Prochelators as broad-spectrum antimicrobial agents and methods of use

Abstract

The present disclosure provides methods of treating (including ameliorating and/or preventing) pathogenic infections by administering a therapeutically effective amount of a prochelator. The present disclosure further provides pharmaceutical compositions and a kit comprising the prochelator therein.

We claim: 
     
         1 . A method of treating pathogenic infections in a subject comprising administering to the subject a therapeutically effective amount of a prochelator such that the infection is treated. 
     
     
         2 . The method of  claim 1 , wherein said prochelator is a compound of Formula I or Formula II: 
       
         
           
           
               
               
           
         
         wherein:
 Y is a covalent bond or —O—R 7 —R 8 —, where R 7  is —CH 2 — or —CO 2 CH 2 — and R 8  is phenylene; 
 n and m are each an integer from 1 to 3; 
 each R 1  is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy; 
 R 5  and R 6  are independently selected H, alkyl, or haloalkyl, or together form an alkylene bridge, which alkylene bridge may be unsubstituted or substituted from 1 to 4 times with alkyl, halo, cycloalkyl, aryl, a fused cycloalkyl or a fused aryl ring; 
 each X is independently selected from the group consisting of N, O, and CH; and 
 dashed lines represent optional double bonds; 
 or a pharmaceutically acceptable salt or prodrug thereof. 
 
       
     
     
         3 . The method of  claim 2 , wherein said compound is of Formula I and is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         wherein:
 Y is a covalent bond or —O—R 7 —R 8 —, where R 7  is —CH 2 — or —CO 2 CH 2 — and R 8  is phenylene, which phenylene is unsubstituted or substituted from 1 to 4 times with independently selected halo or alkyl; 
 n and m are each an integer from 1 to 3; 
 each R 1  is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkylalkynyl, heterocyclo, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, arylalkyl, arylalkenyl, aryl alkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, alkoxy, halo, mercapto, azido, cyano, formyl, carboxylic acid, hydroxyl, nitro, acyl, aryloxy, alkylthio, amino, alkylamino, arylalkylamino, disubstituted amino, acylamino, acyloxy, ester, amide, sulfoxyl, sulfonyl, sulfonate, sulfonic acid, sulfonamide, urea, alkoxylacylamino, and aminoacyloxy; and 
 R 5  and R 6  are independently selected H, alkyl, or haloalkyl, or together form an alkylene bridge, which alkylene bridge may be unsubstituted or substituted from 1 to 4 times with alkyl, halo, cycloalkyl, aryl, a fused cycloalkyl or a fused aryl ring; 
 or a pharmaceutically acceptable salt or prodrug thereof. 
 
       
     
     
         4 . The method of  claim 2 , wherein Y is a covalent bond or —O—R 7 —R 8 —, where R 7  is —CH 2 — or —CO 2 CH 2 — and said R 8  phenylene is unsubstituted or substituted from 1 to 4 times with independently selected halo or alkyl. 
     
     
         5 . The method of  claim 2 , wherein R 5  and R 6  are independently selected H, alkyl, or haloalkyl. 
     
     
         6 . The method of  claim 2 , wherein R 5  and R 6  together form an alkylene bridge, which alkylene bridge may be unsubstituted or substituted from 1 to 4 times with alkyl, halo, cycloalkyl, aryl, a fused cycloalkyl or a fused aryl ring. 
     
     
         7 . The method of  claim 2 , wherein R 5  and R 6  together form a C2 alkylene bridge having a bicyclic cycloalkyl substituted thereon, which C2 alkylene bridge and/or bicyclic cycloalkyl may be unsubstituted or substituted from 1 to 4 times with alkyl or halo. 
     
     
         8 . The method of  claim 2 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or prodrug thereof. 
       
     
     
         9 . The method of  claim 1 , wherein the pathogen comprises fungal pathogen. 
     
     
         10 . The method as in  claim 9 , wherein the fungal pathogen comprises a yeast. 
     
     
         11 . The method as in  claim 10 , wherein the yeast comprises  C. neoformans.    
     
     
         12 . The method as in  claim 1 , wherein the pathogen comprises bacterial pathogen. 
     
     
         13 . The method as in  claim 12 , wherein the bacterial pathogen comprises a gram-negative bacteria. 
     
     
         14 . The method as in  claim 13 , wherein the gram-negative bacteria comprises  E. coli.    
     
     
         15 . The method as in  claim 12 , wherein the bacterial pathogen comprises a gram-positive bacteria. 
     
     
         16 . The method as in  claim 15 , wherein the gram-positive bacteria is selected from the group consisting of  S. aureus  and  Mycobacterium.    
     
     
         17 . The method according to  claim 15 , wherein the gram-positive bacteria comprises  S. aureus.    
     
     
         18 . The method as in  claim 16 , wherein the  Mycobacterium  comprises  M. tuberculosis, M. marinum , or  M. leprae.    
     
     
         19 . The method of  claim 1 , wherein the prochelator is administered either at the onset of disease, prior to disease symptoms or after the onset of disease symptoms. 
     
     
         20 . The method of  claim 1 , wherein a subject is a mammal. 
     
     
         21 . The method as in  claim 18 , wherein the subject is human.