Structure-activity relationships and molecular modelling of 5-arylidene-2,4-thiazolidinediones active as aldose reductase inhibitors.
The structure-activity relationships (SARs) of 5-arylidene-2,4-thiazolidinediones active as aldose reductase inhibitors (ARIs) were extended by varying the substitution pattern on the 5-arylidene moiety and on N-3. In particular, the introduction of an additional aromatic ring or an H-bond donor group on the 5-benzylidene ring enhanced ALR2 inhibitory potency. Moreover, the presence of a carboxylic anionic chain on N-3 was shown to be an important, although not essential, structural requisite to produce high levels of ALR2 inhibition. The length of this carboxylic chain was critical and acetic acids 4 were the most effective inhibitors among the tested derivatives. Molecular docking simulations into the ALR2 active site accorded with the in vitro inhibition data. They allowed the rationalization of the observed SARs and provided a pharmacophoric model for this class of ARIs.
Maccari
Rosanna
R
Dipartimento Farmaco-chimico, Facoltà di Farmacia, Università di Messina, Viale SS. Annunziata, 98168 Messina, Italy. rmaccari@pharma.unime.it
Ottanà
Rosaria
R
Curinga
Carmela
C
Vigorita
Maria Gabriella
MG
Rakowitz
Dietmar
D
Steindl
Theodora
T
Langer
Thierry
T
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007908:Lens, Crystalline / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D045162:Thiazolidinediones; D000449:Aldehyde Reductase