Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors

Abstract

Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and N-methyl-d-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes.

Synthesis of 1-Hydroxy-3-O-Substituted Xanthone Derivatives and their Structure-activity Relationship on Acetylcholinesterase Inhibitory Effect

“…The standard drug, tacrine, was found to inhibit AChE with an IC 50 value of 0.87 µM. The result is in good agreement with the reported value of tacrine against AChE in past literature 20,45 . All the xanthones, 1 and 2a-2r were rstly evaluated for their AChE inhibition activities at a concentration of 45 µM.…”

Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells

“…All receptor structures were prepared by DockPrep function of UCSF Chimera (version 1.4) and converted to pdbqt-files by AutodockTools (v. 1.5.6) [ 62 , 63 ]. Flexible residues selection was based on previous experience with h AChE selecting the spherical region around the binding cavity [ 64 , 65 , 66 ]. Three-dimensional structures of ligands were built by Open Babel (v. 2.3.1), minimized by Avogadro (v 1.1.0), and converted to pdbqt-file format by AutodockTools [ 67 ].…”

High-Throughput Screening and Molecular Dynamics Simulation of Natural Product-like Compounds against Alzheimer’s Disease through Multitarget Approach

“…All of the ligands were individually docked with each of the targeted enzymes as separate docking runs. The grid dimensions for AChE were selected through discovery studio visualizer (BIOVIA) from the attributes of docked ligand (control inhibitor) in its specific target protein and set to 60 × 60 × 60 Å centered at 4.6 × 70.1 × 65.9 Å, whereas grid dimensions for BChE, MAO-A, and MAO-B were set to 33 × 33 × 33 Å centered at 140.1 × 122.2 × 38.9 Å, 126 × 126 × 126 Å centered at 30.9 × 28.8 × 14.9 Å, and 126 × 126 × 126 Å centered at 53.5 × 147.8 × 24.4 Å, respectively, as discussed in previous reports [ 69 , 70 ]. The results were clustered according to the root-mean-square deviation (RMSD) criterion and in the current study we selected the ligands with lower than 3Å RMSD modes between the best docked pose of natural product-like compound and reference inhibitor.…”