Multitargeted Aza-Arylcarboxamides for Neurodegenerative Diseases: Potent Histamine H ₃ Receptor Ligands with Anticholinesterase and Metal-Chelating Activities

Neurodegenerative diseases are conditions characterized by neuronal loss in the nervous system, leading to diverse symptoms associated with complex pathological mechanisms. Dysregulation of metal ions such as iron and copper is linked to oxidative stress and consequently contributes to neuronal toxicity. Considering this, multitarget agents represent promising therapeutic strategies for the treatment of neurodegenerative disorders. In this study, a series of 24 novel multitarget compounds were designed to interact with histamine H₃ receptors (H₃R) and acetyl- and butyrylcholinesterases (AChE and BChE, respectively), incorporating additional metal-chelating groups. The compounds were synthesized and evaluated for their potency at H₃R, for cholinesterase inhibitionand for metal-chelating activity toward Fe²⁺, Fe³⁺, and Cu²⁺ using spectrophotometric assays. The compounds displayed considerable affinities for H₃R, AChE and BChE, with isoquinoline derivatives <b>LINS05413</b> and <b>LINS05414</b> standing out as multitarget agents due to their nanomolar affinities for H₃R (p<i>K</i>_i = 6.41 and 6.37, respectively), moderate AChE inhibitory activities (pIC₅₀ = 4.31 and 4.03, respectively) and metal-chelating properties. Isoquinoline-based compounds exhibited the strongest metal-chelating properties, particularly against copper, whereas 4-pyridylpiperazine derivatives were more effective in chelating iron ions. Molecular docking analyses revealed the role of aromatic substituents on multitargeting through interactions with key aromatic residues from each target. Structure-activity relationship and ligand efficiency analyses underscored the importance of the benzylpiperazine moiety for multitarget activity, while metal-chelating groups contributed to increased lipophilic ligand efficiency.