Zhi_2026_Eur.J.Med.Chem_316_119050

Metal ions play an important role in the pathogenesis of Alzheimer's disease (AD). The aggregation of beta-amyloid and oxidative stress caused by metal dyshomeostasis are important reasons for the progression of AD. Therefore, metal therapeutics have received increasing attention. In this work, two multifunctional near-infrared porphyrin probes (1 and 2) were designed and synthesized, and the single crystals of their Cu(2+) complexes (1-Cu and 2-Cu) were obtained. Comprehensive biological activity evaluations demonstrated that 1, 2 possessed strong multifunctional anti-AD activities, including metal chelating, self-/Cu(2+)- induced Abeta(1-42) aggregation inhibition, and in vitro/in vivo reactive oxygen species (ROS) elimination. Especially after coordination with copper, the cholinesterase inhibition and ROS elimination abilities were significantly increased. Notably, X-ray single crystal diffraction of 1, 1-Cu and 2-Cu provided crucial molecular-level structural information. Combined with molecular docking, density functional theory (DFT) calculations, and molecular dynamics simulations, these crystallographic data fully elucidated the precise structure-activity relationships, revealing that the larger conjugated plane structure, differences in intermolecular forces and the picket-fence architecture significantly influenced the activities. Meanwhile, both probes exhibited highly selective fluorescence quenching responses to Cu(2+) with very low cytotoxicity, indicating their promising potential as both therapeutic and diagnostic agents for AD.