Studies in 3,4-diaryl-1,2,5-oxadiazoles and their N-oxides: search for better COX-2 inhibitors.

A series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for antiinflammatory activity by the rat paw edema method. p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 micromol L(-1) and COX-1 enzyme inhibition of 44% at 88 micromol L(-1) concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 pmol L(-1)) and higher COX-1 enzyme inhibition (53% at 88 micromol L(-1)) but, marked in vivo anti-inflammatory activity (71% at 25 mg kg(-1)) vs. celecoxib (48% at 12.5 mg kg(-1)). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.