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

Abstract

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 h AChE–OP and two h BChE-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.

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