Docking Studies, Synthesis, and In-vitro Evaluation of Novel Oximes Based on Nitrones as Reactivators of Inhibited Acetylcholinesterase

Document Type: Research article

Authors

1 Department of Chemistry, Faculty of Science, Imam Hossein University, Tehran, Iran.

2 Chemical Injuries Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.

3 Department of Pharmaceutics, Faculty of pharmacy, Baqiyatallah University of Medical Sciences, Tehran, Iran.

4 Department of Biology, Faculty of Science, Imam Hossein University, Tehran, Iran.

Abstract

Acetylcholinesterase has important role in synaptic cleft. It breaks down the acetylcholineat
cholinergic synapsesand terminates the cholinergic effects. Some chemical agents like
organophosphorus compounds (OPCs) including nerve agents and pesticides react with
acetylcholinesteraseirreversibly. They inhibit normal biological enzyme action and result
in accumulation of acetylcholineand show toxic effects andcholinergic symptoms. The
process of Acetylcholinesterase (AChE) inhibition can be reversed by a nucleophilic agent
to dephosphorylate and reactivate the enzyme. In this study, design and docking studies of 15
novel nitrone based onoximes as reactivators were performed by using AutoDock program.
Then, more effective reactivatorsoximes in terms of binding energy and orientation within
the active site were synthesized and evaluated in-vitro on human AChE (hAChE) inhibited by
paraoxon and compared to standard hAChE reactivators (2-PAM and obidoxime). Our results
used to design new derivatives of Oxim with better efficacy than 2-PAM and obidoxime.
Syntheses of some selected bis-pyridiniumoximes based on the nitrones are underway.

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