Synthesis and biological evaluation of 1,3-diphenylprop-2-en-1-ones possessing a methanesulfonamido or an azido pharmacophore as cyclooxygenase-1/-2 inhibitors

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• 作者：Afshin Zarghi ; Tannaz Zebardast ; Farinaz Hakimion ; Farshad H. Shirazi ; P.N. Praveen Rao and Edward E. Knaus
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2006
• 出版时间：15 October 2006
• 年：2006
• 卷：14
• 期：20
• 页码：7044-7050
• 全文大小：288 K

文摘

A group of (E)-1,3-diphenylprop-2-en-1-one derivatives (chalcones) possessing a MeSO₂NH, or N₃, COX-2 pharmacophore at the para-position of the C-1 phenyl ring were synthesized using a facile stereoselective Claisen–Schmidt condensation reaction. In vitro COX-1/COX-2 structure–activity relationships were determined by varying the substituents on the C-3 phenyl ring (4-H, 4-Me, 4-F, and 4-OMe). Among the 1,3-diphenylprop-2-en-1-ones possessing a C-1 para-MeSO₂NH COX-2 pharmacophore, (E)-1-(4-methanesulfonamidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7b) was identified as a selective COX-2 inhibitor (COX-2 IC₅₀ = 1.0 μM; selectivity index >100) that was less potent than the reference drug rofecoxib (COX-2 IC₅₀ = 0.50 μM; SI > 200). The corresponding 1,3-diphenylprop-2-en-1-one analogue possessing a C-1 para-N₃ COX-2 pharmacophore, (E)-1-(4-azidophenyl)-3-(4-methylphenyl)prop-2-en-1-one (7f), exhibited potent and selective COX-2 inhibition (COX-1 IC₅₀ = 22.2 μM; COX-2 IC₅₀ = 0.3 μM; SI = 60). A molecular modeling study where 7b and 7f were docked in the binding site of COX-2 showed that the p-MeSO₂NH and N₃ substituents on the C-1 phenyl ring are oriented in the vicinity of the COX-2 secondary pocket (His90, Arg513, Phe518, and Val523). The structure–activity data acquired indicate that the propenone moiety constitutes a suitable scaffold to design new acyclic 1,3-diphenylprop-2-en-1-ones with selective COX-1 or COX-2 inhibitory activity.