Discovery of benzamide-hydroxypyridinone hybrids as potent multi-targeting agents for the treatment of Alzheimer's disease.

A novel class of benzamide-hydroxypyridinone (HPO) derivatives were innovatively designed, synthesised, and biologically evaluated as potential multitargeting candidates for the treatment of Alzheimer's disease (AD) through pharmacophores-merged approaches based on lead compounds , benzyloxy phenyl analogs, and deferiprone (DFP). These hybrids possessed potent Monoamine oxidase B (MAO-B) inhibition as well as excellent iron chelation, with pFe values ranging from 18.13 to 19.39. Among all the compounds, exhibited the most potent selective MAO-B inhibitor (IC = 68.4 nM, SI = 213). Moreover, showed favourable pharmacokinetic properties and had great potential to penetrate the BBB and PAMPA-BBB assay. Molecular modelling showed that could adopt an extended conformation and have more enhanced interactions with MAO-B than . and assays demonstrated that remarkably resisted Aβ-induced oxidation and ameliorated cognitive impairment induced by scopolamine. Taken collectively, these results suggest that compound is a potential multifunctional candidate for anti-AD treatment.