N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Analogues: Novel Acetyl- and Butyrylcholinesterase inhibitors
The result's identifiers
Result code in 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>
Alternative codes found
RIV/00216275:25310/20:39916319
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide Analogues: Novel Acetyl- and Butyrylcholinesterase inhibitors
Original language description
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'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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Current Topics in Medicinal Chemistry
ISSN
1568-0266
e-ISSN
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Volume of the periodical
20
Issue of the periodical within the volume
23
Country of publishing house
NL - THE KINGDOM OF THE NETHERLANDS
Number of pages
12
Pages from-to
2094-2105
UT code for WoS article
000581020300007
EID of the result in the Scopus database
2-s2.0-85092743236