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

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 stabil...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry Vol. 14; no. 4; pp. 918 - 927
Main Authors:	Gauthier, Marie P., Michaux, Catherine, Rolin, Stéphanie, Vastersaegher, Caroline, de Leval, Xavier, Julémont, Fabien, Pochet, Lionel, Masereel, Bernard
Format:	Journal Article
Language:	English
Published:	Oxford Elsevier Ltd 15-02-2006 Elsevier Science
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 Human COX-2 Ovine COX-1 2-Thioxoimidazolin-4-ones COX inhibition Imidazole derivatives Prostaglandin-endoperoxide synthase Cyclooxygenase 2 Active site Diseases of the osteoarticular system Cyclooxygenase 1 Autoimmune disease Molecular interaction Cyclooxygenase 2 inhibitor Selectivity Modeling Blood Racemic Structure activity relation Molecular model Tumor Chemical synthesis Ungulata Human Immunopathology 2-Thioxo- imidazolin-4-ones Stability Enzyme Enzyme inhibitor Non steroidal antiinflammatory agent Vertebrata Mammalia Animal Rheumatoid arthritis Sheep Artiodactyla Oxidoreductases Thiohydantoine derivatives
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Summary:	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.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0968-0896 1464-3391
DOI:	10.1016/j.bmc.2005.09.005