Francesconi_2026_ACS.Chem.Neurosci__

The escalating number of Alzheimer's disease (AD) cases and the limitations of current therapies pose a significant threat to human health, necessitating the discovery of novel drugs with innovative modes of action. To address this challenge, we pursued multitarget ligand strategy with the expectation of improved disease management. Continuing our efforts to discover new multitarget agents for AD, we decorated the planar 6-Cl-2-OCH(3)-9-aminoacridine core with basic heterocyclic or benzyl side chains as polar and hydrophobic structural features, respectively. All the compounds inhibited acetylcholinesterase, and in several cases also inhibited butyrylcholinesterase, with potencies comparable to or exceeding those of reference drugs. Exploring activity against MAO isoforms, heterocyclic derivatives 2, 5, 6, 9, 11, and 12 proved to be selective MAO-A inhibitors, while the 3,4-dichlorobenzyl derivative 20 provided balanced inhibition of both MAO-A and MAO-B enzymes. Favorable predicted blood-brain barrier permeability and low toxicity toward SH-SY5Y neuronal cells were also observed. Intriguingly, compounds 4, 12 and 20 altered the aggregation morphology of the neurotoxic Abeta(42) peptide, revealing distinct inhibition profiles likely reflecting the different nature of the side chain. Based on these findings, the planar 6-Cl-2-OCH(3)-9-aminoacridine ring emerges as a valuable scaffold for future development of multitargeted anti-AD agents.