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Synthesis, Biological Activity, and Molecular Modeling Studies of Pyrazole and Triazole Derivatives as Selective COX-2 Inhibitors

M. Assali,M. Abualhasan,Hadeel Sawaftah,Mohammed Hawash,A. Mousa

Published 2020 in Journal of chemistry

ABSTRACT

Series of diaryl-based pyrazole and triazole derivatives were designed and synthesized in a facile synthetic approach in order to produce selective COX-2 inhibitor. These series of derivatives were synthesized by different reactions like Vilsmeier–Haack reaction and click reaction. In vitro COX-1 and COX-2 inhibition studies showed that five compounds were potent and selective inhibitors of the COX-2 isozyme with IC50values in 0.551–0.002 μM range. In the diarylpyrazole derivatives, compound4bshowed the best inhibitory activity against COX-2 with IC50 = 0.017 μM as one of theN-aromatic rings was substituted with sulfonamide and the other aromatic ring was unsubstituted. However, when theN-aromatic ring was substituted with sulfonamide and the other aromatic ring was substituted with sulfone (compound4d), best COX-2 selectivity was achieved (IC50 = 0.098 μM, SI = 54.847). In the diaryltriazole derivatives, compound15ashowed the best inhibitory activity in comparison to all synthesized compounds including the reference celecoxib with IC50 = 0.002 μM and SI = 162.5 as it could better fit the extra hydrophobic pocket which is present in the COX-2 enzyme. Moreover, the docking study supports the obtained SAR data and binding similarities and differences on both isozymes.

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