engleski

Synthesis and biological evaluation of heterocyclic meta-biscarbamates

Carbamates are a structural part of many drugs for the treatment of various diseases, including neurodegenerative disorders like Alzheimer’s disease (AD). AD is one of the most common causes of mental deterioration in elderly people caused by a loss of cholinergic innervation in the cerebral cortex and characterized by decreased levels of the neurotransmitter acetylcholine in neurons, which has led to the development of AD drugs that inhibit the activity of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The mechanism of action of carbamates and cholinesterases is similar to that of the physiological substrate of AChE, acetylcholine ; the only difference lies in the turnover rate of the enzyme’s activity where the decarbamylation rate is much slower than the deacetylation. We synthesized 17 new heterocyclic bi scarbamates with aliphatic carbamate groups in meta position on the benzene ring and different substituents in the amino part of the molecule. All biscarbamates were potent inhibitors of both cholinesterases with inhibition rate constants within 10^3-10^6 M^-1 min^-1. The most potent BChE inhibitors were ethyl -methyl carbamates with piperidine or adamantylamine in the amino part of the molecule, while the most potent AChE inhibitor was diethyl carbamate with tert- pentylamine. The inhibition potential and selectivity were analysed by molecular docking studies. Nine biscarbamates were determined to possess the ability to penetrate the blood-brain barrier by passive transport, while seven biscarbamates exhibited one deviation from the recommended values for CNS active drugs. Twelve biscarbamates didn’t exhibited hepatotoxicity, nephrotoxicity not neurotoxicity, while five biscarbamates were toxic to at least one of the cell lines at concentrations in which they showed inhibition activity. The ethyl - methyl biscarbamate with piperidine in the amine moiety could be pointed out as the most promising compound for further evaluation and structural modifications for development as a potential AD drug.

Biscarbamates ; Alzheimer’s disease ; acetylcholinesterase ; butyrylcholinesterase

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