Journal of Medicinal Chemistry p. 757 - 763 (1988)
Update date:2022-09-26
Topics:
Degorre, Francoise
Kiffer, Daniel
Terrier, Francois
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 (k1) with 4-nitrophenyl acetate indicate that the oximate anions have a much higher nucleophilicity than common oxyanions of similar basicities: the α 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 > 1) is intrinsically (k2) 3 times more reactive than the more basic MINA (log P < 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.
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