US EPA

6936128 

Journal Article 

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

Bak, A; Smolinski, A; Jampilek, J; Kozik, V; Kozakiewicz, D; Gajcy, K; Strub, D; Swietlicka, A; Stepankova, S; Imramovsky, A; Polanski, J; , 

2019 

Yes 

International Journal of Molecular Sciences
ISSN: 1422-0067
EISSN: 14220067 

MDPI 

BASEL 

20 

7 

English 

30934674 

10.3390/ijms20071524 

WOS:000464980400024 

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. 

Benzene-based carbamates; CoMSA; In vitro cholinesterase inhibition; IVE-PLS; Molecular docking study; (23, benzyl ethyl(1 oxo 1 phenylpropan 2 yl)carbamatecarbamic acid; benzene; benzyl (1 (3 chlorophenyl) 1 oxopropan 2 yl) (methyl)carbamate); benzyl (1 (4 bromophenyl) 1 oxopropan 2 yl)(methyl)carbamate; benzyl ethyl(1 oxo 1 phenylpropan 2 yl)carbamate; benzyl methyl(1 oxo 1 phenylbutan 2 yl)carbamate; carbamic acid; galantamine; methyl (1 (3 chlorophenyl) 1 oxopropan 2 yl)(methyl)carbamate; methyl (1 (4 bromophenyl) 1 oxopropan 2 yl)(methyl)carbamate; methyl (1 (4 chlorophenyl) 1 oxopropan 2 yl)(methyl)carbamate; methyl (1 (4 methoxyphenyl) 1 oxopropan 2 yl)(methyl)carbamate; methyl (1 (benzo[d][1,3]dioxol 5 yl) 1 oxopropan 2 yl)(methyl)carbamate; methyl ethyl(1 oxo 1 phenylbutan 2 yl)carbamate; methyl ethyl(1 oxo 1 phenylpropan 2 yl)carbamate; methyl methyl(1 (naphthalen 2 yl) 1 oxopropan 2 yl)carbamate; methyl methyl(1 oxo 1 (m tolyl)propan 2 yl)carbamate; methyl methyl(1 oxo 1 (p tolyl)propan 2 yl)carbamate; methyl methyl(1 oxo 1 phenylbutan 2 yl)carbamate; naphthalene derivative; phenyl (1 (3 chlorophenyl) 1 oxopropan 2 yl)(methyl)carbamate; phenyl (1 (3,4 dimethylphenyl) 1 oxopropan 2 yl)(methyl)carbamate; phenyl (1 (4 bromophenyl) 1 oxopropan 2 yl)(methyl)carbamate; phenyl ethyl(1 oxo 1 phenylbutan 2 yl)carbamate; phenyl ethyl(1 oxo 1 phenylpropan 2 yl)carbamate; phenyl methyl(1 oxo 1 (m tolyl)propan 2 yl)carbamate; phenyl methyl(1 oxo 1 phenylbutan 2 yl)carbamate; phenyl methyl(1 oxo 1 phenylpentan 2 yl)carbamate; rivastigmine; unclassified drug; unindexed drug; acetylcholinesterase; benzene; carbamic acid derivative; cholinesterase; cholinesterase inhibitor; ligand; Article; binding site; carbon nuclear magnetic resonance; chemical structure; column chromatography; crystallization; DPPH radical scavenging assay; drug design; drug synthesis; electrospray mass spectrometry; enzyme active site; enzyme activity; human; hydrogen bond; IC50; liquid chromatography-mass spectrometry; mathematical model; molecular docking; molecular dynamics; molecular model; pharmacophore; proton nuclear magnetic resonance; stochastic model; structure activity relation; thin layer chromatography; X ray diffraction; animal; chemistry; Electrophorus; horse; metabolism; principal component analysis; probability; synthesis; Acetylcholinesterase; Animals; Benzene; Butyrylcholinesterase; Carbamates; Cholinesterase Inhibitors; Drug Design; Electrophorus; Horses; Inhibitory Concentration 50; Ligands; Molecular Docking Simulation; Principal Component Analysis; Probability; Structure-Activity Relationship