Journal of Enzyme Inhibition and Medicinal Chemistry (Jan 2021)

Challenging inflammatory process at molecular, cellular and in vivo levels via some new pyrazolyl thiazolones

  • Perihan A. Elzahhar,
  • Rana A. Alaaeddine,
  • Rasha Nassra,
  • Azza Ismail,
  • Hala F. Labib,
  • Mohamed G. Temraz,
  • Ahmed S. F. Belal,
  • Ahmed F. El-Yazbi

DOI
https://doi.org/10.1080/14756366.2021.1887169
Journal volume & issue
Vol. 36, no. 1
pp. 669 – 684

Abstract

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The work reported herein describes the synthesis of a new series of anti-inflammatory pyrazolyl thiazolones. In addition to COX-2/15-LOX inhibition, these hybrids exerted their anti-inflammatory actions through novel mechanisms. The most active compounds possessed COX-2 inhibitory activities comparable to celecoxib (IC50 values of 0.09–0.14 µM) with significant 15-LOX inhibitory activities (IC50s 1.96 to 3.52 µM). Upon investigation of their in vivo anti-inflammatory activities and ulcerogenic profiles, these compounds showed activity patterns equivalent or more superior to diclofenac and/or celecoxib. Intriguingly, the most active compounds were more effective than diclofenac in suppressing monocyte-to-macrophage differentiation and inflammatory cytokine production by activated macrophages, as well as their ability to induce macrophage apoptosis. The latter finding potentially adds a new dimension to the previously reported anti-inflammatory mechanisms of similar compounds. These compounds were effectively docked into COX-2 and 15-LOX active sites. Also, in silico predictions confirmed the appropriateness of these compounds as drug-like candidates.

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