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.