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J Enzyme Inhib Med Chem. 2020 Dec;35(1):460-467. doi: 10.1080/14756366.2019.1707197.

Design, synthesis and cholinesterase inhibitory properties of new oxazole benzylamine derivatives.

Author information

1
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb, Croatia.
2
Institute for Medical Research and Occupational Health, Biochemistry and Analytic Organic Chemistry Unit, Zagreb, Croatia.
3
TEVA, Pliva Tapi R&D, Zagreb, Croatia.

Abstract

The enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are primary targets in attenuating the symptoms of neurodegenerative diseases. Their inhibition results in elevated concentrations of the neurotransmitter acetylcholine which supports communication among nerve cells. It was previously shown for trans-4/5-arylethenyloxazole compounds to have moderate AChE and BChE inhibitory properties. A preliminary docking study showed that elongating oxazole molecules and adding a new NH group could make them more prone to bind to the active site of both enzymes. Therefore, new trans-amino-4-/5-arylethenyl-oxazoles were designed and synthesised by the Buchwald-Hartwig amination of a previously synthesised trans-chloro-arylethenyloxazole derivative. Additionally, naphthoxazole benzylamine photoproducts were obtained by efficient photochemical electrocyclization reaction. Novel compounds were tested as inhibitors of both AChE and BChE. All of the compounds exhibited binding preference for BChE over AChE, especially for trans-amino-4-/5-arylethenyl-oxazole derivatives which inhibited BChE potently (IC50 in µM range) and AChE poorly (IC50≫100 µM). Therefore, due to the selectivity of all of the tested compounds for binding to BChE, these compounds could be applied for further development of cholinesterase selective inhibitors.HIGHLIGHTSSeries of oxazole benzylamines were designed and synthesisedThe tested compounds showed binding selectivity for BChENaphthoxazoles were more potent AChE inhibitors.

KEYWORDS:

Arylethenyl-oxazole; benzylamine; cholinesterase; electrocyclization; naphthoxazole; synthesis

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