Acta Pharm. 57 (2007) 13-30
Original research
paper
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 and RAJANI GIRIDHAR
mryadav11@yahoo.co.in
Pharmacy Department, Faculty of Technology and
Engineering, Kalabhavan, The
M. S. University of Baroda, Vadodara-390 001, India
Accepted November 24, 2006
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