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.
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.
Vigorita
M G
MG
Dipartimento Farmaco-chimico, Facoltà di Farmacia Università di Messina, Viale SS. Annunziata, 98168 Messina, Italy. vigorita@pharma.unime.it
Ottanà
R
R
Monforte
F
F
Maccari
R
R
Monforte
M T
MT
Trovato
A
A
Taviano
M F
MF
Miceli
N
N
De Luca
G
G
Alcaro
S
S
Ortuso
F
F
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008565:Membrane Proteins; D008958:Models, Molecular; D009000:Monocytes / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D013844:Thiazoles; D013929:Thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases