Acetylcholinesterase-Inhibiting Activity of Salicylanilide N-Alkylcarbamates and Their Molecular Docking

Ales Imramovsky,Jarmila Vinsova,Jan Vanco,Sarka Stepankova,Juana Monreal-Ferriz,Josef Jampilek,Karel Pauk

doi:10.3390/molecules170910142

Abstract

A series of twenty-five novel salicylanilide N-alkylcarbamates were investigated as potential acetylcholinesterase inhibitors. The compounds were tested for their ability to inhibit acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.). Experimental lipophilicity was determined, and the structure-activity relationships are discussed. The mode of binding in the active site of AChE was investigated by molecular docking. All the discussed compounds expressed significantly higher AChE inhibitory activity than rivastigmine and slightly lower than galanthamine. Disubstitution by chlorine in C'(3,4) of the aniline ring and the optimal length of hexyl-undecyl alkyl chains in the carbamate moiety provided the most active AChE inhibitors. Monochlorination in C'(4) exhibited slightly more effective AChE inhibitors than in C'(3). Generally it can be stated that compounds with higher lipophilicity showed higher inhibition, and the activity of the compounds is strongly dependent on the length of the N-alkyl chain.

Highlights

IntroductionIt is well-known that salicyl-like compounds show ability to inhibit cyclooxygenase (COX) [1]
It is well-known that salicyl-like compounds show ability to inhibit cyclooxygenase (COX) [1].Various carbamates are known as reversible cholinesterase inhibitors [1]
Comprising the catalytic triad Ser200-His440-Glu327, which is located at the bottom of the gorge; (2) an oxyanion hole (OAH) that stabilizes the tetrahedral intermediate binding of the carbamate carbonyl group; (3) an acyl binding site (ABS) that binds the acetyl group of ACh or the alkyl moiety of carbamate inhibitors; (4) an anionic substrate binding site (AS) that contains a small number of negative charges but many aromatic residues, where the quaternary ammonium pole of ACh and of various active site ligands binds through a preferential interaction of quarternary nitrogens or a partial positive charge generated by electron-withdrawing moieties

Summary

Introduction

It is well-known that salicyl-like compounds show ability to inhibit cyclooxygenase (COX) [1]. AChE inhibitors are used in treatment of various neuromuscular disorders and have provided the first generation of drugs for treatment of Alzheimer’s disease (AD) [20], which is a progressive physical disorder that causes increasingly severe impairment in the cognitive and functional ability of individuals suffering from the disease [21]. The progression of this neurodegenerative disease leads to dementia [22]. The specific orientation of the inhibitors in the AChE binding site was suggested using molecular docking

Chemistry

Lipophilicity

In Vitro Evaluation of AChE-Inhibiting Activity

Molecular Docking

Calculation of Lipophilicity

Conclusions