Identification of novel non-nucleoside vinyl-stilbene analogs as potent norovirus replication inhibitors with a potential host-targeting mechanism

Dipesh S. Harmalkar, Sung Jin Lee, Qili Lu, Mi Il Kim, Jaehyung Park, Hwayoung Lee, Minkyung Park, Ahrim Lee, Choongho Lee, Kyeong Lee

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

Abstract

Norovirus (NV), is the most common cause of acute gastroenteritis worldwide. To date, there is no specific anti-NV drug or vaccine to treat NV infections. In this study, we evaluated the inhibitory effect of different stilbene-based analogs on RNA genome replication of human NV (HNV) using a virus replicon-bearing cell line (HG23). Initial screening of our in-house chemical library against NV led to the identification of a hit containing stilbene scaffold 5 which on initial optimization gave us a vinyl stilbene compound 16c (EC50 = 4.4 μM). Herein we report our structure-activity relationship study of the novel series of vinyl stilbene analogs that inhibits viral RNA genome replication in a human NV-specific manner. Among these newly synthesized compounds, several amide derivatives of vinyl stilbenes exhibited potent anti-NV activity with EC50 values ranging from 1 to 2 μM. A trans-vinyl stilbenoid with an appended substituted piperazine amide (18k), exhibited potent anti-NV activity and also displayed favorable metabolic stability. Compound 18k demonstrated an excellent safety profile, the highest suppressive effect, and was selective for HNV replication via a viral RNA polymerase-independent manner. Its potential host-targeting antiviral mechanism was further supported by specific activation of heat shock factor 1-dependent stress-inducible pathway by 18k. These results suggest that 18k might be a promising lead compound for developing novel NV inhibitors with the novel antiviral mechanism.

Original languageEnglish
Article number111733
JournalEuropean Journal of Medicinal Chemistry
Volume184
DOIs
StatePublished - 15 Dec 2019

Keywords

  • HSF-1
  • Inhibitors
  • Non-nucleoside
  • Norovirus
  • Vinyl-stilbenes

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