Lipophilicity, electronic, steric and topological effects of some phosphoramidates on acethylcholinesterase inhibitory property

The differences in the inhibition potency of organophosphorus agents are manifestations of differing molecular properties of the inhibitors involved in the interaction with the active site of an enzyme. We studied the inhibition potency (IC₅₀) of phosphoramidates with the general formula [(CH₃)₂N]P(O)[p-NHC₆H₄-X]₂, where, X = F (1), Cl (2), Br (3), I (4), and [(CH₃)₂N]P(O)X[p-OC₆H₄-CH₃], where, X = o-NHC₆H₄-CH₃ (5), m-NHC₆H₄-CH₃ (6), p-NHC₆H₄-CH₃ (7), on human acetylcholinesterase (AchE) activity. Inhibition of hAChE was evaluated by a modified Ellman’s method, and spectrophotometric measurements. The ability of the compounds to inhibit AChE was predicted by PASS software (version 1.193). The IC₅₀ values for inhibitors 1–7 were found to be 0.19, 0.35, 0.50, 0.63, 2.70, 2.44 and 1.50 mM, respectively. In addition, logP values, by the experimental and calculated (software) methods, were found to be 1.03, 1.64, 2.17, 2.74, 2.34, 2.28 and 2.23. Finally, parameters of IC₅₀, logP, δ³¹P (phosphorus chemical shifts), σ_p (para-substituent constant), σ⁺ (electron-releasing), steric and topological effects were used for the structure-activity relationships (SAR) studies.