Next-generation broad-spectrum reactivators for effective countermeasure against organophosphorus poisoning

Sustained effort has been dedicated to the development of novel cholinesterase reactivators-the only causal antidotes-to counter organophosphorus (OP) intoxication. As more lethal nerve agents-such as A-agents-continue to emerge, the existing arsenal of causal antidotes remains unchanged. Approved oxime reactivators-2-PAM, HI-6, and LüH-6-are restricted by their limited efficacy spectrum, poor blood-brain barrier permeability, and suboptimal pharmacokinetics. The objective of this study is to design, synthesize, and characterize a new class of asymmetric monoquaternary bisoxime reactivators with broad-spectrum reactivation potential, favorable pharmacokinetics, and dual mechanisms of action-cholinesterase reactivation and direct OP compound degradation. In vitro and in vivo experiments identified LG-1795 as the lead candidate with the broadest OP spectrum. The averaged second-order reactivation constant (k_r2) across five hAChE-OP and two hBChE-OP complexes was 16.8 mM^-1 min^-1, surpassing clinical standards. Notably, LG-1795 reactivated both AChE and BChE, a dual activity not previously reported for reactivators. In vivo, LG-1795 restored both cholinesterase enzymes and demonstrated prophylactic efficacy against GB, VX, and PXE following intramuscular administration, preventing symptoms in sarin-poisoned animals. These findings represent a significant advance in antidotal therapy, providing the first evidence that asymmetric monoquaternary bisoximes deliver broad-spectrum efficacy against nerve agents and pesticides while simultaneously targeting both OP-inhibited cholinesterases. The translational potential of LG-1795 supports its further preclinical development as a next-generation countermeasure for both clinical and regulatory use in chemical defense.