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

Acetylcholinesterase has important role in synaptic cleft. It breaks down the acetylcholineatcholinergic synapsesand terminates the cholinergic effects. Some chemical agents likeorganophosphorus compounds (OPCs) including nerve agents and pesticides react withacetylcholinesteraseirreversibly. They inhibit normal biological enzyme action and resultin accumulation of acetylcholineand show toxic effects andcholinergic symptoms. Theprocess of Acetylcholinesterase (AChE) inhibition can be reversed by a nucleophilic agentto dephosphorylate and reactivate the enzyme. In this study, design and docking studies of 15novel nitrone based onoximes as reactivators were performed by using AutoDock program.Then, more effective reactivatorsoximes in terms of binding energy and orientation withinthe active site were synthesized and evaluated in-vitro on human AChE (hAChE) inhibited byparaoxon and compared to standard hAChE reactivators (2-PAM and obidoxime). Our resultsused 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.