Medicinal Attributes of Nitrogen Heterocycles Directing Aldose Reductase Selectivity and Potency

Abstract

Diabetic complications arise primarily from hyperglycemia-induced metabolic disturbances, among which the polyol pathways play a significant role through the overactivation of aldose reductase. ARLs have therefore emerged as a potent therapeutic approach to prevent or delay diabetes-associated microvascular oxidative damage. In recent years, nitrogen-based heterocyclic compounds have gained prominence as potent ARLS, due to their structural variability and pharmacodynamic profiles. This review comprehensively analyzes the structural features and target interactions of various nitrogen-containing scaffolds, including quinoxalines, pyrazolines, imidazoles, oxadiazoles, pyrazoles, triazoles, pyrimidines, thiazole, and purines, as ARIs. SAR analysis reveals how specific heterocyclic moieties and substituent effects, including electron-withdrawing and donating groups, impact enzyme binding affinity, selectivity, and pharmacokinetic properties. Additionally, molecular interaction studies elucidate the binding mechanism and key residue interactions governing AR inhibition, providing valuable guidance for structure-guided drug design. The findings outlined here establish a robust foundation for developing novel ARIs, offering improved therapeutic outcomes for managing diabetic complications.