Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands

Eur J Med Chem. 2018 Dec 5:160:171-182. doi: 10.1016/j.ejmech.2018.09.046. Epub 2018 Sep 18.

Abstract

We describe the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors with carboxamide derivatives as the P2 ligands. We have specifically designed aminothiochromane and aminotetrahydronaphthalene-based carboxamide ligands to promote hydrogen bonding and van der Waals interactions in the active site of HIV-1 protease. Inhibitors 4e and 4j have shown potent enzyme inhibitory and antiviral activity. High resolution X-ray crystal structures of 4d- and 4k-bound HIV-1 protease revealed molecular insights into the ligand-binding site interactions.

Keywords: Design and synthesis; Drug resistance; HIV-1 protease inhibitors; P2 ligand; X-ray crystal structure.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Chromans / chemistry
  • Chromans / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HIV / drug effects
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Chromans
  • HIV Protease Inhibitors
  • Ligands
  • Naphthalenes
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1