Discovery of 2-pyridone derivatives as potent HIV-1 NNRTIs using molecular hybridization based on crystallographic overlays

Bioorg Med Chem. 2014 Mar 15;22(6):1863-72. doi: 10.1016/j.bmc.2014.01.054. Epub 2014 Feb 6.

Abstract

Based on crystallographic overlays of the known inhibitors TMC125 and R221239 complexed in RT, we designed a novel series of 4-phenoxy-6-(phenylamino)pyridin-2(1H)-one derivatives as HIV NNRTIs by molecular hybridization approach. The biological testing results indicated that 2-pyridone scaffold of these inhibitors was indispensable for their anti-HIV-1 activity, and substitution of halogen at the 3-position of the 2-pyridone ring would decrease the anti-HIV activity. Four most potent compounds had anti-HIV-1 IIIB activities at low micromolar concentrations (EC₅₀=0.15-0.84 μM), comparable to that of nevirapine and delavidine. Some compounds were selected to test their anti-HIV-1 RT inhibitory action and to perform molecular modeling studies to predict the binding mode of these 2-pyridone derivatives.

Keywords: 2-Pyridone; Docking; Drug design; HIV; Molecular hybridization; NNRTIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Crystallization
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Pyridones / chemical synthesis
  • Pyridones / chemistry
  • Pyridones / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Anti-HIV Agents
  • Pyridones
  • Reverse Transcriptase Inhibitors
  • 2-hydroxypyridine
  • HIV Reverse Transcriptase