Preliminary SAR and biological evaluation of potent HIV-1 protease inhibitors with pyrimidine bases as novel P2 ligands to enhance activity against DRV-resistant HIV-1 variants

Eur J Med Chem. 2020 Jan 1:185:111866. doi: 10.1016/j.ejmech.2019.111866. Epub 2019 Nov 9.

Abstract

Introducing pyrimidine bases, the basic components of nucleic acid, to P2 ligands might enhance the potency of Human Immunodeficiency Virus-1 (HIV-1) protease inhibitors because of the carbonyl and amino groups promoting the formation of extensive hydrogen bonding interactions. In this work, we provide evidence that inhibitor 10e, with N-2-(2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetamide as the P2 ligand and a 4-methoxylphenylsulfonamide as the P2' ligand, displayed remarkable enzyme inhibitory and antiviral activity, with the IC50 2.53 nM in vitro and a promising inhibition ratio with 68% against wild-type HIV-1 in vivo, with low cytotoxicity. This inhibitor also exhibited appreciable antiviral activity against DRV-resistant HIV-1 variants, which was of great value for further study.

Keywords: Antiviral activity; DRV-Resistant HIV-1 variants; HIV-1 protease inhibitors; Pyrimidine bases.

MeSH terms

  • Acetamides / chemical synthesis
  • Acetamides / chemistry
  • Acetamides / pharmacology*
  • Amines / chemical synthesis
  • Amines / chemistry
  • Amines / pharmacology*
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • HIV Protease / metabolism*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology
  • Humans
  • Ligands
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Acetamides
  • Amines
  • Anti-HIV Agents
  • Ligands
  • Protease Inhibitors
  • Pyrimidines
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1