Proline-based carbamates as cholinesterase inhibitors
| Autor: | Peter Kollar, Hana Pizova, Michal Oravec, Ales Imramovsky, Pavel Bobal, Tereza Kauerova, Sarka Stepankova, Kozik, Andrzej Bak, Josef Jampilek, Havelkova M |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
in vitro cholinesterase inhibition IVE-PLS in vitro cytotoxicity assay Stereochemistry Molecular Conformation Substituent Pharmaceutical Science carbamates 01 natural sciences Article Analytical Chemistry lcsh:QD241-441 Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound lcsh:Organic chemistry Catalytic Domain Drug Discovery Proline Physical and Theoretical Chemistry proline IC50 Butyrylcholinesterase molecular docking study Cholinesterase Binding Sites biology 010405 organic chemistry Organic Chemistry CoMSA Acetylcholinesterase 0104 chemical sciences Molecular Docking Simulation 030104 developmental biology chemistry Chemistry (miscellaneous) biology.protein Molecular Medicine Cholinesterase Inhibitors Pharmacophore Selectivity Protein Binding |
| Zdroj: | Molecules; Volume 22; Issue 11; Pages: 1969 Molecules, Vol 22, Iss 11, p 1969 (2017) Molecules : A Journal of Synthetic Chemistry and Natural Product Chemistry |
| Popis: | Series of twenty-five benzyl (2S)-2-(arylcarbamoyl)pyrrolidine-1-carboxylates was prepared and completely characterized. All the compounds were tested for their in vitro ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), and the selectivity of compounds to individual cholinesterases was determined. Screening of the cytotoxicity of all the compounds was performed using a human monocytic leukaemia THP-1 cell line, and the compounds demonstrated insignificant toxicity. All the compounds showed rather moderate inhibitory effect against AChE; benzyl (2S)-2-[(2-chlorophenyl)carbamoyl]pyrrolidine-1-carboxylate (IC50 = 46.35 μM) was the most potent agent. On the other hand, benzyl (2S)-2-[(4-bromophenyl)-] and benzyl (2S)-2-[(2-bromophenyl)carbamoyl]pyrrolidine-1-carboxylates expressed anti-BChE activity (IC50 = 28.21 and 27.38 μM, respectively) comparable with that of rivastigmine. The ortho-brominated compound as well as benzyl (2S)-2-[(2-hydroxyphenyl)carbamoyl]pyrrolidine-1-carboxylate demonstrated greater selectivity to BChE. The in silico characterization of the structure–inhibitory potency for the set of proline-based carbamates considering electronic, steric and lipophilic properties was provided using comparative molecular surface analysis (CoMSA) and principal component analysis (PCA). Moreover, the systematic space inspection with splitting data into the training/test subset was performed to monitor the statistical estimators performance in the effort to map the probability-guided pharmacophore pattern. The comprehensive screening of the AChE/BChE profile revealed potentially relevant structural and physicochemical features that might be essential for mapping of the carbamates inhibition efficiency indicating qualitative variations exerted on the reaction site by the substituent in the 3′-/4′-position of the phenyl ring. In addition, the investigation was completed by a molecular docking study of recombinant human AChE. |
| Databáze: | OpenAIRE |
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