Methods of Making and Using Thioxothiazolidine and Rhodanine Derivatives as HIV-1 and JSP-1 Inhibitors

Abstract

The present invention provides methods of making and using 5-(2-(indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one derivatives having HIV-1 or JSP-1 inhibitory activity.

What is claimed is: 
     
         1 . A method of reducing the activity of one or more enzymes comprising the steps of:
 contacting the one or more enzymes with a thioxothiazolidin compound having a 5-(2-(indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one skeleton to reduce the activity of the one or more enzymes, wherein the one or more enzymes are HIV-1 or JNK-stimulating phosphatase-1 (JSP-1) enzymes or both.   
     
     
         2 . The method of  claim 1 , wherein the thioxothiazolidin compound reduces an HIV-1 enzyme activity. 
     
     
         3 . The method of  claim 1 , wherein the thioxothiazolidin compound inhibits the HIV-1 enzyme. 
     
     
         4 . The method of  claim 1 , wherein the thioxothiazolidin compound reduces an JNK-stimulating phosphatase-1 (JSP-1) enzyme activity. 
     
     
         5 . The method of  claim 1 , wherein the thioxothiazolidin compound inhibits an JNK-stimulating phosphatase-1 (JSP-1) enzyme. 
     
     
         6 . The method of  claim 1 , wherein the thioxothiazolidin compound is a 5-(2-(indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one comprising a 5-substituted 2-(indol-3-yl) and a 3, 4, 5 substituted phenyl. 
     
     
         7 . The method of  claim 1 , wherein the thioxothiazolidin compound is (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-2-thioxo-3-p-tolylthiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(3,4-dimethylphenyl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-2-thioxo-3-p-tolylthiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(4-methoxyphenyl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-3-(4-methoxyphenyl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one; (Z)-4-(5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-4-oxo-2-thioxothiazolidin-3-yl)benzonitrile; (Z)-4-(5-(2-(1H-indol-3-yl)-2-oxoethylidene)-4-oxo-2-thioxothiazolidin-3-yl)benzonitrile; (Z)-5-(2-(5-chloro-1H-indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(benzo[d]thiazol-6-yl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(benzo[d]thiazol-6-yl)-2-thioxothiazolidin-4-one; (Z)-3-(2-(3-(benzo[d]thiazol-6-yl)-4-oxo-2-thioxothiazolidin-5-ylidene)acetyl)-1H-indole-5-carbonitrile; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(3,5-dibromo-4-hydroxyphenyl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(3,5-dichloro-4-hydroxyphenyl)-2-thioxothiazolidin-4-one; (Z)-3-(3,5-dibromo-4-hydroxyphenyl)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-2-thioxothiazolidin-4-one; or (Z)-3-(3,5-dichloro-4-hydroxyphenyl)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-2-thioxothiazolidin-4-one. 
     
     
         8 . The method of  claim 1 , wherein the thioxothiazolidin compound has the structure: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . A method of treating a subject having an enzyme disorder comprising the steps of:
 providing a subject having an enzyme disorder;   wherein the enzyme disorder is an increase in an enzyme activity of an enzyme selected from a HIV-1 enzyme, a JNK-stimulating phosphatase-1 (JSP-1) enzymes or both;   contacting the enzyme with a thioxothiazolidin compound having a 5-(2-(indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one skeleton to reduce the enzyme activity.   
     
     
         10 . The method of  claim 9 , wherein the thioxothiazolidin compound reduces an HIV-1 enzyme activity. 
     
     
         11 . The method of  claim 9 , wherein the thioxothiazolidin compound inhibits the HIV-1 enzyme. 
     
     
         12 . The method of  claim 9 , wherein the thioxothiazolidin compound reduces the JNK-stimulating phosphatase-1 (JSP-1) enzyme activity. 
     
     
         13 . The method of  claim 9 , wherein the thioxothiazolidin compound inhibits the JNK-stimulating phosphatase-1 (JSP-1) enzyme. 
     
     
         14 . The method of  claim 9 , wherein the thioxothiazolidin compound is a 5-(2-(indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one comprising a 5-substituted 2-(indol-3-yl) and a 3, 4, 5 substituted phenyl. 
     
     
         15 . The method of  claim 9 , wherein the thioxothiazolidin compound is (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-2-thioxo-3-p-tolylthiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(3,4-dimethylphenyl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-2-thioxo-3-p-tolylthiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(4-methoxyphenyl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-3-(4-methoxyphenyl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one; (Z)-4-(5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-4-oxo-2-thioxothiazolidin-3-yl)benzonitrile; (Z)-4-(5-(2-(1H-indol-3-yl)-2-oxoethylidene)-4-oxo-2-thioxothiazolidin-3-yl)benzonitrile; (Z)-5-(2-(5-chloro-1H-indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(benzo[d]thiazol-6-yl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(benzo[d]thiazol-6-yl)-2-thioxothiazolidin-4-one; (Z)-3-(2-(3-(benzo[d]thiazol-6-yl)-4-oxo-2-thioxothiazolidin-5-ylidene)acetyl)-1H-indole-5-carbonitrile; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(3,5-dibromo-4-hydroxyphenyl)-2-thioxothiazolidin-4-one; (Z)-5-(2-(1H-indol-3-yl)-2-oxoethylidene)-3-(3,5-dichloro-4-hydroxyphenyl)-2-thioxothiazolidin-4-one; (Z)-3-(3,5-dibromo-4-hydroxyphenyl)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-2-thioxothiazolidin-4-one; or (Z)-3-(3,5-dichloro-4-hydroxyphenyl)-5-(2-(5-methoxy-1H-indol-3-yl)-2-oxoethylidene)-2-thioxothiazolidin-4-one. 
     
     
         16 . The method of  claim 9 , wherein the thioxothiazolidin compound has the structure: