SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors
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 potenti...
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Format: | Article |
Language: | English |
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MDPI AG
2019-10-01
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Series: | International Journal of Molecular Sciences |
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Online Access: | https://www.mdpi.com/1422-0067/20/21/5385 |
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doaj-30c6292c35bb4e59b0e38d4438424014 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andrzej Bak Hana Pizova Violetta Kozik Katarina Vorcakova Jiri Kos Jakub Treml Klara Odehnalova Michal Oravec Ales Imramovsky Pavel Bobal Adam Smolinski Zdeněk Trávníček Josef Jampilek |
spellingShingle |
Andrzej Bak Hana Pizova Violetta Kozik Katarina Vorcakova Jiri Kos Jakub Treml Klara Odehnalova Michal Oravec Ales Imramovsky Pavel Bobal Adam Smolinski Zdeněk Trávníček Josef Jampilek SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors International Journal of Molecular Sciences silicon-based carbamates in vitro cholinesterase inhibition comsa ive-pls molecular docking similarity-activity landscape index |
author_facet |
Andrzej Bak Hana Pizova Violetta Kozik Katarina Vorcakova Jiri Kos Jakub Treml Klara Odehnalova Michal Oravec Ales Imramovsky Pavel Bobal Adam Smolinski Zdeněk Trávníček Josef Jampilek |
author_sort |
Andrzej Bak |
title |
SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors |
title_short |
SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors |
title_full |
SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors |
title_fullStr |
SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors |
title_full_unstemmed |
SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE Inhibitors |
title_sort |
sar-mediated similarity assessment of the property profile for new, silicon-based ache/bche inhibitors |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2019-10-01 |
description |
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 (<i>Spinacia oleracea L.</i>) 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<sup>®</sup>, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl <i>N</i>-[(<i>1S</i>)-2-[(<i>tert</i>-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (<b>2</b>) and benzyl <i>N</i>-[(<i>1S</i>)-2-[(<i>tert</i>-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (<b>3</b>) were characterized by fairly high selective indexes. Specifically, compound <b>2</b> was prescribed with the lowest IC<sub>50</sub> value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules <b>3</b> and benzyl-<i>N</i>-[(<i>1S</i>)-2-[(<i>tert</i>-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (<b>4</b>) 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). |
topic |
silicon-based carbamates in vitro cholinesterase inhibition comsa ive-pls molecular docking similarity-activity landscape index |
url |
https://www.mdpi.com/1422-0067/20/21/5385 |
work_keys_str_mv |
AT andrzejbak sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT hanapizova sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT violettakozik sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT katarinavorcakova sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT jirikos sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT jakubtreml sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT klaraodehnalova sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT michaloravec sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT alesimramovsky sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT pavelbobal sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT adamsmolinski sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT zdenektravnicek sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors AT josefjampilek sarmediatedsimilarityassessmentofthepropertyprofilefornewsiliconbasedachebcheinhibitors |
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spelling |
doaj-30c6292c35bb4e59b0e38d44384240142020-11-24T21:10:45ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-10-012021538510.3390/ijms20215385ijms20215385SAR-mediated Similarity Assessment of the Property Profile for New, Silicon-Based AChE/BChE InhibitorsAndrzej Bak0Hana Pizova1Violetta Kozik2Katarina Vorcakova3Jiri Kos4Jakub Treml5Klara Odehnalova6Michal Oravec7Ales Imramovsky8Pavel Bobal9Adam Smolinski10Zdeněk Trávníček11Josef Jampilek12Institute of Chemistry, University of Silesia, Szkolna 9, 40 007 Katowice, PolandDepartment of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech RepublicInstitute of Chemistry, University of Silesia, Szkolna 9, 40 007 Katowice, PolandDepartment of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech RepublicDivision of Biologically Active Complexes and Molecular Magnets, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic, <email>jiri.kos@upol.cz</email> (J.K.)Department of Molecular Biology and Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech RepublicDepartment of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech RepublicGlobal Change Research Institute CAS, Belidla 986/4a, 60300 Brno, Czech RepublicInstitute of Organic Chemistry and Technology, Faculty of Chemical Technology, University of Pardubice, Studentska 573, 532 10 Pardubice, Czech RepublicDepartment of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho 1, 612 42 Brno, Czech RepublicDepartment of Energy Saving and Air Protection, Central Mining Institute, Plac Gwarkow 1, 40 166 Katowice, PolandDivision of Biologically Active Complexes and Molecular Magnets, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic, <email>jiri.kos@upol.cz</email> (J.K.)Division of Biologically Active Complexes and Molecular Magnets, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, Slechtitelu 27, 783 71 Olomouc, Czech Republic, <email>jiri.kos@upol.cz</email> (J.K.)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 (<i>Spinacia oleracea L.</i>) 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<sup>®</sup>, respectively. Generally, most compounds exhibited better inhibition potency towards AChE; however, a wider activity span was observed for BChE. Notably, benzyl <i>N</i>-[(<i>1S</i>)-2-[(<i>tert</i>-butyldimethylsilyl)oxy]-1-[(2-hydroxyphenyl)carbamoyl]ethyl]-carbamate (<b>2</b>) and benzyl <i>N</i>-[(<i>1S</i>)-2-[(<i>tert</i>-butyldimethylsilyl)oxy]-1-[(3-hydroxyphenyl)carbamoyl]ethyl]-carbamate (<b>3</b>) were characterized by fairly high selective indexes. Specifically, compound <b>2</b> was prescribed with the lowest IC<sub>50</sub> value that corresponds quite well with galanthamine inhibition activity, while the inhibitory profiles of molecules <b>3</b> and benzyl-<i>N</i>-[(<i>1S</i>)-2-[(<i>tert</i>-butyldimethylsilyl)oxy]-1-[(4-hydroxyphenyl)carbamoyl]ethyl]carbamate (<b>4</b>) 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).https://www.mdpi.com/1422-0067/20/21/5385silicon-based carbamatesin vitro cholinesterase inhibitioncomsaive-plsmolecular dockingsimilarity-activity landscape index |