Synthesis and evaluation of a highly selective cannabidiol amide cholinesterase inhibitor

The therapeutic mechanism for the treatment of Alzheimer's disease (AD) is mainly by inhibiting the activity of cholinesterase (ChE) and increasing the transmission of choline and the function of neurons. In this study, two series of ChE inhibitors (CA1–CA8 and CB1–CB7) were designed and synthesized by the acylation of a cannabinoid (CBD) with bromoacetyl bromide, or the esterification of a CBD with an amino acid. All the synthesized compounds were tested for in vitro activity to evaluate the compounds as AD therapies. Compound CB7 was identified as a potential butyrylcholinesterase (BuChE) inhibitor (IC50 = 0.31 ± 0.09 μM), which did not display toxicity against HepG2 or PC12 cells at 6.25 μM. Compound CB7 showed good antioxidant behavior, effective anti-tyrosinase activity (IC50 = 0.037 ± 0.003 μM), and anti-acetylcholinesterase (AChE) activity (IC50 = 19.73 ± 0.79 μM). Kinetic studies also showed that CB7 can act as a dual inhibitor. These results provide a theoretical basis for the use of the natural product CBD in the design and development of anti-AD drugs.