Synthesis and anti-acetylcholinesterase properties of novel β- and γ-substituted alkoxy organophosphonates

Activated organophosphate (OP) insecticides and chemical agents inhibit acetylcholinesterase (AChE) to form OP-AChE adducts. Whereas the structure of the OP correlates with the rate of inhibition, the structure of the OP-AChE adduct influences the rate at which post-inhibitory reactivation or aging phenomena occurs. In this report, we prepared a panel of beta-substituted ethoxy and gamma-substituted propoxy phosphonoesters of the type p-NO2PhO-P(X)(R)[(O(CH2)(n)Z] (R = Me, Et; X = O, S; n = 2, 3; Z = halogen, OTs) and examined the inhibition of three AChEs by select structures in the panel. The beta-fluoroethoxy methylphosphonate analog (R = Me, Z = F, n = 2) was the most potent anti-AChE compound comparable (k(i); similar to 6 x 10(6) M-1 min(-1)) to paraoxon against EEAChE. Analogs with Z = Br, I, or OTs were weak inhibitors of the AChEs, and methyl phosphonates (R = Me) were more potent than the corresponding ethyl phosphonates (R = Et). As expected, analogs with a thionate linkage (P=S) were poor inhibitors of the AChEs. (C) 2013 Elsevier Ltd. All rights reserved.