9-Fluorenon-4-carboxamides: Synthesis, conformational analysis, anti-HSV-2, and immunomodulatory evaluation. Note II

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In vitro evaluation of 5-arylidene-2-thioxo-4-thiazolidinones active as aldose reductase inhibitors

2-Thioxo-4-thiazolidinone derivatives were evaluated as aldose reductase inhibitors (ARIs) and most of them exhibited good or excellent in vitro efficacy. Out of the tested compounds, most N-unsubstituted analogues were found to possess inhibitory effects at low micromolar doses and two of them exhibited higher potency than sorbinil, used as a reference drug. The insertion of an acetic chain on N-3 of the thiazolidinone scaffold led to analogues with submicromolar affinity for ALR2 and IC(50) values very similar to that of epalrestat, the only ARI currently used in therapy

Synthesis and Aldose reductase inhibitory activity of 5-arylidene-2,4-thiazolidinediones.

Abstract—Several (Z)-5-arylidene-2,4-thiazolidinediones were synthesized and tested as aldose reductase inhibitors (ARIs). Themost active of the N-unsubstituted derivatives (2) exerted the same inhibitory activity of Sorbinil. The introduction of an acetic sidechain on N-3of the thiazolidinedione moiety led to a marked increase in lending inhibitory activity, conducting to the discovery ofa very potent ARI (4c), whose activity level (IC50=0.13 mM) was in the same range of Tolrestat. Moreover, the correspondingmethyl esters (3), devoid of any acidic functionality, showed appreciable inhibitory activity similar to that of the N-unsubstitutedcompounds. It was also found that the substitution pattern on the 5-benzylidene moiety markedly influenced the activity of Nunsubstituted2,4-thiazolidinediones 2, compounds with substituents at the meta position being generally more effective than thepara-substituted ones; however, this SAR was not evidenced in acetates 3 and acids 4

Structure-activity relationships and molecular modelling of new 5-arylidene-4-thiazolidinone derivatives as aldose reductase inhibitors and potential anti-inflammatory agents.

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

Identification of 5-arylidene-4-thiazolidinone derivatives endowed with dual activity as aldose reductase inhibitors and antioxidant agents for the treatment of diabetic complications

In continuing the search for more effective 5-arylidene-4-thiazolidinones as aldose reductase inhibitors, a new set of suitably substituted compounds (4, 5 and 8) was explored. Acetic acids 5, particularly 5a and 5h, proved to be interesting inhibitors of the enzyme as well as excellent antioxidant agents that are potentially able to counteract the oxidative stress associated with both diabetic complications as well as other pathologies. Molecular docking experiments supported SAR studies