Three novel series of diaryl heterocyclic derivatives bearing the 2-oxo-5H-furan, 2-oxo-3H-1,3-oxazole, and 1H-pyrazole moieties as the central heterocyclic ring were synthesized and their in vitro inhibitory activities on COX-1 and COX-2 isoforms were evaluated using a purified enzyme assay. The 2-oxo-5H-furan derivative 6b was identified as potent COX inhibitor with selectivity toward COX-1 (COX-1 IC(50) = 0.061 mu M and COX-2 IC(50) = 0.325 mu M; selectivity index (SI) = 0.19). Among the 1H-pyrazole derivatives, 11b was found to be a potent COX-2 inhibitor, about 38 times more potent than Rofecoxib (COX-2 IC(50) = 0.011 mu M and 0.398 mu M, respectively), but showed no selectivity for COX-2 isoform. Compound 11c demonstrated strong and selective COX-2 inhibitory activity (COX-1 IC(50) = 1 mu M, COX-2 IC(50) = 0.011 mu M; SI = similar to 92). Molecular docking studies of compounds 6b and 11b-d into the binding sites of COX-1 and COX-2 allowed to shed light on the binding mode of these novel COX inhibitors. (C) 2010 Elsevier Ltd. All rights reserved.