A comprehensive exploration of the structure–activity relationships, multitarget strategies, and therapeutic mechanisms of triazole scaffolds in Alzheimer’s disease

The deposition of the Aβ peptide extracellularly as diffused and neuritic plaques and intracellular hyperphosphorylated tau (p-tau) protein as neurofibrillary tangles (NFTs) are the key pathological changes observed in the progression of AD. Despite advances in the neuroscience research, the discovery and development of effective therapeutic agents have become challenging task for AD. The molecules modulating multiple targets involved in the disease attracted much attention as promising tools for the effective therapeutic efficacy. Triazole scaffold has been consistently rewarded as a promising versatile lead molecule with a pivotal position in modern medicinal chemistry. It has shown potent inhibitory activity against different targets involved in the progression of the AD including activity against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), amyloid beta (Aβ) accumulation, tau aggregation, neuroinflammation and oxidative stress. Recent reviews label 1,2,3-triazole as first choice scaffold for designing multifunctional hybrid molecules for AD. A comprehensive literature search was performed using PubMed, Scopus, Web of Science, and Google Scholar databases covering publications from 2000 to 2026. This review critically analyzes the evolution of triazole-based therapeutics from single-target cholinesterase inhibitors to modern multitarget-directed ligands. We systematically evaluate how the structural versatility of the 1,2,3- and 1,2,4-triazole cores facilitates interactions with key AD pathological hallmarks.