Synthesis and antiviral effect of phosphamide modified vidarabine for treating HSV 1 infections

Bioorg Med Chem Lett. 2021 Nov 15:52:128405. doi: 10.1016/j.bmcl.2021.128405. Epub 2021 Oct 6.

Abstract

Vidarabine (ARA) was one of the earliest marine-related compounds to be used clinically for antiviral therapy, however, its fast metabolism is the main defect of this drug. To overcome this, we designed and synthesized a group of phosphamide-modified ARA compounds using ProTide technology. With a phosphamide modification, these compounds could become the substrate of specific phospholipase enzymes expressed in the liver. Among all 16 synthesized compounds, most showed stronger activity against herpes simplex virus type 1 (HSV-1) than ARA (EC50 of approximately 10 μM). The top three compounds were compound 2 (EC50 = 0.52 ± 0.04 μM), compound 6 (EC50 = 1.05 ± 0.09 μM) and compound 15 (EC50 = 1.18 ± 0.08 μM) (about 2 times higher than Sp type compound 2). This study provides evidence for use of the phosphamide modification, which could give ARA higher activity and liver cell targeting.

Keywords: Anti-HSV 1; Marine drugs; Nucleotide prodrugs; Phosphamide modification; ProTide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Dimethoate / chemistry
  • Dimethoate / pharmacology*
  • Dose-Response Relationship, Drug
  • Herpes Simplex / drug therapy*
  • Herpesvirus 1, Human / drug effects*
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship
  • Vidarabine / chemical synthesis
  • Vidarabine / chemistry
  • Vidarabine / pharmacology*

Substances

  • Antiviral Agents
  • Vidarabine
  • Dimethoate