The Design, Synthesis and Screening of Potential Pyridinium Oxime Prodrugs.

Abstract : In an attempt to improve the delivery of quaternary pyridinium oxime regenerators of acetylcholinesterase (AChE) to the central nervous system (CNS), structural analogs and prodrugs of N-methylpyridinium 2-carbaldoxime (2-PAM) have been synthesized. The potential prodrugs are dihydropyridinium oximes (pro- 2-PAM's) or tetrahydropyridinium oximes, which possess electron-withdrawing substituents in the 3- or 5-position. As precursors to these prodrugs, we have synthesized and characterized a series of 5-substituted-2-PAMs (I, Br, Cl, CH, CN, CONH2-substituted) and a series of 3-substituted PAMs (I, Br, Cl, CH3- substituted). These analogs were tested in vitro for their ability to reactivate diisopropylfluorophosphate (DEP)-inactivated eel AChE.