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Title: Novel Benzene-Based Carbamates for AChE/BChE Inhibition: Synthesis and Ligand/Structure-Oriented SAR Study
Authors: Bąk, Andrzej
Kozik, Violetta
Kozakiewicz, Dariusz
Gajcy, Kamila
Strub, Daniel Jan
Świetlicka, Aleksandra
Stepankova, Sarka
Imramovsky, Ales
Polański, Jarosław
Smoliński, Adam
Jampilek, Josef
Keywords: benzene-based carbamates; in vitro cholinesterase inhibition; CoMSA; IVE-PLS; molecular docking study
Issue Date: 2019
Citation: International Journal of Molecular Sciences, Vol. 20, iss. 7 (2019), Art. No.
Abstract: 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 butyrylcompared 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.
DOI: 10.3390/ijms20071524
ISSN: 1422-0067
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