Carboline Hybrids as Potential Multitarget‐Directed Anti‐Alzheimer's Disease Agents: A Comprehensive Analysis of Design Strategies and Structure–Activity Relationships

The β-carboline hybrids represent innovative therapeutics for Alzheimer's disease (AD) as multitarget-directed ligands (MTDLs), addressing cholinergic deficits through AChE/BuChE inhibition, amyloid-β (Aβ) aggregation, tau hyperphosphorylation via GSK-3β/DYRK1A suppression, neuroinflammation and oxidative stress. Structure-activity relationships (SARs) indicate that fluorine enhances BuChE selectivity through Tyr128 hydrogen bonding, hydrophobic extensions (α-naphthyl substituted β-carboline) optimise Aβ disaggregation and C4-8 spacers (piperazine-linked bivalent β-carboline) facilitate dual-target engagement without compromising blood-brain barrier permeability. Validated pharmacophore models prioritise planar cores for π-stacking, cationic centres for AChE/NMDA targeting and flexible linkers, positioning these hybrids as clinically translatable, disease-modifying candidates. In this extensive review, we summarised the derivatives and hybrids of carboline over the past decade for managing AD. We focus on their design, pharmacological activity and SAR analysis, as well as an exclusive pharmacophore model for both single- and multitarget carboline derivatives. We hope this review enhances the reader's understanding of future exploratory options for carboline hybrids in AD management.