School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
Bioorg Med Chem Lett. 2021 Jun 1;41:128016. doi: 10.1016/j.bmcl.2021.128016. Epub 2021 Apr 8.
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 IC 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.
多靶点导向配体（MTDL）策略已广泛应用于治疗阿尔茨海默病（AD）的新型药物的发现，因为 AD 的多因素病理机制。磷酸二酯酶-2（PDE2）已被确定为 AD 的一个新的有前途的靶点。然而，结合了对 PDE2A 的抑制活性以及其他抗 AD 因子（如抗氧化剂）的 MTDL 尚未得到开发。本文设计、合成并评价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 具有显著的抑制活性和抗氧化活性。选择化合物 6d，其对 PDE2A 的 IC 为 6.1 nM，具有良好的抗氧化活性（ORAC（Trolox）= 8.4 eq.），对 SH-SY5Y 细胞无细胞毒性。分子对接和动力学模拟用于合理设计和解释先导化合物的构效关系（SAR）。
