Zhou_2026_J.Inorg.Biochem_278_113245

Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathogenesis. Currently, there are still no drugs on the market that have a significant therapeutic effect. Zinc, an essential trace element, played a double-edged role in neuronal function-zinc deficiency accelerated cognitive decline and neurodegeneration, however overloaded zinc may cause beta-amyloid (Abeta) aggregation. In contrast, the brains of AD patients exhibited significantly elevated copper concentrations around Abeta plaques, where this localized high copper concentration microenvironment catalyzed oxidative reactions and Abeta aggregation, thereby exacerbating neuronal damage. To address the interconnected pathological targets, a novel carbamate porphyrin derivative (1) and its zinc complex (1-Zn) were designed and synthesized. Single crystals of both compounds were successfully obtained and analyzed. And with further Hirshfeld surface analysis, molecular dynamics predictions and frontier molecular orbital studies, their structure characteristics and intermolecular interactions were systematically analyzed. Subsequently, metal chelation assays, antioxidant activity evaluations, Abeta aggregation inhibition assays, and anticholinesterase assays were performed to assess the multi-target therapeutic potential. Notably, 1-Zn exhibited a dual-function metal dyshomeostasis regulation ability, namely, chelating excess Cu(2+) and at the same time releasing a specific amount of Zn(2+) to the system. In addition, 1 and 1-Zn showed comparable ROS scavenging ability (in vitro and in vivo) and Abeta aggregation inhibition ability to the positive control drugs. 1-Zn also showed similar cholinesterase inhibition activity as rivastigmine. Consequently, this study demonstrated that 1 and 1-Zn held potential as multifunctional anti-AD agents, meriting further investigation for clinical translation.