New pyrazole derivatives: Synthesis, anti-inflammatory activity, cycloxygenase inhibition assay and evaluation of mPGES

• Published in: European journal of medicinal chemistry 2019-06, Vol.171, p.332-342
• Main Authors: Hassan, Ghaneya S., Abdel Rahman, Doaa E., Abdelmajeed, Esraa A., Refaey, Rana H., Alaraby Salem, M., Nissan, Yassin M.
• Format: Article
• Language: English
• Subjects: Benzenesulfonamide; mPGES; Pyrazole; Selective COX-2
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.03.052

New pyrazole derivatives 2–5 were synthesized and evaluated for their COX-1 and COX-2 inhibitory activity in vitro. All compounds showed good inhibitory activity at a nanomolar level and most compounds exhibited selectivity towards COX-2 inhibition. Compounds 2a, 3b, 4a, 5b and 5e exhibited IC50 towards COX-2 enzyme of 19.87, 39.43, 61.24, 38.73 and 39.14 nM, respectively. Furthermore, compounds 3b, 4a, 5b and 5e exhibited a selectivity index of 22.21, 14.35, 17.47 and 13.10, respectively. The most active compounds were further subjected to in vivo anti-inflammatory assay. The tested compounds showed better or comparable activity to celecoxib as positive control. In order to explore their binding mode and selectivity behaviour, molecular docking in the active site of COX-2 was carried out for these derivatives. Analysis of the docked poses of the compounds showed that they adopt similar conformations to the highly selective COX-2 inhibitor, SC-558. The docking pose of compound 3b was confirmed by molecular dynamics. All the tested compounds exhibited potent inhibitory effect on the production of PGE2, in addition to their inhibition of COX-2 enzyme. [Display omitted] •Novel pyrazole derivatives bearing benzenesulfonamide.•In vitro COX-1 and COX-2 inhibition assay.•In vitro PGE2 determination and mPGES1 expression.•In vivo anti-inflammatory assay.•Molecular docking study on the active site of COX-1 and COX-2.