(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids as potent and selective aldose reductase inhibitors

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. 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.

Basic information

Original name

(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids as potent and selective aldose reductase inhibitors

Authors

KUCEROVA-CHLUPACOVA, M., M. HALAKOVA, D. MAJEKOVA, Jakub TREML (203 Czech Republic, belonging to the institution), J. STEFEK and M. PRNOVA

Edition

Chemico-Biological Interactions, Clare, Elsevier Ireland Ltd. 2020, 0009-2797

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Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.192

RIV identification code

RIV/00216224:14160/20:00118249

Organization unit

Faculty of Pharmacy

DOI

http://dx.doi.org/10.1016/j.cbi.2020.109286

UT WoS

000595953700005

Keywords in English

4-Oxo-2-thioxothiazolidin-3-yl)acetic acids; Rhodanine acetic acid; Aldose reductase inhibition; Cytotoxicity; Diabetes complication

Tags

rivok, ÚMF

Tags

International impact, Reviewed

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Abstract

V originále

(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.