Dual COX‐2 and 15‐LOX inhibition study of novel 4‐arylidine‐2‐mercapto‐1‐phenyl‐1H‐imidazolidin‐5(4H)‐ones: Design, synthesis, docking, and anti‐inflammatory activity

Abstract

Novel arylidene‐5(4H)‐imidazolone derivatives 4a–r were designed and evaluated as multidrug‐directed ligands, that is, inflammatory, proinflammatory mediators, and reactive oxygen species (ROS) inhibitors. All of the tested compounds showed cyclooxygenase (COX)‐1 inhibitory effect more than celecoxib and less than indomethacin and also demonstrated an improved inhibitory activity against 15‐lipoxygenase (15‐LOX). Compounds 4f, 4l, and 4p exhibited COX‐2 selectivity comparable to that of celecoxib, while 4k was the most selective COX‐2 inhibitor. Interestingly, the screened results showed that compound 4k exhibited a superior inhibition effect against 15‐LOX and was found to be the most selective COX‐2 inhibitor over celecoxib, whereas compound 4f showed promising COX‐2 and 15‐LOX inhibitory activities besides its inhibitory effect against ROS production and its lowering effect of both tumor necrosis factor‐α and interleukin‐6 levels by ∼80%. Moreover, compound 4f attenuated the lipopolysaccharide‐mediated increase in NF‐κB activation in RAW 264.7 macrophages. The preferred binding affinity of these molecules was confirmed by docking studies. We conclude that arylidene‐5(4H)‐imidazolone scaffolds provide promising hits for developing new synthons with anti‐inflammatory and antioxidant activities.

Identification of novel human 15-lipoxygenase-2 (h15-LOX-2) inhibitors using a virtual screening approach

“…8 Nevertheless, only a few h15-LOX-2 inhibitors have been reported in the literature so far. 6,8,[27][28][29][30][31] Among them, nordihydroguaiaretic acid (NDGA) and some flavonoid-based compounds have been described as moderately potent and non-selective inhibitors that act by reducing the active site's catalytic iron. 28 More recently, a series of low-micromolar h15-LOX-2 inhibitors that display some selectivity against other LOXs and cyclooxygenases (COXs) have also been reported.…”

“…Six novel h15-LOX-2 inhibitors, with inhibitory potencies in the micromolar range, were identified through in vitro enzyme inhibition assays for VS experimental validation. The identified inhibitors are structurally diverse from the h15-LOX-2 inhibitors reported in the literature so far, 6,8,[27][28][29][30][31] show drug-like properties, and were predicted to interact with the more solvent-accessible arm of the U-shaped active site cavity.…”