Synthesis novel bis-Coumarin derivatives as potential acetylcholinestrase inhibitors: An in vitro, molecular docking, and molecular dynamics simulations study

Alzheimer's disease is an irreversible and progressive brain disorder that slowly destroys memory and thinking skills and ultimately the ability to do the simplest things and can lead to death. Cholinesterases (ChEs) play an important role in controlling cholinergic transmission, and subsequently, by inhibiting CHEs, acetylcholine levels in the brain are elevated. Coumarins have been shown to exhibit the inhibitory effect of cholinesterase, where the aromatic component leads to the design of new candidates that can inhibit Ab accumulation. Hence the present work is an in vitro activity, along with docking and molecular dynamics (MD) simulation studies of synthesized coumarin derivatives, to explore the plausible binding mode of these compounds inside the acetylcholinesterase (AChE) enzyme. The assayed compounds exhibited good inhibitory activity against AChE, with IC50 values ranging from 0.100-0.02µM. In order to better understand the ligand binding site interaction of compounds and the stability of protein-ligand complexes, a molecular docking with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for AChE.  We concluded that coumarin derivatives L14 and L15 were tested, leading to potent and effective AChE inhibitors.