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

摘要: BACKGROUND Development of acetyl- (AChE) and butyrylcholinesterase (BuChE) inhibitors belongs to viable strategies for the treatment dementia other diseases related decrease in cholinergic neurotransmission. OBJECTIVE That is why we designed twenty-two analogues a dual AChEBuChE salicylanilide inhibitor, N-[3,5-bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide 1, 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 core analogues. The derivatives were evaluated vitro against AChE from electric eel BuChE equine serum spectrophotometric Ellman's method. RESULTS compounds showed moderate inhibition both IC50 18.2 196.6 μmol.L-1 9.2 196.2 μmol.L-1, respectively. Importantly, based on substitution pattern, it possible modulate selectivity or some also produced balanced inhibition. In general, most promising N-alkyl (C2-C6) isomers changed position phenolic hydroxyl. N-[3,5-Bis(trifluoromethyl)phenyl]-3-bromo-5- hydroxybenzamide 4a was best inhibitor cholinesterases. CONCLUSION A wide range improved activity hit they superior carbamate drug rivastigmine them BuChE. fit physicochemical space structural features CNS drugs together an escalated lipophilicity.