Design, synthesis and molecular modelling of novel methyl[4-oxo-2-(aroylimino)-3-(substituted phenyl)thiazolidin-5-ylidene]acetates as potent and selective aldose reductase inhibitors

A series of new iminothiazolidin-4-one acetate derivatives was synthesized and evaluated as aldehyde reductase (ALR1) and aldose reductase (ALR2) inhibitors. Methyl[4-oxo-2-(substituted benzoylimino)-3-(substituted phenyl)thiazolidin-5-ylidene]acetate derivatives were obtained in excellent yields by cyclocondensation of 1-aroyl-3-aroylthioureas (2a-n) with dimethylacetylene dicarboxylate (DMAD) in methanol at room temperature. Compounds were characterized by available spectroscopic techniques and compound 2k was also confirmed by X-ray crystallography. The highest ALR2 inhibitory potency in the series was observed for methyl[4-oxo-2-(benzoylimino)-3-(2-methoxyphenyl)thiazolidin-5-ylidene]acetate (2a) and methyl[4-oxo-2-(2-bromobenzoylimino)-3-(2,4-diehlorophenyl)thiazolidin-5-ylidene]acetate (2k) with IC50 values of 2.82 and 2.54 mu M, respectively. The combined use of docking and molecular dynamics simulations shed light on the observed structure-selectivity relationships and binding modes of the inhibitors with the active site of ALR2. Aldose reductase inhibitors have potential as novel drugs for the treatment of diabetic complications.