Abstract
Herein, the design and synthesis of some novel 1,3,4-trisubstituted pyrazole derivatives was carried out through the structural modification of lonazolac. All the synthesized compounds were investigated for
in vitro
COX-1 & COX-2 inhibition and
in vivo
anti-inflammatory activity by a carrageenan rat paw edema model. Among them, the chalcones
2a
and
2b
were the most COX-2 selective derivatives (S.I. = 8.22 and 9.31, respectively) and revealed very good
in vivo
anti-inflammatory potency. Similarly, the compounds
4a
,
6b
,
7a
and
8a
exhibited good COX-2 selectivity and
in vivo
anti-inflammatory activity. The active compounds were selected to further investigate their ulcerogenic activity, and they were found to be less ulcerogenic (ulcer indices = 2.4–8.4) as compared to indomethacin (ulcer index = 17.6) and nearly as ulcerogenic as celecoxib (ulcer index = 8.1). Moreover, histological studies were performed to evaluate the safety of these compounds on the stomach, liver and kidney. Furthermore, a docking study was performed to determine possible binding of the most active compounds
2a
and
2b
, which showed high docking scores (−9.461 and −7.962 kcal mol
−1
, respectively) that were comparable to that of celecoxib (−8.692 kcal mol
−1
).