engleski

Biscarbamates as cholinesterase inhibitors in the treatment of Alzheimer’s disease

Due to their very good chemical and proteolytic stability, ability to penetrate the cell membranes and resemblance to peptide bond, carbamate derivatives have received much attention and get an important role in modern drug discovery and medicinal chemistry Today, carbamate rivastigmine is one of six FDA approved drugs, which improvs the Alzheimer’s disease patient’s condition increasing levels of acetylcholine in the brain by inhibiting acetylcholinesterase Considering the role of butyrylcholinesterase in symptom progression and pathophysiology of Alzheimer’s disease, treatment with compounds with the ability to inhibit both, butyrylcholinesterase and acetylcholinesterase, represents a promising 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 diseaseWe synthesized twenty-seven biscarbamates modelled after the bambuterol, a biscarbamate indicated for the treatment of asthma and known potent and selective inhibitor of butyrylcholinesterase. Two of these carbamates, bisdimethyl carbamates with carbamate gr oups 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[1] Retaining the meta- position of carbamate groups, we synthesised twenty-five biscarbamates where various substituents at the carbamoyl and amino part were introduced All the synthesized biscarbamates displayed a time-dependent inhibition with inhibition rate constants within 10-3 M-1 min-1 range for acetylcholinesterase and 10-6 M-1 min-1 for butyrylcholiesterase All compounds were selective to butyrylcholinesterase compared to acetylcholinesterase The exceptions were compounds 2EN, 6DE and 3EN being more selective to acetylcholinesterase The most selective butyrylcholinesterase inhibitor is compound 6P, which is 1300 times more selective compared to acetylcholinesterase The rates of decarbamylation was deter mined for all of the compounds In addition, as Alzheimer’s disease is a multifactorial disease that involves several pathophysiological changes wher e oxidative stress makes a large part of it, we determined the ability of synthesised compounds to chelate Cu2+, Zn2+ and Fe2+, biometals known to be responsible for oxidative stress by enhancing ROS production and neuronal cell death Generally, all compounds have ability to chelate at least one of biometal and ther efore could provide a more effective defence to maintain oxidative homeostasis Furthermore, since these compounds are considered to be CNS active drugs, we performed an in silico analysis of their physicochemical properties and estimate their ability to cross the blood-brain barrier by passive transport Sixteen compounds should be able to cross the blood-brain barrier by passive transport, while for nine the passage would be limited In conclusion, compound 6P pointed up as the most promising for further evaluation as drug for treatment of Alzheimer’s disease.

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

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