New neurogenic lipoic-based hybrids as innovative Alzheimer's drugs with σ-1 agonism and β-secretase inhibition

et al.[Background]: Neurogenic agents emerge as innovative drugs for the treatment of Alzheimer's disease (AD), whose pathological complexity suggests strengthening research in the multi-target directed ligands strategy. [Results]: By combining the lipoic acid structure with N-benzylpiperidine or N,N-dibenzyl(N-methyl)amine fragments, new multi-target directed ligands were obtained that act at three relevant targets in AD: σ-1 receptor (σR), β-secretase-1 (BACE1) and acetylcholinesterase (AChE). Moreover, they show potent neurogenic properties, good antioxidant capacity and favorable CNS permeability. Molecular modeling studies on AChE, σR and BACE1 highlight relevant drug-protein interactions that may contribute to the development of new disease-modifying drugs. [Conclusion]: New lipoic-based σ agonists endowed with neurogenic, antioxidant, cholinergic and amyloid β-peptide-reducing properties have been discovered for the potential treatment of AD.Financial support from the Spanish Ministry of Economy and Competitiveness (MINECO, grants SAF2012-31035 and SAF2015-64948 to MIRF; grants SAF2010-16365 and SAF2014-52940-R to APC), Fundación de Investigación Médica Mutua Madrileña Automovilística (grant AP103952012 to MIRF), and Consejo Superior de Investigaciones Científicas (CSIC, grant PIE-201580E109 to MIRF) is gratefully acknowledged. ME thanks COLCIENCIAS (Colombia) for a Ph.D. fellowship. ES, and EL and SP thank CESGA (Santiago de Compostela, Spain) and CINECA (Bologna, Italy – Project SIMBIOSY) supercomputer centres, respectively, for providing access to computational resources.Peer Reviewe

New neurogenic lipoic-based hybrids as innovative Alzheimer\u2019s drugs with \u3c3-1 agonism and \u3b2-secretase inhibition

Neurogenic agents emerge as innovative drugs for the treatment of Alzheimer\u2019s disease (AD), whose pathological complexity suggests strengthening research in the multi-target directed ligands strategy. Results: By combining the lipoic acid structure with N-benzylpiperidine or N,N-dibenzyl(N-methyl)amine fragments, new multi-target directed ligands were obtained that act at three relevant targets in AD: \u3c3\u20101 receptor (\u3c31R), \u3b2-secretase\u20101 (BACE1) and acetylcholinesterase (AChE). Moreover, they show potent neurogenic properties, good antioxidant capacity and favorable CNS permeability. Molecular modeling studies on AChE, \u3c31R and BACE1 highlight relevant drug\u2013protein interactions that may contribute to the development of new disease-modifying drugs. Conclusion: New lipoic-based \u3c31 agonists endowed with neurogenic, antioxidant, cholinergic and amyloid \u3b2-peptide-reducing properties have been discovered for the potential treatment of AD