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.
Yadav
Mange Ram
MR
Pharmacy Department, Faculty of Technology and Engineering, Kalabhavan, The M. S. University of Baroda, Vadodara-390 001, India. mryadav11@yahoo.co.in
Shirude
Shrikant T
ST
Puntambekar
Devendra S
DS
Patel
Pinkal J
PJ
Prajapati
Hetal B
HB
Parmar
Arvind
A
Balaraman
R
R
Giridhar
Rajani
R
D000818:Animals; D002351:Carrageenan; D051546:Cyclooxygenase 2 / Q000737:chemistry; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005528:Foot / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D010087:Oxides; D051381:Rats; D017207:Rats, Sprague-Dawley; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared
D052246:Cyclooxygenase 2 Inhibitors; D010069:Oxadiazoles; D010087:Oxides; D002351:Carrageenan; D051546:Cyclooxygenase 2