Privileged quinolylnitrones for the combined therapy of ischemic stroke and alzheimer’s disease

Cerebrovascular diseases such as ischemic stroke are known to exacerbate dementia caused by neurodegenerative pathologies such as Alzheimer’s disease (AD). Besides, the increasing number of patients surviving stroke makes it necessary to treat the co-occurrence of these two diseases with a single and combined therapy. For the development of new dual therapeutic agents, eight hybrid quinolylnitrones have been designed and synthesized by the juxtaposition of selected pharmacophores from our most advanced lead-compounds for ischemic stroke and AD treatment. Biological analyses looking for efficient neuroprotective effects in suitable phenotypic assays led us to identify MC903 as a new small quinolylnitrone for the potential dual therapy of stroke and AD, showing strong neuroprotection on (i) primary cortical neurons under oxygen–glucose deprivation/normoglycemic reoxygenation as an experimental ischemia model; (ii), neuronal line cells treated with rotenone/oligomycin A, okadaic acid or β-amyloid peptide Aβ25–35, modeling toxic insults found among the effects of AD.This work was supported by the Instituto de Salud Carlos III and cofinanced by the Euro- pean Development Regional Fund (FEDER), grant number PI18/00255 and RETICS RD16/0019/0006, to A.A, Programa Miguel Servet CPII19/00005, PI19/00082 to JE, and by MINECO (Government of Spain) grant number SAF-2015-65586-R to J.M.-C. D.D.-I. thanks the Spanish Ministry of Science, Innovation and Universities for predoctoral FPU grant. A.E.-P. thanks Instituto de Salud Carlos III for the predoctoral contract IFI18/00011