Design and synthesis of new 2-aryl, 3-benzyl-(1,3-oxazolidine or 1,3-thiazolidine)-4-ones as selective cyclooxygenase (COX-2) inhibitors |
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Authors: | A Zarghi H Arefi O G Dadrass S Torabi |
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Institution: | (1) Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University (M.C.), Tehran, Iran;(2) School of Pharmacy, Azad University, Pharmaceutical Sciences Unit, Tehran, Iran;(3) Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University (M.C.), P.O. Box: 14155-6153, Tehran, Iran |
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Abstract: | A new series of 2-aryl, 3-benzyl-(1,3-oxazolidine or 1,3-thiazolidine)-4-ones, possessing a methylsulfonyl pharmacophore,
were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1
and COX-2 isozyme inhibition studies were performed to acquire structure-activity relationship data with respect to the point
that molecular modeling studies showed that designed compounds bind in the primary binding site such that the C-2 para-SO2Me substituent inserts into the 2° pocket present in COX-2 enzyme. COX-1 and COX-2 inhibition studies showed that all compounds
were selective inhibitors of the COX-2 isozyme with IC50 values in the highly potent 0.21 to 0.34 μM range, and COX-2 selectivity indexes in the 222.3 to >476 range. 3-Benzyl-2-(4-methylsulfonylphenyl)-1,3-oxazolidine-4(5H)-one
was identified as the most potent (IC50 = 0.21 μM) and selective (S.I. > 476) COX-2 inhibitor among the synthesized compounds. It also was a more selective COX-2
inhibitor than the parent reference compound celecoxib (S.I. > 403). |
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