engleski

New naphthoxazole benzylamines synthesized by Buchwald-Hartwig amination from the electrocyclization photoproducts are potential cholinesterase inhibitors

Neurodegenerative disorders like Alzheimers desease (AD) are becoming more frequent. There is no cure, and the available treatment effects are symptomatic. According to cholinergic hypothesis, low levels of neurotransmitter acetylcholine lead to cognitive decline. Inhibition of cholinesterases interrupts the hydrolysis of acetylcholine prolonging its half-life in the synaptic cleft. Compounds that inhibit acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) are so far the best strategy for treatment of AD. The primary physiological role of AChE is the hydrolysis of acetylcholine by which the transmission of nerve impulses in the cholinergic synapses of the central and peripheral nervous system is controlled. The role of related enzyme BChE is not essential, but it is engaged in detoxification (organophosphates and carbamate pesticides, cocaine, aspirin, succinyldicholine, etc.) and bioactivation (bambuterol, heroin, etc.) of xenobiotics, and also serves as a co-regulator of cholinergic neurotransmission i.e., is capable of catalyzing the hydrolysis of acetylcholine. Reversible inhibitors of AChE and BChE like tacrine, donepezil, galantamine and physostigmine, or pseudoirreversible inhibitor like rivastigmine are, or have been used in therapy. Various naphthoxazoles have been previously investigated as potential antibacterial, antituberculosis, and anticancer agents. On the other side, aryl amines are very important compounds in organic synthesis because of their role in pharmaceutical industry and they are present in many natural products and druglike substances. Herein, we synthesized a series of new naphthoxazole benzylamines by Buchwald-Hartwig amination from the photoproducts obtained by efficient photochemical electrocyclization reaction. New compounds were tested as inhibitors of both human AChE and BChE. IC50 values were determined to be 28-160 µM for BChE. However, the compounds inhibited maximally 20% of AChE activity at the highest concentration (100 µM) possible to test, and the IC50 for AChE could not be determined. Therefore, the tested compounds exhibit selectivity for binding to BChE and such could be used for further development of cholinesterase selective inhibitors.

acetylcholinesterase, butyrylcholinesterase, reversible inhibitors, neurodegenerative disorders, naphthoxazole benzylamines

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