Bacterial thioredoxin reductase inhibitors and methods for use thereof

Abstract

The mechanism of action of Ebselen differentiates between bacterial and mammalian thioredoxin reductase (TrxR). It displays fast oxidation of mammalian Trx and via the NADPH-TrxR catalyzed turnover of ebselen selenol with hydrogen peroxide, and therefore are mammalian antioxidants. Ebselen, and its diselenide, are strong competitive inhibitors of E. coli TrxR with K i of 0.14 μM and 0.46 μM, respectively. E. coli mutants lacking glutathione reductase or glutathione were much more sensitive to inhibition by ebselen. Since either glutaredoxin or thioredoxin systems are electron donors to ribonucleotide reductase, ebselen targets primarily glutathione and glutaredoxin-negative bacteria, a class which includes major pathogens. Ebselen, and similar compounds are therefore useful as antibacterial agents, even for multiresistant strains. Two major pathogenic bacteria, which previously had not been known to be sensitive to ebselen, Mycobacterium tuberculosis (tuberculosis) and Helicobacter pylori (stomach ulcer and cancer), were shown to be excellent targets. Helicobacter pylori was also sensitive to ebsulfur.

1 . A method for treating a prokaryotic infection in an animal or human, comprising administering at least one compound according to Formula I or a pharmaceutically acceptable salt thereof: 
     
       
         
         
             
             
         
       
       wherein X is selected from the group consisting of sulfur and selenium, and 
       wherein R is selected from the group consisting of:
 H, 
 alkyl having a carbon chain of 1 to 14 carbon atoms wherein the carbon chain is branched or unbranched which is optionally substituted with bensisoselenazol-3(2H)-one-2-yl, bensisothiazol-3(2H)-one-2-yl, OH, alkoxyl, SH, NH 2 , N-alkylamino, N,N-dialkylamino, COOH, aryl which is optionally substituted with C 1 -C 5  alkyl, OH, alkoxyl, SH, NH 2 , N-alkylamino, N,N-dialkylamino, COOH, CHO, NO 2 , F, Cl, Br, I, and heteroaryl which is optionally substituted with C 1 -C 5  alkyl, OH, alkoxyl, SH, NH 2 , N-alkylamino, N,N-dialkylamino, COOH, CHO, NO 2 , F, Cl, Br, and I, 
 aryl which is optionally substituted with C 1 -C 5  alkyl, OH, alkoxyl, SH, NH 2 , N-alkylamino, N,N-dialkylamino, COOH, CHO, NO 2 , F, Cl, Br, and I, 
 heteroaryl which is optionally substituted with C 1 -C 5  alkyl, OH, alkoxyl, SH, NH 2 , N-alkylamino, N,N-dialkylamino, COOH, CHO, NO 2 , F, Cl, Br, and I, and 
 
       wherein A represents a saturated, unsaturated or polyunsaturated 3 to 6 member carbon chain wherein N may optionally substitute for one or more carbons, and which is optionally substituted with one or more of OR, SR, and alkylamino, C 1 -C 5  alkyl, OH, alkoxyl, SH, NH 2 , N-alkylamino, N,N-dialkylamino, COOH, CHO, NO 2 , F, Cl, Br, and I, 
       or pharmaceutically acceptable derivatives thereof. 
     
   
   
       2 . The method according to  claim 1 , wherein the prokaryotic infection comprises infection with a bacteria lacking glutathione. 
   
   
       3 . The method according to  claim 1 , wherein the animal is a mammal, and wherein the compound is a selective prokaryotic thioredoxin reductase inhibitor which does not substantially inhibit mammalian thioredoxin reductase, administered in an effective amount. 
   
   
       4 . The method according to  claim 1 , wherein the prokaryotic infection comprises  Mycobacterium tuberculosis.    
   
   
       5 . The method according to  claim 1 , wherein the prokaryotic infection comprises  Helicobacter pylori.    
   
   
       6 . The method according to  claim 1 , further comprising the step of determining a glutathione and glutathione reductase expression of the prokaryote causing the prokaryotic infection and the sensitivity of thioredoxin reductase to inhibition. 
   
   
       7 . A method for prophylaxing an animal or human being against infection with a bacteria lacking glutathione and glutathione reductase, comprising administering at least one composition or a pharmaceutically acceptable salts thereof, selected from the group consisting of ebselen, ebselen diselenide and ebsulfur, pharmaceutically acceptable derivatives thereof. 
   
   
       8 . The method according to  claim 7 , wherein the bacteria comprises  Mycobacterium tuberculosis.    
   
   
       9 . The method according to  claim 7 , wherein the bacteria comprises  Helicobacter pylori.    
   
   
       10 . A method of treating a mammal infected with a prokaryote, comprising administering at least one selective prokaryotic thioredoxin reductase inhibitor which does not substantially inhibit mamalian thioredoxin reductase, in an effective amount. 
   
   
       11 . A method of treating a mammal infected with a prokaryotic organism having thioredoxin reductase, comprising administering a sufficient amount of at least one composition: 
     
       
         
         
             
             
         
       
       wherein R is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, pyridynyl, and substituted pyridinyl, and pharmaceutically acceptable salts and derivatives thereof. 
     
   
   
       12 . The method according to  claim 11 , wherein R is H. 
   
   
       13 . The method according to  claim 11 , wherein R is phenyl. 
   
   
       14 . The method according to  claim 11 , wherein R is pyridyl. 
   
   
       15 . The method according to  claim 11 , wherein R is an alkyl substituted with benzisoselenazol-3(2H)-one or a derivative thereof. 
   
   
       16 . The method according to  claim 11 , wherein R is 4-benzoic acid. 
   
   
       17 . The method according to  claim 11 , wherein R is 4-chloro phenyl. 
   
   
       18 . The method according to  claim 11 , wherein R is 4-chloro, 2-methyl phenyl. 
   
   
       19 . The method according to  claim 11 , wherein the composition comprises bis(2-carbamoyl)phenyl diselenide. 
   
   
       20 . A method of treating a mammal infected with  H. pylori , comprising administering the  H. pylori  thioredoxin reductase inhibitor ebsulfur or a pharmaceutically acceptable derivative thereof or pharmaceutically acceptable salts thereof.