Quantum Chemical and Physicochemical Studies of Oximes (Prophylactics against and Reactivators of Phosphorylated AChE)

摘要

The ultimate goal of our interdisciplinary research under this Army contract is to delineate the stereoelectronic and physicochemical requisites for oximes to be effective reactivators of acetylcholinesterase (AChE) inhibited by organophosphorus compounds. This is being done by carrying out theoretical high quality three-dimensional ab-initio quantum chemical calculations on the oximes and from these wave functions generating three-dimensional electrostatic molecular potential contour (EMPC) maps around these oximes as well as experimental determinations of their lipophilicities. In addition to our theoretical work, we have been carrying out experimental determinations of the lipophilicities (their tendency to partition from aqueous to lipid phases) of these oxime reactivators. We have carried out these lipophilicity determinations, first with our microelectrometric technique. It turns out that neither these quaternary oximes nor their deprotonated species are very lipophilic. However, since there have been reports that some oxime reactivators are effective at low concentrations, we have set up and are also using a more sensitive UV spectrophotometric procedure to establish quantitatively and directly just how much of these compounds is partitioning into the lipid phase.