Design, synthesis, and evaluation of carboxyl-modified oseltamivir derivatives with improved lipophilicity as neuraminidase inhibitors

Bioorg Med Chem Lett. 2018 Nov 15;28(21):3477-3482. doi: 10.1016/j.bmcl.2018.09.014. Epub 2018 Sep 12.

Abstract

In this study, a series of carboxyl-modified oseltamivir analogs with improved lipophilicity were designed and synthesized, and their inhibitory activities against neuraminidase from influenza A virus H5N1 subtype were evaluated. The results demonstrated that compound 5m exhibited potent inhibitory activity (IC50 = 1.30 ± 0.23 μM), and it targeted the recently discovered 430-cavity. Compound 5m (LogD = -0.12) is more lipophilic than oseltamivir carboxylate (LogD = -1.69) at pH 7.4, which is potentially propitious to improved membrane permeability and oral drug absorption. Meanwhile, 5m showed high stability in human liver microsomes. The findings of this study can be valuable in identifying neuraminidase inhibitors with optimal lipophilicity and in the exploration of 430-cavity.

Keywords: Influenza virus; Neuraminidase inhibitors; Oseltamivir derivatives.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry*
  • Antiviral Agents / metabolism
  • Catalytic Domain
  • Drug Design
  • Drug Stability
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Influenza A Virus, H5N1 Subtype / drug effects
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Neuraminidase / antagonists & inhibitors*
  • Neuraminidase / chemistry
  • Oseltamivir / analogs & derivatives*
  • Oseltamivir / chemical synthesis
  • Oseltamivir / metabolism

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Oseltamivir
  • Neuraminidase