A Blood‐Brain Barrier‐Penetrant Ag(III) Corrole Compound Rescues Alzheimer's Disease Pathology by Targeting Aβ42‐Induced Oxidative Stress

Abstract Alzheimer's disease (AD) lacks disease‐modifying therapies, partly due to the blood‐brain barrier (BBB) limiting drug delivery and the multifaceted toxicity of amyloid‐β (Aβ42) oligomers. Here, this work reports the design, synthesis, and comprehensive characterization of a rationally designed silver(III) corrole complex, (Mor‐Cor)Ag(III) featuring a morpholino substituent at the periphery of the macrocycle, engineered to overcome these challenges through: (1) a morpholino moiety enabling BBB penetration (validated by mass spectrometry and fluorescence imaging), and (2) a redox‐active Ag(III) center that scavenges Aβ42‐induced reactive oxygen species (ROS). Detailed structural, spectroscopic, and density functional theory (DFT) analyses are performed to elucidate the electronic features of the complex. Further through multimodal biological validation in in vitro and in vivo transgenic AD models, (Mor‐Cor)Ag(III) is shown to disrupt Aβ42 aggregation and decrease ROS levels leading to decrease in dystrophic neurites, neuronal hyperactivity and neuronal death. (Mor‐Cor)Ag(III) significantly outperformed its unsubstituted analog, (Cor)Ag(III) in its ability to provide neuroprotection. This work establishes morpholine‐appended metallocorroles as a new class of neuroprotective drugs to address unmet therapeutic needs in AD.