N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Analogues: Novel Acetyl- and Butyrylcholinesterase inhibitors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11160%2F20%3A10418011" target="_blank" >RIV/00216208:11160/20:10418011 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216275:25310/20:39916319

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=YbLXe6WkrI" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=YbLXe6WkrI</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.2174/1568026620666200819154722" target="_blank" >10.2174/1568026620666200819154722</a>

Jazyk výsledku

angličtina

Název v původním jazyce

N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Analogues: Novel Acetyl- and Butyrylcholinesterase inhibitors

Popis výsledku v původním jazyce

Background: Development of acetyl- (AChE) and butyrylcholinesterase (BuChE) inhibitors belongs to viable strategies for the treatment of dementia and other diseases related to decrease in cholinergic neurotransmission. Objective: That is why we designed twenty-two analogues of a dual AChE-BuChE salicylanilide inhibitor, N[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide *1*, to improve its potency. Methods: We prepared N,N-disubstituted (thio)carbamates via direct acylation with (thio)carbamoyl chloride, N-n-alkyl monosubstituted carbamates using isocyanates as well as its salicylanilide core analogues. The derivatives were evaluated in vitro against AChE from electric eel and BuChE from equine serum using spectrophotometric Ellman&apos;s method. Results: The compounds showed moderate inhibition of both AChE and BuChE with IC50 from 18.2 to 196.6 mu mol.L-1 and 9.2 to 196.2 mu mol.L-1, respectively. Importantly, based on the substitution pattern, it is possible to modulate selectivity against AChE or BuChE and some derivatives also produced a balanced inhibition. In general, the most promising analogues were N-alkyl (C-2-C-6) carbamates and isomers with a changed position of phenolic hydroxyl. N-[3,5-Bis(trrfluoromethyl)phenyl]-3-bromo-5-hydroxybenzamide *4a* was the best inhibitor of both cholinesterases. Conclusion: A wide range of the derivatives improved the activity of the hit *1*, they were superior to carbamate drug rivastigmine against AChE and some of them also against BuChE. The most promising derivatives also fit physicochemical space and structural features for CNS drugs together with an escalated lipophilicity.

Název v anglickém jazyce

N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Analogues: Novel Acetyl- and Butyrylcholinesterase inhibitors

Popis výsledku anglicky

Background: Development of acetyl- (AChE) and butyrylcholinesterase (BuChE) inhibitors belongs to viable strategies for the treatment of dementia and other diseases related to decrease in cholinergic neurotransmission. Objective: That is why we designed twenty-two analogues of a dual AChE-BuChE salicylanilide inhibitor, N[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide *1*, to improve its potency. Methods: We prepared N,N-disubstituted (thio)carbamates via direct acylation with (thio)carbamoyl chloride, N-n-alkyl monosubstituted carbamates using isocyanates as well as its salicylanilide core analogues. The derivatives were evaluated in vitro against AChE from electric eel and BuChE from equine serum using spectrophotometric Ellman&apos;s method. Results: The compounds showed moderate inhibition of both AChE and BuChE with IC50 from 18.2 to 196.6 mu mol.L-1 and 9.2 to 196.2 mu mol.L-1, respectively. Importantly, based on the substitution pattern, it is possible to modulate selectivity against AChE or BuChE and some derivatives also produced a balanced inhibition. In general, the most promising analogues were N-alkyl (C-2-C-6) carbamates and isomers with a changed position of phenolic hydroxyl. N-[3,5-Bis(trrfluoromethyl)phenyl]-3-bromo-5-hydroxybenzamide *4a* was the best inhibitor of both cholinesterases. Conclusion: A wide range of the derivatives improved the activity of the hit *1*, they were superior to carbamate drug rivastigmine against AChE and some of them also against BuChE. The most promising derivatives also fit physicochemical space and structural features for CNS drugs together with an escalated lipophilicity.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Current Topics in Medicinal Chemistry

ISSN

1568-0266

e-ISSN

—

Svazek periodika

20

Číslo periodika v rámci svazku

23

Stát vydavatele periodika

NL - Nizozemsko

Počet stran výsledku

12

Strana od-do

2094-2105

Kód UT WoS článku

000581020300007

EID výsledku v databázi Scopus

2-s2.0-85092743236