Design, synthesis and biological evaluation of new ( E)- and ( Z)-1,2,3-triaryl-2-propen-1-ones as selective COX-2 inhibitors

A group of ( E)-and ( Z)-1,2,3-triaryl-2-propen-1-one derivatives possessing a methylsulfonyl COX-2 pharmacophore at the para position of the C-1 phenyl ring were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure–activity relationships were determined by varying the substituents on the C-3 propenone moiety. Among the 1,2,3-triaryl-2-propen-1-ones, ( Z)-1-(4-(methylsulfonyl)phenyl)-2,3-diphenylprop-2-en-1-one ( 3b) showed the most potency and selectivity on COX-2 inhibition (COX-2 IC 50 = 0.07 μM; selectivity index = 201). The Z-propenones were also found to be more potent and selective than their E-isomers for COX-2 inhibitory activity. The structure–activity data acquired indicate that the geometry of propenone and also the type of substituents on the C-3 propenone are important for COX-2 inhibitory activity. A group of ( E)- and ( Z)-1,2,3-triaryl-2-propen-1-one derivatives were synthesized and evaluated as selective COX-2 inhibitors. In vitro COX-1/COX-2 structure–activity relationships were determined by varying the substituents on the C-3 propenone moiety. [Display omitted]