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 (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.
Keywords: AChE; AD; Alzheimer's disease; BACE1; N,N-dibenzyl(N-methyl)amine; N-benzylpiperidine; acetylcholinesterase; lipoic acid; multi-target directed ligands; neurogenic properties; β-secretase-1; σ-1 receptor; σ1R.