Hassan G.S.Abdel Rahman D.E.Abdelmajeed E.A.Refaey R.H.Alaraby Salem M.Nissan Y.M.Pharmaceutical Chemistry DepartmentFaculty of PharmacyCairo UniversityKasr Elini St.Cairo11562Egypt; Pharmaceutical Chemistry DepartmentFaculty of PharmacyBadr University in CairoBadr CityCairo11829Egypt; National Cancer InstituteCairo UniversityFomElkhaligKasr Elaini St.Cairo11796Egypt; Pharmaceutical Chemistry DepartmentFaculty of PharmacyOctober University for Modern Sciences and Arts (MSA)GizaEgypt2020-01-092020-01-0920192235234https://doi.org/10.1016/j.ejmech.2019.03.052PubMed ID 30928706https://t.ly/JKlwYScopusNew 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. � 2019 Elsevier Masson SASEnglishBenzenesulfonamidemPGESPyrazoleSelective COX-22 chloro n [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl]acetamide3 chloro n [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl]acetamide4 [4 cyano 5 (3,5 dimethoxybenzylidene)amino 1h pyrazol 1 yl]benzene sulfonamide4 [4 cyano 5 (4 fluorobenzylidene)amino 1h pyrazol 1 yl]benzenesulfonamide4 [4 cyano 5 (4 methoxybenzylidene)amino 1h pyrazol 1 yl]benzene sulfonamide4 [5 (4 bromobenzylidene)amino cyano 1h pyrazol 1 yl]benzenesulfonamide4 [5 (4 bromophenyl) 3 trifluoromethyl 1h pyrazol 1 yl]benzenesulfonamide4 [5 (4 chlorobenzylidene)amino cyano 1h pyrazol 1 yl]benzenesulfonamide4 [5 (benzylidene)amino 4 cyano 1h pyrazol 1 yl]benzenesulfonamideantiinflammatory agentcelecoxibcyclooxygenase 1cyclooxygenase 1 inhibitorcyclooxygenase 2cyclooxygenase 2 inhibitorisoenzymen [4 (5 acetamido 4 cyano 1h pyrazol 1 yl)phenyl]sulfonylacetamiden [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl] 2 morpholinoacetamiden [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl] 2 morpholinopropionamiden [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl] 3 morpholinopropionamiden [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl]benzamideprostaglandin E2 synthasepyrazole derivativesulfonamideunclassified drugcyclooxygenase 1cyclooxygenase 2nonsteroid antiinflammatory agentprostaglandin synthaseprostaglandin synthase inhibitorpyrazolepyrazole derivativeanimal experimentanimal modelantiinflammatory activityArticlecarbon nuclear magnetic resonancecarrageenan-induced paw edemacontrolled studycytosoldrug synthesisenzyme immunoassayhydrogen bondIC50malemicrosomemolecular dockingmolecular dynamicsnonhumanproton nuclear magnetic resonanceratselectivity indexchemical structurechemistrydose responsedrug effectenzymologyhumanmetabolismstructure activity relationsynthesisAnti-Inflammatory Agents, Non-SteroidalCyclooxygenase 1Cyclooxygenase 2Cyclooxygenase InhibitorsDose-Response Relationship, DrugHumansMicrosomesMolecular Docking SimulationMolecular StructureProstaglandin-Endoperoxide SynthasesPyrazolesStructure-Activity RelationshipArticlehttps://doi.org/10.1016/j.ejmech.2019.03.052PubMed ID 30928706