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.

Department of Biological and Biochemical Sciences Faculty of Chemical Technology University of Pardubice Studentska 573 532 10 Pardubice Czech Republic

Department of Chemistry Faculty of Science J E Purkinje University Ceske mladeze 8 400 96 Ústi nad Labem Czech Republic

Department of Organic and Bioorganic Chemistry Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 500 05 Hradec Kralove Czech Republic

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