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(4-Oxo-2-thioxothiazolidin-3-yl)acetic acids as potent and selective aldose reductase inhibitors
M. Kucerova-Chlupacova, D. Halakova, M. Majekova, J. Treml, M. Stefek, M. Soltesova Prnova,
Jazyk angličtina Země Irsko
Typ dokumentu časopisecké články
- MeSH
- aldehydreduktasa antagonisté a inhibitory metabolismus MeSH
- buňky Hep G2 MeSH
- inhibitory enzymů chemická syntéza chemie farmakologie MeSH
- kyselina octová chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- oční čočka účinky léků enzymologie MeSH
- potkani Wistar MeSH
- rhodanin analogy a deriváty chemie farmakologie MeSH
- thiazolidiny chemie farmakologie MeSH
- vazebná místa MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články 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.
Citace poskytuje Crossref.org
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- $a Kucerova-Chlupacova, Marta $u Charles University, Faculty of Pharmacy in Hradec Kralove, Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Heyrovskeho 1203, 500 05, Hradec Kralove, Czech Republic. Electronic address: kucerom@faf.cuni.cz.
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- $a (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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- $a Halakova, Dominika $u Centre of Experimental Medicine of Slovak Academy of Sciences, Institute of Experimental Pharmacology and Toxicology, Department of Biochemical Pharmacology, Dubravska Cesta 9, 841 04, Bratislava, Slovak Republic. Electronic address: dominika.halakova@gmail.com.
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- $a Majekova, Magdalena $u Centre of Experimental Medicine of Slovak Academy of Sciences, Institute of Experimental Pharmacology and Toxicology, Department of Biochemical Pharmacology, Dubravska Cesta 9, 841 04, Bratislava, Slovak Republic. Electronic address: magdalena.majekova@savba.sk.
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- $a Treml, Jakub $u Masaryk University, Faculty of Pharmacy, Department of Molecular Pharmacy, Palackeho Tr. 1946/1, 612 00, Brno, Czech Republic. Electronic address: tremlj@pharm.muni.cz.
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- $a Stefek, Milan $u Centre of Experimental Medicine of Slovak Academy of Sciences, Institute of Experimental Pharmacology and Toxicology, Department of Biochemical Pharmacology, Dubravska Cesta 9, 841 04, Bratislava, Slovak Republic. Electronic address: milan.stefek@savba.sk.
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- $a Soltesova Prnova, Marta $u Centre of Experimental Medicine of Slovak Academy of Sciences, Institute of Experimental Pharmacology and Toxicology, Department of Biochemical Pharmacology, Dubravska Cesta 9, 841 04, Bratislava, Slovak Republic. Electronic address: marta.prnova@savba.sk.
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