Novel rhodanine based inhibitors of aldose reductase of non-acidic nature with p-hydroxybenzylidene functional group.
Eur J Med Chem
; 246: 114922, 2023 Jan 15.
Article
en En
| MEDLINE
| ID: mdl-36455357
Aldose reductase, the first enzyme of the polyol pathway represents a key drug target in therapy of diabetic complications. In this study a series of six novel rhodanine based inhibitors of aldose reductase was designed, synthesized, and tested for their ability to inhibit aldose reductase and for selectivity relative to structurally related aldehyde reductase. Aldose reductase inhibitory activities of the compounds were characterized by the IC50 values ranging from 2000 nM to 20 nM. The values of selectivity factors relative to aldehyde reductase were decreasing in the same array from 24 to 5. In silico docking into the inhibitor binding site of aldose reductase revealed a specific binding pattern of the compounds comprising interaction of the deprotonated 4-hydroxybenzylidene group with the anion-binding sub-pocket of aldose reductase, creating a strong H-bond and charge interactions. Predicted pH-distribution profiles of the novel compounds into octanol, supported by experimentally determined distribution ratios, favour drug uptake at the physiological pH, as a result of the presence of the low-acidic phenolic group, instead of the more acidic carboxymethyl functional group.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Rodanina
/
Inhibidores Enzimáticos
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Eur J Med Chem
Año:
2023
Tipo del documento:
Article
País de afiliación:
República Checa
Pais de publicación:
Francia