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.

Department of Biological and Biochemical Sciences Faculty of Chemical Technology University of Pardubice Studentska 573 532 10 Pardubice Czech Republic

Department of Chemical Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Palackeho 1 612 42 Brno Czech Republic

Department of Human Pharmacology and Toxicology Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Palackeho 1 612 42 Brno Czech Republic

Department of Pharmaceutical Chemistry Faculty of Pharmacy Comenius University Odbojarov 10 832 32 Bratislava Slovakia

Department of Synthesis Chemistry Faculty of Mathematics Physics and Chemistry University of Silesia Szkolna 9 40 007 Katowice Poland

Global Change Research Institute CAS Belidla 986 4a 603 00 Brno Czech Republic

Institute of Chemistry University of Silesia Szkolna 9 40 007 Katowice Poland

Institute of Organic Chemistry and Technology Faculty of Chemical Technology University of Pardubice Studentska 573 532 10 Pardubice Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc18024488

003      

CZ-PrNML

005      

20180710095255.0

007      

ta

008      

180709s2017 sz f 000 0|eng||

009      

AR

024    7_

$a 10.3390/molecules22111969 $2 doi

035    __

$a (PubMed)29135926

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a sz

100    1_

$a Pizova, Hana $u Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech Republic. pizovah@gmail.com.

245    10

$a Proline-Based Carbamates as Cholinesterase Inhibitors / $c H. Pizova, M. Havelkova, S. Stepankova, A. Bak, T. Kauerova, V. Kozik, M. Oravec, A. Imramovsky, P. Kollar, P. Bobal, J. Jampilek,

520    9_

$a 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.

650    _2

$a acetylcholinesterasa $x chemie $7 D000110

650    _2

$a vazebná místa $7 D001665

650    _2

$a butyrylcholinesterasa $x chemie $7 D002091

650    _2

$a karbamáty $x chemická syntéza $x chemie $x farmakologie $7 D002219

650    _2

$a katalytická doména $7 D020134

650    _2

$a cholinesterasové inhibitory $x chemická syntéza $x chemie $x farmakologie $7 D002800

650    _2

$a molekulární konformace $7 D008968

650    _2

$a simulace molekulového dockingu $7 D062105

650    12

$a prolin $x chemie $7 D011392

650    _2

$a vazba proteinů $7 D011485

650    _2

$a vztahy mezi strukturou a aktivitou $7 D013329

655    _2

$a časopisecké články $7 D016428

700    1_

$a Havelkova, Marketa $u Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech Republic. F14042@vfu.cz.

700    1_

$a Stepankova, Sarka $u Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic. pavelbobal@yahoo.com.

700    1_

$a Bak, Andrzej $u Institute of Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland. sarka.stepankova@upce.cz.

700    1_

$a Kauerova, Tereza $u Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech Republic. tereza.kauerova@gmail.com.

700    1_

$a Kozik, Violetta $u Department of Synthesis Chemistry, Faculty of Mathematics, Physics and Chemistry, University of Silesia, Szkolna 9, 40-007 Katowice, Poland. andrzej.bak@us.edu.pl.

700    1_

$a Oravec, Michal $u Global Change Research Institute CAS, Belidla 986/4a, 603 00 Brno, Czech Republic. kollarp@vfu.cz.

700    1_

$a Imramovsky, Ales $u Institute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech Republic. violetta.kozik@us.edu.pl.

700    1_

$a Kollar, Peter $u Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech Republic. oravec.m@czechglobe.cz.

700    1_

$a Bobal, Pavel $u Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech Republic. ales.imramovsky@upce.cz.

700    1_

$a Jampilek, Josef $u Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 832 32 Bratislava, Slovakia. josef.jampilek@gmail.com.

773    0_

$w MED00180394 $t Molecules (Basel, Switzerland) $x 1420-3049 $g Roč. 22, č. 11 (2017)

856    41

$u https://pubmed.ncbi.nlm.nih.gov/29135926 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y a $z 0

990    __

$a 20180709 $b ABA008

991    __

$a 20180710095545 $b ABA008

999    __

$a ok $b bmc $g 1316619 $s 1021409

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2017 $b 22 $c 11 $e 20171114 $i 1420-3049 $m Molecules $n Molecules $x MED00180394

LZP    __

$a Pubmed-20180709