Novel di-aryl chalcone derived pyrazole linked to methane sulfonyl pharmacophore as potent selective COX-2 inhibitors; design, synthesis, molecular modeling, <i>in vitro</i> and <i>in vivo</i> anti-inflammatory activities

Based on the structural features of both lonazolac and celecoxib, as an attempt to improve COX-2 selectivity, a series of novel di-aryl-chalcone derived pyrazole (<b>16a-l</b>) was designed, synthesized, and evaluated for its COX-2 selective anti-inflammatory inhibitory activity. Derivatives <b>16d</b>, <b>16f</b>, <b>16k</b>, and <b>16l</b> displayed approximately two-folds greater COX-2 inhibitory effects (IC₅₀) than celecoxib, scoring IC₅₀ of 0.446, 0.686, 0.348, and 0.771 μM, respectively, compared to 0.685 μM for celecoxib. <b>16d</b>, <b>16f</b>, <b>16k</b>, and <b>16l</b> compounds additionally demonstrated remarkable COX-2 selectivity index (S.I.) in the range of (S.I. = 25.56–70.40) in contrast to celecoxib (S.I. = 24.09). Moreover, In-vivo anti-inflammatory activity study of the most potent derivatives <b>16d</b>, <b>16f</b>, and <b>16k</b> reinforced the in-vitro results. For instance, compound <b>16k</b> induced 53% edema inhibition at the 5^th hour, comparable to that observed with celecoxib. The compounds <b>16d</b>, <b>16f</b>, <b>16k</b>, and <b>16l</b> resulted in significant attenuation of pro-inflammatory mediators (PGE2, IL-6, TNF-α, and NF-Kβ) that produced from carrageenan-induced edema. Molecular docking and dynamics results of derivatives <b>16d</b>, <b>16f</b>, <b>16k</b>, <b>16l</b> indicate to their relatively stable interactions within the COX-2 active site. The present work paves the way for further development of potent selective COX-2 inhibitors with anti-inflammatory activity.