Activated transformations of organophosphorus insecticides in the case of non-AChE inhibitory oxons.
Many organophosphorus (OP) compounds are of the thiono form and in insects or animals are converted by microsomal mixed function oxidases (MFO) into the oxon forms which inhibit acetylcholinesterase (AChE) and give toxic activity. However, certain S-alkyl phosphorothiolates (RS-P(O) <) such as methamidophos, profenophos and prothiophos oxon are strongly insecticidal, but very poor inhibitors of AChE in vitro. Their oxons are converted further to the S-oxides, which either inhibit AChE or decompose, depending on the alkyl substituents on the sulfur atom. It is also inferred in the case of prothiophos oxon that its S-oxide not only inhibits AChE but also conjugates with glutathione (GSH) by the action of glutathione S-transferase (GST), and the conjugate inhibits AChE. Certain phosphoramidates (R2N-P(O) <) such as isofenphos oxon, schradan and propetamphos oxon are weak AChE inhibitors, but strongly insecticidal. It is well known that isofenphos oxon is converted into the stable N-desalkyl form (H2N-P(O) <) by oxidative dealkylation to inhibit AChE. The authors have studied activation of phosphoramidates using 2,4-dichlorophenyl methyl N-alkylphosphoramidates as model compounds using various approaches including computational chemistry, and these studies indicated that the O-aminophosphate structure (R2N-O-P(O) <) is an activated form.
Kasagami
Takeo
T
Department of Applied Biology and Chemistry, Tokyo University of Agriculture, Tokyo 156-8502, Japan. kasagami@nodai.ac.jp
Miyamoto
Toru
T
Yamamoto
Izuru
I
D000110:Acetylcholinesterase / Q000187:drug effects*; D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D002417:Cattle; D002723:Chlorobenzoates / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects; D005278:Fenitrothion / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D005982:Glutathione Transferase / Q000378:metabolism; D006793:Houseflies / Q000187:drug effects; D020128:Inhibitory Concentration 50; D007306:Insecticides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D007928:Lethal Dose 50; D015394:Molecular Structure; D009249:NADP / Q000378:metabolism; D063086:Organothiophosphates / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D009946:Organothiophosphorus Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010084:Oxidation-Reduction; D010756:Phosphoric Acids / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
D000577:Amides; D002723:Chlorobenzoates; D002800:Cholinesterase Inhibitors; D007306:Insecticides; D063086:Organothiophosphates; D009946:Organothiophosphorus Compounds; D010756:Phosphoric Acids; C007711:fenitrooxone; D009249:NADP; C011067:phosphoramidic acid; D005982:Glutathione Transferase; D000110:Acetylcholinesterase; C000433:3-chloroperbenzoic acid; C035967:propetamphos; C032072:prothiophos; D005278:Fenitrothion