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

• Published in: Bioorganic & medicinal chemistry 2006-02, Vol.14 (4), p.918-927
• Main Authors: Gauthier, Marie P., Michaux, Catherine, Rolin, Stéphanie, Vastersaegher, Caroline, de Leval, Xavier, Julémont, Fabien, Pochet, Lionel, Masereel, Bernard
• Format: Article
• Language: English
• Subjects: 2-Thioxoimidazolin-4-ones; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; COX inhibition; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Human COX-2; Humans; Imidazolidines - chemical synthesis; Imidazolidines - chemistry; Imidazolidines - pharmacology; Medical sciences; Models, Molecular; Molecular Structure; Ovine COX-1; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - metabolism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.09.005

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. 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 < 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.