Synthesis, lipophilicity study and in vitro evaluation of some rodenticides as acetylcholinesterase reversible inhibitors

Abstract

The anti-AChE activity of phosphoramidates has been noticed for many years. Because of the wide application of phosphoramidates in recent years, there has been a continuing research for synthesis, purification and identification of effective and safe derivatives. In this study some rodenticides with the general formula Me 2 NP(O)( p-OC 6 H 4 -X) 2 , where X ¼ H, CH 3 , Cl, have been synthesized in water (without organic solvent) and characterized by 31 P, 31 P { 1 H}, 13 C and 1 H NMR spectroscopy. Since lipophilicity has been recognized for its importance in QSAR studies, efforts have been made to determine the logP values. The ability of these rodenticides to inhibit human acetylcholinesterase (hAChE) has been predicted with PASS (Prediction of Activity Spectra for Substances) software (version 1.917) and then has been evaluated by a modified Ellman's assay and spectrophotometric measurements.

Structure-activity study of phosphoramido acid esters as acetylcholinesterasf inhibitors

“…The logP values were experimentally determined by the shake-flask method [3], and the results are shown in Table II.…”

“…In previous work [3], lipophilicity and AChE inhibition was studied for some rodenticides (CH 3 ) 2-NP(O)( p-OC 6 H 4 -X) 2 , where X ¼ H, CH 3 , Cl. To extend this study we synthesized (CH 3 ) 2-NP(O)X(p-OC 6 H 4 -CH 3 ) compounds (X ¼ Cl (1), OCH 3 (2), F (3), (C 2 H 5 ) 2 N (4), CN (5) and C 4 H 8 NO (6)) which in addition to P-N and P-O bonds in (CH 3 ) 2 NP(O)( p-OC 6 H 4 -CH 3 ) moiety, contain another different bond with P atoms (P-F, P-Cl, P-C, P-O and P-N).…”

“…Even when reversible ligands bind only to the anionic site of the enzyme, the catalytic site can be protected from phosphorylation. Binding sites of reversible ligands and their affinities for cholinesterases can be evaluated by different approaches [3]. Inhibition of AChE by OPs generally is governed by the following molecular properties:…”

N,N-DimethylO-p-tolyl phosphoramidocyanidate

“…For a review of organophosphorus compounds as used as pesticides, see: Fulton & Key (2001). For related literature, see: Corbridge (1995); Ghadimi et al (2007); Munro et al (1994); du Plessis et al (1982). Mo K radiation = 0.23 mm À1 T = 100 (2) K 0.60 Â 0.12 Â 0.10 mm…”

“…(Fulton & Key, 2001). For some phosphoramido acid, esters inhibiting acetylcholinesterase (AChE) activity was reported, resulting in an accumulation of acetylcholine (ACh) in neural and non-neural tissues (Ghadimi et al, 2007). Tabun (CH 3 ) 2 NP(O)CN(OC 2 H 5 )) is one of the well known nerve agent with very high toxicity (Munro et al, 1994).…”