A set of 25 novel, silicon-based carbamate derivatives as potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors was synthesized and characterized by their in vitro inhibition profiles and the selectivity indexes (SIs). The prepared compounds were also tested for their inhibition potential on photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. In fact, some of the newly prepared molecules revealed comparable or even better inhibitory activities compared to the marketed drugs (rivastigmine or galanthamine) and commercially applied pesticide Diuron®, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (2) and benzyl N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (3) were characterized by fairly high selective indexes. Specifically, compound 2 was prescribed with the lowest IC50 value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules 3 and benzyl-N-[(1S)-2-[(tert-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (4) are in line with rivastigmine activity. Moreover, a structure–activity relationship (SAR)-driven similarity evaluation of the physicochemical properties for the carbamates examined appeared to have foreseen the activity cliffs using a similarity–activity landscape index for BChE inhibitory response values. The ‘indirect’ ligand-based and ‘direct’ protein-mediated in silico approaches were applied to specify electronic/steric/lipophilic factors that are potentially valid for quantitative (Q)SAR modeling of the carbamate analogues. The stochastic model validation was used to generate an ‘average’ 3D-QSAR pharmacophore pattern. Finally, the target-oriented molecular docking was employed to (re)arrange the spatial distribution of the ligand property space for BChE and photosystem II (PSII).
Tertiary amines 3-(dialkylamino)-2-hydroxypropyl 4-[(alkoxycarbonyl)amino]benzoates and their quaternary ammonium salts were synthesized. The final step of synthesis of quaternary ammonium salts was carried out by microwave-assisted synthesis. Software-calculated data provided the background needed to compare fifteen new resulting compounds by their physicochemical properties. The acid dissociation constant (pKa) and lipophilicity index (log P) of tertiary amines were determined; while quaternary ammonium salts were characterized by software-calculated lipophilicity index and surface tension. Biological evaluation aimed at testing acetylcholinesterase and butyrylcholinesterase-inhibiting activity of synthesized compounds. A possible mechanism of action of these compounds was determined by molecular modelling study using combined techniques of docking; molecular dynamics simulations and quantum mechanics calculations.
Abstract:Nine new dihydrochloride salts of 3-(4-arylpiperazin-1-yl)-2-hydroxypropyl 4-alkoxyethoxybenzoates were designed and synthesized. The physicochemical properties such as lipophilicity index (log k w ) and dissociation constant (pK a ) were experimentally determined and compared to the software calculated data. The lipophilicity index was determined by means of reversed-phase high performance liquid chromatography (RP-HPLC). The pK a values were determined by means of capillary zone electrophoresis. The "drug-likeness" properties according to the Lipinski Rule of Five and prediction of possible blood-brain barrier penetration were computed and discussed.
The paper extends
applicability of the internal standard method
published in 2009 (Fuguet E.
et al.
,
J. Chromatogr.
A
2009,
1216
(17), 3646). Although
the original capillary zone electrophoresis method was suggested to
determine thermodynamic acidity constants of compounds sparingly soluble
in aqueous solutions by carrying out only runs at two different pH
values (
i.e.
, without the need to perform many experiments
over the appropriate pH range including the form of a low-ionized
analyte), we proved that the approach also virtually overcomes any
interactions of the analyte in mixed solvents, so that the experiments
can be carried out in a methanol–water buffer where the solubility
is much better. Applicability of the extended method is illustrated
on six selected β-blockers.
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