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@article{1745788,
author = {KucerovaandChlupacova, M. and Halakova, M. and Majekova, D. and Treml, Jakub and Stefek, J. and Prnova, M.},
article_location = {Clare},
article_number = {109286},
doi = {http://dx.doi.org/10.1016/j.cbi.2020.109286},
keywords = {4-Oxo-2-thioxothiazolidin-3-yl)acetic acids; Rhodanine acetic acid; Aldose reductase inhibition; Cytotoxicity; Diabetes complication},
language = {eng},
issn = {0009-2797},
journal = {Chemico-Biological Interactions},
title = {(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids as potent and selective aldose reductase inhibitors},
url = {https://www.sciencedirect.com/science/article/pii/S0009279720313375},
volume = {332},
year = {2020}
}
TY - JOUR
ID - 1745788
AU - Kucerova-Chlupacova, M. - Halakova, M. - Majekova, D. - Treml, Jakub - Stefek, J. - Prnova, M.
PY - 2020
TI - (4-Oxo-2-thioxothiazolidin-3-yl)acetic acids as potent and selective aldose reductase inhibitors
JF - Chemico-Biological Interactions
VL - 332
IS - 109286
SP - 1-7
EP - 1-7
PB - Elsevier Ireland Ltd.
SN - 00092797
KW - 4-Oxo-2-thioxothiazolidin-3-yl)acetic acids
KW - Rhodanine acetic acid
KW - Aldose reductase inhibition
KW - Cytotoxicity
KW - Diabetes complication
UR - https://www.sciencedirect.com/science/article/pii/S0009279720313375
N2 - (4-Oxo-2-thioxothiazolidin-3-yl)acetic acids exhibit a wide range of pharmacological activities. Among them, the only derivative used in clinical practice is the aldose reductase inhibitor epalrestat. Structurally related compounds, [(5Z)-(5-arylalkylidene-4-oxo-2-thioxo-1,3-thiazolidin-3-yl)]acetic acid derivatives were prepared previously as potential antifungal agents. This study was aimed at the determination of aldose reductase inhibitory action of the compounds in comparison with epalrestat and evaluation of structure-activity relationships (SAR). The aldose reductase (ALR2) enzyme was isolated from the rat eye lenses, while aldehyde reductase (ALR1) was obtained from the kidneys. The compounds studied were found to be potent inhibitors of ALR2 with submicromolar IC50 values. (Z)-2-(5-(1-(5-butylpyrazin-2-yl)ethylidene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid (3) was identified as the most efficacious inhibitor (over five times more potent than epalrestat) with mixed-type inhibition. All the compounds also exhibited low antiproliferative (cytotoxic) activity to the HepG2 cell line. Molecular docking simulations of 3 into the binding site of the aldose reductase enzyme identified His110, Trp111, Tyr48, and Leu300 as the crucial interaction counterparts responsible for the high-affinity binding. The selectivity factor for 3 in relation to the structurally related ALR1 was comparable to that for epalrestat. SAR conclusions suggest possible modifications to improve further inhibition efficacy, selectivity, and biological availability in the group of rhodanine carboxylic acids.
ER -
KUCEROVA-CHLUPACOVA, M., M. HALAKOVA, D. MAJEKOVA, Jakub TREML, J. STEFEK and M. PRNOVA. (4-Oxo-2-thioxothiazolidin-3-yl)acetic acids as potent and selective aldose reductase inhibitors. \textit{Chemico-Biological Interactions}. Clare: Elsevier Ireland Ltd., 2020, vol.~332, No~109286, p.~1-7. ISSN~0009-2797. Available from: https://dx.doi.org/10.1016/j.cbi.2020.109286.
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