Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine Fused 2‑Pyridone Polyheterocycles Binding to α‑Synuclein and Amyloid‑β Fibrils

• Published in: Journal of organic chemistry Vol. 85; no. 21; pp. 14174 - 14189
• Main Authors: Adolfsson, Dan E, Tyagi, Mohit, Singh, Pardeep, Deuschmann, Adrian, Ådén, Jörgen, Gharibyan, Anna L, Jayaweera, Sanduni Wasana, Lindgren, Anders E. G, Olofsson, Anders, Almqvist, Fredrik
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06-11-2020
• Subjects: Alkyls; alpha-Synuclein; Amyloid; Amyloid beta-Peptides; Column chromatography; Mixtures; Nanofibers; Peptides and proteins; Pyridones
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/acs.joc.0c01699

A BF3·OEt2 catalyzed intramolecular Povarov reaction was used to synthesize 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with several O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogues substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.