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

doi:10.2174/1568026620666200819154722

Paper

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

Published Aug 19, 2020 · M. Krátký, Karolína Jaklová, Šárka Štěpánková

Current topics in medicinal chemistry

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Abstract

BACKGROUND Development of acetyl- (AChE) and butyrylcholinesterase (BuChE) inhibitors belongs to viable strategies for 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 a moderate inhibition of both AChE and BuChE with IC50 from 18.2 to 196.6 µmol.L-1 and 9.2 to 196.2 µmol.L-1 , respectively. Importantly, based on 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 (C2-C6) carbamates and isomers with changed position of phenolic hydroxyl. N-[3,5- Bis(trifluoromethyl)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.

In Vitro Study

Study Snapshot

N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide 1 analogues show potential as effective acetyl- and butyrylcholinesterase inhibitors, with potential for treating dementia and other cholinergic neurotransmission-related

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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

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