Design, synthesis and biological evaluation of HIV-1 protease inhibitors with morpholine derivatives as P2 ligands in combination with cyclopropyl as P1' ligand

Bioorg Med Chem Lett. 2020 Apr 1;30(7):127019. doi: 10.1016/j.bmcl.2020.127019. Epub 2020 Feb 5.

Abstract

A series of novel HIV-1 protease inhibitors has been designed and synthesized, which contained morpholine derivatives as the P2 ligands and hydrophobic cyclopropyl as the P1' ligand at the meantime in this study, with the aim of improving the interactions between the active sites of HIV-1 protease and the inhibitors. Twenty-eight compounds were synthesized and assessed, among which inhibitors m18 and m1 exhibited excellent inhibitory effect on the activity of HIV-1 protease with IC50 value of 47 nM and 53 nM, respectively. The molecular modeling of m1 revealed possible hydrogen bondings or van der Waals between the inhibitor and the protease, worthy of in-depth study.

Keywords: Biological evaluation; Cyclopropyl; HIV-1 protease inhibitors; Molecular modeling; Morpholine; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Drug Design
  • Enzyme Assays
  • HIV Protease / chemistry
  • HIV Protease / metabolism*
  • HIV Protease Inhibitors / chemical synthesis
  • HIV Protease Inhibitors / chemistry*
  • HIV Protease Inhibitors / metabolism
  • HIV-1 / enzymology
  • Hydrogen Bonding
  • Molecular Docking Simulation
  • Morpholines / chemical synthesis
  • Morpholines / chemistry*
  • Morpholines / metabolism
  • Protein Binding
  • Static Electricity

Substances

  • HIV Protease Inhibitors
  • Morpholines
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1