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

Aim: 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 (16a-l) was designed, synthesized, and evaluated for its COX-2 selective anti-inflammatory inhibitory activity.

Results: Derivatives 16d, 16f, 16k, and 16l 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. 16d, 16f, 16k, and 16l 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 16d, 16f, and 16k reinforced the in-vitro results. For instance, compound 16k induced 53% edema inhibition at the 5^th hour, comparable to that observed with celecoxib. The compounds 16d, 16f, 16k, and 16l 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 16d, 16f, 16k, 16l indicate to their relatively stable interactions within the COX-2 active site.

Conclusions: The present work paves the way for further development of potent selective COX-2 inhibitors with anti-inflammatory activity.