Targeting Oxidative Stress in Alzheimer’s Disease Through Mechanistic Design of SOD-Mimicking Copper and Manganese Macrocycles

Abstract

Reactive oxygen species (ROS) are byproducts of normal cellular metabolism and play important roles in cell signaling and immune defense. However, when their production exceeds the cell’s antioxidant capacity, ROS accumulation leads to oxidative stress, damaging proteins, lipids, and DNA. In the brain, this oxidative imbalance has been closely linked to the development and progression of neurodegenerative diseases like Alzheimer’s. Under normal conditions, superoxide dismutase (SOD) enzymes play a key role in protecting cells by breaking down harmful superoxide radicals. Yet, reduced SOD activity and impaired regulation have been consistently observed in patients with neurodegeneration, including Alzheimer’s disease. Small-molecule mimics of SOD, therefore, represent a promising therapeutic approach. In this study, we evaluate an expanded library of tetra-aza macrocyclic ligands chelating either copper or manganese metals. Mechanistic analysis reveals how structural modifications to the macrocyclic ring, particularly R-group substitutions that alter steric environment and electronic properties, directly influence catalytic reactivity and stability. Evaluation of Cu- and Mn-based complexes highlights distinct trends in activity and identifies structural motifs that enhance SOD-like function. These findings provide design principles for developing antioxidant therapeutics targeting oxidative stress.