Exploration of the novel phthalimide-hydroxypyridinone derivatives as multifunctional drug candidates against Alzheimer’s disease

A novel series of phthalimide-hydroxypyridinone derivatives were rationally designed and evaluated as potential anti-Alzheimer's disease (AD) agents. Bioactivity tests showed that all compounds displayed great iron ions-chelating activity (pFe 3+ = 17.07–19.52), in addition to potent inhibition of human monoamine oxidase B ( h MAO-B). Compound 11n emerged as the most effective anti-AD lead compound with a pFe 3+ value of 18.51, along with selective h MAO-B inhibitory activity (IC 50  = 0.79 ± 0.05 μM, SI > 25.3). The results of cytotoxicity assays demonstrated that 11n showed extremely weak toxicity in PC12 cell line at 50 μM. Additionally, compound 11n displayed a cytoprotective effect against H 2 O 2 -induced oxidative damage. Moreover, compound 11n exhibited ideal blood–brain barrier (BBB) permeability in the parallel artificial membrane permeation assay (PAMPA), and significantly improved scopolamine-induced cognitive and memory impairment in mice behavioral experiments. In conclusion, these favorable experimental results suggested compound 11n deserved further investigation as an anti-AD lead compound.