Multitargeted Aza-Arylcarboxamides for Neurodegenerative Diseases: Potent Histamine H3 Receptor Ligands with Anticholinesterase and Metal-Chelating Activities

TL;DR

This paper introduces new multitarget compounds that act on brain receptors and enzymes, and also bind metal ions, which could help treat neurodegenerative diseases like Alzheimer's.

Contribution

The study introduces novel multitarget aza-arylcarboxamides with combined H3R ligand, anticholinesterase, and metal-chelating properties for neurodegenerative diseases.

Findings

Isoquinoline derivatives LINS05413 and LINS05414 showed nanomolar affinities for H3R and moderate AChE inhibition.

Isoquinoline-based compounds exhibited strong copper chelation, while 4-pyridylpiperazine derivatives were better at iron chelation.

Benzylpiperazine moieties and metal-chelating groups enhanced multitarget activity and ligand efficiency.

Abstract

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 LINS05413 and LINS05414 standing out as multitarget
agents due to their nanomolar affinities for H3R (pK
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.

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