Design, synthesis and biological evaluation of cyclic biscarbamates as selective butyrylcholinesterase inhibitors in the treatment of Alzheimer`s disease (CROSBI ID 720504)
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Podaci o odgovornosti
Matošević, Ana ; Knežević, Anamarija ; Maraković, Nikola ; Kovarik, Zrinka ; Bosak, Anita
engleski
Design, synthesis and biological evaluation of cyclic biscarbamates as selective butyrylcholinesterase inhibitors in the treatment of Alzheimer`s disease
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease characterized by a progressive loss of memory, cognitive function and behavioural changes. Currently, the most successful strategy in AD treatment is increasing the concentration of the neurotransmitter acetylcholine in the brain by inhibiting enzymes responsible for its hydrolysis, acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In the middle and late stages of AD, the activity of BChE increases, indicating that selective inhibition of BChE could be a new approach in the treatment of AD. With the aim to determine new drug candidates for the treatment of AD as selective inhibitors for BChE, we used bambuterol, a potent and selective inhibitor of BChE in use as a bronchodilator, as a structural basis for the design of new biscarbamates able to cross the blood-brain barrier acting additionally also as antioxidants by chelating bio-metals. Starting from 3, 5- dihidoxyacetophenone and using a five-step synthetic pathway, we obtained eight biscarbamates with pyrolidine, piperidine or methylphenyl in carbamoyl and various substituents on the amino part of the molecule. The biscarbamates were obtained at 10-70 % yield as oils. Their structures were confirmed with NMR and HRMS spectra. The purity was determined by HPLC and was higher than 95%. We evaluated their inhibition potency toward cholinesterases, AChE and BChE and their metal chelating abillity. All of the tested biscarbamates proved to be very fast inhibitors of both cholinesterases, AChE and BChE with inhibition rate constants within 103-106 M-1 min-1 range. The highest selectivity for BChE over AChE was determined for the biscarbamate with pyrolidine in the carbamoyl and tert-pentylamine in the amino part of the molecule, inhibiting BChE 1000-fold faster than AChE. The inhibition potential and selectivity were analysed by molecular docking studies. The in silico evaluated ability of compounds to cross the blood–brain barrier (BBB) showed that three biscarbamates should to be able to cross the BBB by active transport. All eight biscarbamates are chelators of biometals Zn, Fe and Cu and thus they could have the ability to reduce the neurotoxic effects of biometal imbalances. This study pointed out biscarbamates with a cyclic carbamoyl group as a good structural motif for the development of more effective drugs for the treatment of middle and late stages of AD.
biscarbamates ; butyrylcholinesterase ; inhibition ; Alzheimer’s disease
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Podaci o prilogu
85-86.
2022.
objavljeno
Podaci o matičnoj publikaciji
Podaci o skupu
41st European School of Medicinal Chemistry (ESMEC 2022)
poster
03.07.2022-07.07.2022
Urbino, Italija