A series of 5-(carbamoylmethoxy)benzylidene-2-oxo/thioxo-4-thiazolidinone derivatives (6-9) were synthesized as inhibitors of aldose reductase (AR), enzyme which plays a crucial role in the development of diabetes complications as well as in the inflammatory processes associated both to diabetes mellitus and to other pathologies. In vitro inhibitory activity indicated that compounds 6-9a-d were generally good AR inhibitors. Acetic acid derivatives 8a-d and 9a-d were shown to be the best enzyme inhibitors among the tested compounds endowed with significant inhibitory ability levels reaching submicromolar IC50 values. Moreover, some representative AR inhibitors (7a, 7c, 9a, 9c, 9d) were assayed in cultures of human keratinocytes in order to evaluate their capability to reduce NF-kB activation and iNOS expression. Compound 9c proved to be the best derivative endowed with both interesting AR inhibitory effectiveness and ability to reduce NF-kB activation and iNOS expression. Molecular docking and molecular dynamics simulations were undertaken to investigate the binding modes of selected compounds into the active site of AR in order to rationalize the inhibitory effectiveness of these derivatives.
Keywords: 5-(carbamoylmethoxy)benzylidene-2-oxo/thioxo-4-thiazolidinone derivatives; 5-Arylidene-4-thiazolidinone derivatives; Aldose reductase; Anti-inflammatory agents; Enzyme inhibitors; Molecular modelling.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.