New pyrazole–pyridazine hybrids as selective COX-2 inhibitors: design, synthesis, molecular docking, <i>in silico</i> studies and investigation of their anti-inflammatory potential by evaluation of TNF-α, IL-6, PGE-2 and NO in LPS-induced RAW264.7 macrophages
Eman O. Osman, Nadia A. Khalil, Alaa Magdy, Yara El‐Dash
Abstract
values of 1.50 and 1.15 μM, respectively. Bromo derivative 6e demonstrated a COX-2 inhibitory activity comparable to celecoxib. Further, the ability of compounds 5f, 6e, and 6f to inhibit the generation of specific pro-inflammatory cytokines and mediators, including nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and prostaglandin-E2 (PGE-2), in RAW264.7 macrophages stimulated by LPS was also estimated. Compounds 5f and 6f demonstrated the most potent activity. Morover, according to the investigation using molecular modeling studies, derivatives 5f and 6f showed respectable binding affinity towards the COX-2 active site compared to the reference ligand. Moreover, the ADME parameters, physicochemical characteristics, pharmacokinetic characteristics, and l of the most potent compounds were also computed.