Cell-active carbazole derivatives as inhibitors of the zika virus protease

Eur J Med Chem. 2019 Oct 15:180:536-545. doi: 10.1016/j.ejmech.2019.07.007. Epub 2019 Jul 17.


Zika virus (ZIKV) infection recently resulted in an international health emergency the Americas in and despite its high profile there is currently no approved treatment for ZIKV infection with millions of people being at risk. ZIKV is a member of Flaviviridae family which includes prominent members such as dengue virus (DENV) and West Nile virus (WNV). One of the best validated targets for developing anti-flaviviral treatment for DENV and WNV infection is the NS2B/NS3 protease. However the inhibitors reported to date have shown limited promise for further clinical development largely due to poor cellular activity. Prompted by the conserved nature of the viral NS2B/NS3 protease across flaviviruses, we envisaged that small molecule inhibitors of the ZIKVpro may be developed by applying rational design on previously reported scaffolds with demonstrated activity against other flaviviral proteases. Starting with an earlier WNVpro hit we performed a scaffold hopping exercise and discovered that certain carbazole derivatives bearing amidine groups possessed submicromolar potency and significant cellular activity against ZIKV. We successfully addressed various issues with the synthesis of novel N-substituted carbazole-based amidines thus permitting a targeted SAR campaign. The in vitro biochemical and cell-based inhibitory profiles exhibited by the lead molecule described in this work (ZIKVpro IC50 0.52 μM, EC50 1.25 μM), is among the best reported to date. Furthermore, these molecules possess capacity for further optimization of pharmacokinetics and may evolve to broad spectrum flaviviral protease inhibitors.

Keywords: Amidines; Carbazoles; Flavivirus; Inhibitors; Protease; Zika.

MeSH terms

  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Carbazoles / chemistry
  • Carbazoles / pharmacology*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology*
  • RNA Helicases / antagonists & inhibitors
  • RNA Helicases / metabolism
  • Serine Endopeptidases / metabolism
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism
  • Zika Virus / drug effects*
  • Zika Virus / enzymology*


  • Antiviral Agents
  • Carbazoles
  • NS2B protein, flavivirus
  • NS3 protein, flavivirus
  • Protease Inhibitors
  • Viral Nonstructural Proteins
  • carbazole
  • Serine Endopeptidases
  • RNA Helicases