Design, synthesis and biological evaluation of new 5,5-diarylhydantoin derivatives as selective cyclooxygenase-2 inhibitors |
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Authors: | Zarghi Afshin Javid Farin Sattary Ghodsi Razieh Dadrass Orkideh G Daraei Bahram Hedayati Mehdi |
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Institution: | Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. |
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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 IC(50) = 0.077 μM; selectivity index > 1298). It was more selective than the reference drug celecoxib (COX-2 IC(50) = 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-MeSO(2) 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. |
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Keywords: | 5 5-Diarylhydantoin derivatives COX-2 inhibition Molecular modeling studies SAR |
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