Multi-Target Quinoxaline Derivatives for Alzheimer's Disease: Inhibitory Activities Against AChE and BACE-1 Enzymes

Abstract

New choline esterase inhibitors and B-secretase inhibitors present promising treatment options for the treatment of Alzheimer's disease (AD). In this study, molecular docking was performed using our chemistry library to discover lead compounds. Molecular docking was employed to predict binding affinities, while molecular dynamics (MD) simulations provided insights into the stability of the ligand-enzyme interactions. To improve the activity, 12 new derivatives were designed and synthesized based on the lead compound obtained. The structures of the synthesized compounds were identified by 1H-NMR,13C-NMR, and HRMS techniques. Their activities on choline esterase enzymes and Beta-secretase 1 enzyme were elucidated through in vitro studies. Compound 4f had an IC50 = 0.026 +/- 0.001 mu. value against the acetylcholinesterase (AChE) enzyme and an IC50 = 0.125 +/- 0.005 mu. value against the BACE-1 enzyme. The excellent activity of compound 4f was supported by molecular docking and MD simulation studies.