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. ARIs 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 ARIs 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, thiazoles, and purines, as ARIs. SAR analysis reveals that acidic or bioisosteric head groups and electrostatic interactions with key ALR2 residues, such as Tyr48, His110, and Trp111, thereby increase potency and selectivity over related aldo–keto reductases. Similarly, physicochemical parameters, including lipophilicity, pK_a, and H-bond donor and acceptor properties, influence tissue penetration and pharmacokinetic behavior. Additionally, molecular docking and binding analyses reveal common interaction patterns in the anion-binding and specificity pockets of ALR2, providing mechanistic insight into heterocycle-mediated inhibition. Overall, this review identifies design trends and limitations in nitrogen heterocycle-based ARIs, offering valuable guidance for structure-guided drug design of selective, potent, and clinically therapeutic agents for managing diabetic complications.