New multi-target-directed small molecules against Alzheimer's disease: a combination of resveratrol and clioquinol

作者：Mao, Fei; Yan, Jun; Li, Jianheng; Jia, Xian; Miao, Hui; Sun, Yang; Huang, Ling^*; Li, Xingshu

来源：Organic and Biomolecular Chemistry, 2014, 12(31): 5936-5944.

DOI：10.1039/c4ob00998c

• AMYLOID AGGREGATION INHIBITORS
• A-BETA
• NEURODEGENERATIVE DISORDERS
• OXIDATIVE STRESS
• DESIGN
• COPPER
• PREDICTION
• ASSAY
• ACETYLCHOLINESTERASE
• ANTIOXIDANTS

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 beta-amyloid (A beta) aggregation and copper(II)-induced A beta 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 A beta aggregation (IC50 = 8.50 mu M) and copper(II)-induced A beta aggregation and to disassemble the well-structured A beta fibrils generated by self- and copper(II)-induced A beta aggregation. Note that 10c could also control Cu(I/II)-triggered hydroxyl radical (OH center dot) 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.

• 出版日期2014-8-21
• 单位沈阳药科大学; 中山大学