Novel Dual Ligands Targeting Sigma1 Receptor and Acetylcholinesterase Endowed with Antioxidant Properties ^†

Neurodegenerative disorders represent one of the main therapeutic challenges of our time. An effective strategy to counteract such pathologies may be the multitarget-directed ligand approach, and there is a growing interest in the identification of compounds acting simultaneously on diverse biological targets. Our strategy consists in targeting the Acetylcholinesterase (AChE) enzyme along with Sigma1 Receptor (S1R). Indeed, AChE inhibitors have noteworthy pharmacological application in the treatment of neurological disorders manifestations such as Alzheimer’s disease, Parkinson’s disease, and myasthenia gravis. Moreover, S1R agonists have emerged as promising pharmacological tools in the fight against neurodegenerative disorders. We prepared a small compound library endowed with both anti-AChE activity and S1R affinity, combined with antioxidant properties. The new compounds series is characterized by a arylalkylaminoketone scaffold, which bears the structural elements of our developed S1R agonist RC-33, the well-known AChE inhibitor Donepezil and the antioxidant molecule Curcumin. Their affinity and selectivity towards S1R, their inhibition of AChE and their antioxidant profile were determined [1,2,3]. In the present communication we present the structure optimization of hit compounds, with the final aim to achieve viable tools for the treatment of neurodegenerative pathologies.