Naweephattana P.Kongkaew N.Surawatanawong P.Kungwan N.Fang Y.Wolschann P.Maitarad P.Hengphasatporn K.Shigeta Y.Rungrotmongkol T.Vangnai A.S.Mahidol University2025-06-062025-06-062025-01-01Journal of Physical Chemistry B (2025)15206106https://repository.li.mahidol.ac.th/handle/123456789/110481Organophosphate (OP) compounds, such as paraoxon (POX), inhibit enzymes critical for neurotransmission, causing severe neurotoxic effects. Pralidoxime (2-pyridine aldoxime methyl chloride) or 2-PAM is commonly employed to reverse this inhibition, but its reactivation efficiency is limited. This study computationally explores the reactivation mechanisms of 2-PAM and its methyl-substituted analogs, 4-methyl-2-PAM (4-Met-2-PAM), and 4,6-dimethyl-2-PAM (4,6-Dimet-2-PAM). The reactivation process involves several key steps, such as hydrogen transfer and nucleophilic substitution (S<inf>N</inf>2). Introducing methyl groups at positions 4 and 6 increases the negative charge on the oxime oxygen, improving nucleophilicity and reactivity. Both 4-Met-2-PAM and 4,6-Dimet-2-PAM show better reactivity than 2-PAM, with 4,6-Dimet-2-PAM demonstrating the greatest improvement. This enhanced reactivity shifts the rate-determining step from nucleophilic substitution to the initial hydrogen transfer. These findings offer valuable insights for designing more effective oxime-based antidotes for organophosphate poisoning.Materials ScienceChemistryArticleSCOPUS10.1021/acs.jpcb.5c013752-s2.0-10500675785015205207