Design, synthesis and evaluation of novel HIV-1 NNRTIs with dual structural conformations targeting the entrance channel of the NNRTI binding pocket

Eur J Med Chem. 2016 Jun 10:115:53-62. doi: 10.1016/j.ejmech.2016.02.068. Epub 2016 Mar 3.

Abstract

On the basis of structure-based bioisosteric replacement and molecular hybridization strategy, a series of novel dual structural-conformation inhibitors targeting the "entrance channel" of HIV-1 NNRTIs binding pocket (NNIBP) were designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells using the MTT method. Five compounds exhibited moderate to excellent potencies inhibiting wild-type (wt) HIV-1 replication with EC50 values ranging from 31.36 μM to 0.11 μM. Among them, compound 15b was identified as the most potent inhibitor with EC50 values of 0.11 μM and 2.18 μM against wt and K103N/Y181C double mutant HIV-1 strain (RES056), respectively. In addition, preliminary structure-activity relationships (SARs) and molecular simulation studies were discussed, which may provide valuable insights for further optimization.

Keywords: DAPY derivatives; Dual structural conformations; Entrance channel; HIV-1 NNRTIs; SARs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Binding Sites / drug effects
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Virus Replication / drug effects

Substances

  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase