title: New multi-target-directed small molecules against Alzheimer's disease: a combination of resveratrol and clioquinol.
abstract: Alzheimer's disease (AD) is currently one of the most difficult and challenging diseases to treat. Based on the ‘multi-target-directed ligands’ (MTDLs) strategy, we designed and synthesised a series of new compounds against AD by combining the pharmacophores of resveratrol and clioquinol. The results of biological activity tests showed that the hybrids exhibited excellent MTDL properties: a significant ability to inhibit self-induced β-amyloid (Aβ) aggregation and copper(II)-induced Aβ aggregation, potential antioxidant behaviour (ORAC-FL value of 0.9–3.2 Trolox equivalents) and biometal chelation. Among these compounds, (E)-5-(4-hydroxystyryl)quinoline-8-ol (10c) showed the most potent ability to inhibit self-induced Aβ aggregation (IC50 = 8.50 μM) and copper(II)-induced Aβ aggregation and to disassemble the well-structured Aβ fibrils generated by self- and copper(II)-induced Aβ aggregation. Note that 10c could also control Cu(I/II)-triggered hydroxyl radical (OH˙) production by halting copper redox cycling via metal complexation, as confirmed by a Cu–ascorbate redox system assay. Importantly, 10c did not show acute toxicity in mice at doses of up to 2000 mg kg−1 and was able to cross the blood–brain barrier (BBB), according to a parallel artificial membrane permeation assay. These results indicate that compound 10c is a promising multifunctional compound for the development of novel drugs for AD.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. huangl72@mail.sysu.edu.cn lixsh@mail.sysu.edu.cn.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Jianheng
authors.initials: J
authors.lastname: Li
authors.forename: Xian
authors.initials: X
authors.lastname: Jia
authors.forename: Hui
authors.initials: H
authors.lastname: Miao
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: D065567:Absorption, Physiological / Q000187:drug effects; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000648:ultrastructure; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology; D002614:Chelating Agents / Q000737:chemistry / Q000627:therapeutic use; D007464:Clioquinol / Q000737:chemistry / Q000627:therapeutic use*; D003300:Copper / Q000633:toxicity; D015195:Drug Design; D017665:Hydroxyl Radical / Q000737:chemistry; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D066329:Protein Aggregates / Q000187:drug effects; D000077185:Resveratrol; D054852:Small Molecule Libraries / Q000737:chemistry / Q000627:therapeutic use*; D013056:Spectrophotometry, Ultraviolet; D013267:Stilbenes / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002614:Chelating Agents; D066329:Protein Aggregates; D054852:Small Molecule Libraries; D013267:Stilbenes; D017665:Hydroxyl Radical; D003300:Copper; D007464:Clioquinol; D000077185:Resveratrol