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 (<b>6a-6ah</b> and <b>8a</b>-<b>8m</b>). The synthesized ligands (<b>6a-6ah</b> and <b>8a-8m</b>) were systematically screened for their neuroinflammatory and MAO-B inhibitory efficacy, among which, the pyrrole-appended triazole derivative <b>6a</b> emerged as the most prominent candidate. Additionally, we analyzed the correlation of the <i>in vitro</i> efficacy with <i>in silico</i> studies and found that both align well. Also, <b>6a</b> exhibited appreciable BBB permeability. Further, the multitargeted efficacy of <b>6a</b> 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 <b>6a</b> as a novel multi-target-directed ligand, highlighting its potential as a modifiable agent for attenuating AD symptoms.