Abstract:
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.
journal_name
Curr Top Med Chemjournal_title
Current topics in medicinal chemistryauthors
Krátký M,Jaklová K,Štěpánková Š,Svrčková K,Pflégr V,Vinšová Jdoi
10.2174/1568026620666200819154722subject
Has Abstractpub_date
2020-01-01 00:00:00pages
2094-2105issue
23eissn
1568-0266issn
1873-4294pii
CTMC-EPUB-109312journal_volume
20pub_type
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