Pyridinium-2-carbaldoximes with quinolinium carboxamide moiety are simultaneous reactivators of acetylcholinesterase and butyrylcholinesterase inhibited by nerve agent surrogates

The pyridinium-2-carbaldoximes with quinolinium carboxamide moiety were designed and synthesised as cholinesterase reactivators. The prepared compounds showed intermediate-to-high inhibition of both cholinesterases when compared to standard oximes. Their reactivation ability was evaluated in vitro on human recombinant acetylcholinesterase (hrAChE) and human recombinant butyrylcholinesterase (hrBChE) inhibited by nerve agent surrogates (NIMP, NEMP, and NEDPA) or paraoxon. In the reactivation screening, one compound was able to reactivate hrAChE inhibited by all used organophosphates and two novel compounds were able to reactivate NIMP/NEMP-hrBChE. The reactivation kinetics revealed compound 11 that proved to be excellent reactivator of paraoxon-hrAChE better to obidoxime and showed increased reactivation of NIMP/NEMP-hrBChE, although worse to obidoxime. The molecular interactions of studied reactivators were further identified by in silico calculations. Molecular modelling results revealed the importance of creation of the pre-reactivation complex that could lead to better reactivation of both cholinesterases together with reducing particular interactions for lower intrinsic inhibition by the oxime.

Automated summary

The designed and synthesised pyridinium-2-carbaldoximes with quinolinium carboxamide moiety showed intermediate-to-high inhibition of both cholinesterases compared to standard oximes. In vitro evaluation revealed their reactivation ability on human recombinant acetylcholinesterase (hrAChE) and human recombinant butyrylcholinesterase (hrBChE), with one compound showing reactivation of all used organophosphates on hrAChE, and two novel compounds able to reactivate NIMP/NEMP-hrBChE. The molecular modelling results highlighted the importance of creating a pre-reactivation complex for better reactivation of both cholinesterases.