The A-series is the most recent generation of chemical warfare nerve agents (CWA) which act directly on the inhibition of the human acetylcholinesterase (HssAChE) enzyme. These compounds lack accurate experimental data on their physicochemical properties, and there is no evidence that traditional antidotes effectively reactivate HssAChE inhibited by them. In the search for potential antidotes, we employed virtual screening, molecular docking, and molecular dynamics (MD) simulations for the theoretical assessment of the performance of a library of Mannich phenols as potential reactivators of HssAChE inhibited by the Novichok agents A-230, A-232, and A-234, in comparison with the commercial oximes pralidoxime (2-PAM), asoxime (HI-6), trimedoxime (TMB-4), and obidoxime. Following the near-attack conformation (NAC) approach, our results suggest that the compounds assessed would face difficulties in triggering the proposed nucleophilic in-line displacement mechanism. Despite this, it was observed that certain Mannich phenols presented similar or superior results to those obtained by reference oximes against A-232 and A-234 model, suggesting that these compounds can adopt more favourable conformations. Additional binding energy calculations confirmed the stability of the model/ligands complexes and the reactivating potential observed in the molecular docking and MD studies. Our findings indicate that the Mannich phenols could be alternative antidotes and that their efficacy should be evaluated experimentally against the A-series CWA.

Department of Chemistry Military Institute of Engineering Rio de Janeiro RJ 22290 270 Brazil

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering 22290 270 Rio de Janeiro RJ Brazil

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering 22290 270 Rio de Janeiro RJ Brazil; Université du Québec INRS Centre Armand Frappier Santé et Biotechnologie 531 Boulevard des Prairies Laval QC Canada; Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanskeho 62 500 03 Hradec Kralove Czech Republic

TNO Department CBRN Protection Lange Kleiweg 137 2288GJ Rijswijk the Netherlands

Université du Québec INRS Centre Armand Frappier Santé et Biotechnologie 531 Boulevard des Prairies Laval QC Canada

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Synthesis and in vitro assessment of the reactivation profile of clinically available oximes on the acetylcholinesterase model inhibited by A-230 nerve agent surrogate