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 AChEBuChE
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 μmol.L-1 and 9.2 to 196.2 μmol.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 (C2-C6) carbamates and isomers
with a 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.
2-Arachidonoylglycerol mobilization following brief synaptic stimulation in the dorsal lateral striatum requires glutamatergic and cholinergic neurotransmission
