Design, Synthesis, and Evaluation of Multitarget-Directed Selenium-Containing Clioquinol Derivatives for the Treatment of Alzheimer’s Disease

A series of selenium-containing clioquinol derivatives were designed, synthesized, and evaluated as multifunctional anti-Alzheimer's disease (AD) agents. In vitro examination showed that several target compounds exhibited activities such as inhibition of metal-induced Aβ aggregation, antioxidative properties, hydrogen peroxide scavenging, and the prevention of copper redox cycling. A parallel artificial membrane permeation assay indicated that selenium-containing clioquinol derivatives possessed significant blood-brain barrier (BBB) permeability. Compound 8a, with a propynylselanyl group linked to the oxine, demonstrated higher hydrogen peroxide scavenging and intracellular antioxidant activity than clioquinol. Furthermore, 8a exhibited significant inhibition of Cu(II)-induced Aβ1-42 aggregation and was capable of disassembling the preformed Cu(II)-induced Aβ aggregates. Therefore, 8a is an excellent multifunctional promising compound for development of novel drugs for AD.