Issue 9, 2016

Design, synthesis and evaluation of clioquinol–ebselen hybrids as multi-target-directed ligands against Alzheimer's disease

Abstract

A novel series of compounds obtained by fusing the metal-chelating agent clioquinol and the antioxidant ebselen were designed, synthesized and evaluated as multi-target-directed ligands against Alzheimer's disease (AD). Specifically, compared with their parent compounds clioquinol and ebselen, these hybrids demonstrated significant potency in inhibiting self- and Cu(II)-induced amyloid-β (Aβ) aggregation and acted as remarkable antioxidants and biometal chelators. In addition, the hybrids showed considerable improvements in ebselen-related pharmacological properties, including the ability to mimic glutathione peroxidase and scavenge H2O2. Of these molecules, compound 10h was identified as a potential lead compound for AD therapy. Importantly, this compound was found to possess rapid H2O2 scavenging activity and glutathione peroxidase-like (GPx-like) activity. Moreover, compound 10h was able to efficiently disassemble preformed self- and Cu(II)-induced Aβ aggregates. Furthermore, 10h was able to penetrate the central nervous system (CNS) and did not exhibit any acute toxicity in mice at doses up to 2000 mg kg−1.

Graphical abstract: Design, synthesis and evaluation of clioquinol–ebselen hybrids as multi-target-directed ligands against Alzheimer's disease

Supplementary files

Article information

Article type
Paper
Submitted
15 dec 2015
Accepted
04 jan 2016
First published
07 jan 2016

RSC Adv., 2016,6, 7139-7158

Design, synthesis and evaluation of clioquinol–ebselen hybrids as multi-target-directed ligands against Alzheimer's disease

Z. Wang, W. Li, Y. Wang, X. Li, L. Huang and X. Li, RSC Adv., 2016, 6, 7139 DOI: 10.1039/C5RA26797H

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