Synthesis, biological evaluation and molecular modeling studies of substituted N-benzyl-2-phenylethanamines as cholinesterase inhibitors

Abstract

In this work, we report the synthesis of a series of derivatives of N-benzyl-2-phenylethanamine which is the framework of norbelladine, the natural common precursor of the Amaryllidaceae alkaloids. These compounds were assessed in the inhibition of both AChE and BChE which are the enzymes responsible for the breakdown of acetylcholine and hence they constitute targets in the palliative treatment of Alzheimer's disease. In particular, brominated derivatives exhibited the lowest IC₅₀ values against AChE. Interestingly, the presence of iodine in one of the aromatic rings highly increased the inhibition of BChE compared to its analogues, with an IC₅₀ value similar to that of galantamine, which is the reference compound currently used in the treatment of AD. A possible mechanism of action for these compounds was determined by molecular modeling studies using combined techniques of docking and molecular dynamics simulations.