J. Iran. Chem. Soc., Vol. 6, No. 4 December 2009, pp.838~848.

Current location: JICS Archive > Vol. 6 > No. 4 > Articles : 23

Lipophilicity, Electronic, Steric and Topological Effects of Some Phosphoramidates on Acethylcholinesterase Inhibitory Property

S. Ghadimi* and A.A. Ebrahimi-Valmoozi

Department of Chemistry, Imam Hossein University, P.O. Box 16575-347, Tehran, Iran

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), σp (para-substituent constant), σ+ (electron-releasing), steric and topological effects were used for the structure-activity relationships (SAR) studies.

Keywords: Phosphoramidate, Acetylcholinesterase, Structure-activity relationships, Lipophilicity, Inhibitor, Topological effect

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