1 .