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Molecules 2017, 22(11), 1969; doi:10.3390/molecules22111969

Proline-Based Carbamates as Cholinesterase Inhibitors

1
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech Republic
2
Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
3
Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland
4
Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech Republic
5
Department of Synthesis Chemistry, Faculty of Mathematics, Physics and Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland
6
Global Change Research Institute CAS, Belidla 986/4a, 603 00 Brno, Czech Republic
7
Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic
8
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 832 32 Bratislava, Slovakia
Preliminary results were presented at the 46th Europe Congress on Drug Synthesis and Analysis, Bratislava, Slovakia, 5–8 September 2017 (paper P-68).
*
Authors to whom correspondence should be addressed.
Received: 25 September 2017 / Revised: 28 October 2017 / Accepted: 10 November 2017 / Published: 14 November 2017
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Abstract

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. View Full-Text
Keywords: proline; carbamates; in vitro cholinesterase inhibition; in vitro cytotoxicity assay; CoMSA; IVE-PLS; molecular docking study proline; carbamates; in vitro cholinesterase inhibition; in vitro cytotoxicity assay; CoMSA; IVE-PLS; molecular docking study
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MDPI and ACS Style

Pizova, H.; Havelkova, M.; Bobal, P.; Stepankova, S.; Kauerova, T.; Bak, A.; Kollar, P.; Kozik, V.; Oravec, M.; Imramovsky, A.; Jampilek, J. Proline-Based Carbamates as Cholinesterase Inhibitors. Molecules 2017, 22, 1969.

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