Pharmacophore and structure-activity relationships of integrase inhibition within a dual inhibitor scaffold of HIV reverse transcriptase and integrase

Bioorg Med Chem. 2010 Jun 15;18(12):4202-11. doi: 10.1016/j.bmc.2010.05.004. Epub 2010 May 7.


Rational design of dually active inhibitors against human immunodeficiency virus (HIV) reverse transcriptase (RT) and integrase (IN) has proved viable with 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) type of non-nucleoside RT inhibitors (NNRTIs). To establish the pharmacophore and study the structure-activity relationships (SAR) of integrase inhibition within a previously disclosed RT/IN dual inhibitor scaffold, new analogues featuring substitution at different sites of the HEPT ring were designed and synthesized. These studies have revealed an IN inhibition pharmacophore that is merged with the known RT pharmacophore through a shared C-6 benzyl group. Further SAR also demonstrated that optimal IN inhibition within our dual inhibitor scaffold requires a regiospecific (N-1) diketoacid (DKA)-carrying pendant with a certain length.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • Drug Design
  • HIV Integrase / chemistry*
  • HIV Integrase / metabolism
  • HIV Integrase Inhibitors / chemical synthesis
  • HIV Integrase Inhibitors / chemistry*
  • HIV Integrase Inhibitors / pharmacology
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • Heterocyclic Compounds / chemistry
  • Humans
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship


  • Anti-HIV Agents
  • HIV Integrase Inhibitors
  • Heterocyclic Compounds
  • Reverse Transcriptase Inhibitors
  • HIV Integrase
  • HIV Reverse Transcriptase