Design, synthesis and evaluation of new classes of nonquaternary reactivators for acetylcholinesterase inhibited by organophosphates

Authors: Wei Z, Bi H, Liu Y, Nie H, Yao L, Wang S, Yang J, Wang Y, Liu X, Zheng Z
Publication: Bioorg Chem
Keywords: BBB penetration prediction, human acetylcholinesterase, lipophilicity prediction, nerve agent, nonquaternary reactivator, peripheral site ligand, pesticides
Software: ADMET Predictor®

Abstract

A new series of nonquaternary conjugates for reactivation of both nerve agents and pesticides inhibited hAChE were described in this paper. It was found that substituted salicylaldehydes conjugated to aminobenzamide through piperidine would produce efficient reactivators for sarin, VX and tabun inhibited hAChE, such as L6M1R3, L6M1R5 to L6M1R7, L4M1R3 and L4M1R5 to L4M1R7. The in vitro reactivation experiment for pesticides inhibited hAChE of these new synthesized oximes were conducted for the first time. Despite they were less efficient than obidoxime, some of them were highlighted as equal or more efficient reactivators in comparison to 2-PAM. It was found that introduction of peripheral site ligands could increase oximes’ binding affinity for inhibited hAChE in most cases, which resulted in greater reactivation ability.