Identification of new non-carboxylic acid containing inhibitors of aldose reductase.
Non-carboxylic acid containing bioisosteres of (5-arylidene-2,4-dioxothiazolidin-3-yl)acetic acids, which are active as aldose reductase (ALR2) inhibitors, were designed by replacing the carboxylic group with the trifluoromethyl ketone moiety. The in vitro evaluation of the ALR2 inhibitory effects of these trifluoromethyl substituted derivatives led to the identification of two inhibitors effective at low micromolar doses. It was further confirmed that a carboxylic chain on N-3 of the thiazolidinedione scaffold is a determining requisite to obtain the highest efficacy levels; however, it is not essential for the interaction with the target enzyme and it can be replaced by different polar groups, thus obtaining less ionised or unionised inhibitors.
Maccari
Rosanna
R
Dipartimento Farmaco-chimico, University of Messina, Polo Universitario dell'Annunziata, 98168 Messina, Italy. rmaccari@pharma.unime.it
Ciurleo
Rosella
R
Giglio
Marco
M
Cappiello
Mario
M
Moschini
Roberta
R
Corso
Antonella Del
AD
Mura
Umberto
U
Ottanà
Rosaria
R
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D005617:Chlorofluorocarbons, Methane; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones
D005617:Chlorofluorocarbons, Methane; D004791:Enzyme Inhibitors; D007659:Ketones; D045162:Thiazolidinediones; D000449:Aldehyde Reductase; C009554:fluoroform