Synthesis, molecular modelling and enzymatic evaluation of (±)3,5-diphenyl-2-thioxoimidazolidin-4-ones as new potential cyclooxygenase inhibitors

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 μM. 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 < t1/2 < 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.

Substituted (±)2-thioxoimidazolin-4-ones were synthesized in order to design new type-2 cyclooxygenase (COX-2) inhibitors. Some of them completely inhibit human recombinant COX-2 at 50 μM. In human blood, the inhibitory potency of these drugs was disappointing and attributed to a poor aqueous stability of these imidazolidinones.Figure optionsDownload as PowerPoint slide