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Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking.

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'(?,?) 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'(?) exhibited slightly more effective AChE inhibitors than in C'(?). 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.

SUBMITTER: Imramovsky A

PROVIDER: S-EPMC6268027 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking.

Imramovsky Ales A Stepankova Sarka S Vanco Jan J Pauk Karel K Monreal-Ferriz Juana J Vinsova Jarmila J Jampilek Josef J

Molecules (Basel, Switzerland) 20120824 9

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 high ...[more]

PMID: 22922284

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Project description:Alzheimer's disease (AD) is a chronic neurodegenerative disease which leads to the gradual loss of neuronal cells. Several hypotheses for AD exists (e.g., cholinergic, amyloid, tau hypotheses, etc.). As per the cholinergic hypothesis, the deficiency of choline is responsible for AD; therefore, the inhibition of AChE is a lucrative therapeutic strategy for the treatment of AD. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine that is essential for cognition and memory. A large non-redundant data set of 2,570 compounds with reported IC50 values against AChE was obtained from ChEMBL and employed in quantitative structure-activity relationship (QSAR) study so as to gain insights on their origin of bioactivity. AChE inhibitors were described by a set of 12 fingerprint descriptors and predictive models were constructed from 100 different data splits using random forest. Generated models afforded R (2), [Formula: see text] and [Formula: see text] values in ranges of 0.66-0.93, 0.55-0.79 and 0.56-0.81 for the training set, 10-fold cross-validated set and external set, respectively. The best model built using the substructure count was selected according to the OECD guidelines and it afforded R (2), [Formula: see text] and [Formula: see text] values of 0.92 ± 0.01, 0.78 ± 0.06 and 0.78 ± 0.05, respectively. Furthermore, Y-scrambling was applied to evaluate the possibility of chance correlation of the predictive model. Subsequently, a thorough analysis of the substructure fingerprint count was conducted to provide informative insights on the inhibitory activity of AChE inhibitors. Moreover, Kennard-Stone sampling of the actives were applied to select 30 diverse compounds for further molecular docking studies in order to gain structural insights on the origin of AChE inhibition. Site-moiety mapping of compounds from the diversity set revealed three binding anchors encompassing both hydrogen bonding and van der Waals interaction. Molecular docking revealed that compounds 13, 5 and 28 exhibited the lowest binding energies of -12.2, -12.0 and -12.0 kcal/mol, respectively, against human AChE, which is modulated by hydrogen bonding, ?-? stacking and hydrophobic interaction inside the binding pocket. These information may be used as guidelines for the design of novel and robust AChE inhibitors.

Dataset Information

Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking.

Publications

Acetylcholinesterase-inhibiting activity of salicylanilide N-alkylcarbamates and their molecular docking.

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