Kolic_2026_Eur.J.Med.Chem_313_118895

Organophosphorus compounds (OP), like pesticides and nerve agents, are potent inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) due to the phosphylation of their catalytic serine. Current treatment is limited, as approved oximes lack broad-spectrum efficacy and are poor reactivators of inhibited BChE. An alternative approach is pseudo-catalytic OP bioscavenging in which BChE and an efficient reactivator rapidly degrade OP in circulation, preventing it from reaching target tissues enriched with AChE. As imidazolium oximes were previously identified as potent BChE reactivators, we prepared eight novel N-substituted imidazolium oximes and tested them as reactivators of both human AChE and BChE inhibited by pesticide derivative paraoxon, and nerve warfare agents (sarin, cyclosarin, tabun VX, and five A-series agents). Oxime 3 (1,3-dibenzyl-2-hydroxy (imino)methylimidazolium bromide) was identified as the most potent reactivator, showing nanomolar affinity with native BChE and reactivation efficacy superior to standard oximes for cyclosarin-, sarin-, and tabun-BChE conjugate that was 1400-fold, 20-fold and 40-fold higher, respectively. In human whole blood, 30 microM cyclosarin was pseudo-catalytically decomposed by supplemented BChE and oxime 3, restoring 65% of total cholinesterase activity within 10 min. Although less potent, we identified two oximes capable of reactivating A-230-BChE conjugate. Furthermore, oxime 3 was not toxic to neural SH-SY5Y and hepatic HepG2 cells in concentrations relevant for biological activity. These findings highlight oxime 3 as well as the N,N'-dibenzyl imidazolium scaffold as the most potent BChE reactivators reported to date, providing a critical foundation for the advancement of bioscavenging-based therapies for OP poisoning.