Design, Synthesis, and Structure–Activity Relationship of <i>N</i>‑Arylnaphthylamine Derivatives as Amyloid Aggregation Inhibitors

Dyes like CR are able to inhibit the aggregation of Aβ fibrils. Thus, a screening of a series of dyes including ABBB (<b>1</b>) was performed. Its main component <b>2</b> tested in an in vitro assay (i.e., ThT assay) showed good potency at inhibiting fibrils association. Congeners <b>4</b>–<b>9</b> have been designed and synthesized as inhibitors of Aβ aggregation. A number of these newly synthesized compounds have been found to be active in the ThT assay with IC₅₀ of 1–57.4 μM. The most potent compound of this series, <b>4k</b>, showed micromolar activity in this test. Another potent derivative <b>4q</b> (IC₅₀ = 5.6 μM) rapidly crossed the blood–brain barrier, achieving whole brain concentrations higher than in plasma. So <b>4q</b> could be developed to find novel potent antiaggregating βA agents useful in Alzheimer disease as well as other neurological diseases characterized by deposits of amyloid aggregates