Medicinal chemistry approaches for dual inhibition of amyloid-β and tau aggregation in Alzheimer's disease.

Proteinopathies play a complex interplay in the pathogenesis of multifactorial neurological disorders. In Alzheimer's disease (AD), the extracellular deposition of amyloid-β (Aβ) plaques and intracellular accumulation of hyperphosphorylated tau into neurofibrillary tangles are the two principal pathological hallmarks. In both cases, nucleation-dependent self-assembly triggers fibril formation and consequent aggregation that disrupts synaptic integrity and accelerates neuronal degeneration. The emerging interconnection between both the proteinopathies, wherein Aβ oligomers promote tau hyperphosphorylation and subsequent aggregation, highlights the need for developing multifunctional dual Aβ-tau aggregation inhibitors. Over the past decade, several dual-acting small molecules have been reported, including synthetic scaffolds (sulfonamides, thiophenes, acridones, isoquinolinium analogues), semi-synthetic derivatives (curcumin, tacrine, ferulic acid), and naturally derived compounds (neferine, pyrogallol, chrysin). While these molecules demonstrate promising in vitro inhibition of both Aβ and tau aggregation through the disruption of β-sheet formation and, in some cases, disaggregation of preformed fibrils; however, their translational potential is often constrained by suboptimal brain penetration, moderate potency, or limited correlation between aggregation inhibition and neuroprotection. This review provides comprehensive molecular mechanisms of Aβ and tau aggregation and a detailed structure-activity relationships (SAR) of reported dual inhibitors to guide the rational design of future novel multitarget therapeutics with improved drug-likeness and disease-modifying potential for AD.