The aim of this research was to determine whether a series of novel pyridinium oximes that were synthesized to incorporate phenoxyalkyl moieties to increase lipophilicity, and thereby increase their likelihood of crossing the blood-brain barrier, could effectively reactivate phosphorylated AChE in vitro. An experimental OP was synthesized as a surrogate for sarin to test the reactivation potential of the oximes, phthalimidyl isopropyl methylphosphonate (PIMP). The reactivation activities of the novel pyridinium oximes on PIMP exposed AChE and structure activity relationships were examined. Differences in reactivation potential in comparison to the widely used 2-PAM were also examined. All the novel oximes tested demonstrated some ability to reactivate inhibited AChE. Percent reactivations varied among the oximes (24%-78%), and the novel oximes were not as effective as 2-PAM or TMB-4, which reactivated 91 and 97%, respectively. The lipophilicity for all oximes was greater than 2-PAM or TMB-4 by 3- to 374- fold. A few of the novel oximes showed combined higher lipophilicity and reactivation potential approaching that of 2-PAM, and therefore suggest some potential efficacy as brain-penetrating oxime reactivators.