Quantitative structure–activity relationship of a series of N‐Aryl O‐Aryl phosphoramidate insecticides

Abstract

A series of O‐ethyl O‐aryl N‐aryl phosphoramidates was prepared and examined for housefly contact toxicity and acetylcholinesterase (AChE) inhibition. Results showed a moderate toxicity and enzyme inhibition effect. These biological properties correlated to Hammett sigma constants in the direction of increasing activity with increasing electron donation of the substituents on either the phenolic or anilinic ring of the phosphoramidates. These correlations suggest the formation of a positive charge on the phosphorus atom that is stabilized by electron‐donating groups. This result invokes the mechanism of the electropholic attack of phosphorus on a nucleophilic center of AChE. The moderate toxicity of phosphoramidates is attributed to the reduction of the positive charge on the phosphorus atom by the effect of the neighboring nitrogen atom during the course of the enzyme‐inhibitor interaction and hence decreasing the inhibition effect. Mass spectra of these compounds are also discussed in some detail.

Inhibition and recovery of serum, liver and brain acetylcholinesterase activities in rats exposed to new groups ofO-ethyl phosphoramidates and benzo-1,3,2-dioxaphospholenes

“…The moderate activity of the phosphoramidates is due to the overlapped nitrogen p-orbital with the neighboring phosphorus d-orbital, which allows resonance of the nitrogen lone pair. This resonance reduces the partial positive charge and hence the electrophilicity of the phosphorus atom responsible for the enzyme phosphorylation [26,27]. Second, It was established, from the X-ray crystallographic structure of cholinesterase and various quantitative structure-activity relationship studies, that hydrophobicity plays an important role in determining the activity of the AChE inhibitors suggesting hydrophobic interaction between the chemical probe of inhibitor and the enzyme active site; in addition, the enzyme active site is more hydrophobic in vertebrates than in invertebrates and thus more hydrophobic compounds bind stronger with the vertebrate enzyme [28].…”

Synthesis and bioactivity ofO-ethyl phosphorodiamidates derived from quinazolin-4-ones and either amino acid esters or fatty amines

“…In addition, some 4-quinazolineamines showed fungicidal activity [8]. In our research on the adverse effects of some organophosphorus pesticides on food and their structure-activity relationship [9][10][11], we found it interesting to prepare a series of phosphorodiamidates containing 3-amino-2-methyl-3H-quinazolin-4-one and either an amino acid ester or a fatty amine. Amino acid esters were incorporated in some drugs to lower their toxicity and improve the cellular uptake [12].…”