Figure 1

Structures of oxime scaffolds that were explored in our synthetic campaigns. (a) Explored chemical moieties are aligned by the oxime warhead. 2-PAM, RS-194B, and LLNL-02 (1) compounds are shown for comparison. 2-PAM contains a permanently positively charged quaternary nitrogen atom which limits its passive diffusion across the BBB. LLNL-02 (1) and RS-194B both contain a tertiary amine in the azepine ring that is subject to an equilibrium between charged and uncharged chemical species at a synaptic pH of 7.2. All three compounds contain an oxime moiety with pK_a values of about 8, thereby driving the equilibrium towards a predominantly neutral oxime at pH 7.2. (b) The fraction of AChE reactivated is plotted against permeability. Ideal candidates occupy the upper right quadrant, exhibiting properties of both elevated permeability and moderate or better reactivation efficacy. Reactivation of NIMP-adducted acetylcholinesterase measured 30 min after addition of compound. Compound class is specified by the indicated color legend, where each compound represented is an analog of the indicated class.