Identification of an N-phenylsulfonyl-2-(piperazin-1-yl)methyl-benzonitrile derivative as Zika virus entry inhibitor

Bioorg Chem. 2023 Jan;130:106265. doi: 10.1016/j.bioorg.2022.106265. Epub 2022 Nov 16.


Zika virus (ZIKV) infection could cause severe neurological complications such as neonatal microcephaly, Guillain-Barré syndrome, and myelitis in adults. No vaccine or therapeutic drug is available for prevention and control of ZIKV infection yet. Based on previously reported anti-ZIKV hit compound 1, a series of novel N-benzoyl or phenylsulfonyl substituted 2-(piperazin-1-yl)methyl-benzonitrile (PMBN) derivatives was designed, synthesized, and investigated for the antiviral activity against ZIKV replication in different cell-based phenotypic assays. The results indicated that N-phenylsulfonyl-PMBN derivative 24 displayed the comparable antiviral activity and higher oral availability than hit compound 1. Meanwhile, mechanism of action study confirmed that compound 24 acts on the early entry stage of ZIKV life cycle. The identification of this new ZIKV entry inhibitor chemotype provided a promising lead for further optimization to develop new drug for ZIKV infection.

Keywords: Antiviral; N-phenylsulfonyl-2-(piperazin-1-yl)methyl-benzonitrile; N-substituted-2-(piperazin-1-yl)methyl-benzonitrile; Virus entry inhibitor; Zika virus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology
  • Antiviral Agents / therapeutic use
  • HIV Fusion Inhibitors*
  • Humans
  • Piperazine / therapeutic use
  • Virus Internalization
  • Zika Virus Infection* / drug therapy
  • Zika Virus*


  • benzonitrile
  • Antiviral Agents
  • Piperazine
  • HIV Fusion Inhibitors