The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; The Key Llaboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China.
The Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University; The Key Llaboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, 230032, China.
Eur J Med Chem. 2021 Jan 1;209:112874. doi: 10.1016/j.ejmech.2020.112874. Epub 2020 Sep 28.
Pleiotropic intervention has prominent advantages for complex pathomechanisms, such as Alzheimer's disease (AD). In this study, a series of novel 3-(4-pyridyl)-5-(4- sulfamido-phenyl)-1,2,4-oxadiazole derivatives were designed and synthesized following the multitarget-directed ligand-based strategy. All compounds were evaluated for glycogen synthase kinase 3β (GSK-3β) inhibition and antineuroinflammatory and neuroprotective activities. Given that abnormal glucose metabolism plays an important role in AD occurrence and development, the effects of all compounds on glucose consumption in HepG2 cells was evaluated. Compounds 5e and 10b showed good dual potency in GSK-3β inhibition (IC: 5e = 1.52 μM, 10b = 0.19 μM) and antineuroinflammatory potency (IC: 5e = 0.47 ± 0.64 μM, 10b = 6.94 ± 2.33 μM). The effect of compound 10b on glucose consumption was higher than that of positive drug metformin. These compounds exerted a certain neuroprotective effect. Compound 10b dramatically reduced Aβ-induced Tau hyperphosphorylation, thus inhibiting GSK-3β at the cellular level. Notably, compounds 5e and 10b exhibited good inhibitory effects on the formation of intracellular reactive oxygen species (ROS). Moreover, these compounds displayed proper blood-brain barrier permeability and lacked neurotoxicity up to 50 μM concentration. Finally, in vivo experiments revealed that compound 10b improved cognitive impairment in scopolamine-induced mouse models. Results indicated that compound 10b deserves further study as a multifunctional lead compound.
多靶点干预在治疗阿尔茨海默病（AD）等复杂发病机制方面具有显著优势。本研究基于多靶点导向配体策略，设计并合成了一系列新型 3-(4-吡啶基)-5-(4-磺酰胺基苯基)-1,2,4-恶二唑衍生物。所有化合物均进行了糖原合酶激酶 3β（GSK-3β）抑制活性、抗炎和神经保护活性评价。鉴于异常的葡萄糖代谢在 AD 的发生和发展中起着重要作用，评估了所有化合物对 HepG2 细胞葡萄糖消耗的影响。化合物 5e 和 10b 对 GSK-3β 抑制（IC：5e = 1.52 μM，10b = 0.19 μM）和抗炎活性（IC：5e = 0.47 ± 0.64 μM，10b = 6.94 ± 2.33 μM）均具有较好的双重活性。化合物 10b 对葡萄糖消耗的影响高于阳性对照药二甲双胍。这些化合物具有一定的神经保护作用。化合物 10b 显著降低 Aβ 诱导的 Tau 过度磷酸化，从而在细胞水平上抑制 GSK-3β。值得注意的是，化合物 5e 和 10b 对细胞内活性氧（ROS）的形成具有良好的抑制作用。此外，这些化合物具有适当的血脑屏障渗透性，在 50 μM 浓度下无神经毒性。最后，体内实验表明，化合物 10b 改善了东莨菪碱诱导的小鼠模型的认知障碍。结果表明，化合物 10b 作为一种多功能先导化合物值得进一步研究。
