title: Identification of new non-carboxylic acid containing inhibitors of aldose reductase.
abstract: 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.
authors.affiliation: Dipartimento Farmaco-chimico, University of Messina, Polo Universitario dell'Annunziata, 98168 Messina, Italy. rmaccari@pharma.unime.it
authors.forename: Rosanna
authors.initials: R
authors.lastname: Maccari
authors.forename: Rosella
authors.initials: R
authors.lastname: Ciurleo
authors.forename: Marco
authors.initials: M
authors.lastname: Giglio
authors.forename: Mario
authors.initials: M
authors.lastname: Cappiello
authors.forename: Roberta
authors.initials: R
authors.lastname: Moschini
authors.forename: Antonella Del
authors.initials: AD
authors.lastname: Corso
authors.forename: Umberto
authors.initials: U
authors.lastname: Mura
authors.forename: Rosaria
authors.initials: R
authors.lastname: Ottanà
mesh_terms: 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
chemical_list: D005617:Chlorofluorocarbons, Methane; D004791:Enzyme Inhibitors; D007659:Ketones; D045162:Thiazolidinediones; D000449:Aldehyde Reductase; C009554:fluoroform