Synthesis and evaluation of arylquinones as BACE1 inhibitors, β-amyloid peptide aggregation inhibitors, and destabilizers of preformed β-amyloid fibrils

• Published in: Bioorganic & medicinal chemistry letters 2011-04, Vol.21 (8), p.2183-2187
• Main Authors: Ortega, Andrea, Rincón, Ángela, Jiménez-Aliaga, Karim L., Bermejo-Bescós, Paloma, Martín-Aragón, Sagrario, Molina, María Teresa, Csákÿ, Aurelio G.
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Alzheimer Disease - drug therapy; Alzheimer's disease; amyloid; Amyloid - chemistry; Amyloid aggregation; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - metabolism; Amyloid precursor protein; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Amyloidogenesis; Antibiotics; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; Aβ fibrils; BACE1; beta -Amyloid; beta -Site APP cleaving enzyme 1; Biological and medical sciences; Diabetes mellitus; Disaggregation; Drug development; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - therapeutic use; Fibrils; Human immunodeficiency virus 1; Humans; Lipophilic; Medical sciences; natural products; Neurodegenerative diseases; Neuropharmacology; new drugs; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Quinone; Quinones; Quinones - chemical synthesis; Quinones - chemistry; Quinones - therapeutic use; RNA-directed DNA polymerase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2011.03.023

BACE1 activity, inhibition of Aβ aggregation, and disaggregation of preformed Aβ fibrils constitute the three major targets in the development of small-molecule lipophilic new drugs for the treatment of Alzheimer’s disease (AD). Quinones are widely distributed among natural products and possess relevant and varied biological activities including antitumor and antibiotic, inhibition of HIV-1 reverse transcriptase, antidiabetic, or COX-inhibition, among others. We report herein the interaction of several arylquinones and their derivatives with the amyloidogenic pathway of the amyloid precursor protein processing. Our studies put forward that these compounds are promising candidates in the development of new drugs which are effective simultaneously towards the three major targets of AD.