• Something wrong with this record ?

Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors

B. Svobodova, E. Mezeiova, V. Hepnarova, M. Hrabinova, L. Muckova, T. Kobrlova, D. Jun, O. Soukup, ML. Jimeno, J. Marco-Contelles, J. Korabecny,

. 2019 ; 9 (8) : . [pub] 20190819

Language English Country Switzerland

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc20023738

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 N-methyl-d-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.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc20023738
003      
CZ-PrNML
005      
20221024103726.0
007      
ta
008      
201125s2019 sz f 000 0|eng||
009      
AR
024    7_
$a 10.3390/biom9080379 $2 doi
035    __
$a (PubMed)31430943
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a sz
100    1_
$a Svobodova, Barbora $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
245    10
$a Exploring Structure-Activity Relationship in Tacrine-Squaramide Derivatives as Potent Cholinesterase Inhibitors / $c B. Svobodova, E. Mezeiova, V. Hepnarova, M. Hrabinova, L. Muckova, T. Kobrlova, D. Jun, O. Soukup, ML. Jimeno, J. Marco-Contelles, J. Korabecny,
520    9_
$a 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 N-methyl-d-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.
650    _2
$a acetylcholinesterasa $x metabolismus $7 D000110
650    _2
$a butyrylcholinesterasa $x metabolismus $7 D002091
650    _2
$a cholinesterasové inhibitory $x chemická syntéza $x chemie $x farmakologie $7 D002800
650    _2
$a vztah mezi dávkou a účinkem léčiva $7 D004305
650    _2
$a lidé $7 D006801
650    _2
$a kinetika $7 D007700
650    _2
$a molekulární modely $7 D008958
650    _2
$a molekulární struktura $7 D015394
650    _2
$a chinin $x analogy a deriváty $x chemie $x farmakologie $7 D011803
650    _2
$a vztahy mezi strukturou a aktivitou $7 D013329
650    _2
$a takrin $x chemie $x farmakologie $7 D013619
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Mezeiová, Eva $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry, Juan de la Cierva 3, 28006-Madrid, Spain. $7 xx0277560
700    1_
$a Hepnarova, Vendula $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
700    1_
$a Hrabinova, Martina $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
700    1_
$a Muckova, Lubica $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
700    1_
$a Kobrlová, Tereza, $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. $d 1991- $7 xx0277928
700    1_
$a Jun, Daniel $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
700    1_
$a Soukup, Ondrej $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
700    1_
$a Jimeno, María Luisa $u Centro de Química Orgánica "Lora-Tamayo" (CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain.
700    1_
$a Marco-Contelles, José $u Laboratory of Medicinal Chemistry, Institute of General Organic Chemistry, Juan de la Cierva 3, 28006-Madrid, Spain. jlmarco@iqog.csic.es.
700    1_
$a Korabecny, Jan $u Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic. jan.korabecny@fnhk.cz. Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. jan.korabecny@fnhk.cz.
773    0_
$w MED00188737 $t Biomolecules $x 2218-273X $g Roč. 9, č. 8 (2019)
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31430943 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20201125 $b ABA008
991    __
$a 20221024103724 $b ABA008
999    __
$a ok $b bmc $g 1596057 $s 1114414
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2019 $b 9 $c 8 $e 20190819 $i 2218-273X $m Biomolecules $n Biomolecules $x MED00188737
LZP    __
$a Pubmed-20201125

Find record

Citation metrics

Archiving options