N-Propargylamine-hydroxypyridinone hybrids as multitarget agents for the treatment of Alzheimer’s disease

AD is a progressive brain disorder. Because of the lack of remarkable single-target drugs against neurodegenerative disorders, the multitarget-directed ligand strategy has received attention as a promising therapeutic approach. Herein, we rationally designed twenty-nine hybrids of N -propargylamine-hydroxypyridinone. The designed hybrids possessed excellent iron-chelating activity (pFe 3+ = 17.09–22.02) and potent monoamine oxidase B inhibitory effects. Various biological evaluations of the optimal compound 6b were performed step by step, including inhibition screening of monoamine oxidase ( h MAO-B IC 50  = 0.083 ± 0.001 µM, h MAO-A IC 50  = 6.11 ± 0.08 µM; SI = 73.5), prediction of blood–brain barrier permeability and mouse behavioral research. All of these favorable results proved that the N -propargylamine-hydroxypyridinone scaffold is a promising structure for the discovery of multitargeted ligands for AD therapy.