New cinnamic – N-benzylpiperidine and cinnamic – N,N-dibenzyl(N-methyl)amine hybrids as Alzheimer-directed multitarget drugs with antioxidant, cholinergic, neuroprotective and neurogenic properties

Here we describe new families of multi-target directed ligands obtained by linking antioxidant cinnamic-related structures with N-benzylpiperidine (NBP) or N,N-dibenzyl(N-methyl)amine (DBMA) fragments. Resulting hybrids, in addition to their antioxidant and neuroprotective properties against mitochondrial oxidative stress, are active at relevant molecular targets in Alzheimer’s disease, such as cholinesterases (hAChE and hBuChE) and monoamine oxidases (hMAO-A and hMAO-B). Hybrids derived from umbellic – NBP (8), caffeic – NBP (9), and ferulic – DBMA (12) displayed balanced biological profiles, with IC50s in the low-micromolar and submicromolar range for hChEs and hMAOs, and an antioxidant potency comparable to vitamin E. Moreover, the caffeic – NBP hybrid 9 is able to improve the differentiation of adult SGZ-derived neural stem cells into a neuronal phenotype in vitro.Financial support from the Spanish Ministry of Economy and Competitiveness (MINECO, grants SAF2012-31035 and SAF2015-64948-C2-1-R to MIRF; grant SAF2014-52940-R to APC) partially financed by FEDER funds, and Consejo Superior de Investigaciones Científicas (CSIC, grant PIE-201580E109) is gratefully acknowledged. ME thanks COLCIENCIAS (Colombia) for a Ph.D. fellowship.Peer reviewe