(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids as potent and selective aldose reductase inhibitors
Language English Country Ireland Media print-electronic
Document type Journal Article
PubMed
33038328
DOI
10.1016/j.cbi.2020.109286
PII: S0009-2797(20)31337-5
Knihovny.cz E-resources
- Keywords
- 4-Oxo-2-thioxothiazolidin-3-yl)acetic acids, Aldose reductase inhibition, Cytotoxicity, Diabetes complication, Rhodanine acetic acid,
- MeSH
- Aldehyde Reductase antagonists & inhibitors metabolism MeSH
- Hep G2 Cells MeSH
- Enzyme Inhibitors chemical synthesis chemistry pharmacology MeSH
- Acetic Acid chemical synthesis chemistry pharmacology MeSH
- Humans MeSH
- Ligands MeSH
- Lens, Crystalline drug effects enzymology MeSH
- Rats, Wistar MeSH
- Rhodanine analogs & derivatives chemistry pharmacology MeSH
- Thiazolidines chemistry pharmacology MeSH
- Binding Sites MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Aldehyde Reductase MeSH
- epalrestat MeSH Browser
- Enzyme Inhibitors MeSH
- Acetic Acid MeSH
- Ligands MeSH
- Rhodanine MeSH
- Thiazolidines MeSH
(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.
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