title: Diversification of edaravone via palladium-catalyzed hydrazine cross-coupling: Applications against protein misfolding and oligomerization of beta-amyloid.
abstract: 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.
authors.affiliation: Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO Box 15000, Halifax, NS B3H 4R2, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: MacLean
authors.affiliation: Toronto Western Research Institute, University Health Network, University of Toronto, Krembil Discovery Tower, 4th Floor 4KD-472, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.
authors.forename: Elena
authors.initials: E
authors.lastname: Diez-Cecilia
authors.affiliation: Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO Box 15000, Halifax, NS B3H 4R2, Canada.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Lavery
authors.affiliation: Treventis Corporation, 1411 Oxford Street, Halifax, NS B3H 3Z1, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Reed
authors.affiliation: Toronto Western Research Institute, University Health Network, University of Toronto, Krembil Discovery Tower, 4th Floor 4KD-472, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada.
authors.forename: Yanfei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO Box 15000, Halifax, NS B3H 4R2, Canada; Toronto Western Research Institute, University Health Network, University of Toronto, Krembil Discovery Tower, 4th Floor 4KD-472, 60 Leonard Avenue, Toronto, ON M5T 2S8, Canada; Treventis Corporation, 1411 Oxford Street, Halifax, NS B3H 3Z1, Canada. Electronic address: weaver@uhnres.utoronto.ca.
authors.forename: Donald F
authors.initials: DF
authors.lastname: Weaver
authors.affiliation: Department of Chemistry, Dalhousie University, 6274 Coburg Road, PO Box 15000, Halifax, NS B3H 4R2, Canada. Electronic address: mark.stradiotto@dal.ca.
authors.forename: Mark
authors.initials: M
authors.lastname: Stradiotto
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D004305:Dose-Response Relationship, Drug; D000077553:Edaravone; D006834:Hydrazines / Q000737:chemistry*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry; D010165:Palladium / Q000737:chemistry*; D017510:Protein Folding / Q000187:drug effects*; D055503:Protein Multimerization / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D006834:Hydrazines; D009942:Organometallic Compounds; C029424:hydrazine; D010165:Palladium; D000077553:Edaravone; D000983:Antipyrine
keywords: Alzheimer’s disease; Beta-amyloid; Hydrazine; Palladium-catalyzed aminations