New uncharged 2-thienostilbene oximes as reactivators of organophosphate-inhibited cholinesterases
Autor: | Zrinka Kovarik, Ana Ratković, Tena Čadež, Kornelija Lasić, Danijela Barić, Milena Mlakić, Ivana Puček, Irena Škorić, Željko Marinić |
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Jazyk: | chorvatština |
Rok vydání: | 2021 |
Předmět: |
reactivation
spectroscopy Stereochemistry Pharmaceutical Science AChE BChE heterostilbenes docking Article 03 medical and health sciences chemistry.chemical_compound Pharmacy and materia medica 0302 clinical medicine Drug Discovery medicine Butyrylcholinesterase 030304 developmental biology Nerve agent ADME 0303 health sciences Organophosphate Oxime Acetylcholinesterase 3. Good health RS1-441 Chemistry chemistry Docking (molecular) Lipophilicity Medicine Molecular Medicine 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Pharmaceuticals Volume 14 Issue 11 Pharmaceuticals, Vol 14, Iss 1147, p 1147 (2021) |
Popis: | 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 trans,anti- and trans,syn-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. |
Databáze: | OpenAIRE |
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