A number of 5-arylidene-2,4-thiazolidinediones containing a hydroxy or a carboxymethoxy group in their 5-benzylidene moiety have been synthesised and evaluated as in vitro aldose reductase (ALR2) inhibitors. Most of them exhibited strong inhibitory activity, with IC(50) values in the range between 0.20 and 0.70 microM. Molecular docking simulations into the ALR2 active site highlighted that the phenolic or carboxylic substituents of the 5-benzylidene moiety can favourably interact, in alternative poses, either with amino acid residues lining the lipophilic pocket of the enzyme, such as Leu300, or with the positively charged recognition region of the ALR2 active site.