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Open AccessArticle

Novel Benzene-Based Carbamates for AChE/BChE Inhibition: Synthesis and Ligand/Structure-Oriented SAR Study

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Institute of Chemistry, University of Silesia, Szkolna 9, 40 007 Katowice, Poland
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Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Science and Technology, Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland
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Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
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Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
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Department of Energy Saving and Air Protection, Central Mining Institute, Plac Gwarkow 1, 40 166 Katowice, Poland
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Division of Biologically Active Complexes and Molecular Magnets, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Slechtitelu 27, 78371 Olomouc, Czech Republic
7
Institute of Neuroimmunology, Slovak Academy of Sciences, Dubravska cesta 9, 84510, Bratislava, Slovakia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(7), 1524; https://doi.org/10.3390/ijms20071524
Received: 1 March 2019 / Revised: 19 March 2019 / Accepted: 23 March 2019 / Published: 27 March 2019
(This article belongs to the Special Issue QSAR and Chemoinformatics Tools for Modeling)
A series of new benzene-based derivatives was designed, synthesized and comprehensively characterized. All of the tested compounds were evaluated for their in vitro ability to potentially inhibit the acetyl- and butyrylcholinesterase enzymes. The selectivity index of individual molecules to cholinesterases was also determined. Generally, the inhibitory potency was stronger against butyryl- compared to acetylcholinesterase; however, some of the compounds showed a promising inhibition of both enzymes. In fact, two compounds (23, benzyl ethyl(1-oxo-1-phenylpropan-2-yl)carbamate and 28, benzyl (1-(3-chlorophenyl)-1-oxopropan-2-yl) (methyl)carbamate) had a very high selectivity index, while the second one (28) reached the lowest inhibitory concentration IC50 value, which corresponds quite well with galanthamine. Moreover, comparative receptor-independent and receptor-dependent structure–activity studies were conducted to explain the observed variations in inhibiting the potential of the investigated carbamate series. The principal objective of the ligand-based study was to comparatively analyze the molecular surface to gain insight into the electronic and/or steric factors that govern the ability to inhibit enzyme activities. The spatial distribution of potentially important steric and electrostatic factors was determined using the probability-guided pharmacophore mapping procedure, which is based on the iterative variable elimination method. Additionally, planar and spatial maps of the host–target interactions were created for all of the active compounds and compared with the drug molecules using the docking methodology. View Full-Text
Keywords: benzene-based carbamates; in vitro cholinesterase inhibition; CoMSA; IVE-PLS; molecular docking study benzene-based carbamates; in vitro cholinesterase inhibition; CoMSA; IVE-PLS; molecular docking study
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Bak, A.; Kozik, V.; Kozakiewicz, D.; Gajcy, K.; Strub, D.J.; Swietlicka, A.; Stepankova, S.; Imramovsky, A.; Polanski, J.; Smolinski, A.; Jampilek, J. Novel Benzene-Based Carbamates for AChE/BChE Inhibition: Synthesis and Ligand/Structure-Oriented SAR Study. Int. J. Mol. Sci. 2019, 20, 1524.

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