Synthesis, induced-fit docking investigations, and in vitro aldose reductase inhibitory activity of non-carboxylic acid containing 2,4-thiazolidinedione derivatives.
In continuation of our studies, we here report a series of non-carboxylic acid containing 2,4-thiazolidinedione derivatives, analogues of previously synthesized carboxylic acids which we had found to be very active in vitro aldose reductase (ALR2) inhibitors. Although the replacement of the carboxylic group with the carboxamide or N-hydroxycarboxamide one decreased the in vitro ALR2 inhibitory effect, this led to the identification of mainly non-ionized derivatives with micromolar ALR2 affinity. The 5-arylidene moiety deeply influenced the activity of these 2,4-thiazolidinediones. Our induced-fit docking studies suggested that 5-(4-hydroxybenzylidene)-substituted derivatives may bind the polar recognition region of the ALR2 active site by means of the deprotonated phenol group, while their acetic chain and carbonyl group at position 2 of the thiazolidinedione ring form a tight net of hydrogen bonds with amino acid residues of the lipophilic specificity pocket of the enzyme.
Maccari
Rosanna
R
Dipartimento Farmaco-chimico, Facoltà di Farmacia, Università di Messina, Polo Universitario dell'Annunziata, 98168 Messina, Italy. rmaccari@pharma.unime.it
Ottanà
Rosaria
R
Ciurleo
Rosella
R
Rakowitz
Dietmar
D
Matuszczak
Barbara
B
Laggner
Christian
C
Langer
Thierry
T
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002264:Carboxylic Acids / Q000737:chemistry; D002417:Cattle; D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism*; D005985:Glyceraldehyde / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D040681:Structural Homology, Protein; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*
D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D008024:Ligands; D045162:Thiazolidinediones; D005985:Glyceraldehyde; C089946:2,4-thiazolidinedione; C484670:AKR1B1 protein, human; D000449:Aldehyde Reductase