Cationic substituted benzofurans as antimicrobial agents

Abstract

A method of treating a Mycobacterium tuberculosis infection in a subject in need thereof by administering to the subject an effective amount of a cationic substituted benzofuran compound. Methods of treating microbial infections, including infections from protozoan pathogens, such as Leishmania donovani, Trypanosoma brucei rhodesiense , a Trypanosoma cruzi , and Plasmodium falciparum , and fungal pathogens, such as Candida albicans, Aspergillus fumigatus , and Cryptococcus neoformans , in a subject in need thereof by administering to the subject an effective amount of a cationic substituted benzofuran compound. Methods of synthesizing novel cationic substituted benzofuran compounds and the novel compounds themselves.

1 - 10 . (canceled) 
     
     
         11 . A method of treating a microbial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 p and q are integers from 0 to 3; 
 R 1  and R 2  are each independently selected from the group consisting of alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl; and 
 R 3  and R 4  are each independently selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein:
 R 6 , R 7 , R 8 , and R 9  are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or 
 R 6  and R 7  together represent a C 2  to C 10  alkyl, C 2  to C 10  hydroxyalkyl, or C 2  to C 10  alkylene. 
 
       
     
     
         12 . The method of  claim 11 , wherein the microbial infection is selected from the group consisting of a  Mycobacterium tuberculosis  infection, a  Leishmania donovani  infection, a  Trypanosoma brucei rhodesiense  infection, a  Trypanosoma cruzi  infection, a  Plasmodium falciparum  infection, a  Candida albicans  infection, an  Aspergillus fumigatus  infection, and a  Cryptococcus neoformans  infection. 
     
     
         13 . The method of  claim 11 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         14 . The method of  claim 11 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         15 . The method of  claim 11 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         16 . The method of  claim 11 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         17 . The method of  claim 11 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         18 . The method of  claim 11 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; 
         R 4  is at one of the 3′-position and 4′-position of ring A; 
         p is 1; 
         R 1  is —OCH 3 ; and 
         R 1  is in the 7-position of ring C. 
       
     
     
         19 . The method of  claim 11 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; 
         R 4  is at one of the 3′-position and 4′-position of ring A; 
         p is 1; 
         R 1  is —OCH 3 ; and 
         R 1  is in the 7-position of ring C. 
       
     
     
         20 . The method of  claim 11 , wherein the compound is selected from the group consisting of: 
       2-(4-carbamimidoylphenyl)benzofuran-5-carboxamidine; 
       2-(4-(N-isopropylcarbamimidoyl)phenyl)-N-isopropylbenzofuran-5-carboxamidine; 
       2-(4-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)phenyl)-4,5-dihydro-1H-imidazole; 
       2-(3-carbamimidoylphenyl)benzofuran-5-carboxamidine; 
       2-(3-(N-isopropylcarbamimidoyl)phenyl)-N-isopropylbenzofuran-5-carboxamidine; 
       2-(3-(5-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)phenyl)-4,5-dihydro-1H-imidazole; 
       2-(3-carbamimidoylphenyl)benzofuran-6-carboxamidine; 
       2-(3-(N-isopropylcarbamimidoyl)phenyl)-N-isopropylbenzofuran-6-carboxamidine; 
       2-(3-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)phenyl)-4,5-dihydro-1H-imidazole; 
       2-(4-carbamimidoylphenyl)benzofuran-6-carboxamidine; 
       2-(4-(N-isopropylcarbamimidoyl)phenyl)-N-isopropylbenzofuran-6-carboxamidine; 
       2-(4-(6-(4,5-dihydro-1H-imidazol-2-yl)benzofuran-2-yl)phenyl)-4,5-dihydro-1H-imidazole; 
       2-(4-carbamimidoylphenyl)-7-methoxybenzofuran-5-carboxamidine; 
       2-(4-(5-(4,5-dihydro-1H-imidazol-2-yl)-7-methoxybenzofuran-2-yl)phenyl)-4,5-dihydro-1H-imidazole; 
       2-(4-(N-hydroxycarbamimidoyl)phenyl)-N-hydroxybenzofuran-5-carboxamidine; 
       2-(4-(N-methoxycarbamimidoyl)phenyl)-N-methoxybenzofuran-5-carboxamidine; 
       2-(3-(N-hydroxycarbamimidoyl)phenyl)-N-hydroxybenzofuran-6-carboxamidine; and 
       2-(4-(N-hydroxycarbamimidoyl)phenyl)-N-hydroxybenzofuran-6-carboxamidine. 
     
     
         21 . The method of  claim 11 , wherein the compound of Formula II is administered in the form of a pharmaceutically acceptable salt. 
     
     
         22 . The method of  claim 21 , wherein the pharmaceutically acceptable salt is a hydrochloride salt. 
     
     
         23 - 41 . (canceled) 
     
     
         42 . A compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 p and q are integers from 0 to 3; 
 R 1  and R 2  are each independently selected from the group consisting of alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl; and 
 R 3  and R 4  are each independently selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein:
 R 6 , R 7 , R 8 , and R 9  are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or
 R 6  and R 7  together represent a C 2  to C 10  alkyl, C 2  to C 10  hydroxyalkyl, or C 2  to C 10  alkylene. 
 
 
       
     
     
         43 . The compound of  claim 42 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         44 . The compound of  claim 42 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         45 . The compound of  claim 42 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         46 . The compound of  claim 42 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         47 . The compound of  claim 42 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; and 
         R 4  is at one of the 3′-position and 4′-position of ring A. 
       
     
     
         48 . The compound of  claim 42 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; 
         R 4  is at one of the 3′-position and 4′-position of ring A; 
         p is 1; 
         R 1  is —OCH 3 ; and 
         R 1  is in the 7-position of ring C. 
       
     
     
         49 . The compound of  claim 42 , wherein:
 R 3  and R 4  are each   
       
         
           
           
               
               
           
         
         R 3  is at one of the 5-position and 6-position of ring C; 
         R 4  is at one of the 3′-position and 4′-position of ring A; 
         p is 1; 
         R 1  is —OCH 3 ; and 
         R 1  is in the 7-position of ring C. 
       
     
     
         50 . A pharmaceutically acceptable salt of a compound of  claim 42 . 
     
     
         51 . The pharmaceutically acceptable salt of  claim 50 , wherein the salt is a hydrochloride salt. 
     
     
         52 - 61 . (canceled) 
     
     
         62 . A pharmaceutical formulation comprising:
 (a) a compound of Formula (II); and   (b) a pharmaceutically acceptable carrier.   
     
     
         63 - 66 . (canceled) 
     
     
         67 . A method of preparing a compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       wherein:
 p and q are integers from 0 to 3; 
 R 1  and R 2  are each independently selected from the group consisting of alkyl, halo, hydroxyl, alkoxyl, aryloxyl, and aralkyloxyl; 
 R 3  and R 4  are each independently selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         wherein:
 R 6 , R 7 , R 8 , and R 9  are each independently selected from the group consisting of H, alkyl, cycloalkyl, aryl, aralkyl, hydroxyl, alkoxyl, hydroxyalkyl, hydroxycycloalkyl, alkoxycycloalkyl, aminoalkyl, acyloxyl, alkylaminoalkyl, and alkoxycarbonyl; or
 R 6  and R 7  together represent a C 2  to C 10  alkyl, C 2  to C 10  hydroxyalkyl, or C 2  to C 10  alkylene; 
 
 
         the method comprising:
 (a) mixing anhydrous 1,4-dioxane and an anhydrous alkyl alcohol to form a first reaction mixture; 
 (b) saturating the first reaction mixture with an anhydrous gaseous acid to form a second reaction mixture; 
 (c) adding a (cyanophenyl)benzofuran carbonitrile to the second reaction mixture to form a diimidate; 
 (d) suspending the diimidate in an anhydrous protic solvent to form a third reaction mixture; and 
 (e) saturating the third reaction mixture with an amine to form a compound of Formula (II). 
 
       
     
     
         68 . The method of  claim 67 , wherein the (cyanophenyl)benzofuran carbonitrile is prepared by the method comprising:
 (a) contacting a halogenated hydroxybenzonitrile and a alkynylbenzonitrile with a metal oxide in an anhydrous polar aprotic solvent to form a first reaction mixture; and   (b) stirring the first reaction mixture for a period of time to form a (cyanophenyl)benzofuran carbonitrile.   
     
     
         69 . The method of  claim 67 , wherein the (cyanophenyl)benzofuran carbonitrile is prepared by the method comprising:
 (a) contacting a halogenated hydroxybenzoate and an alkynylbenzoate with a metal oxide in an anhydrous polar aprotic solvent to form a first reaction mixture;   (b) stirring the first reaction mixture for a period of time to form a (alkyl-oxycarbonylphenyl)benzofuran carboxylate;   (c) passing anhydrous NH 3  through an anhydrous nonpolar aprotic solvent for a period of time to form a second reaction mixture;   (d) adding a solution of a metal alkyl in a nonpolar aprotic solvent to the second reaction mixture to form a third reaction mixture;   (e) passing NH 3  through the third reaction mixture for a period of time to form a fourth reaction mixture; and   (f) adding the (alkyl-oxycarbonylphenyl)benzofuran carboxylate to the fourth reaction mixture to form a (cyanophenyl)benzofuran carbonitrile.   
     
     
         70 . The method of  claim 67 , wherein the (cyanophenyl)benzofuran carbonitrile is prepared by the method comprising:
 (a) contacting a halogenated hydroxyalkoxybenzaldehyde and a alkynylbenzonitrile with a metal oxide in an anhydrous polar aprotic solvent to form a first reaction mixture;   (b) stirring the first reaction mixture for a period of time to form a ((cyanophenyl)alkoxy)benzofurancarbaldehyde;   (c) adding the ((cyanophenyl)alkoxy)benzofurancarbaldehyde and a hydroxylamine to a melted pyridine hydrochloride to form a formaldehyde oxime; and   (d) refluxing the formaldehyde oxime in a solution of an acid anhydride for a period of time to form a ((cyanophenyl)alkoxy)benzofuran carbonitrile.   
     
     
         71 - 75 . (canceled) 
     
     
         76 . A method of preparing a bis-amidoxime compound of Formula (II), the method comprising:
 (a) adding an alkali metal alcoholate to a solution of NH 2 OH_HCl in an anhydrous polar aprotic solvent to form a first reaction mixture;   (b) adding a benzofuran carbonitrile to the first reaction mixture to form a second reaction mixture;   (c) stirring the second reaction mixture for a period of time;   (d) pouring the second reaction mixture into ice water to form a precipitate;   (e) filtering the precipitate;   (f) washing the precipitate with a mixture of protic solvents;   (g) drying the washed precipitate; and   (h) recrystallizing the washed precipitate to form a bis-amidoxime.   
     
     
         77 . A method for preparing a bis-alkylamidoxime of Formula (II), the method comprising:
 (a) adding an aqueous hydroxide solution to a stirred solution of a benzofuran carboxamidine in a polar aprotic solvent to form a first reaction mixture;   (b) cooling the first reaction mixture;   (c) adding a dialkyl sulfate to the cooled first reaction mixture to form a second reaction mixture;   (d) stirring the second reaction mixture for a period of time;   (e) diluting the second reaction mixture with a protic solvent to form a residue;   (f) separating the residue;   (g) purifying the residue; and   (h) recrystallizing the residue from aqueous acid to form a bis-alkylamidoxime.   
     
     
         78 - 79 . (canceled)