Alzheimer’s disease is a chronic and irreversible pathological process that has become the most prevalent neurodegenerative disease. Currently, it is considered a multifactorial disease where oxidative stress and chronic neuroinflammation play a crucial role in its onset and development. Its characteristic neuronal loss has been related to the formation of neurofibrillary tangles mainly composed by hyperphosphorylated tau protein. Hyperphosphorylation of tau protein is related to the over-activity of GSK-3β, a kinase that participates in several pathological mechanisms including neuroinflammation. Neuronal loss is also related to cytosolic Ca²⁺ homeostasis dysregulation that triggers apoptosis and free radicals production, contributing to oxidative damage and, finally, neuronal death. Under these premises, we have obtained a new family of 4,7-dihydro-2H-pyrazolo[3–b]pyridines as multitarget directed ligands showing potent antioxidant properties and able to scavenge both oxygen and nitrogen radical species, and also, with anti-inflammatory properties. Further characterization has demonstrated their capacity to inhibit GSK-3β and to block L-type voltage dependent calcium channels. Novel derivatives have also demonstrated an interesting neuroprotective profile on in vitro models of neurodegeneration. Finally, compound 4g revokes cellular death induced by tau hyperphosphorylation in hippocampal slices by blocking reactive oxygen species (ROS) production. In conclusion, the multitarget profile exhibited by these compounds is a novel therapeutic strategy of potential interest in the search of novel treatments for Alzheimer’s disease.

中文翻译：

---

新型1,4-二氢吡啶衍生物的抗氧化，抗炎和神经保护作用，可治疗阿尔茨海默氏病。

阿尔茨海默氏病是一种慢性且不可逆的病理过程，已成为最普遍的神经退行性疾病。目前，它被认为是一种多因素疾病，其中氧化应激和慢性神经炎症在其发作和发展中起着至关重要的作用。其特征性神经元丢失与主要由高磷酸化tau蛋白组成的神经原纤维缠结的形成有关。tau蛋白的过度磷酸化与GSK-3β的过度活性有关，GSK-3β是一种参与多种病理机制（包括神经炎症）的激酶。神经元丢失也与胞质Ca ^2+有关稳态失调，触发细胞凋亡和自由基产生，导致氧化损伤，最终导致神经元死亡。在这些前提下，我们获得了一个新的4,7-二氢-2 H-吡唑并[3- b ]吡啶家族，作为多靶标定向配体，具有强效的抗氧化性能，能够清除氧自由基和氮自由基，并且抗炎特性。进一步的表征表明它们具有抑制GSK-3β和阻断L型电压依赖性钙通道的能力。新型衍生物还在神经变性的体外模型上显示出有趣的神经保护作用。最后加4克通过阻断活性氧（ROS）的产生，消除海马切片中tau过度磷酸化诱导的细胞死亡。总之，这些化合物表现出的多靶点概况是寻找阿尔茨海默氏病新疗法中潜在的新型治疗策略。