title: Design, synthesis, and evaluation of multitarget-directed selenium-containing clioquinol derivatives for the treatment of Alzheimer's disease.
abstract: 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.
authors.affiliation: Institute of Drug Synthesis and Pharmaceutical Processing, School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, China.
authors.forename: Zhiren
authors.initials: Z
authors.lastname: Wang
authors.forename: Yali
authors.initials: Y
authors.lastname: Wang
authors.forename: Wenrui
authors.initials: W
authors.lastname: Li
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.forename: Xingshu
authors.initials: X
authors.lastname: Li
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002199:Capillary Permeability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D007464:Clioquinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D003300:Copper / Q000633:toxicity; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008567:Membranes, Artificial; D008954:Models, Biological; D018697:Nootropic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects; D018036:Selenium Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013552:Swine
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D008567:Membranes, Artificial; D018697:Nootropic Agents; D010446:Peptide Fragments; D018036:Selenium Compounds; C075222:amyloid beta-protein (1-42); D003300:Copper; D007464:Clioquinol; D006861:Hydrogen Peroxide
keywords: Alzheimer’s disease; antioxidative properties; inhibition of metal-induced Aβ aggregation; selenium-containing clioquinol derivatives