The misuse of novichok agents in assassination attempts has been reported in the international media since 2018. These relatively new class of neurotoxic agents is claimed to be more toxic than the agents of the G and V series and so far, there is no report yet in literature about potential antidotes against them. To shed some light into this issue, we report here the design and synthesis of NTMGMP, a surrogate of A-242 and also the first surrogate of a novichok agent useful for experimental evaluation of antidotes. Furthermore, the efficiency of the current commercial oximes to reactivate NTMGMP-inhibited acetylcholinesterase (AChE) was evaluated. The Ellman test was used to confirm the complete inhibition of AChE, and to compare the subsequent rates of reactivation in vitro as well as to evaluate aging. In parallel, molecular docking, molecular dynamics and MM-PBSA studies were performed on a computational model of the human AChE (HssAChE)/NTMGMP complex to assess the reactivation performances of the commercial oximes in silico. Experimental and theoretical studies matched the exact hierarchy of efficiency and pointed to trimedoxime as the most promising commercial oxime for reactivation of AChE inhibited by A-242.

Chemical Engineering Department Military Institute of Engineering Rio de Janeiro Brazil

Department of Chemistry Faculty of Science University of Hradec Kralove Hradec Kralove Czech Republic

Federal Institute of Education Science and Technology of Espírito Santo Units Vila Velha and Vitória Vitória ES Brazil

Federal University of Espírito Santo Unit Goiabeiras Vitória ES Brazil

Institute of Chemical Biological Radiological and Nuclear Defense Rio de Janeiro Brazil

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

Université de Québec INRS Centre Armand Frappier Santé Biotechnologie Laval Québec H7V 1B7 Canada

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