Acta Pharmaceutica, Vol. 57 No. 1, 2007.
Original scientific paper
https://doi.org/10.2478/v10007-007-0002-z
Studies in 3,4-diaryl-1,2,5-oxadiazoles and their N-oxides: Search for better COX-2 inhibitors
Mange Ram Yadav
Shrikant T. Shirude
Devendra S. Puntambekar
Pinkal J. Patel
Hetal. B. Prajapati
Arvind Parmar
R. Balaraman
Rajani Giridhar
Abstract
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 anti-inflammatory 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 µmol L-1 and COX-1 enzyme inhibition of 44% at 88 µmol 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 µmol L-1) and higher COX-1 enzyme inhibition (53% at 88 µmol 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 the COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that the p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.
Keywords
1,2,5-oxadiazoles; 1,2,5-oxadiazole N-oxides; COX-2 inhibitors
Hrčak ID:
8684
URI
Publication date:
1.3.2007.
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