Design, synthesis, and biological activity studies of novel iron-chelating hybrids targeting pathological pathways associated with Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease involving neuroinflammation, oxidative stress, and metal dyshomeostasis, supporting the development of multifunctional therapeutic candidates. In this study, we rationally designed, synthesized, and characterized a new series of six phthalimide-acetohydroxamic acid derivatives combining h MAO-B inhibitory and iron-chelating properties. Spectroscopic and fluorescence studies demonstrated their selective interaction with iron ions. Several hybrids exhibited potent and selective inhibition of h MAO-B, with DES 5a and DES 5a′ showing IC 50 values in the nanomolar range (28 and 40 nM, respectively). These compounds also displayed myeloperoxidase (MPO) inhibitory activity, supporting their potential to modulate oxidative pathways. In silico ADME prediction revealed favorable drug-like and CNS-related properties, while cytotoxicity evaluation on differentiated SH-SY5Y neuronal cells confirmed satisfactory safety profiles (CC 50 > 100 μM for all hybrids), with DES 5a′ identified as the safest compound. This compound also displayed inhibitory activity against A β 1−42 self-aggregation (38.8 ± 1.5%) at 12.5 μM. Overall, these findings highlight this new class of hybrids as promising multifunctional candidates for further development against AD.