Novel Lawsone-Quinoxaline Hybrids as New Dual Binding Site Acetylcholinesterase Inhibitors.

A new family of lawsone-quinoxaline hybrids was designed, synthesized, and evaluated as dual binding site cholinesterase inhibitors (ChEIs). In vitro tests revealed that compound 6d was the most potent AChEI (IC 50 = 20 nM) and BChEI (IC 50 = 220 nM). The compound 6d did not show cytotoxicity against the SH-SY5Y neuronal cells (GI 50 > 100 μM). In silico and enzyme kinetic experiments demonstrated that compound 6d bound to both the catalytic anionic site and the peripheral anionic site of Hu AChE. The lawsone-quinoxaline hybrids exhibited potential for further development of potent acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.