Novel 1,5-diaryl pyrazole-3-carboxamides as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxicity effects

O. M. Hendawy, Hesham A.M. Gomaa, Sami I. Alzarea, Mutariah S. Alshammari, Fatma A.M. Mohamed, Yaser A. Mostafa, Ahmed H. Abdelazeem, Mostafa H. Abdelrahman, Laurent Trembleau*, Bahaa G.M. Youssif* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

COX-2 selective drugs have been withdrawn from the market due to cardiovascular side effects, just a few years after their discovery. As a result, a new series of 1,5-diaryl pyrazole carboxamides 19–31 was synthesized as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxic properties. The target compounds were synthesized and tested in vitro against COX-1, COX-2, and sEH enzymes. Compounds 20, 22 and 29 exhibited the most substantial COX-2 inhibitory activity (IC50 values: 0.82–1.12 µM) and had SIs of 13, 18, and 16, respectively, (c.f. celecoxib; SI = 8). Moreover, compounds 20, 22, and 29 were the most potent dual COX-2/sEH inhibitors, with IC50 values of 0.95, 0.80, and 0.85 nM against sEH, respectively, and were more potent than the standard AUDA (IC50 = 1.2 nM). Furthermore, in vivo studies revealed that these compounds were the most active as analgesic/anti-inflammatory derivatives with a good cardioprotective profile against cardiac biomarkers and inflammatory cytokines. Finally, the most active dual inhibitors were docked inside COX-2/sEH active sites to explain their binding modes.

Original languageEnglish
Article number105302
Number of pages14
JournalBioorganic Chemistry
Volume116
Early online date24 Aug 2021
DOIs
Publication statusE-pub ahead of print - 24 Aug 2021

Keywords

  • Cardiomyopathy
  • COX-2/sEH
  • NSAIDS
  • Pyrazoles

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