Inhibition of Cholinesterases by Β‐carboline Derivatives

Multiple factors contribute to the development of Alzheimer's disease (AD). The cholinergic hypothesis of AD attributes its symptoms to low concentrations of acetylcholine, a neurotransmitter. Concentrations of acetylcholine can be increased through inhibition of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Novel compounds with β‐carboline core structure were synthesized with an environmentally friendly method and subjected to Ellman's colorimetric enzyme activity assay. The potency of these molecules as cholinesterase inhibitors were compared to galantamine, a drug currently on the market. In general, the tested β‐carbolines showed negligible effect on the activity of AChE, however, they were highly active in the inhibition of BuChE; over 60% of the studied compounds appeared to be a better inhibitor of BuChE than galantamine. Compounds that inhibited BuChE more than 50% in the preliminary screening at the concentration of 10 mM were further assayed in order to determine their IC 50 values. Molecular docking of the most effective compounds in the active site of BuChE, and for comparison of AChE, was also carried out using the Glide module of the Schrodinger package. A few compounds with IC 50 in the nanomolar to low micromolar range have emerged as promising candidates for further lead development.