Bioactivation of Isofenphos and Analogues by Oxidative N-Dealkylation and Desulfuration

Greg W. Gorder, Osamu Kirino, Akinori Hirashima, John E. Casida

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Isofenphos [O-ethyl O-[2-(isopropoxycarbonyl)phenyl] isopropylphosphoramidothionate] is bioactivated by mixed-function oxidases (MFOs) in two steps that ultimately give N-desisopropylisofenphos oxon, a product with 2300-fold greater inhibitory potency than isofenphos oxon toward house fly head acetylcholinesterase (AChE). Bioactivation of N-alkyl analogues of isofenphos oxon depends on an N-alkyl a-carbon proton and the steric bulk of the largest a-carbon substituent as described by Hansch regression analysis. These reactions are largely mediated by cytochrome P-450 and probably involve N-dealkylation via a-carbon oxidation without formation of AChE-inhibitory intermediates. Thiono oxidation is also required for the phosphorothionates, but MFO inhibition accompanying desulfuration slows the overall bioactivation. Findings on house fly toxicities are generally consistent with the in vitro bioactivation models. The isofenphos isomers, resolved on a chiral HPLC column, have the same stereospecificity for MFO-activated anti-AChE activity and toxicity to house flies, possibly due to enantiomeric differences in AChE inhibitory potency.

Original languageEnglish
Pages (from-to)941-947
Number of pages7
JournalJournal of Agricultural and Food Chemistry
Volume34
Issue number6
DOIs
Publication statusPublished - Jan 1 1986

Fingerprint

isofenphos
Dealkylation
Acetylcholinesterase
acetylcholinesterase
mixed function oxidase
Musca domestica
Mixed Function Oxygenases
Diptera
Carbon
Toxicity
carbon
oxidation
toxicity
Oxidation
cytochrome P-450
Regression analysis
Isomers
Cytochrome P-450 Enzyme System
protons
isomers

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Agricultural and Biological Sciences(all)

Cite this

Bioactivation of Isofenphos and Analogues by Oxidative N-Dealkylation and Desulfuration. / Gorder, Greg W.; Kirino, Osamu; Hirashima, Akinori; Casida, John E.

In: Journal of Agricultural and Food Chemistry, Vol. 34, No. 6, 01.01.1986, p. 941-947.

Research output: Contribution to journalArticle

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N2 - Isofenphos [O-ethyl O-[2-(isopropoxycarbonyl)phenyl] isopropylphosphoramidothionate] is bioactivated by mixed-function oxidases (MFOs) in two steps that ultimately give N-desisopropylisofenphos oxon, a product with 2300-fold greater inhibitory potency than isofenphos oxon toward house fly head acetylcholinesterase (AChE). Bioactivation of N-alkyl analogues of isofenphos oxon depends on an N-alkyl a-carbon proton and the steric bulk of the largest a-carbon substituent as described by Hansch regression analysis. These reactions are largely mediated by cytochrome P-450 and probably involve N-dealkylation via a-carbon oxidation without formation of AChE-inhibitory intermediates. Thiono oxidation is also required for the phosphorothionates, but MFO inhibition accompanying desulfuration slows the overall bioactivation. Findings on house fly toxicities are generally consistent with the in vitro bioactivation models. The isofenphos isomers, resolved on a chiral HPLC column, have the same stereospecificity for MFO-activated anti-AChE activity and toxicity to house flies, possibly due to enantiomeric differences in AChE inhibitory potency.

AB - Isofenphos [O-ethyl O-[2-(isopropoxycarbonyl)phenyl] isopropylphosphoramidothionate] is bioactivated by mixed-function oxidases (MFOs) in two steps that ultimately give N-desisopropylisofenphos oxon, a product with 2300-fold greater inhibitory potency than isofenphos oxon toward house fly head acetylcholinesterase (AChE). Bioactivation of N-alkyl analogues of isofenphos oxon depends on an N-alkyl a-carbon proton and the steric bulk of the largest a-carbon substituent as described by Hansch regression analysis. These reactions are largely mediated by cytochrome P-450 and probably involve N-dealkylation via a-carbon oxidation without formation of AChE-inhibitory intermediates. Thiono oxidation is also required for the phosphorothionates, but MFO inhibition accompanying desulfuration slows the overall bioactivation. Findings on house fly toxicities are generally consistent with the in vitro bioactivation models. The isofenphos isomers, resolved on a chiral HPLC column, have the same stereospecificity for MFO-activated anti-AChE activity and toxicity to house flies, possibly due to enantiomeric differences in AChE inhibitory potency.

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