The multi-target-directed-ligand (MTDL) strategy has been widely applied in the discovery of novel drugs for the treatment of Alzheimer’s disease (AD) because of the multifactorial pathological mechanisms of AD. Phosphodiesterase-2 (PDE2) has been identified to be a novel and promising target for AD. However, MTDL combining with the inhibitory activity against PDE2A and other anti-AD factors such as antioxidants has not been developed yet. Herein, a novel series of PDE2 inhibitors with antioxidant capacities were designed, synthesized, and evaluated. Most compounds showed remarkable inhibitory activities against PDE2A as well as antioxidant activities. Compound 6d was selected, which showed good IC₅₀ of 6.1 nM against PDE2A, good antioxidant activity (ORAC (Trolox) = 8.4 eq.) and no cytotoxicity to SH-SY5Y cells. Molecular docking and dynamics simulations were applied for the rational design and explanation of structure–activity relationship (SAR) of lead compounds.

由于AD的多因素病理机制，多靶点定向配体（MTDL）策略已广泛应用于发现治疗阿尔茨海默病（AD）的新药。磷酸二酯酶-2 (PDE2) 已被确定为 AD 的新靶点。然而，尚未开发出结合对 PDE2A 和其他抗 AD 因子（如抗氧化剂）的抑制活性的 MTDL。在此，设计、合成和评估了一系列具有抗氧化能力的新型 PDE2 抑制剂。大多数化合物对 PDE2A 显示出显着的抑制活性以及抗氧化活性。选择化合物6d，IC ₅₀良好对 PDE2A 为 6.1 nM，具有良好的抗氧化活性（ORAC (Trolox) = 8.4 eq.）并且对 SH-SY5Y 细胞没有细胞毒性。分子对接和动力学模拟被应用于先导化合物构效关系（SAR）的合理设计和解释。