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

Abstract

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 <i>in vivo</i> 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, <i>in silico</i> predictions confirmed the appropriateness of these compounds as drug-like candidates.