The primary toxicological mechanism of organophosphorus compounds (OPCs) is the irreversible inhibition of acetylcholinesterase (AChE), leading to the accumulation of acetylcholine and subsequent cholinergic crisis, which can result in fatal respiratory failure. Conventional oxime reactivators, such as pralidoxime and obidoxime, are limited by their inability to permeate the blood-brain barrier (BBB) and inconsistent efficacy across different OPC types. To address these limitations, we designed a novel non-quaternary oxime reactivator codenamed K1396, with enhanced lipophilicity for improved BBB penetration and dual-binding capability at both the peripheral anionic site (PAS) and the catalytic active site (CAS) of AChE. This study compares the in vitro reactivation potency, cytotoxicity, and BBB penetration potential of K1396 with standard oximes. K1396 demonstrated comparable or superior reactivation potency, particularly against VX-inhibited AChE, and showed lower cytotoxicity in specific cell lines. Furthermore, K1396 exhibited favorable permeability across the lipid layer, suggesting potential CNS availability. The findings support the therapeutic potential of K1396 as an effective and broad-spectrum reactivator for OPC poisoning.

Keywords: reactivator; A-agents; acetylcholinesterase; cytotoxicity; enzyme kinetics; uncharged reactivator; blood-brain barrier; organophosphorus compounds; nerve agents