Grondona_2026_ChemMedChem_21_e202501097

Alzheimer's disease (AD) is a complex, multifactorial neurodegenerative disorder in which numerous interconnected pathological processes, such as cholinergic deficits, Abeta and tau aggregation, oxidative stress, metal dyshomeostasis, mitochondrial dysfunction, and neuroinflammation, synergistically drive neuronal damage and cognitive decline. This heterogeneity has limited the effectiveness of the clinically available single-target therapies which only provide symptomatic relief and underscores the need for molecular frameworks capable of addressing multiple pathogenic pathways simultaneously to stop the progression of the disease. Hydrazones have emerged as highly versatile scaffolds in medicinal chemistry thanks to their straightforward synthesis, structural adaptability, and rich repertoire of interaction modes with different biological targets. In recent literature, an increasing number of hydrazone-based molecules have been designed as multitarget-directed ligands (MTDLs) to modulate key enzymes and pathological mechanisms relevant to AD. This review provides a comprehensive and critical overview of hydrazone-containing compounds reported over the last years (2020-2025) with potential application in AD therapy, highlighting their activity on classical targets, especially cholinesterases (ChEs), as well as emerging targets including carbonic anhydrase, BACE1, and alpha-glycosidase. Particular emphasis is placed on structure-activity relationships (SARs), multitarget profiles, and rational design strategies aimed at exploiting the hydrazone moiety to address the multifactorial nature of AD.