<abstract xml:lang="en" xmlns="http://www.w3.org/1999/xhtml"><p>We investigated interactions of bispyridinium <italic>para</italic>-aldoximes <italic>N,N'</italic>-(propano)bis(4-hydroxyiminomethyl) pyridinium bromide (TMB-4), <italic>N,N'</italic>-(ethano)bis(4-hydroxyiminomethyl)pyridinium methanosulphonate (DMB-4), and <italic>N,N'</italic>-(methano)bis(4-hydroxyiminomethyl)pyridinium chloride (MMB-4) with human erythrocyte acetylcholinesterase phosphorylated by tabun. We analysed aldoxime conformations to determine the flexibility of aldoxime as an important feature for binding to the acetylcholinesterase active site. Tabun-inhibited human erythrocyte acetylcholinesterase was completely reactivated only by the most flexible bispyridinium aldoxime - TMB-4 with a propylene chain between two rings. Shorter linkers than propylene (methylene or ethylene) as in MMB-4 and DMB-4 did not allow appropriate orientation in the active site, and MMB-4 and DMB-4 were not efficient reactivators of tabun-phosphorylated acetylcholinesterase. Since aldoximes are also reversible inhibitors of native acetylcholinesterase, we determined dissociation constants and their protective index against acetylcholinesterase inactivation by tabun.</p></abstract>

We investigated interactions of bispyridinium para-aldoximes N,N'-(propano)bis(4-hydroxyiminomethyl) pyridinium bromide (TMB-4), N,N'-(ethano)bis(4-hydroxyiminomethyl)pyridinium methanosulphonate (DMB-4), and N,N'-(methano)bis(4-hydroxyiminomethyl)pyridinium chloride (MMB-4) with human erythrocyte acetylcholinesterase phosphorylated by tabun. We analysed aldoxime conformations to determine the flexibility of aldoxime as an important feature for binding to the acetylcholinesterase active site. Tabun-inhibited human erythrocyte acetylcholinesterase was completely reactivated only by the most flexible bispyridinium aldoxime - TMB-4 with a propylene chain between two rings. Shorter linkers than propylene (methylene or ethylene) as in MMB-4 and DMB-4 did not allow appropriate orientation in the active site, and MMB-4 and DMB-4 were not efficient reactivators of tabun-phosphorylated acetylcholinesterase. Since aldoximes are also reversible inhibitors of native acetylcholinesterase, we determined dissociation constants and their protective index against acetylcholinesterase inactivation by tabun.

Structure-Activity Approach in the Reactivation of Tabun-Phosphorylated Human Acetylcholinesterase with Bispyridinium <italic>para</italic>-Aldoximes

Institute for Medical Research and Occupational Health, Ksaverska cesta 2, HR-10000 Zagreb, Croatia

Archives of Industrial Hygiene and Toxicology

Structure-Activity Approach in the Reactivation of Tabun-Phosphorylated Human Acetylcholinesterase with Bispyridinium -Aldoximes

We investigated interactions of bispyridinium para-aldoximes N,N'-(propano)bis(4-hydroxyiminomethyl) pyridinium bromide (TMB-4),...

Structure-Activity Approach in the Reactivation of Tabun-Phosphorylated Human Acetylcholinesterase with Bispyridinium para-Aldoximes

Publicado en línea: 11 jun 2007

Páginas: 201 - 209

DOI: https://doi.org/10.2478/v10004-007-0013-7

Palabras clave
antidoti, organofosforni spojevi, živčani bojni otrovi

This content is open access.