5-Arylidene-2-imino-4-thiazolidinones: design and synthesis of novel anti-inflammatory agents.
The synthesis and pharmacological activity of 5-arylidene-2-imino-4-thiazolidinones (3a-8a) are described. All derivatives exhibited significant activity levels in models of acute inflammation such as carrageenan-induced paw and pleurisy edema in rats. In particular, 5-(3-methoxyphenylidene)-2-phenylimino-3-propyl-4-thiazolidinone (3a) displayed high levels of carrageenan-induced paw edema inhibition comparable to those of indomethacin. In addition the ability of such a new class of anti-inflammatory agents to inhibit COX isoforms was assessed in murine monocyte/macrophage J774 cell line assay. 5-(4-Methoxyphenylidene)-2-phenylimino-3-propyl-4-thiazolidinone (6a), the most interesting compound in such an experiment, was docked in the known active site of COX-2 protein and showed that its 4-methoxyarylidene moiety can easily occupy the COX-2 secondary pocket considered as the critical interaction for COX-2 selectivity.
Ottanà
Rosaria
R
Dipartimento Farmaco-chimico, Facoltà di Farmacia, Università di Messina, Viale SS. Annunziata, 98168 Messina, Italy. ottana@pharma.unime.it
Maccari
Rosanna
R
Barreca
Maria Letizia
ML
Bruno
Giuseppe
G
Rotondo
Archimede
A
Rossi
Antonietta
A
Chiricosta
Giuseppa
G
Di Paola
Rosanna
R
Sautebin
Lidia
L
Cuzzocrea
Salvatore
S
Vigorita
Maria Gabriella
MG
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D002351:Carrageenan; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
C503655:5-(3-methoxyphenylidene)-2-phenylimino-3-propyl-4-thiazolidinone; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D045162:Thiazolidinediones; D002351:Carrageenan; D009195:Peroxidase; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases