A new series of 2,4-thiazolidinediones endowed with potent aldose reductase inhibitory activity

5-(2-Hydroxy-3-methylbenzylidene)thiazolidine-2,4-dione (3) was identified as the most potent AR inhibitor in this series, exerting uncompetitive inhibition with a Kivalue of 0.445 ± 0.013 μM. © 2021 De Gruyter. All rights reserved.; 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 Ki value of 0.445 ± 0.013 μM. The IC50 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. © 2021 Belgin Sever et al., published by De Gruyter 2021.