title: Synthesis, molecular modelling and enzymatic evaluation of (+/-)3,5-diphenyl-2-thioxoimidazolidin-4-ones as new potential cyclooxygenase inhibitors.
abstract: A series of substituted (+/-)3,5-diphenyl-2-thioxoimidazolin-4-ones was synthesized in order to design new type-2 cyclooxygenase (COX-2) inhibitors. This study has led to molecules which completely inhibit human recombinant COX-2 at 50 microM. Molecular modelling highlighted drug interactions with the active site of both cyclooxygenases and suggested modifications to enhance the selectivity of the compounds. In human blood, COX-2 expression was then induced by LPS, and the inhibitory potency of these drugs was disappointing. This weak activity was attributed to a poor aqueous stability of these imidazolidinones substituted by two aryl in position 3 and 5 (15 min < t(1/2) < 130 min). The improvement of the stability of this heterocycle could generate a novel template to treat COX-associated diseases such as arthritis, rheumatoid polyarthritis and cancer.
authors.affiliation: Department of Pharmacy, University of Namur, FUNDP, Belgium.
authors.forename: Marie P
authors.initials: MP
authors.lastname: Gauthier
authors.forename: Catherine
authors.initials: C
authors.lastname: Michaux
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rolin
authors.forename: Caroline
authors.initials: C
authors.lastname: Vastersaegher
authors.forename: Xavier
authors.initials: X
authors.lastname: de Leval
authors.forename: Fabien
authors.initials: F
authors.lastname: Julémont
authors.forename: Lionel
authors.initials: L
authors.lastname: Pochet
authors.forename: Bernard
authors.initials: B
authors.lastname: Masereel
mesh_terms: D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D048289:Imidazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D016861:Cyclooxygenase Inhibitors; D048289:Imidazolidines; D011451:Prostaglandin-Endoperoxide Synthases