Sulfur derivatives of 2-oxopropanal oxime as reactivators of organophosphate-inhibited acetylcholinesterase in vitro: synthesis and structure-reactivity relationships

Abstract

We have prepared four new oximes, 1b-e, which conform to the general structure RCH2COCH = NOH where R = CH3S, CH3SO, CH3SO2, and (CH3)2S+, respectively, and have the same E configuration as the parent 2-oxopropanal oxime 1a (R = H, MINA). The pKa values range from 6.54 (1e) to 8.16 (1b), as compared with 8.30 for 1a. Rates of reaction (kappa 1) with 4-nitrophenyl acetate indicate that the oximate anions have a much higher nucleophilicity than common oxyanions of similar basicities: the alpha effects measured for 1a-e are of the order of 200-250. The abilities of 1b-e to reactivate acetylcholinesterase (AChE) inhibited by organophosphates have been evaluated. In vitro experiments reveal a significant reactivation potency of 1b-e against VX-, sarin-, and paraoxon-inhibited immobilized eel AChE. The highly lipophilic methylthio oxime 1b (log P greater than 1) is intrinsically (kappa 2) 3 times more reactive than the more basic MINA (log P less than 1). The sulfonium oxime 1e is a potent reactivator against paraoxon. Interestingly, both 1b and 1e have a low toxicity and they exhibit a significant antidotal effect at a relative low dose against paraoxon in rats.