Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole and related heterocycles

Bioorg Med Chem Lett. 2013 Feb 1;23(3):750-6. doi: 10.1016/j.bmcl.2012.11.093. Epub 2012 Dec 1.

Abstract

A series of potent arenavirus inhibitors sharing a benzimidazole core were previously reported by our group. SAR studies were expanded beyond the previous analysis, which involved the attached phenyl rings and methylamino linker portion, to include modifications focused on the benzimidazole core. These changes included the introduction of various substituents to the bicyclic benzimidazole ring system along with alternate core heterocycles. Many of the analogs containing alternate nitrogen-based bicyclic ring systems were found to retain antiviral potency compared to the benzimidazole series from which we derived our lead compound, ST-193. In fact, 21 h, built on an imidazopyridine core, possessed a near tenfold increase in potency against Lassa virus pseudotypes compared to ST-193. As found with the benzimidazole series, broad-spectrum arenavirus activity was also observed for a number of the analogs discovered during this study.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Arenavirus / drug effects*
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology
  • Drug Discovery*
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Lassa virus / drug effects
  • Structure-Activity Relationship

Substances

  • Antiviral Agents
  • Benzimidazoles
  • Heterocyclic Compounds
  • ST-193