In the present study, 23 novel carvacrol derivatives involving the amide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and tested in vitro as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. 2-(5-Isopropyl-2-methylphenoxy)-N-(quinolin-8-yl)acetamide (5v) revealed the highest inhibition properties against AChE and BuChE with the IC50 values of 1.93 and 0.05 µM, respectively. The blood-brain barrier (BBB) permeability of the potent inhibitor (5v) was also assessed by the widely used parallel artificial membrane permeability assay (PAMPA-BBB). The results showed that 5v is capable of crossing the BBB. Pharmacokinetic and toxicity profiles of the studied molecule predictions were investigated by MetaCore/MetaDrug comprehensive systems biology analysis suite. Bioactive conformations of the synthesized molecules, their predicted binding energies as well as structural and dynamical profiles of molecules at the binding pockets of AChE and BuChE targets were also investigated using different docking algorithms and molecular dynamics (MD) simulations.Communicated by Ramaswamy H. Sarma.
Keywords: Acetylcholinesterase; Alzheimer’s disease; butyrylcholinesterase; carvacrol; molecular docking; molecular dynamics (MD) simulations.