Nonnucleoside inhibitors of reverse transcriptase, composite binding pocket and methods for use thereof

Abstract

Novel compounds that are potent inhibitors of HIV reverse transcriptase (RT) are described in the invention. Thes novel compounds also inhibit replication of a retrovirus, such as human immunodeficiency virus-1 (HIV-1). The novel compounds of the invention include analogs and derivatives of phenethylthiazolylthiourea (PETT), of dihydroalkoxybenzyloxopyrimidine (DABO), and of 1-[( 2 -hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). The invention additionally provides a composite HIV reverse-transcriptase (RT) nonnucleoside inhibitor (NNI) binding pocket constructed from a composite of multiple NNI-RT complexes The composite RT-NNI binding pocket provides a unique and useful tool for designing and identifying novel, potent inhibitors of reverse transcriptase.

1 - 24 . (canceled)  
     
     
         25 . A compound comprising the formula:  
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are hydrogen, halo, alkyl, alkenyl, ydroxyl, alkoxy, thioalkyl, thiol, phosphino, ROH, or RNH 2  group, where R is alkyl, and  
         R 3  is alkyl, alkenyl, aryl, aralkyl, ROH, or RNH 2  group, where R is alkyl, and  
         X and Y are independently O or S, or a pharmaceutically acceptable salt thereof.  
       
     
     
         26 . The compound of  claim 25 , wherein R 1  is alkyl, alkenyl, ROH, or RNH 2 .  
     
     
         27 . The compound of  claim 25 , wherein R 1  is methyl, ethyl, or isopropyl.  
     
     
         28 . The compound of  claim 25 , wherein R 2  is halo, alkyl, or C1-C3 alkoxy.  
     
     
         29 . The compound of  claim 25 , wherein X is S.  
     
     
         30 . The compound of  claim 25 , wherein X and Y are each S.  
     
     
         31 . The compound of  claim 25 , wherein R 3  is C1-C3 alkyl.  
     
     
         32 - 62 . (canceled)  
     
     
         63 . A method for treating a subject infected with a retrovirus, the method comprising administering to the subject an effective antiviral dose of any one of the compounds of  claim 25 .  
     
     
         64 . A method for killing HIV virus in a cell, the method comprising administering to the cell an effective anti-viral amount of any one of the compounds of  claim 25 .  
     
     
         65 . A method for inhibiting the growth of HIV in a cell, the method comprising administering to the cell an effective inhibitory dose of any of the compounds of  claim 25 .  
     
     
         66 - 130 . (canceled)