Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors
Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for A...
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2019-08-01
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Online Access: | https://www.mdpi.com/2218-273X/9/8/379 |
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doaj-fb20ff896efd4e35bc8a5bbdbb1a00d42020-11-25T02:25:26ZengMDPI AGBiomolecules2218-273X2019-08-019837910.3390/biom9080379biom9080379Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase InhibitorsBarbora Svobodova0Eva Mezeiova1Vendula Hepnarova2Martina Hrabinova3Lubica Muckova4Tereza Kobrlova5Daniel Jun6Ondrej Soukup7María Luisa Jimeno8José Marco-Contelles9Jan Korabecny10Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech RepublicDepartment of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech RepublicDepartment of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech RepublicDepartment of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech RepublicDepartment of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech RepublicDepartment of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech RepublicDepartment of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech RepublicDepartment of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech RepublicCentro de Química Orgánica “Lora-Tamayo” (CSIC), C/Juan de la Cierva 3, 28006-Madrid, SpainLaboratory of Medicinal Chemistry, Institute of General Organic Chemistry, Juan de la Cierva 3, 28006-Madrid, SpainDepartment of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech RepublicTacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes.https://www.mdpi.com/2218-273X/9/8/379tacrinebis(7)-tacrine6-chlorotacrine7-methoxytacrinesquaramidesAlzheimer’s diseasecholinesterasesin vitroin silico |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Barbora Svobodova Eva Mezeiova Vendula Hepnarova Martina Hrabinova Lubica Muckova Tereza Kobrlova Daniel Jun Ondrej Soukup María Luisa Jimeno José Marco-Contelles Jan Korabecny |
spellingShingle |
Barbora Svobodova Eva Mezeiova Vendula Hepnarova Martina Hrabinova Lubica Muckova Tereza Kobrlova Daniel Jun Ondrej Soukup María Luisa Jimeno José Marco-Contelles Jan Korabecny Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors Biomolecules tacrine bis(7)-tacrine 6-chlorotacrine 7-methoxytacrine squaramides Alzheimer’s disease cholinesterases in vitro in silico |
author_facet |
Barbora Svobodova Eva Mezeiova Vendula Hepnarova Martina Hrabinova Lubica Muckova Tereza Kobrlova Daniel Jun Ondrej Soukup María Luisa Jimeno José Marco-Contelles Jan Korabecny |
author_sort |
Barbora Svobodova |
title |
Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors |
title_short |
Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors |
title_full |
Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors |
title_fullStr |
Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors |
title_full_unstemmed |
Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors |
title_sort |
exploring structure-activity relationship in tacrine-squaramide derivatives as potent cholinesterase inhibitors |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2019-08-01 |
description |
Tacrine was the first drug to be approved for Alzheimer’s disease (AD) treatment, acting as a cholinesterase inhibitor. The neuropathological hallmarks of AD are amyloid-rich senile plaques, neurofibrillary tangles, and neuronal degeneration. The portfolio of currently approved drugs for AD includes acetylcholinesterase inhibitors (AChEIs) and <i>N</i>-methyl-<span style="font-variant: small-caps;">d</span>-aspartate (NMDA) receptor antagonist. Squaric acid is a versatile structural scaffold capable to be easily transformed into amide-bearing compounds that feature both hydrogen bond donor and acceptor groups with the possibility to create multiple interactions with complementary sites. Considering the relatively simple synthesis approach and other interesting properties (rigidity, aromatic character, H-bond formation) of squaramide motif, we combined this scaffold with different tacrine-based derivatives. In this study, we developed 21 novel dimers amalgamating squaric acid with either tacrine, 6-chlorotacrine or 7-methoxytacrine representing various AChEIs. All new derivatives were evaluated for their anti-cholinesterase activities, cytotoxicity using HepG2 cell line and screened to predict their ability to cross the blood-brain barrier. In this contribution, we also report in silico studies of the most potent AChE and BChE inhibitors in the active site of these enzymes. |
topic |
tacrine bis(7)-tacrine 6-chlorotacrine 7-methoxytacrine squaramides Alzheimer’s disease cholinesterases in vitro in silico |
url |
https://www.mdpi.com/2218-273X/9/8/379 |
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