New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases

The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises...

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Autores principales:	Milena Mlakić, Tena Čadež, Danijela Barić, Ivana Puček, Ana Ratković, Željko Marinić, Kornelija Lasić, Zrinka Kovarik, Irena Škorić
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	AChE BChE reactivation heterostilbenes spectroscopy docking Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/5763d45f2b984dcf9de9603574d238fa
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spelling	oai:doaj.org-article:5763d45f2b984dcf9de9603574d238fa2021-11-25T18:39:43ZNew Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases10.3390/ph141111471424-8247https://doaj.org/article/5763d45f2b984dcf9de9603574d238fa2021-11-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1147https://doaj.org/toc/1424-8247The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by the Wittig reaction, converted to aldehydes by Vilsmeier formylation, and transformed to the corresponding uncharged oximes in very high yields. Eight <i>trans,anti</i>- and <i>trans,syn</i>-isomers of oximes were tested as reactivators of nerve-agent-inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, and in silico evaluated ADME properties regarding lipophilicity and CNS activity, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.Milena MlakićTena ČadežDanijela BarićIvana PučekAna RatkovićŽeljko MarinićKornelija LasićZrinka KovarikIrena ŠkorićMDPI AGarticleAChEBChEreactivationheterostilbenesspectroscopydockingMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1147, p 1147 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	AChE BChE reactivation heterostilbenes spectroscopy docking Medicine R Pharmacy and materia medica RS1-441
spellingShingle	AChE BChE reactivation heterostilbenes spectroscopy docking Medicine R Pharmacy and materia medica RS1-441 Milena Mlakić Tena Čadež Danijela Barić Ivana Puček Ana Ratković Željko Marinić Kornelija Lasić Zrinka Kovarik Irena Škorić New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases
description	The inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) by organophosphates (OPs) as nerve agents and pesticides compromises normal cholinergic nerve signal transduction in the peripheral and central nervous systems (CNS) leading to cholinergic crisis. The treatment comprises an antimuscarinic drug and an oxime reactivator of the inhibited enzyme. Oximes in use have quaternary nitrogens, and therefore poorly cross the brain–blood barrier. In this work, we synthesized novel uncharged thienostilbene oximes by the Wittig reaction, converted to aldehydes by Vilsmeier formylation, and transformed to the corresponding uncharged oximes in very high yields. Eight <i>trans,anti</i>- and <i>trans,syn</i>-isomers of oximes were tested as reactivators of nerve-agent-inhibited AChE and BChE. Four derivatives reactivated cyclosarin-inhibited BChE up to 70% in two hours of reactivation, and docking studies confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on the moderate binding affinity of both AChE and BChE for all selected oximes, and in silico evaluated ADME properties regarding lipophilicity and CNS activity, these compounds present a new class of oximes with the potential for further development of CNS-active therapeutics in OP poisoning.
format	article
author	Milena Mlakić Tena Čadež Danijela Barić Ivana Puček Ana Ratković Željko Marinić Kornelija Lasić Zrinka Kovarik Irena Škorić
author_facet	Milena Mlakić Tena Čadež Danijela Barić Ivana Puček Ana Ratković Željko Marinić Kornelija Lasić Zrinka Kovarik Irena Škorić
author_sort	Milena Mlakić
title	New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases
title_short	New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases
title_full	New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases
title_fullStr	New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases
title_full_unstemmed	New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases
title_sort	new uncharged 2-thienostilbene oximes as reactivators of organophosphate-inhibited cholinesterases
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5763d45f2b984dcf9de9603574d238fa
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New Uncharged 2-Thienostilbene Oximes as Reactivators of Organophosphate-Inhibited Cholinesterases

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