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

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 (σ1R), 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, σ1R and BACE1 highlight relevant drug–protein interactions that may contribute to the development of new disease-modifying drugs. Conclusion: New lipoic-based σ1 agonists endowed with neurogenic, antioxidant, cholinergic and amyloid β-peptide-reducing properties have been discovered for the potential treatment of AD.