The complex pathogenesis of Alzheimer’s disease (AD) requires using multi-target ligands (MTLs) for disease management. We synthesized, characterized and evaluated a series of novel triazine analogues as MTLs for AD. The biological screening results indicated that most of our compounds displayed potent inhibitory activities against β-site APP-cleaving enzyme 1 (BACE1) using a FRET-based assay. Compounds 6c and 6m were found to possess significant BACE1 inhibitory properties with IC₅₀ values of 0.91 (±0.25) µM and 0.69 (±0.20) µM, respectively. DPPH radical scavenging activity evaluation showed that compounds with hydroxyl and pyrrole moieties had antioxidant effects. Docking evaluations provided insight into enzyme inhibitory interactions of novel synthesized compounds with the BACE1 active site involving a critical role for Gln73 and/or Phe108 alongside of Asp32. Metal chelation tests confirmed that compound 6m is a chelator for Fe²⁺, Fe³⁺, Zn²⁺, Cu²⁺. Moreover 6m as the most potent BACE1 inhibitor did not show any toxicity against PC12 neuronal cells. These findings demonstrate the high potential of triazine scaffolds in the design of MTLs for treatment of AD.

阿尔茨海默氏病（AD）的复杂发病机理需要使用多靶点配体（MTL）进行疾病管理。我们合成，表征和评估一系列新型三嗪类似物作为AD的MTL。生物学筛选结果表明，使用基于FRET的检测方法，我们大多数化合物对β位APP裂解酶1（BACE1）均显示出强大的抑制活性。发现化合物6c和6m具有IC _50的显着BACE1抑制特性值分别为0.91（±0.25）µM和0.69（±0.20）µM。DPPH自由基清除活性评估表明具有羟基和吡咯部分的化合物具有抗氧化作用。对接评估提供了新的合成化合物与BACE1活性位点的酶抑制相互作用的见解，该位点与Gln73和/或Phe108以及Asp32都起着至关重要的作用。金属螯合测试证实了化合物6m是Fe 2 ⁺，Fe ³⁺，Zn 2 ⁺，Cu ²⁺的螯合剂。而且6m因为最有效的BACE1抑制剂对PC12神经元细胞没有任何毒性。这些发现证明三嗪支架在设计用于治疗AD的MTL中具有很高的潜力。