Synthesis and evaluation of novel analogues of vitamin B6 as reactivators of tabun and paraoxon inhibited acetylcholinesterase

• Published in: Chemico-biological interactions Vol. 187; no. 1-3; pp. 234 - 237
• Main Authors: Gaso-Sokac, Dajana, Katalinić, Maja, Kovarik, Zrinka, Busić, Valentina, Kovac, Spomenka
• Format: Journal Article
• Language: English
• Published: Ireland 06.09.2010
• Subjects: Acetylcholinesterase - metabolism; Cholinesterase Inhibitors - pharmacology; Cholinesterase Reactivators - chemical synthesis; Cholinesterase Reactivators - chemistry; Cholinesterase Reactivators - pharmacology; Enzyme Activation - drug effects; Humans; Organophosphates - pharmacology; Oximes - chemical synthesis; Oximes - chemistry; Oximes - pharmacology; Paraoxon - pharmacology; Vitamin B 6 - analogs & derivatives; Vitamin B 6 - chemical synthesis; Vitamin B 6 - pharmacology
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2010.02.004

A series of novel pyridinium oximes was prepared by reactions of quaternization of pyridoxal oxime with substituted phenacyl bromides in acetone at room temperature. The structures of compounds were determined according to the data obtained by IR spectroscopy, mass spectrometry, (1)H and (13)C nuclear magnetic resonance spectroscopy as well as by elemental analysis. We tested pyridoxal oxime (1) and five prepared oximes in 1mM concentration as reactivators of human erythrocytes acetylcholinesterase (AChE) inhibited by organophosphorus compounds tabun and paraoxon: 1-phenacyl-3-hydroxy-4-hydroxyiminomethyl-5-hydroxymethyl-2-methylpyridinium bromide (2), 1-(4'-chlorophenacyl)-3-hydroxy-4-hydroxyiminomethyl-5-hydroxymethyl-2-methylpyridinium bromide (3), 1-(4'-fluorophenacyl)-3-hydroxy-4-hydroxyiminomethyl-5-hydroxymethyl-2-methylpyridinium bromide (4), 3-hydroxy-4-hydroxyiminomethyl-5-hydroxymethyl-2-methyl-1-(4'-methylphenacyl)pyridinium bromide (5), 3-hydroxy-4-hydroxyiminomethyl-5-hydroxymethyl-2-methyl-1-(4'-methoxyphenacyl)pyridinium bromide (6). However, tested oximes were not efficient in reactivation of either tabun or paraoxon inhibited AChE. The maximum restored enzyme activity in 24h was below 25%. Therefore, this class of compounds cannot be considered as potential improvement in a search for new and more efficient antidotes against OP poisoning.