engleski

Heterocyclic carbamates as potential drugs for the treatment of the neurodegenrative diseases

Neurodegenerative diseases (ND) affect more than 50 million people worldwide and that number is growing every day. The treatment of NDs related to the changes in neurotransmitter acetylcholine levels or acetylcholine receptors in neurons such as Alzheimer`s disease (AD), Parkinson's disease (PD) and Myasthenia gravis (MG), respectively, is based on the use of compounds that decrease or inhibit the action of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes capable of hydrolysing acetylcholine. Four cholinesterase inhibitors approved for the treatment of NDs, rivastigmine and physostigmine for the treatment of AD and PD, and neostigmine and pyridostigmine for the treatment of MG, are heterocyclic carbamates. These drugs generally alleviate the symptoms of the disease but do not affect the development, course and final outcome of the disease. The mechanism of action of carbamates and cholinesterases is similar to the mechanism of action of AChE and its physiological substrate acetylcholine ; the difference lies in the stability of the carbamylated AChE which decarbamylates more slowly than its acetylated AChE counterpart. Since heterocyclic carbamates are an integral part of ND drugs that show significant positive effects on cognitive symptoms, and due to their chemical and proteolytic stability, the ability to cross cell membranes and create favourable intra- and inter- molecular drug-target interactions, great efforts have been made to develop new heterocyclic carbamates with improved features like effect on the course of AD and lesser side effects and find those that can act on the outcome of the disease. We designed and synthesised heterocyclic biscarbamates using resorcinole as a structural scaffold. From a five-step synthetic pathway, starting from 3, 5- dihidoxyacetophenone, we successfully synthesised five groups of heterocyclic biscarbamates with different aliphatic and cyclic substituents on the carbamoyl and amino parts of the molecule. To date, six structurally diverse biscarbamates were biologically evaluated as human AChE and BChE inhibitors. All of the tested biscarbamates proved to be very fast inhibitors of both cholinesterases with an inhibition rate constant within 106 M-1 min-1, where biscarbamate 6P, with cyclopentyl in the carbamoyl moiety and tert-pentylamine in the amino moiety, showed a 1000-fold higher selectivity for BChE. Based on the structure of the biscarbamates that will show the highest inhibition potential towards AChE and/or BChE or higher selectivity for AChE or BChE, their monocarbamate derivates will be synthesized and biologically evaluated. Also, the effect of heterocyclic biscarbamates on other hallmarks of NDs such as Aβ aggregation, oxidative stress and bimetal dyshomeostasis will be examined.

central nervous system diseases ; heterocyclic carbamates ; cholinesterases

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