3-Hydroxy-4-pyridinone derivatives designed for fluorescence studies to determine interaction with amyloid protein as well as cell permeability.

Abstract Finding a cure for Alzheimer’s disease is an urgent goal. Multifunctional metal binders are used to elucidate its pathological features and investigated as potential therapeutics. The use of physicochemical and TD-DFT calculations constituted successful strategy in the design of 1-(4-(benzo[ d ]oxazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1 H )-one ( HL 21 ) and 1-(4-(benzo[ d ]thiazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1 H )-one ( HL 22 ). We report the synthesis and full characterization of these compounds, including X-ray crystallography. Using fluorescent signal as the readout, it was determined that HL 22 interacts with amyloid-beta protein fibrils, and permeates into bEnd.3 cells used as a mimic of the blood–brain barrier. This provides the first example of direct investigation of our hydroxypyridinone compounds within a biological setting.