engleski

Design, synthesis and biological evaluation of compounds as active drugs in the central and peripheral nervous system

Nervous system diseases are caused by the gradual and progressive death of neurons, which in turn leads to dysfunctions of the nervous system and causes problems in the mental and physical functioning of patients. Alzheimer's (AD) and Parkinson's disease and myasthenia gravis are complex neurological disorders currently treated with drugs that inhibit the activity of acetylcholine hydrolyzing enzymes (acetylcholinesterase and butyrylcholinesterase) or are N-methyl-D- aspartate receptor antagonists. However, these drugs act only on the symptoms, not on the course and outcome of the disease. As these are diseases whose development and progression are affected by multiple pathological factors, the pharmaceutical industry and the scientific community have recently made great efforts to find new effective drugs, with a tendency to replace current "single-targeted" drugs with those that act on multi targets – “multi- target-directed ligands” (MTDL). The primary goal of the HRZZ project IP-2020- 02-9343 "Development of bioactive molecules for the treatment of neurodegenerative diseases" is the development of MTDL compounds with the potential to alleviate symptoms and slow down the progression of ND (especially AD). The development of such compounds will have two main goals: the development of compounds active in the central nervous system (CNS) and the development of peripherally active compounds, depending on their ability to cross the blood- brain barrier. Part of the research is focused on the design and synthesis of biscarbamate compounds, structural analogues of resorcinol, as potential cholinesterase's inhibitors. To date, four groups of compounds with different aliphatic and cyclic substituents in the carbamoyl and amino parts of the molecule have been synthesized. Compounds of appropriate purity (>97%) were kinetically evaluated as human cholinesterase inhibitors and proven to be fast inhibitors of both cholinesterases with inhibition rate constants within 106 M-1 min-1. In addition, the tested compounds showed no toxic effect on liver and neuroblastoma cells at concentrations showing an inhibitory effect on cholinesterases, and some were estimated to be able to cross the blood-brain barrier by active transport. The obtained results will enable the definition of guidelines for structural refining of compounds that could be more effective in the treatment of ND than the currently available drugs.

neurodegenerative diseases ; cholinseterases ; carbamates ; 4-aminoquinolines

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