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 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.
Highlights
Several clinically implemented drug and pesticide molecules contain amide (–CONH–) and/or carbamate (–OCONH–) groups that can be variously substituted to form privileged structural fragments [1,2,3,4]
It was observed that the methyl-substituted carbamates generally exhibited a lower inhibitor ability compared to their phenyl or benzyl counterparts
Compounds 17 and 29, which had a methoxy group in the same position, were weaker inhibitors—the presence of the hydrophilic electron-donating -OCH3 substituent of the phenyl ring at the para-position decreased the potency of the compounds, especially against the BChE enzyme
Summary
Several clinically implemented drug and pesticide molecules contain amide (–CONH–) and/or carbamate (–OCONH–) groups that can be variously substituted to form privileged structural fragments [1,2,3,4]. These molecular motifs are able to interact with a wide range of receptors/enzymes to induce a biological response [5,6,7]. 7.35 3.03.885 6.1.358 5.119..21147 3.14.382 7.13.5575 of 26 01.835.93 16.456.8787 115.581.3..462116 11..610.7967 111..85522.31
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