Hybrids of selective COX-2 inhibitors and active derivatives of edaravone as COX-2 selective NSAIDs with free radical scavenging activity: Design, synthesis and biological activities

Novel hybrids of selective COX -2 inhibitors (coxibs) and active derivatives of free radical scavenger edaravone were designed to overcome the risk of cardiovascular events and stroke increased by NSAIDs (nonsteroidal antiinflammatory drugs) in this study. All the hybrids were assayed for the COX -2 inhibitory and DPPH (2, 2diphenyl-1-picrylhydrazyl) free radical scavenging activities in vitro. Finally, we found a series of hybrids with good inhibitory activity and selectivity of COX -2 and excellent free radical scavenging activity in vitro. The most promising compound 6a (WYZ90) exhibited very potent COX -2 inhibitory activity (COX -2, IC50 = 75 nM), weak COX -1 inhibitory activity (COX -1, IC50 = 5734 nM), better free radical scavenging activity (DPPH, IC50 = 19.9 mu M) than edaravone, moderate drug -likeness and ADME properties in silico, acceptable pharmacokinetic properties (T1/2 = 4.16 h, 10 mg/kg, o.p.) and oral bioavailability (F% = 36.03 %) in mice. In addition, compound WYZ90 showed similar analgesic activity to the selective COX -2 inhibitor celecoxib in acetic acid -induced mice and better antioxidant activity in Fe2+-induced lipid peroxidation in mouse liver tissue homogenate than edaravone. In conclusion, this study provided a novel class of coxibs containing edaravone moiety as COX -2 selective NSAIDs with free radical scavenging activity and the candidate compound WYZ90 showed not only similar selective COX -2 inhibitory and analgesic activity to celecoxib but also better free radical scavenging and antioxidant activity than edaravone.