Evaluation of monoquaternary pyridinium oximes potency to reactivate tabun-inhibited human acetylcholinesterase

Monoquaternary N-benzyl-4-hydroxyiminomethylpyridinium bromide (Py-4-H) and its analogous with diverse substituents introduced into the phenyl ring (Py-4-CH3, Py-4-Br, Py-4-Cl and Py-4-NO2) were synthesized in order to examine their potency as reactivators of tabun-inhibited human erythrocyte acetylcholinesterase (AChE; EC 3.1.1.7). Within 24 h, the reactivation of tabun-inhibited AChE reached 80% with Py-4-CH3, Py-4-Br and Py-4-Cl, 40% with Py-4-NO2, and 30% with Py-4-H. The overall reactivation rate constants were up to 5.0 min(-1) M-1. All oximes inhibited human AChE reversibly, and the inhibition potency increased in the following order Py-4-Br < Py-4-Cl < Py-4-CH3 < Py-4-H < Py-4-NO2. Although oximes Py-4-H and Py-4-NO2 did not show significant reactivation ability, these oximes might be of interest as pre-treatment drugs due to their high affinity for the native AChE. Docking studies were carried out to elucidate the differences in oximes potency. The orientations of all studied oximes in the active site of human AChE have been proposed by flexible ligand docking with AutoDock 3.0. Analyses of the obtained complexes revealed the presence of numerous hydrogen bonds and close contacts between the oximes and the residues in the active site. Final docked energies predicted correctly the relative order of the inhibition potency of compounds (except in the case of Py-4-CH3) as well as the most probable orientation of the best reactivator, Py-4-Br, which can result in an attack on the phosphorus atom of the tabun-phosphorylated human AChE. (C) 2006 Elsevier Ireland Ltd. All rights reserved.