Chiral 3,3′-(1,2-Ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones] with anti-inflammatory activity. Part 11: Evaluation of COX-2 selectivity and modelling

• Published in: Bioorganic & medicinal chemistry Vol. 11; no. 6; pp. 999 - 1006
• Main Authors: Vigorita, M.G, Ottanà, R, Monforte, F, Maccari, R, Monforte, M.T, Trovato, A, Taviano, M.F, Miceli, N, De Luca, G, Alcaro, S, Ortuso, F
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 20-03-2003; Elsevier Science
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Binding Sites; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chemical Phenomena; Chemistry, Physical; Crystallography, X-Ray; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - pharmacology; Humans; In Vitro Techniques; Isoenzymes - chemistry; Isoenzymes - metabolism; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Medical sciences; Membrane Proteins; Models, Molecular; Monocytes - drug effects; Pharmacology. Drug treatments; Prostaglandin-Endoperoxide Synthases - chemistry; Prostaglandin-Endoperoxide Synthases - metabolism; Protein Conformation; Stereoisomerism; Structure-Activity Relationship; Substrate Specificity; Thiazoles - chemical synthesis; Thiazoles - pharmacology; Thromboxane B2 - antagonists & inhibitors; Prostaglandin-endoperoxide synthase; Enantioselectivity; Enzyme; Isozyme; Cyclooxygenase 2; Enzyme inhibitor; Cyclooxygenase 2 inhibitor; Binding site; Selectivity; In vitro; Modeling; Biological activity; Non steroidal antiinflammatory agent; Synthetic product; Molecular model; Oxidoreductases
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(02)00518-7

Anti-inflammatory/analgesic 3,3′-(1,2-ethanediyl)-bis[2-(3,4-dimethoxyphenyl)-4-thiazolidinones]
1, obtained as racemic mixtures (
a) and mesoforms (
b), have two equivalent stereogenic centres (C-2 and C-2′) and exist as
RR,
SS and
RS isomers. The enantioseparation of
1a provided the single enantiomers that displayed different in vitro cyclooxygenase-1/cyclooxygenase-2 selectivity ratios. In particular the dextrorotatory compound is a highly selective COX-2 inhibitor and the levorotatory one is moderately selective. Instead,
RS-
meso isomer (
1b) exhibited similar levels of inhibitory activity on both COX isozymes. The diastereo- and enantioselectivity has been explained by molecular modelling of
RR,
SS and
RS compounds into COX-1 and COX-2 binding sites. Theoretical results indicated
SS>RS>RR affinity order towards COX-2 isoenzyme, in agreement with in vitro and previous in vivo pharmacological results.
The titled bisthiazolidinones were found to be diastereo- and enantioselective preferential COX-2 inhibitors.