Multitarget-Directed Benzylideneindanone Derivatives: Anti-β-Amyloid (Aβ) Aggregation, Antioxidant, Metal Chelation, and Monoamine Oxidase B (MAO-B) Inhibition Properties against Alzheimer’s Disease

• Published in: Journal of medicinal chemistry 2012-10, Vol.55 (19), p.8483-8492
• Main Authors: Huang, Ling, Lu, Chuanjun, Sun, Yang, Mao, Fei, Luo, Zonghua, Su, Tao, Jiang, Huailei, Shan, Wenjun, Li, Xingshu
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Amyloid - chemistry; Amyloid beta-Peptides - chemistry; Antioxidants - chemical synthesis; Antioxidants - chemistry; Benzylidene Compounds - chemical synthesis; Benzylidene Compounds - chemistry; Cations, Divalent; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Copper - chemistry; Humans; Indans - chemical synthesis; Indans - chemistry; Iron - chemistry; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Molecular Docking Simulation; Monoamine Oxidase - chemistry; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine Oxidase Inhibitors - chemistry; Peptide Fragments - chemistry; Recombinant Proteins - chemistry; Structure-Activity Relationship; Zinc - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300978h

A novel series of benzylideneindanone derivatives were designed, synthesized, and evaluated as multitarget-directed ligands against Alzheimer’s disease. The in vitro studies showed that most of the molecules exhibited a significant ability to inhibit self-induced β-amyloid (Aβ1–42) aggregation (10.5–80.1%, 20 μM) and MAO-B activity (IC50 of 7.5–40.5 μM), to act as potential antioxidants (ORAC-FL value of 2.75–9.37), and to function as metal chelators. In particular, compound 41 had the greatest ability to inhibit Aβ1–42 aggregation (80.1%), and MAO-B (IC50 = 7.5 μM) was also an excellent antioxidant and metal chelator. Moreover, it is capable of inhibiting Cu(II)-induced Aβ1–42 aggregation and disassembling the well-structured Aβ fibrils. These results indicated that compound 41 is an excellent multifunctional agent for the treatment of AD.