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Issue 10, 2019
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Discovery of new non-acidic lonazolac analogues with COX-2 selectivity as potent anti-inflammatory agents

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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).

Graphical abstract: Discovery of new non-acidic lonazolac analogues with COX-2 selectivity as potent anti-inflammatory agents

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Publication details

The article was received on 17 Apr 2019, accepted on 17 Jul 2019 and first published on 22 Jul 2019


Article type: Research Article
DOI: 10.1039/C9MD00228F
Med. Chem. Commun., 2019,10, 1775-1788

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    Discovery of new non-acidic lonazolac analogues with COX-2 selectivity as potent anti-inflammatory agents

    M. F. Harras, R. Sabour and O. M. Alkamali, Med. Chem. Commun., 2019, 10, 1775
    DOI: 10.1039/C9MD00228F

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