Synthesis and bio-activities of bifunctional tetrahydrosalen Cu (II) chelators with potential efficacy in Alzheimer's disease therapy

The dyshomeostasis of metal ions in the brain leads to the accumulation of excess metals in extracellular and inter-neuronal locations and the Amyloid β peptide (Aβ) binds these transition metals, which ultimately cause the Aβ aggregation and severe oxidative stress in the brain. The aggregation of Aβ and oxidative stress are important factors to trigger Alzheimer's disease (AD). Metal chelation therapy is a promising approach to removing metals from Aβ-M species and relieve the oxidative stress. Therefore, 4 tetrahydrosalens containing benzothiazole moiety were designed and synthesized. Their biological activities for Alzheimer's disease therapy in vitro were determined by Turbidity assay, BCA protein assay, MTT assay and fluorescent probe of DCFH-DA. The results were comparing with that of non-specific chelator (cliquinol, CQ) and non-benzothiazole functionalized tetrahydrosalens, the results demonstrated that benzothiazole functionalized chelators had more efficient bio-activities in preventing Cu²⁺-induced Aβ aggregation, attenuating cytotoxicity mediated by Aβ-Cu²⁺ species and decrease the level of reactive oxygen species (ROS) in Cu²⁺-Aβ treated PC12 cells than that of cliquinol and non-benzothiazole functionalized analogues.