Mechanistic Insights into Enhanced Reactivation of Organophosphate-Inhibited Enzymes by Methyl-Substituted 2-Pralidoxime Analogs
Issued Date
2025-01-01
Resource Type
ISSN
15206106
eISSN
15205207
Scopus ID
2-s2.0-105006757850
Journal Title
Journal of Physical Chemistry B
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Physical Chemistry B (2025)
Suggested Citation
Naweephattana P., Kongkaew N., Surawatanawong P., Kungwan N., Fang Y., Wolschann P., Maitarad P., Hengphasatporn K., Shigeta Y., Rungrotmongkol T., Vangnai A.S. Mechanistic Insights into Enhanced Reactivation of Organophosphate-Inhibited Enzymes by Methyl-Substituted 2-Pralidoxime Analogs. Journal of Physical Chemistry B (2025). doi:10.1021/acs.jpcb.5c01375 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/110481
Title
Mechanistic Insights into Enhanced Reactivation of Organophosphate-Inhibited Enzymes by Methyl-Substituted 2-Pralidoxime Analogs
Corresponding Author(s)
Other Contributor(s)
Abstract
Organophosphate (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.