engleski

Design, synthesis and biological evaluation of biscarbamates as potential selective butyrylcholinesterase inhibitors for the treatment of Alzheimer`s disease

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease that affects more than 50 million people worldwide. Currently, the treatment of AD is based on increasing the concentration of the neurotransmitter acetylcholine in the brain by inhibiting enzymes responsible for its hydrolysis, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Recent findings on the role of BChE in the symptoms progression and pathophysiology of Alzheimer's disease indicated that selective inhibition of BChE can represent a promising pathway in treating AD. With the aim to determine new drug candidates for the treatment of AD as selective inhibitors for BChE, we used bambuterol, a selective inhibitor of BChE , as a structural basis and synthesized 25 biscarbamates with different substituents at the carbamoyl and hydroxyaminoethyl chain and evaluated their inhibition potency toward AChE and BChE. Their cytotoxic profile, ability to cross the BBB by passive transport and to chelate biometals were also evaluated. All biscarbamates proved to be very potent inhibitors of AChE and BChE with inhibition rate constants up to 106 M­1 min­1, with generally higher preference to BChE. The inhibition potential and selectivity were analysed by molecular docking as well. For three biscarbamates, it was determined that they should be able to pass the BBB by passive transport, while for nine biscarbamates this ability was slightly limited. Twenty­one biscarbamates were neither hepatotoxic, nephrotoxic nor neurotoxic. All biscarbamates have the ability to chelate at least one of biometals (Zn, Fe and Cu) and thus they could be able to reduce the neurotoxic effects of biometal imbalances. This study pointed out biscarbamates as a promising structural motif for the development of more effective drugs for the treatment of middle and late stages of AD.

biscarbamates ; butyrylcholinesterase ; inhibition ; metal chelating ; Alzheimer’s disease

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