Antiviral Compounds and Methods of Using Thereof

Abstract

Disclosed herein are compounds which exhibit antiviral activity against a plurality of viruses belonging to different families such as Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Arenaviridae, Bunyaviridae, Orthomyxoviridae, and Poxviridae. Thus, methods of preventing, inhibiting, or reducing the viral activity of various viruses are provided as well as methods of treating viral infections.

1 . A method of preventing, inhibiting, or reducing the viral activity of a virus on or in a cell or a subject which comprises administering to the cell or the subject an effective amount of a compound having a structural formula selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein
 Y is 
 
       
         
           
           
               
               
           
         
         n is 1 or 2; 
         X 1 , X 2 , X 3 , X 4 , X 5  and X 6  are each independently C, N, S, O, SO 2 , CR 7  or NR 8 ; 
         L is a linker which may be a direct bond or 
       
       
         
           
           
               
               
           
         
       
       where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, aryl, amide;
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate, or an amide possessing an alkyl substituent; 
 R 8  is hydrogen, OH, a halogen, or an optionally substituted alkyl; and 
 R 9  and R 10  are each independently optionally substituted mercapto alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, or alkylhydroxymate. 
 
     
     
         2 . The method of  claim 1 , wherein at least one of X 1  or X 2  is N, S, O, SO 2 , or NR 8 . 
     
     
         3 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       wherein
 X a  and X b  are each independently C, N, NH, S, O, or CH; 
 W a  and W b  are each independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; 
 R a  and R b  are each independently N, NH, O, OH, an oxime, an alkyloxime, an alkyl or a fused ring system such that R a —CH 2 —CH 2 —R b  form an imidazole ring; and 
 R c  and R d  are each independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, or part of fused ring systems such that R c  and R d  form a cycloalkyl or heterocycloalkyl ring. 
 
     
     
         4 . The method of  claim 1 , wherein the compound is NSC 240890, NSC 240891, NSC 240893, NSC 240894, NSC 240895, NSC 240898, NSC 240899, NSC 266472, NSC 240900, NSC 278995, NSC 278997, NSC 278999, NSC 290107, NSC 290108, NSC 290111, NSC 291103, NSC 294199, NSC 294202, NSC 294206, NSC 294208, NSC 300509, NSC 300510, NSC 300511, NSC 308569, NSC 308570, NSC 308571, NSC 308572, NSC 308573, NSC 330688, NSC 330689, NSC 341909, NSC 341911, NSC 352341, NSC 369723, NSC 607617, NSC 23767, NSC 95397, NSC 128981, NSC 240899, NSC 264136, NSC 291103, NSC 369715 or NSC 306365. 
     
     
         5 . The method of  claim 1 , wherein the virus is a negative strand RNA virus or a double stranded DNA virus. 
     
     
         6 . The method of  claim 1 , wherein the virus belongs to a family selected from the group consisting of Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Arenaviridae, Bunyaviridae, Orthomyxoviridae, and Poxviridae. 
     
     
         7 . The method of  claim 1 , wherein the virus is an Ebolavirus, a Marburgvirus, an Arenavirus, an Influenzavirus, and an Orthopoxvirus. 
     
     
         8 . The method of  claim 1 , wherein the virus is Zaire Ebolavirus, Reston Ebolavirus, Sudan Ebolavirus, Ivory Coast Ebolavirus, Bundibugyo Ebolavirus, Marburgvirus, Lassa virus, Influenzavirus A, Cowpox virus, or Monkeypox virus. 
     
     
         9 . The method of  claim 1 , wherein the virus is not a reverse transcribing diploid single-stranded RNA virus or a reverse transcribing circular double-stranded DNA virus. 
     
     
         10 . The method of  claim 1 , wherein if the virus is an oncornavirus, the compound is an excluded compound. 
     
     
         11 . A method of treating an infection in a cell or a subject caused by a virus which comprises administering to the cell or the subject an effective amount of a compound having a structural formula selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       wherein
 Y is 
 
       
         
           
           
               
               
           
         
         n is 1 or 2; 
         X 1 , X 2 , X 3 , X 4 , X 5  and X 6  are each independently C, N, S, O, SO 2 , CR 7  or NR 8 ; 
         L is a linker which may be a direct bond or 
       
       
         
           
           
               
               
           
         
       
       where Z is an optionally substituted alkyl, alkenyl, dialkenyl, trialkenyl, aryl, amide;
 R 1 , R 2 , R 3 , R 4 , R 5 , R 6  and R 7  are each independently hydrogen, amino, amine with stabilized carbocations, carboxyl, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, alkylhydroxymate, or an amide possessing an alkyl substituent; 
 R 8  is hydrogen, OH, a halogen, or an optionally substituted alkyl; and 
 R 9  and R 10  are each independently optionally substituted mercapto alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, or alkylhydroxymate. 
 
     
     
         12 . The method of  claim 11 , wherein at least one of X 1  or X 2  is N, S, O, SO 2 , or NR 8 . 
     
     
         13 . The method of  claim 11 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       wherein
 X a  and X b  are each independently C, N, NH, S, O, or CH; 
 W a  and W b  are each independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, or aryl; 
 R a  and R b  are each independently N, NH, O, OH, an oxime, an alkyloxime, an alkyl or a fused ring system such that R a —CH 2 —CH 2 —R b  form an imidazole ring; and 
 R c  and R d  are each independently alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryoxy, cycloalkoxy, heteroaryloxy, alkoxycarbonyl, alkylamino, carbamoyl, alkylaminocarbonyl, alkylsulfhydryl, or part of fused ring systems such that R c  and R d  form a cycloalkyl or heterocycloalkyl ring. 
 
     
     
         14 . The method of  claim 11 , wherein the compound is NSC 240890, NSC 240891, NSC 240893, NSC 240894, NSC 240895, NSC 240898, NSC 240899, NSC 266472, NSC 240900, NSC 278995, NSC 278997, NSC 278999, NSC 290107, NSC 290108, NSC 290111, NSC 291103, NSC 294199, NSC 294202, NSC 294206, NSC 294208, NSC 300509, NSC 300510, NSC 300511, NSC 308569, NSC 308570, NSC 308571, NSC 308572, NSC 308573, NSC 330688, NSC 330689, NSC 341909, NSC 341911, NSC 352341, NSC 369723, NSC 607617, NSC 23767, NSC 95397, NSC 128981, NSC 240899, NSC 264136, NSC 291103, NSC 369715 or NSC 306365. 
     
     
         15 . The method of  claim 11 , wherein the virus is a negative strand RNA virus or a double stranded DNA virus. 
     
     
         16 . The method of  claim 11 , wherein the virus belongs to a family selected from the group consisting of Bornaviridae, Filoviridae, Paramyxoviridae, Rhabdoviridae, Arenaviridae, Bunyaviridae, Orthomyxoviridae, and Poxviridae. 
     
     
         17 . The method of  claim 11 , wherein the virus is an Ebolavirus, a Marburgvirus, an Arenavirus, an Influenzavirus, and an Orthopoxvirus. 
     
     
         18 . The method of  claim 11 , wherein the virus is Zaire Ebolavirus, Reston Ebolavirus, Sudan Ebolavirus, Ivory Coast Ebolavirus, Bundibugyo Ebolavirus, Marburgvirus, Lassa virus, Influenzavirus A, Cowpox virus, or Monkeypox virus. 
     
     
         19 . The method of  claim 11 , wherein the virus is not a reverse transcribing diploid single-stranded RNA virus or a reverse transcribing circular double-stranded DNA virus. 
     
     
         20 . The method of  claim 11 , wherein if the virus is an oncornavirus, the compound is an excluded compound.