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Non-carboxylic acid inhibitors of aldose reductase based on N-substituted thiazolidinedione derivatives.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Nov 05; Vol. 223, pp. 113630. Date of Electronic Publication: 2021 Jun 12. - Publication Year :
- 2021
-
Abstract
- In search of dually active PPAR-modulators/aldose reductase (ALR2) inhibitors, 16 benzylidene thiazolidinedione derivatives, previously reported as partial PPARγ agonists, together with additional 18 structural congeners, were studied for aldose reductase inhibitory activity. While no compounds had dual property, our efforts led to the identification of promising inhibitors of ALR2. Eight compounds (11, 15-16, 20-24, 30) from the library of 33 compounds were identified as potent and selective inhibitors of ALR2. Compound 21 was the most effective and selective inhibitor with an IC <subscript>50</subscript> value of 0.95 ± 0.11 and 13.52 ± 0.81 μM against ALR2 and aldehyde reductase (ALR1) enzymes, respectively. Molecular docking and dynamics studies were performed to understand inhibitor-enzyme interactions at the molecular level that determine the potency and selectivity. Compound 21 was further subjected to in silico and in vitro studies to evaluate the pharmacokinetic profile. Being less acidic (pKa = 9.8), the compound might have a superior plasma membrane permeability and reach the cytosolic ALR2. This fact together with excellent drug-likeness criteria points to improved bioavailability compared to the clinically used compound Epalrestat. The designed compounds represent a novel group of non-carboxylate inhibitors of aldose reductase with an improved physicochemical profile.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Aldehyde Reductase chemistry
Aldehyde Reductase metabolism
Animals
Caco-2 Cells
Catalytic Domain
Dogs
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors metabolism
Enzyme Inhibitors pharmacokinetics
Humans
Hypoglycemic Agents chemical synthesis
Hypoglycemic Agents metabolism
Hypoglycemic Agents pharmacokinetics
Hypoglycemic Agents pharmacology
Madin Darby Canine Kidney Cells
Male
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Protein Binding
Rats, Wistar
Structure-Activity Relationship
Thiazolidinediones chemical synthesis
Thiazolidinediones metabolism
Thiazolidinediones pharmacokinetics
Rats
Aldehyde Reductase antagonists & inhibitors
Enzyme Inhibitors pharmacology
Thiazolidinediones pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 223
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34175538
- Full Text :
- https://doi.org/10.1016/j.ejmech.2021.113630