Rhodamine-Based Metal Chelator: A Potent Inhibitor of Metal-Catalyzed Amyloid Toxicity

[Image: see text] Alzheimer’s disease (AD) exhibits a multitude of syndromes which add up to its complex nature. In AD, amyloid plaques are deposited along with abnormal accumulation of transition-metal ions. These transition-metal ions are redox-active and help to induce the formation of various polymorphic forms of amyloid-β. Amyloid oligomeric and fibrillar aggregates are the main cause for neuronal toxicity. Another reason for neuronal toxicity arises from generation of reactive oxygen species (ROS) catalyzed by redox-active metal ions through Fenton’s reaction. In this direction, an Aβ inhibitor possessing the metal chelation property will be the most promising approach against multifaceted AD. Herein, a rhodamine-B-based compound (Rh-BT) has been designed and synthesized. Rhodamine was attached with benzothiazole as a recognition unit for amyloid-β aggregates. The molecule can effectively capture redox metal ions from the Aβ–Cu(2+) complex as well as inhibit Aβ self-assembly such as toxic oligomeric and fibrillar aggregates. Various biophysical assays show that Rh-BT interacts with the Aβ peptide, is capable of decreasing metal-induced ROS generation, and inhibits Aβ–Cu(2+)-induced cytotoxicity. All these results support the multifunctional nature of Rh-BT, which has an Aβ-specific recognition unit. In addition to the above properties, Rh-BT also exhibits good serum stability in vivo and blood–brain barrier permeability. Therefore, Rh-BT can be considered as a potent multifunctional therapeutic for the treatment of AD.