Quaternary salts of 4,3′ and 4,4′ bis-pyridinium monooximes. Part 2: Synthesis and biological activity

Article abstract of DOI:10.1016/j.bmcl.2006.01.065

In continuation of our investigations of unsymmetrical bisquaternary monooximes, we synthesized four new series of compounds bridged by hexyl, heptyl, octyl and nonyl groups. All eight monooximes viz., dibromides of 1-(4-hydroxyiminomethylpyridinium)6-(3/4-carbamoylpyridinium)hexane, 1-(4-hydroxyiminomethylpyridinium)-7-(3/4-carbamoylpyridinium)heptane, 1-(4-hydroxyiminomethylpyridinium)-8-(3/4-carbamoylpyridinium)octane, 1-(4-hydroxyiminomethylpyridinium)-9-(3/4-carbamoylpyridinium)nonane as well as the corresponding bis-oximes were synthesized and characterized by spectral data. Their ability to reactivate tetraethylpyrophosphate (TEPP) inhibited mouse total brain cholinesterase was investigated and compared with the conventional oxime 2-pyridinealdoxime chloride (2-PAM). Mouse brain homogenate was used as the source of acetylcholinesterase. Among all the compounds, tested the compound with the hexylene bridge (6b) and a 3-carbamoyl group on the second pyridine ring was found to be the most active acetylcholinesterase reactivator (72%) which is greater than that of 2-PAM (56%). However, the activity was reversed; as the chain length increased from a heptylene to a nonylene bridge, they potentiated the inhibitory effect of TEPP rather than reactivation. It is interesting to note that compound 6b with a carbamoyl group at the 3rd position of the pyridine ring showed dose dependent reactivation whereas the corresponding compound 6a with the carbamoyl group present at the 4th position of the pyridine ring showed reactivation at lower concentration (30 μM) and potentiation of TEPP inhibition at higher concentrations (100 and 300 μM).