Abstract
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•Novel and selective COX-2 inhibitors based on bumetanide scaffold were developed.•Compounds 6b, 9a, and 9c were more potent than celecoxib.•Compounds 6b, 9a, and 9c were remarkably selective toward COX-2 over COX-1.•Docking showed a unique binding mode for 6b, 9a, and 9c in the active site of COX-2.•Selected compounds showed low ulcerogenic activity when administrated orally.
Herein, we describe the design and synthesis of new benzenesulfonamide derivatives as selective COX-2 inhibitors based on bumetanide scaffold. Benzenesulfonamides bearing both the pyrazole 6b and the triazoles 9a, 9c were good inhibitors of COX-2 with IC50 values of 0.32, 0.28 and 0.17 µM, respectively. These benzenesulfonamides 6b, 9a and 9c exhibited a higher selectivity index than the reference drug celecoxib. Molecular modeling study showed that incorporation of bumetanide led to a unique binding mode that is most likely the reason for the observed significant COX-2 selectivity. The anti-inflammatory activity of synthesized compounds revealed that triazoles 9a and 9c demonstrated higher efficacy than celecoxib upon using in vivo carrageenan-induced rat paw edema model. Most of the prepared compounds possess low ulcerogenic potential when administered orally. Therefore, these compounds have a great potential to be developed as safe therapeutics for inflammation, pain, and other diseases where COX-2 plays important role in their pathophysiology.