Cu2+-selective porphyrin probes with multifunctional anti-AD activities and the structural-activity insights from X-ray single crystal analysis.

Metal ions play an important role in the pathogenesis of Alzheimer's disease (AD). The aggregation of β-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 Cu2+ 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-/Cu2+- induced Aβ1-42 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 Cu2+ with very low cytotoxicity, indicating their promising potential as both therapeutic and diagnostic agents for AD.