New 1-phenyl-5-(1 H -pyrrol-1-yl)-1 H -pyrazole-3-carboxamides inhibit hepatitis C virus replication via suppression of cyclooxygenase-2

Dinesh Manvar, Sveva Pelliccia, Giuseppe La Regina, Valeria Famiglini, Antonio Coluccia, Anna Ruggieri, Simona Anticoli, Jin Ching Lee, Amartya Basu, Ozge Cevik, Lucia Nencioni, Anna Teresa Palamara, Claudio Zamperini, Maurizio Botta, Johan Neyts, Pieter Leyssen, Neerja Kaushik-Basu, Romano Silvestri

Research output: Contribution to journalArticlepeer-review

Abstract

We report here the synthesis and mechanism of inhibition of pyrazolecarboxamide derivatives as a new class of HCV inhibitors. Compounds 6, 7, 8 and 16 inhibited the subgenomic HCV replicon 1b genotype at EC50 values between 5 and 8 μM and displayed an even higher potency against the infectious Jc1 HCV 2a genotype. Compound 6 exhibited an EC50 of 6.7 μM and selectivity index of 23 against HCV 1b, and reduced the RNA copies of the infectious Jc1 chimeric 2a clone by 82% at 7 μM. Evaluation of the mode of anti-HCV activity of 6 revealed that it suppressed HCV-induced COX-2 mRNA and protein expression, displaying an IC50 of 3.2 μM in COX-2 promoter-linked luciferase reporter assay. Conversely, the anti-HCV activity of 6 was abrogated upon over-expression of COX-2. These findings suggest that 6 as a representative of these pyrazolecarboxamides function as anti-HCV agents via targeting COX-2 at both the transcription and translation levels.

Original languageEnglish
Pages (from-to)497-506
Number of pages10
JournalEuropean Journal of Medicinal Chemistry
Volume90
DOIs
Publication statusPublished - Jan 27 2015

Keywords

  • Cyclooxigenase-2
  • HCV
  • Pyrazolecarboxamide
  • Subgenomic replicon 1b genotype

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology
  • Medicine(all)

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