Compounds for inhibition of HIV infection by blocking HIV entry

Abstract

A group of compounds that inhibit HIV replication by blocking HIV entry was identified. Two representative compounds, designated NB-2 and NB-64, inhibited HIV replication (p24 production) with IC 50 values <0.5 μg/ml. It was proved that NB-2 and NB-64 are HIV entry inhibitors by targeting the HIV gp41 since: 1) they inhibited HIV-mediated cell fusion; 2) they inhibited HIV replication only when they were added to the cells less than one hour after virus addition; 3) they did not block the gp120-CD4 binding; 4) they did not interact with the coreceptor CXCR4 since they failed to block anti-CXCR4 antibody binding to CXCR4-expressing cells; 5) they blocked the formation of the gp41 core that is detected by sandwich enzyme linked immunosorbent assay (ELISA) using a conformation-specific MAb NC-1; 6) they inhibited the formation of the gp41 six-helix bundle revealed by fluorescence native-polyacrylamide gel electrophoresis (FN-PAGE); and 7) they blocked binding of D-peptide to the hydrophobic cavity within gp41 coiled coil domain, modeled by peptide IQN17. These results suggested that NB-2 and NB-64 may interact with the hydrophobic cavity and block the formation of the fusion-active gp41 coiled coil domain, resulting in inhibition of HIV-1 mediated membrane fusion and virus entry.

1 . A compound of molecular weight from 200 to 1200 Daltons, and logP of −2.0 to +5.5, capable of interacting with the hydrophobic cavity and blocking the formulation of the fusion-active gp41 coiled core domain.  
     
     
         2 . The compound of  claim 1 , which is negatively charged.  
     
     
         3 . A compound having the following formula:  
       
         
           
           
               
               
           
         
         Wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  contains COOH or other acidic groups.  
       
     
     
         4 . The compound of  claim 3 , wherein X can be C or N; when C or N is at any X position, the corresponding R group may or may not be there.  
     
     
         5 . The compound of  claim 3 , wherein X is either O or S; when X is either O or S, the bond with the next atom, such as C, will be a single bond and O or S will be unsubstituted.  
     
     
         6 . A compound having formula I, wherein X is a carbon or its pharmaceutically acceptable salts, 
 Wherein: 
 R 1  and R 2  are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, halogen, CN, nitro, OH and OR, where R is alkyl;  
 R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  are each independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, tetrazolyl, halogen, OH, CN, NO 2  and OR, where R is alkyl, NHR, where R is H and alkyl, COOR, where R is H, and alkyl, SO 3 R, where R is H and alkyl, SO 2 NHR, where R is H and alkyl.  
   
     
     
         7 . The compound of  claim 4 , wherein the group alkyl is substituted straight or branched alkyl chains carrying 1 to 6 carbon atoms.  
     
     
         8 . The compound of  claim 5 , wherein alkyl is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or tert-butyl.  
     
     
         9 . The compound of  claim 4 , wherein alkenyl is substituted straight or branched alkenyl chains carrying 2 to 6 carbon atoms.  
     
     
         10 . The compound of  claim 9 , wherein the alkenyl is vinyl, 1-propenyl, 2-propenyl, i-propenyl, butenyl or its isomers.  
     
     
         11 . The compound of  claim 4 , wherein alkynyl is substituted straight or branched alkynyl chains carrying 2 to 6 carbon atoms.  
     
     
         12 . The compound of  claim 11 , wherein alkynyl group is ethynyl, propynyl or its isomers, or butynyl or its isomers.  
     
     
         13 . The compound of  claim 4 , wherein suitable substituents of alkyl, alkenyl and alkynyl can be selected from one or more of amino, cyano, halogen, hydroxy, alkoxy, aryloxy, aryl, heterocyclyl, carboxy, nitro, alkyl sulfonyl, aryl sulfonyl, thio, alkyl thio, or aryl thio.  
     
     
         14 . The compound of  claim 4 , wherein cycloalkyl is substituted cycloalkyl groups containing 3 to 6 carbon atoms.  
     
     
         15 . The compound of  claim 14 , wherein the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.  
     
     
         16 . The compound of  claim 14 , wherein the cycloalkyl is benz-fused to an aromatic cyclic group.  
     
     
         17 . The compound of  claim 13 , wherein the aryl is substituted phenyl or napthyl.  
     
     
         18 . The compound of  claim 4 , wherein the group heterocyclic is optionally substituted with saturated, partially saturated, or aromatic cyclics, which contain one or more heteroatoms selected from nitrogen, oxygen or sulfur.  
     
     
         19 . The compound of  claim 18 , which is benz-fused to a substituted aromatic cyclic or heterocyles.  
     
     
         20 . The compound of  claim 4 , wherein the heterocyclic group is quinolinyl, pyridyl, indolyl, furyl, oxazolyl, thienyl, triazolyl, pyrazolyl, imidazolyl, benzothiazolyl, benzimidazolyl, piperzinyl, or benzothiazolyl.  
     
     
         21 - 38 . (canceled)