Abstract

Pyridinium-based compounds have emerged as promising multifunctional agents for Alzheimer’s disease therapy, demonstrating remarkable dual inhibition of acetylcholinesterase and butyrylcholinesterase. This comprehensive analysis of more than 100 derivatives revealed that strategic structural modifications significantly enhance their therapeutic potential. Disubstituted analogues, representing more than half of the reported compounds, show particular promise, with many achieving exceptional potency below 100 nM, surpassing reference drugs such as donepezil, in optimized cases. Molecular Insights confirmed the presence of important interactions within the catalytic active site (CAS) and peripheral active site (PAS), explaining their robust inhibitory activity and highlighting several successful design approaches. Incorporating cationic groups at the 1,3-positions dramatically improves catalytic site binding, as seen in compounds such as Bb4, with an impressive 6.2 nM activity. Bulky aromatic extensions, such as naphthyl moieties, effectively target peripheral sites, while optimal C7-C12 linkers in bivalent structures enable the simultaneous engagement of both catalytic and peripheral sites. Planar fused-ring systems, particularly β-carboline derivatives, demonstrate enhanced blood-brain barrier penetration, which is a crucial challenge in CNS drug development. These compounds showed potential beyond cholinesterase in hibition, with selected derivatives exhibiting additional benefits against β-amyloid aggregation, oxidative stress, and NMDA) receptor modulation. However, their path to clinical application requires overcoming significant hurdles, particularly in demonstrating reliable blood-brain barrier penetration and establishing comprehensive safety profiles. Future progress depends on rigorous in vivo validation using disease-relevant models coupled with systematic optimization of pharmacokinetic properties. By addressing these challenges, pyridinium-based scaffolds could evolve into valuable multifunctional therapeutics, offering new hope for Alzheimer’s patients through their unique combination of mechanisms and tunable chemical properties.