A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity
Belgin Sever, Mehlika Dilek Altıntop, Yeliz Demir, Cüneyt Türkeş, Kaan Özbaş, Gülşen Akalın Çiftçi, Şükrü Beydemir, Ahmet Özdemır
Abstract
Abstract In an effort to identify potent aldose reductase (AR) inhibitors, 5-(arylidene)thiazolidine-2,4-diones ( 1 – 8 ), which were prepared by the solvent-free reaction of 2,4-thiazolidinedione with aromatic aldehydes in the presence of urea, were examined for their in vitro AR inhibitory activities and cytotoxicity. 5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione ( 3 ) was the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a K i value of 0.445 ± 0.013 µM. The IC 50 value of compound 3 for L929 mouse fibroblast cells was determined as 8.9 ± 0.66 µM, pointing out its safety as an AR inhibitor. Molecular docking studies suggested that compound 3 exhibited good affinity to the binding site of AR (PDB ID: 4JIR). Based upon in silico absorption, distribution, metabolism, and excretion data, the compound is predicted to have favorable pharmacokinetic features. Taking into account the in silico and in vitro data, compound 3 stands out as a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as nondiabetic diseases.