Synthesis and biological evaluation of 1,3-diphenylprop-2-en-1-ones possessing a methanesulfonamido or an azido pharmacophore as cyclooxygenase-1/-2 inhibitors Afshin Zarghi, a Tannaz Zebardast, a Farinaz Hakimion, a Farshad H. Shirazi, a P. N. Praveen Rao b and Edward E. Knaus b, * a Department of Pharmaceutical Chemistry and Toxicology, School of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran b Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G 2N8 Received 19 April 2006; revised 7 June 2006; accepted 8 June 2006 Available online 22 June 2006 Abstract—A group of (E)-1,3-diphenylprop-2-en-1-one derivatives (chalcones) possessing a MeSO 2 NH, or N 3 , COX-2 pharmaco- phore 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-MeSO 2 NH 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 IC 50 = 1.0 lM; selectivity index >100) that was less potent than the reference drug rofecoxib (COX-2 IC 50 = 0.50 lM; SI > 200). The corresponding 1,3-diphenylprop-2-en-1-one analogue possessing a C-1 para-N 3 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 IC 50 = 22.2 lM; COX-2 IC 50 = 0.3 lM; SI = 60). A molecular modeling study where 7b and 7f were docked in the binding site of COX-2 showed that the p-MeSO 2 NH and N 3 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. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction The clinical use of traditional nonsteroidal anti-inflam- matory drugs (NSAIDs) such as aspirin and indometh- acin for the treatment of inflammation and pain is often accompanied by adverse gastrointestinal effects. Their anti-inflammatory activity is due to inhibition of cyclooxygenases (COXs), which catalyze the bioconver- sion of arachidonic acid to inflammatory prostaglandins (PGs). 1,2 PGs that are produced via the inducible COX-2 isozyme are responsible for inflammation, pain, and fever, whereas the constitutively expressed COX-1 isozy- me produces PGs that exhibit beneficial cytoprotective properties. 3 The initial euphoria surrounding the launch of selective cyclooxygenase-2 (COX-2) inhibitors that exhibited reduced gastrointestinal toxicity in the late 1990s 4,5 proved to be short lived. The recent withdrawal of diarylheterocyclic selective COX-2 inhibitors such as rofecoxib and valdecoxib due to their adverse cardiovas- cular side effects 6,7 clearly delineates the need to explore and evaluate new structural ring templates (scaffolds) possessing COX inhibitory activity. Recently, we reported several investigations describing the design, synthesis, and anti-inflammatory properties for a novel class of compounds possessing an acyclic tri- aryl/diaryl olefin structural template. 8–11 For example, the acyclic 1-alkyl-1,2-diaryl (E)-olefin (see structure 1 in Fig. 1) 11 possessing a trans-stilbenoid structure with a 4-methylsulfonylphenyl COX-2 pharmacophore at the C-1 position exhibited selective cyclooxygenase-2 (COX-2) inhibition, whereas the triphenyl acyclic olefin (2) possessing either a methanesulfonamido (MeSO 2 NH) or a linear azido (N 3 ) pharmacophore at Bioorganic & Medicinal Chemistry 14 (2006) 7044–7050 0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2006.06.022 Keywords: Cyclooxygenase inhibition; Propenone moiety; Azido pharmacophore. * Corresponding author. Tel.: +1 780 492 5993; fax: +1 780 492 1217; e-mail: eknaus@pharmacy.ualberta.ca