engleski

Design, synthesis and biological evaluation of biscarbamates as potent and selective butyrylcholinesterase inhibitors

Recent findings on the role of butyrylcholinesterase in symptom progression and pathophysiology of Alzheimer's disease indicated that the treatment with compounds with the ability to inhibit butyrylcholinesterase may be a new therapeutic strategy in the regulation of brain acetylcholine levels and consequently long-term stabilisation of cognitive and behavioural symptoms in advanced stages of Alzheimer`s disease. Biscarbamate bambuterol is a known potent and selective inhibitor of butyrylcholinesterase. We synthesized nine biscarbamates modelled after the bambuterol scaffold. Two of these carbamates, bisdimethyl carbamates with carbamate groups in ortho- position on the benzene ring were 20-200 times less potent butyrylcholinesterase inhibitors than bambuterol, meaning that the meta-position of carbamate groups on the benzene ring is needed for an easier entrance of biscarbamates and its orientation into the active site of butyrylcholinesterase. Retaining the meta- position of carbamate groups, we synthesised seven biscarbamates where various substituents at the carbamoyl and amino part were introduced. All seven biscarbamates were potent butyrylcholinesterase inhibitors with inhibition rate constants in the same order of magnitude as for bambuterol. Compounds with a cyclopentyl ring or dimethyl groups in the carbamoyl part of the molecule showed about a 200-1000 times higher selectivity towards butyrylcholinesterase compared to acetylcholinesterase. The lipophilicity of all seven biscarbamates was higher than that of bambuterol, which increases their chance as a potential central nervous system active drug. We further determined the cytotoxic effect of synthesised carbamates on HepG2 and SH-SY5Y cell lines to determine the possible limits for in vivo application. Results on cytotoxicity screening showed that both cell lines are almost equally sensitive to the tested carbamates. The lowest cytotoxicity was that of a carbamate with a cyclopentyl ring in the carbamoyl and diethylpentyl substituent on the amino part, the most selective compound.

biscarbamates ; butyrylcholinesterase ; Alzheimer's disease ; bambuterol

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