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Novel substituted N-benzyl(oxotriazinoindole) inhibitors of aldose reductase exploiting ALR2 unoccupied interactive pocket.
- Source :
-
Bioorganic & medicinal chemistry [Bioorg Med Chem] 2021 Jan 01; Vol. 29, pp. 115885. Date of Electronic Publication: 2020 Nov 22. - Publication Year :
- 2021
-
Abstract
- Recently we have developed novel oxotriazinoindole inhibitors (OTIs) of aldose reductase (ALR2), characterized by high efficacy and selectivity. Herein we describe novel OTI derivatives design of which is based on implementation of additional intermolecular interactions within an unoccupied pocket of the ALR2 enzyme. Four novel derivatives, OTI-(7-10), of the previously developed N-benzyl(oxotriazinoindole) inhibitor OTI-6 were synthetized and screened. All of them revealed 2 to 6 times higher ALR2 inhibitory efficacy when compared to their non-substituted lead compound OTI-6. Moreover, the most efficient ALR2 inhibitor OTI-7 (IC <subscript>50</subscript>  = 76 nM) possesses remarkably high inhibition selectivity (S <subscript>F</subscript>  ≥ 1300) in relation to structurally related aldehyde reductase (ALR1). Derivatives OTI-(8-10) bearing the substituents -CONH <subscript>2</subscript> , -COOH and -CH <subscript>2</subscript> OH, possess 2-3 times lower inhibitory efficacy compared to OTI-7, but better than the reference inhibitor OTI-6. Desolvation penalty is suggested as a possible factor responsible for the drop in ALR2 inhibitory efficacy observed for derivatives OTI-(8-10) in comparison to OTI-7.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Aldehyde Reductase metabolism
Animals
Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
Indoles chemical synthesis
Indoles chemistry
Lens, Crystalline enzymology
Male
Molecular Docking Simulation
Molecular Structure
Rats
Rats, Wistar
Structure-Activity Relationship
Triazines chemical synthesis
Triazines chemistry
Aldehyde Reductase antagonists & inhibitors
Enzyme Inhibitors pharmacology
Indoles pharmacology
Triazines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3391
- Volume :
- 29
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 33271452
- Full Text :
- https://doi.org/10.1016/j.bmc.2020.115885