Show simple item record
dc.contributor.author |
Kos, Jiri
|
|
dc.contributor.author |
Kozik, Violetta
|
|
dc.contributor.author |
Pindjakova, Dominika
|
|
dc.contributor.author |
Jankech, Timotej
|
|
dc.contributor.author |
Smolinski, Adam
|
|
dc.contributor.author |
Štěpánková, Šárka
|
|
dc.contributor.author |
Hosek, Jan
|
|
dc.contributor.author |
Oravec, Michal
|
|
dc.contributor.author |
Jampilek, Josef
|
|
dc.contributor.author |
Bak, Andrzej
|
|
dc.date.accessioned |
2022-06-03T12:32:46Z |
|
dc.date.available |
2022-06-03T12:32:46Z |
|
dc.date.issued |
2021 |
|
dc.identifier.issn |
1661-6596 |
|
dc.identifier.uri |
https://hdl.handle.net/10195/79351 |
|
dc.description.abstract |
A library of novel 4-{[(benzyloxy)carbonyl]amino}-2-hydroxybenzoic acid amides was designed and synthesized in order to provide potential acetyl- and butyrylcholinesterase (AChE/BChE) inhibitors; the in vitro inhibitory profile and selectivity index were specified. Benzyl(3-hydroxy-4-{[2-(trifluoromethoxy)phenyl]carbamoyl}phenyl)carbamate was the best AChE inhibitor with the inhibitory concentration of IC50 = 36.05 mu M in the series, while benzyl{3-hydroxy-4-[(2-methoxyphenyl)carbamoyl]phenyl}-carbamate was the most potent BChE inhibitor (IC50 = 22.23 mu M) with the highest selectivity for BChE (SI = 2.26). The cytotoxic effect was evaluated in vitro for promising AChE/BChE inhibitors. The newly synthesized adducts were subjected to the quantitative shape comparison with the generation of an averaged pharmacophore pattern. Noticeably, three pairs of fairly similar fluorine/bromine-containing compounds can potentially form the activity cliff that is manifested formally by high structure-activity landscape index (SALI) numerical values. The molecular docking study was conducted for the most potent AChE/BChE inhibitors, indicating that the hydrophobic interactions were overwhelmingly generated with Gln119, Asp70, Pro285, Thr120, and Trp82 aminoacid residues, while the hydrogen bond (HB)-donor ones were dominated with Thr120. pi-stacking interactions were specified with the Trp82 aminoacid residue of chain A as well. Finally, the stability of chosen liganded enzymatic systems was assessed using the molecular dynamic simulations. An attempt was made to explain the noted differences of the selectivity index for the most potent molecules, especially those bearing unsubstituted and fluorinated methoxy group. |
eng |
dc.format |
p. 3444 |
eng |
dc.language.iso |
eng |
|
dc.publisher |
MDPI |
eng |
dc.relation.ispartof |
International Journal of Molecular Sciences, volume 22, issue: April |
eng |
dc.rights |
open access |
eng |
dc.rights.uri |
https://creativecommons.org/licenses/by/4.0/ |
|
dc.subject |
4-aminosalicylanilides |
eng |
dc.subject |
carbamate synthesis |
eng |
dc.subject |
lipophilicity |
eng |
dc.subject |
cholinesterase inhibition |
eng |
dc.subject |
CoMSA |
eng |
dc.subject |
molecular docking |
eng |
dc.subject |
similarity-activity landscape index |
eng |
dc.subject |
4-aminosalicylanilidy |
cze |
dc.subject |
syntéza karbamátů |
cze |
dc.subject |
lipofilita |
cze |
dc.subject |
inhibice cholinesteráz |
cze |
dc.subject |
molekulární docking |
cze |
dc.title |
Synthesis and Hybrid SAR Property Modeling of Novel Cholinesterase Inhibitors |
eng |
dc.title.alternative |
Syntéza a hybridní modelování vlastností SAR nových inhibitorů cholinesteráz |
cze |
dc.type |
article |
eng |
dc.description.abstract-translated |
Byla navržena a syntetizována knihovna nových amidů kyseliny 4-{[(benzyloxy)karbonyl]amino}-2-hydroxybenzoové za účelem poskytnutí potenciálních inhibitorů acetyl- a butyrylcholinesterázy (AChE/BChE); byl specifikován in vitro inhibiční profil a index selektivity. Benzyl(3-hydroxy-4-{[2-(trifluormethoxy)fenyl]karbamoyl}fenyl)karbamát byl nejlepším inhibitorem AChE s inhibiční koncentrací IC50 = 36,05 uM, zatímco benzyl{3-hydroxy-4- [(2-methoxyfenyl)karbamoyl]fenyl}karbamát byl nejúčinnějším inhibitorem BChE (IC50 = 22,23 uM) s nejvyšší selektivitou pro BChE (SI = 2,26). Cytotoxický účinek byl hodnocen in vitro u slibných inhibitorů AChE/BChE. Nově syntetizované adukty byly podrobeny kvantitativnímu srovnání tvaru s vytvořením zprůměrovaného vzoru farmakoforu. Studie molekulárního dokování byla provedena pro nejúčinnější inhibitory AChE/BChE, což ukazuje, že hydrofobní interakce byly v drtivé většině generovány zbytky aminokyselin Gln119, Asp70, Pro285, Thr120 a Trp82, zatímco donor vodíkové vazby (HB) dominoval Thr120. pi-stacking interakce byly specifikovány také s Trp82 aminokyselinovým zbytkem řetězce A. Nakonec byla pomocí molekulárně dynamických simulací hodnocena stabilita vybraných ligandových enzymatických systémů. Byl učiněn pokus vysvětlit zaznamenané rozdíly indexu selektivity pro nejúčinnější molekuly, zejména ty, které nesou nesubstituovanou a fluorovanou methoxyskupinu. |
cze |
dc.peerreviewed |
yes |
eng |
dc.publicationstatus |
published version |
eng |
dc.identifier.doi |
10.3390/ijms22073444 |
|
dc.relation.publisherversion |
https://www.mdpi.com/1422-0067/22/7/3444 |
|
dc.identifier.wos |
000638674200001 |
|
dc.identifier.scopus |
2-s2.0-85103003910 |
|
dc.rights.license |
CC BY 4.0 |
|
dc.identifier.obd |
39886359 |
|
This item appears in the following Collection(s)
Show simple item record
Except where otherwise noted, this item's license is described as open access
|
Search DSpace
Browse
-
All of DSpace
-
This Collection
My Account
|