Modeling and biological evaluation of 3,3'-(1,2-ethanediyl)bis[2-(4-methoxyphenyl)-thiazolidin-4-one], a new synthetic cyclooxygenase-2 inhibitor.
Within the series of chiral 3,3'-(1,2-ethanediyl)bis[2-arylthiazolidin-4-ones], the 3,4-dimethoxyphenyl substituted derivative was found in the primary anti-inflammatory screening to be endowed with superior in vivo properties and good safety profile. Such a lead compound was modified by eliminating 3-methoxy group while retaining 4-methoxy group on the aryl rings at 2 and 2' stereogenic carbons. The 2R,2'S-meso isomer (VIG3b) of the resulting bisthiazolidinone has been widely investigated. The inhibitory effects on cyclo-oxygenase-1 and cyclo-oxygenase-2 isoenzymes were measured in a human whole blood assay. VIG3b was almost 50 times more selective on the inducible isoform. The cyclo-oxygenase-2 preferential selectivity has been confirmed by modeling VIG3b into the cyclo-oxygenase-1 and cyclo-oxygenase-2 active sites. Furthermore, VIG3b was assayed in the experimental model of carrageenan-induced lung injury by evaluating its ability to inhibit: (1) fluid accumulation in the pleural cavity, (2) neutrophil infiltration, (3) prostaglandin E(2) production and (4) lung injury. VIG3b exhibited interesting activity in all these tests.
Dipartimento Farmaco-chimico, Facoltà di Farmacia, Università di Messina, Vl. SS. Annunziata, Messina 98168, Italy.
Rosaria
R
Ottaná
Emanuela
E
Mazzon
Laura
L
Dugo
Francesca
F
Monforte
Rosanna
R
Maccari
Lidia
L
Sautebin
Grazia
G
De Luca
Maria Gabriella
MG
Vigorita
Stefano
S
Alcaro
Francesco
F
Ortuso
Achille P
AP
Caputi
Salvatore
S
Cuzzocrea
D000818:Animals; D002351:Carrageenan; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010998:Pleurisy / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D053778:Thiazolidines
C470826:3,3'-(1,2-ethanediyl)bis(2-(4-methoxyphenyl)thiazolidin-4-one); D016861:Cyclooxygenase Inhibitors; D013844:Thiazoles; D053778:Thiazolidines; D002351:Carrageenan