Design, Synthesis and Biological Evaluation of New 5,5-Diarylhydantoin Derivatives as Selective Cyclooxygenase-2 Inhibitors

• Main Authors: Afshin ZARGHI, Farin SATTARY JAVID, Razieh GHODSI, Orkideh G. DADRASS, Bahram DARAEI, Mehdi HEDAYATI
• Format: Article
• Language: English
• Published: Österreichische Apotheker-Verlagsgesellschaft m. b. H. 2011-07-01
• Series: Scientia Pharmaceutica
• Subjects: 5,5-Diarylhydantoin derivatives; COX-2 inhibition; Molecular modeling studies; SAR
• Online Access: http://www.mdpi.com/2218-0532/79/3/449
• ISSN: 2218-0532

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.