Abstract

A new group of 5,5-diarylhydantoin derivatives bearing a methylsulfonyl COX-2 pharmacophore at the para position of the C-5 phenyl ring were designed and synthesized as selective COX-2 inhibitors. In vitro COX-1/COX-2 inhibition structure-activity relationships identified 5-[4-(methylsulfonyl)phenyl]-5-phenyl-hydantoin (4) as a highly potent and selective COX-2 inhibitor (COX-2 IC50 = 0.077 μM; selectivity index > 1298). It was more selective than the reference drug celecoxib (COX-2 IC50 = 0.060 μM; selectivity index = 405). A molecular modeling study where 4 was docked in the binding site of COX-2 indicated that the p-MeSO2 COX-2 pharmacophore group on the C-5 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket. The results of this study showed that the type of substituent on the N-3 hydantoin ring substituent is important for COX-2 inhibitory activity.

Highlights

  • Non-steroidal anti-inflammatory drugs (NSAIDs) are widely utilized for the treatment of various inflammatory conditions such as rheumatic fever, rheumatoid arthritis and osteoarthritis

  • A molecular modeling study where 4 was docked in the binding site of COX-2 indicated that the p-MeSO2 COX-2 pharmacophore group on the C-5 phenyl ring is oriented in the vicinity of the COX-2 secondary pocket

  • It is known that selective COX-2 inhibitors can provide antiinflammatory agents devoid of the undesirable effects associated with classical non selective NSAIDs

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Summary

Open Access

Afshin ZARGHI * 1, Farin SATTARY JAVID 1, Razieh GHODSI 1, Orkideh G. DADRASS 2, Bahram DARAEI 3, Mehdi HEDAYATI 4. © Zarghi et al.; licensee Österreichische Apotheker-Verlagsgesellschaft m.

Results and Discussion
MeS O d NH
Docking Studies
Biological Assay

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