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

Hassan G.S.; Abdel Rahman D.E.; Abdelmajeed E.A.; Refaey R.H.; Alaraby Salem M.; Nissan Y.M.

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

Hassan G.S.; Abdel Rahman D.E.; Abdelmajeed E.A.; Refaey R.H.; Alaraby Salem M.; Nissan Y.M.

Full Text link: https://t.ly/JKlwY

Date issued: 2019

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Doi: https://doi.org/10.1016/j.ejmech.2019.03.052 PubMed ID 30928706

Publisher: Elsevier Masson SAS

Series Info: European Journal of Medicinal Chemistry
171

Type: Article

Keywords: Benzenesulfonamide , mPGES , Pyrazole , Selective COX-2 , 2 chloro n [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl]acetamide , 3 chloro n [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl]acetamide , 4 [4 cyano 5 (3,5 dimethoxybenzylidene)amino 1h pyrazol 1 yl]benzene sulfonamide , 4 [4 cyano 5 (4 fluorobenzylidene)amino 1h pyrazol 1 yl]benzenesulfonamide , 4 [4 cyano 5 (4 methoxybenzylidene)amino 1h pyrazol 1 yl]benzene sulfonamide , 4 [5 (4 bromobenzylidene)amino cyano 1h pyrazol 1 yl]benzenesulfonamide , 4 [5 (4 bromophenyl) 3 trifluoromethyl 1h pyrazol 1 yl]benzenesulfonamide , 4 [5 (4 chlorobenzylidene)amino cyano 1h pyrazol 1 yl]benzenesulfonamide , 4 [5 (benzylidene)amino 4 cyano 1h pyrazol 1 yl]benzenesulfonamide , antiinflammatory agent , celecoxib , cyclooxygenase 1 , cyclooxygenase 1 inhibitor , cyclooxygenase 2 , cyclooxygenase 2 inhibitor , isoenzyme , n [4 (5 acetamido 4 cyano 1h pyrazol 1 yl)phenyl]sulfonylacetamide , n [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl] 2 morpholinoacetamide , n [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl] 2 morpholinopropionamide , n [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl] 3 morpholinopropionamide , n [4 cyano 1 (4 sulfamoylphenyl) 1h pyrazol 5 yl]benzamide , prostaglandin E2 synthase , pyrazole derivative , sulfonamide , unclassified drug , cyclooxygenase 1 , cyclooxygenase 2 , nonsteroid antiinflammatory agent , prostaglandin synthase , prostaglandin synthase inhibitor , pyrazole , pyrazole derivative , animal experiment , animal model , antiinflammatory activity , Article , carbon nuclear magnetic resonance , carrageenan-induced paw edema , controlled study , cytosol , drug synthesis , enzyme immunoassay , hydrogen bond , IC50 , male , microsome , molecular docking , molecular dynamics , nonhuman , proton nuclear magnetic resonance , rat , selectivity index , chemical structure , chemistry , dose response , drug effect , enzymology , human , metabolism , structure activity relation , synthesis , Anti-Inflammatory Agents, Non-Steroidal , Cyclooxygenase 1 , Cyclooxygenase 2 , Cyclooxygenase Inhibitors , Dose-Response Relationship, Drug , Humans , Microsomes , Molecular Docking Simulation , Molecular Structure , Prostaglandin-Endoperoxide Synthases , Pyrazoles , Structure-Activity Relationship

Abstract:

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. � 2019 Elsevier Masson SAS