Evaluating Quinolines: Molecular Dynamics Approach to Assess Their Potential as Acetylcholinesterase Inhibitors for Alzheimer's Disease

Quinoline represents a promising scaffold for developing potential drugs because of the wide range of biological and pharmacological activities that it exhibits. In the present study, quinoline derivatives obtained from CADMA‐Chem docking protocol were investigated in the mean of molecular dynamics simulations as potential inhibitors of acetylcholinesterase enzyme. The examined species can be partitioned between neutral, dq815 (2,3 dihydroxyl‐quinoline‐4‐carbaldehyde), dq829 (2,3 dihydroxyl‐quinoline‐8‐carboxylic acid methane ester), dq1356 (3,4 dihydroxyl‐quinoline‐6‐carbaldehyde), dq1368 (3,4 dihydroxyl‐quinoline‐8‐carboxylic acid methane ester) and dq2357 (5,6 dihydroxyl‐quinoline‐8‐carboxylic acid methane ester), and deprotonated, dq815_dep, dq829_dep, dq1356_dep and dq2357_dep. Twelve molecular dynamics simulations were performed including those of natural acetylcholine, of the well‐known donepezil inhibitor and of the founder quinoline chosen as reference. Key intermolecular interactions were detected and discussed to describe the different dynamic behavior of all the considered species. Binding energies calculation from MMPBSA well accounts for the dynamic behavior observed in the simulation time proposing dq1368 as promising candidate for the inhibition of acetylcholinesterase. Retrosynthetic route for the production of the investigated compounds is also proposed. A number of dihydroxyl‐quinolines obtained from CADMA‐chem protocol are tested as inhibitors of acetylcholinesterase enzyme, an important target for therapies, in the framework of molecular dynamics simulations. Energetic and structural analysis of the trajectories allow the identification of dq1368 (3,4 dihydroxyl‐quinoline‐8‐carboxylic acid methane ester) as potential new drug. Retrosynthetic route is furthermore proposed.