Multi-Target-Directed Triazole Derivatives: Design, Synthesis, and Evaluation of Synergistic Modulation in Alzheimer’s Disease

The multifaceted nature of Alzheimer's disease (AD) paves the way for the development of multitarget-directed ligands (MTDLs) as potential therapeutic agents. Herein, we report a series of triazole-based ligands that function as MTDLs via a fragment splicing strategy (6a-6ah and 8a–8m). The synthesized ligands (6a-6ah and 8a-8m) were systematically screened for their neuroinflammatory and MAO-B inhibitory efficacy, among which, the pyrrole-appended triazole derivative 6a emerged as the most prominent candidate. Additionally, we analyzed the correlation of the in vitro efficacy with in silico studies and found that both align well. Also, 6a exhibited appreciable BBB permeability. Further, the multitargeted efficacy of 6a was evaluated via ROS scavenging ability, Aβ-induced neuroprotection, and mitigation of various pathogenic mechanisms, including metal dyshomeostasis, mitochondrial dysfunction, and neurodegeneration. Consequently, our findings established 6a as a novel multi-target-directed ligand, highlighting its potential as a modifiable agent for attenuating AD symptoms.