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

Abstract

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-dichlorophenyl)thiazolidin-5-ylidene]acetate (2k) with IC₅₀ values of 2.82 and 2.54 μM, 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.