Design, synthesis and evaluation of cholinesterase hybrid inhibitors using a natural steroidal alkaloid as precursor

Abstract

To date, Alzheimers disease is the most alarming neurodegenerative disorder worldwide. This illness is multifactorialin nature and cholinesterase inhibitors have been the ones used in clinical treatments. In this context,many of these drugs selectively inhibit the acetylcholinesterase enzyme interacting in both the active site and theperipheric anionic site. Besides, some agents have exhibited extensive benefits being able to co-inhibitbutyrylcholinesterase.In this contribution, a strategy previously explored by numerous authors is reported; the synthesis of hybridcholinesterase inhibitors. This strategy uses a molecule of recognized high inhibitory activity (tacrine) togetherwith a steroidal alkaloid of natural origin using different connectors. The biological assays demonstrated theimprovement in the inhibitory activity compared to the alkaloidal precursor, together with the reinforcement ofthe interactions in multiple sites of the enzymatic cavity. This strategy should be explored and exploited in thisarea.Docking and molecular dynamic studies were performed to explain enzyme-ligand interactions, assisting astructure activity relationship analysis.