Interactions of dye compounds that are structurally related to methylene blue with acetylcholinesterase and butyrylcholinesterase

Abstract

AbstractThe phenothiazine dye, methylene blue, is reported to be an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Inhibitors of these enzymes are established medications for the treatment of Alzheimer's disease, whilst methylene blue has been investigated for its potential to slow cognitive decline in Alzheimer's disease. Based on these observations, 31 dye compounds that are structurally related to methylene blue were evaluated as inhibitors of human AChE and equine BuChE. This study attempted to derive structure–activity relationships for the inhibition of AChE and BuChE by dye compounds, whilst discovering good potency inhibitors amongst the dyes. The results showed that several dyes exhibit good potency AChE (11 compounds) and BuChE (15 compounds) inhibition with IC50 < 10 µM. Methylene green (IC50 = 0.467 µM) and new methylene blue N (IC50 = 0.799 µM) were found to be particularly potent AChE inhibitors, whilst acridine orange (IC50 = 0.220 µM), 1,9‐dimethyl‐methylene blue (IC50 = 0.277 µM), acridine yellow G (IC50 = 0.509 µM), Nile blue (IC50 = 0.678 µM) and pyronin B (IC50 = 0.946 µM) proved to be highly potent BuChE inhibitors. These dye compounds thus exhibit improved inhibition compared to methylene blue [IC50(AChE) = 2.74 μM; IC50(BuChE) = 2.27 μM].