Synthesis, molecular modelling and enzymatic evaluation of (+/-)3,5-diphenyl-2-thioxoimidazolidin-4-ones as new potential cyclooxygenase inhibitors.
Bioorganic & medicinal chemistry 2006 Feb 15; 14(4):918-27
Gauthier M MP, Michaux C C, Rolin S S, Vastersaegher C C, de Leval X X, Julémont F F, Pochet L L, Masereel B B
Department of Pharmacy, University of Namur, FUNDP, Belgium.
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.