Design, synthesis, and biological evaluation of 1,3-diarylprop-2-en-1-ones : a novel class of cyclooxygenase-2 inhibitors.
A group of regioisomeric (E)-1,3-diarylprop-2-en-1-one derivatives possessing a COX-2 SO2Me pharmacophore at the para position of the C-1 or C-3 phenyl ring, in conjunction with a C-3 or C-1 phenyl (4-H) or substituted-phenyl ring (4-F, 4-OMe and 4-Me), were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. These target (E)-1,3-diarylprop-2-en-1-ones were synthesized via a Claisen-Schmidt condensation reaction. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified (E)-1-(4-methanesulfonylphenyl)-3-(4-methylphenyl)prop-2-en-1-one (9f) as a potent COX-2 inhibitor (IC50=0.3 microM) with a high COX-2 selectivity index (SI=106) comparable to that of the reference drug rofecoxib (COX-2 IC50=0.5 microM; COX-2 SI>200). A molecular modeling study where 9f was docked in the binding site of COX-2 showed that the para-SO2Me substituent on the C-1 phenyl ring is oriented in the vicinity of the secondary COX-2 binding site near Val523. The structure-activity data acquired indicate that the propenone moiety constitutes a suitable scaffold to design novel acyclic 1,3-diarylprop-2-en-1-ones with selective COX-2 inhibitory activity.
Zarghi
Afshin
A
Department of Pharmaceutical Chemistry, School of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran.
Arfaee
Sara
S
Rao
P N Praveen
PN
Knaus
Edward E
EE
D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008958:Models, Molecular; D013055:Spectrophotometry, Infrared
D000475:Alkenes; D016861:Cyclooxygenase Inhibitors; C013658:propylene; D051546:Cyclooxygenase 2