Diversification of edaravone via palladium-catalyzed hydrazine cross-coupling: Applications against protein misfolding and oligomerization of beta-amyloid

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 1; pp. 100 - 104
• Main Authors: MacLean, Mark A., Diez-Cecilia, Elena, Lavery, Christopher B., Reed, Mark A., Wang, Yanfei, Weaver, Donald F., Stradiotto, Mark
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.01.2016; Elsevier
• Subjects: Alzheimer’s disease; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Antipyrine - analogs & derivatives; Antipyrine - chemical synthesis; Antipyrine - chemistry; Antipyrine - pharmacology; Beta-amyloid; Catalysis; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Hydrazine; Hydrazines - chemistry; Life Sciences & Biomedicine; Molecular Structure; Organometallic Compounds - chemistry; Palladium - chemistry; Palladium-catalyzed aminations; Pharmacology & Pharmacy; Physical Sciences; Protein Folding - drug effects; Protein Multimerization - drug effects; Science & Technology; Structure-Activity Relationship; Aβ; ThT; AD; Alzheimer’s disease; Palladium-catalyzed aminations; bio-Aβ42; SAR; Beta-amyloid; OFB; Hydrazine; ALZHEIMERS-DISEASE; Alzheimer's disease; DERIVATIVES; PEPTIDE
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.11.022

[Display omitted] N-Aryl derivatives of edaravone were identified as potentially effective small molecule inhibitors of tau and beta-amyloid aggregation in the context of developing disease-modifying therapeutics for Alzheimer’s disease (AD). Palladium-catalyzed hydrazine monoarylation protocols were then employed as an expedient means of preparing a focused library of 21 edaravone derivatives featuring varied N-aryl substitution, thereby enabling structure–activity relationship (SAR) studies. On the basis of data obtained from two functional biochemical assays examining the effect of edaravone derivatives on both fibril and oligomer formation, it was determined that derivatives featuring an N-biaryl motif were four-fold more potent than edaravone.