Rivastigmine-centered molecular hybridization strategies for multi-targeted intervention in Alzheimer's disease:...

Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disorder characterized by cholinergic dysfunction, amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, mitochondrial impairment, metal dyshomeostasis, and chronic neuroinflammation, collectively leading to irreversible cognitive decline and neuronal degeneration. Despite decades of intensive research, currently approved therapeutic agents, including cholinesterase inhibitors (ChEI) and NMDA receptor antagonists, provide only symptomatic relief and do not substantially alter disease progression. Among the clinically available ChEI, rivastigmine (RIV) has attracted considerable attention owing to its dual inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), pseudo-irreversible mode of action, and established clinical efficacy in AD management. In recent years, RIV has emerged as a highly promising pharmacophoric scaffold for the development of multifunctional hybrid molecules designed according to the multi-target-directed ligand (MTDL) strategy to modulate multiple pathological pathways involved in AD simultaneously. This review comprehensively summarizes and critically analyzes advances reported from 2020 to 2026 in the design, synthesis, biological evaluation, and therapeutic potential of RIV-based hybrid molecules and scaffold modifications for AD treatment. The review places particular emphasis on the rational hybridization of RIV with diverse bioactive pharmacophores, including tryptamine, coumarin, flavonoids, melatonin, tacrine, ferulic acid, cannabidiol, benzimidazole, piperidine, aryloxacetic acid, and antioxidant motifs, to generate multifunctional agents with enhanced pharmacological profiles. The reviewed hybrids demonstrated remarkable multifunctional properties, including potent inhibition of AChE and BChE, suppression of Aβ aggregation, antioxidant and metal-chelating activities, anti-inflammatory effects, modulation of monoamine oxidases, neuroprotection, mitochondrial stabilization, and improved blood-brain barrier permeability. Several derivatives exhibited significantly greater potency and broader neuroprotective profiles than RIV itself, highlighting the therapeutic value of molecular hybridization approaches in AD drug discovery.