A Study on Neuro-Irreversible Factor of Dechlorinated Products for Chlorpyrifos and its Oxon Compounds

Abstract

We focused on dechlorinated compounds of chlorpyrifos (CPF) that is well-known as one of the organophosphorus insecticides. We synthesized some of them and observed their acetylcholinesterase 50% inhibitory concentration, IC₅₀, by using the Ellman's method. It was found that the relative activity defined as Log₁₀ (IC₅₀^Gal / IC₅₀) in term of IC₅₀^Gal of galantamine was estimated as follows; CPFoxon ; 3.16, 3,5Cl-CPFoxon; 1.84, 6Cl-CPFoxon; 1.04, NonCl-CPFoxon; 1.93, and CPF; −0.39. In addition, we carried out docking simulation, and it was found that the relative activity depends on the length between the ligand-binding site of acetylcholinesterase and the P-atom in ligand molecule. Next, in order to evaluate the irreversible inhibition-abilities of the synthesized compounds, we introduced neurotoxicity factor, NIF, defined as Log₁₀(IC₅₀^Gal / IC₅₀^4h) using IC₅₀^4h observed after 4 h of reaction. The NIF values were estimated as follows; CPFoxon; 4.6, 3,5Cl-CPFoxon; 3.2, 6Cl-CPFoxon; 2.0, NonCl-CPFoxon; 2.5, and CPF; 1.2. It was found that the dechlorinated CPFoxons exhibited not only marked relative activity, but also irreversible inhibition-abilities judging from the NIF. Therefore, we concluded that NIF can be regarded as a useful index to reveal the irreversible inhibition-abilities induced by the CPFoxons and its dechlorinated relatives, because the irreversibility should be considered to clarify the detailed neurotoxic risk.