【作者】 王敏；

【导师】 李增；

【作者基本信息】 安徽医科大学 ， 药物化学， 2021， 硕士

【摘要】 阿尔茨海默症（Alzheimer’s disease,AD）是一种多发于老年人的神经退行性疾病,其主要的临床表现是记忆丧失和语言障碍。尽管进行了大量的研究,但AD确切的发病机制仍然未知。目前在临床上也尚无有效的药物可以完全治愈此病。AD典型的病理特征是细胞外的老年斑和细胞内的神经纤维缠结。此外,神经炎症、氧化应激、脑内葡萄糖代谢紊乱也是促进AD发生发展的重要因素。近年来,已经探索了与AD神经病理学相关的许多信号传导途径,其中包括糖原合酶激酶3β（Glycogen synthase kinase 3β,GSK-3β）,而该激酶被认为是治疗这种疾病的可能候选靶标。研究表明,GSK-3β的过度活跃将导致Aβ产生、Tau蛋白过度磷酸化、胆碱能神经元和轴突的退化以及认知障碍发生,这些都是AD的病理特征。因此GSK-3β可能是用于治疗AD的一个非常有吸引力的药物靶点。多效性干预对于具有复杂的发病机制疾病（例如:AD）的治疗具有显着优势。所以,在这项研究中,基于多靶标导向配体策略,设计并合成了一系列新型的3-（4-吡啶基）-5-（4-磺酰胺基-苯基）-1,2,4-噁二唑衍生物,并评价了所有的目标化合物的糖原合酶激酶3β（GSK-3β）抑制作用、抗神经炎症和神经保护作用。考虑到异常葡萄糖代谢在AD的发生和发展中起着重要作用,因此评估了所有化合物对Hep G2细胞葡萄糖消耗的影响。结果表明,化合物5e和10b在抑制GSK-3β(IC₅₀:5e=1.52μM,10b=0.19μM)和抗神经炎症(IC₅₀:5e=0.47±0.64μM,10b=6.94±2.33μM)方面显示出良好的双重作用。化合物10b对葡萄糖消耗的影响高于阳性药物二甲双胍。这些化合物也具有一定的神经保护作用。Western Blot实验表明化合物10b显着降低了Aβ诱导的Tau过度磷酸化,证明了化合物10b在细胞水平上对GSK-3β抑制作用。值得注意的是,化合物5e和10b对细胞内活性氧（ROS）的产生表现出良好的抑制作用。此外,这些化合物显示出适当的血脑屏障渗透性,并且在浓度高达50μM时缺乏神经毒性。最后,体内实验表明,化合物10b改善了东莨菪碱诱导AD小鼠模型认知障碍。这些结果表明,化合物10b作为多功能先导化合物值得进一步研究。更多还原

【Abstract】 Alzheimer’s disease（AD）is a neurodegenerative disorder with multiple onsets in the elderly,main clinical feature by progressive memory loss and speech disorder.Despite intense research,the exact pathogenesis of the disease remains unknown,and there are no effective drugs completely curing for it at the present.Senile plaques outside neurons and neurofibrillary tangles（NFTs）inside neurons are the main pathological features of AD.In addition,neuroinflammation,oxidative stress,and disturbance of glucose metabolism in the brain are important factors that promote AD occurrence and development.In recent years,many signaling pathways associated with AD neuropathology have been explored as possible candidate targets for the treatment of this condition including glycogen synthase kinase-3β（GSK-3β）.Research studies indicated that hyperactivity of GSK-3βinduce the hyperphosphorylation of tau,Aβgeneration,loss of cholinergic neurons and axons and cognitive impairment,which are hallmark features of AD.Consequently,an effective measure to inhibit GSK-3βactivity may be a very attractive drug target in AD.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 Hep G2 cells was evaluated.Compounds 5e and 10b showed good dual potency in GSK-3βinhibition(IC₅₀:5e=1.52μM,10b=0.19μM)and antineuroinflammatory potency(IC₅₀:5e=0.47±0.64μM,10b=6.94±2.33μM).The effect of compound 10b on glucose consumption was higher than that of positive drug metformin.These compounds exerted a certain neuroprotective effect.Compound10b dramatically reduced Aβ-induced Tau hyperphosphorylation,thus inhibiting GSK-3βat 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 50μM 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.更多还原