Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands

Bioorg Med Chem Lett. 2017 Nov 1;27(21):4925-4931. doi: 10.1016/j.bmcl.2017.09.003. Epub 2017 Sep 6.

Abstract

Design, synthesis, and evaluation of a new class of HIV-1 protease inhibitors containing diverse flexible macrocyclic P1'-P2' tethers are reported. Inhibitor 5a with a pyrrolidinone-derived macrocycle exhibited favorable enzyme inhibitory and antiviral activity (Ki=13.2nM, IC50=22nM). Further incorporation of heteroatoms in the macrocyclic skeleton provided macrocyclic inhibitors 5m and 5o. These compounds showed excellent HIV-1 protease inhibitory (Ki=62pM and 14pM, respectively) and antiviral activity (IC50=5.3nM and 2.0nM, respectively). Inhibitor 5o also remained highly potent against a DRV-resistant HIV-1 variant.

Keywords: Drug resistance; HIV protease; Macrocyclic inhibitors; P1′-P2′ ligands; Structure-based design.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design*
  • HIV Protease / chemistry
  • HIV Protease / genetics
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemical synthesis*
  • HIV Protease Inhibitors / chemistry
  • HIV Protease Inhibitors / metabolism
  • HIV-1 / enzymology
  • Inhibitory Concentration 50
  • Ligands
  • Macrocyclic Compounds / chemical synthesis
  • Macrocyclic Compounds / chemistry*
  • Macrocyclic Compounds / metabolism
  • Molecular Dynamics Simulation
  • Mutation
  • Protein Structure, Tertiary
  • Pyrrolidinones / chemistry
  • Structure-Activity Relationship

Substances

  • HIV Protease Inhibitors
  • Ligands
  • Macrocyclic Compounds
  • Pyrrolidinones
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1