Advancing diabetic foot ulcer therapy: structure-activity relationship approaches for combating reactive oxygen species.

Diabetic foot ulcer (DFU) is a severe complication of diabetes mellitus, driven by excessive reactive oxygen species (ROS) and disrupted redox homeostasis. This study presents a medicinal chemistry–oriented evaluation of synthetic and natural ROS-modulating agents, emphasizing structure–activity relationships (SAR) and pharmacophore features. Synthetic classes—including SGLT2 inhibitors and thiazolidinediones—attenuate ROS via mitochondrial stabilization and NOX enzyme suppression, while natural compounds such as resveratrol and sulforaphane activate AMPK–SIRT1 and Nrf2 pathways. SAR analysis reveals that phenyl and hydroxyl substitutions enhance antioxidant potency, signaling fidelity, and bioavailability. These insights provide a rational framework for designing targeted therapeutics and delivery systems for DFU treatment and clinical translation.