Naslov
Reversible inhibition of cholinesterases with aromatic N-substituted 2-hydroxyiminoacetamides

Autori
Maraković, Nikola ; Knežević, Anamarija ; Vinković, Vladimir ; Kovarik, Zrinka ; Šinko, Goran

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Book of Abstracts of the Congress of the Croatian Society of Biochemistry and Molecular Biology "The Interplay of Biomolecules", HDBMB 2014 / Katalinić, M. ; Kovarik, Z. - Zagreb : The Croatian Society of Biochemistry and Molecular Biology, 2014, 110-110

ISBN
978-953-95551-5-1

Skup
The Congress of the Croatian Society of Biochemistry and Molecular Biology "The Interplay of Biomolecules", HDBMB 2014

Mjesto i datum
Zadar, Hrvatska, 24.09.2014. - 27.09.2014

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
uncharged ligands; AChE peripheral binding site; AChE/BChE selectivity

Sažetak
Acetylcholinesterase (AChE ; EC 3.1.1.7) and butyrylcholinesterase (BChE ; EC 3.1.1.8) are class of hydrolases that play important role in neurotransmission and biotransformation of xenobiotics. Organophosphorus (OP) nerve agents acting as an irreversible AChE inhibitors represent a persistent threat to general population as a consequence of their use as warfare agents in armed conflicts and terrorist attacks or as pest control agents. Thus, current therapy in case of OP nerve agent poisoning includes reactivation of AChE by quaternary pyridinuim oximes. However, due to their permanent positive charge, these compounds do not readily cross the blood-brain barrier and thus cannot reactivate AChE in central nervous system. We evaluated affinity of AChE and BChE for novel class of centrally acting reactivators derived from previously reported N-substituted 2-hydroxyiminoacetamide scaffold. We introduced a phenyl ring in the structure of N-substituted 2-hydroxyiminoacetames using cinnamyl alcohol as starting compound. 1-phenyl-allylamine was prepared from cinnamyl alcohol in Overman reaction and an azide group was introduced via a three-step process. An azide group has enabled us to prepare more elaborate structures by the well-known copper catalysed azide-alkyne cycloaddition. Novel aromatic N-substituted 2-hydroxyiminoacetamides differ in their AChE peripheral site binding moiety ranging from an azide group to functionalized heterocycles connected with central N-(1-phenylpropyl)-2-hydroxyiminoacetamide scaffold via 1, 2, 3-triazole ring. Structural diversity of new compounds allowed us to determine the importance of ligand peripheral site binding properties for the overall stabilization and binding affinity. Molecular docking studies were performed on all new compounds to help us rationalize observed differences between their binding affinities. Difference in AChE/BChE affinity will indicate whether new compounds are selective ligands of AChE or can be further developed as general type of ligands for both AChE and BChE. These compounds lack a permanent positive charge and, therefore, it is expected for them to cross the blood-brain barrier with greater capacity than quaternary pyridinuim oximes in use.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija

Napomena
This work has been supported in part by the Croatian Science Foundation (project 4307).

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